NDA 21-686

Ximelagatran (H376/95)

 

 

 

 

Indication: Prevention of stroke and thromboembolic complications associated with atrial fibrillation

 

 

 

 

 

 

 

 

 

Mehul Desai, M.D.

Medical Officer

Division of Cardiovascular and Renal Drug Products

 

 

 

 

 

 

NOTE: This is a preliminary/draft review that is not intended to provide any recommendations on the approvability of NDA 21,686.  Any opinions expressed in the review do not necessarily reflect those of the Division/Office.   
Table of Contents

 

I.      Recommendations............................................................................................................... 10

A.       Recommendation on Approvability................................................................................ 10

B.       Recommendation on Phase 4 Studies and/or Risk Management Steps............................ 11

II.     Summary of Clinical Findings............................................................................................... 11

A.       Brief Overview of Clinical Program............................................................................... 11

B.       Efficacy........................................................................................................................ 12

C.       Safety........................................................................................................................... 12

D.       Dosing.......................................................................................................................... 13

E.        Special Population........................................................................................................ 14

Clinical Review................................................................................................................................ 15

III.   Introduction and Background............................................................................................... 15

A.       Drug Established and Proposed Trade Name, Drug Class, Sponsor’s Proposed Indication(s), Dose Regimens, Age Groups............................................................................................................................ 15

B.       State of Armamentarium for Indication(s)...................................................................... 15

C.       Important Milestones in Product Development............................................................... 15

IV.   Clinically Relevant Findings from From Chemistry, Animal Pharmacology and Toxicology, Microbiology, Biopharmaceutics, Statistics and/or Other Consultant Reviews...................................................... 16

V.    Human Pharmacokinetics and Pharmacodynamics................................................................ 16

A.       Pharmacokinetics.......................................................................................................... 16

B.       Pharmacodynamics....................................................................................................... 19

VI.   Description of Clinical Data and Sources.............................................................................. 22

A.       Overall Data................................................................................................................. 22

B.       Tables Listing the Clinical Trials..................................................................................... 23

C.       Postmarketing Experience............................................................................................. 23

D.       Literature Review......................................................................................................... 24

VII.  Clinical Review Methods..................................................................................................... 31

A.       How the Review was Conducted.................................................................................. 31

B.       Overview of Materials Consulted in Review.................................................................. 31

C.       Overview of Methods Used to Evaluate Data Quality and Integrity................................ 31

D.       Were Trials Conducted in Accordance with Accepted Ethical Standards....................... 31

E.        Evaluation of Financial Disclosure.................................................................................. 32

VIII. Integrated Review of Efficacy.............................................................................................. 32

A.       Brief Statement of Conclusions...................................................................................... 32

B.       General Approach to Review of the Efficacy of the Drug............................................... 33

C.       Detailed Review of Trials by Indication.......................................................................... 33

1.       SPORTIF V........................................................................................................... 33

a.       Study dates......................................................................................................... 33

b.      Protocol amendments:......................................................................................... 33

c.       Study Design:...................................................................................................... 35

d.      Rationale for doses selected................................................................................. 38

e.       Blinding/Randomization........................................................................................ 38

f.       Pre-specified Study Objectives............................................................................ 39

g.       Definitions of study endpoints............................................................................... 39

h.       Inclusion/Exclusion Criteria.................................................................................. 41

i.        Statistical considerations (please refer to statistical review for details).................... 42

j.       Study patient disposition...................................................................................... 45

k.      Protocol deviations.............................................................................................. 47

l.        Demographics and other patient characteristics..................................................... 48

m.      Primary endpoint results....................................................................................... 52

n.       Secondary and Tertiary endpoint results............................................................... 54

o.      Adequacy of anticoagulation in the warfarin arm................................................... 56

2.       SPORTIF III.......................................................................................................... 57

a.       Study dates......................................................................................................... 57

b.      Protocol Amendments......................................................................................... 57

c.       Study Design:...................................................................................................... 59

d.      Rationale for doses selected................................................................................. 60

e.       Blinding/Randomization:....................................................................................... 60

f.       Pre-specified study objectives.............................................................................. 60

g.       Definitions of study endpoints............................................................................... 60

h.       Inclusion/Exclusion Criteria:................................................................................. 60

i.        Statistical Considerations (please refer to the statistical review for details):............. 60

j.       Study patient disposition...................................................................................... 60

k.      Protocol deviations.............................................................................................. 62

l.        Demographics and other patient characteristics..................................................... 63

m.      Primary endpoint results....................................................................................... 67

n.       Secondary and Tertiary endpoint results............................................................... 69

o.      Adequacy of anticoagulation in the warfarin arm................................................... 70

D.       Efficacy Conclusions..................................................................................................... 71

IX.   Integrated Review of Safety................................................................................................. 72

A.       Brief Statement of Conclusions...................................................................................... 72

B.       Description of Patient Exposure.................................................................................... 73

C.       Methods and Specific Findings of Safety Review........................................................... 74

1.       Study population definitions..................................................................................... 74

2.       Deaths.................................................................................................................... 75

3.       Serious Adverse Events other than death.................................................................. 76

4.       Discontinuations due to Adverse Events................................................................... 78

5.       Adverse Bleeding Events......................................................................................... 79

6.       Hepatobiliary Adverse Events.................................................................................. 84

7.       Most commonly reported adverse events (AE’s)...................................................... 90

8.       Pancreatic Adverse Events...................................................................................... 91

9.       Other Laboratory Test Adverse events.................................................................... 92

10.     Adverse events related to vital signs, ECG, physical findings..................................... 93

D.       Adequacy of Safety Testing.......................................................................................... 93

E.        Summary of Critical Safety Findings and Limitations of Data.......................................... 93

X.    Dosing, Regimen, and Administration Issues......................................................................... 93

XI.   Use in Special Populations................................................................................................... 94

A.       Evaluation of Sponsor’s Gender Effects Analyses and Adequacy of Investigation........... 94

B.       Evaluation of Evidence for Age, Race, or Ethnicity Effects on Safety or Efficacy............. 94

C.       Evaluation of Pediatric Program.................................................................................... 94

D.       Comments on Data Available or Needed in Other Populations....................................... 94

XII.  Conclusions and Recommendations..................................................................................... 94

A.       Conclusions.................................................................................................................. 94

B.       Recommendations........................................................................................................ 95

XIII. Appendix............................................................................................................................ 95

A.       Other Relevant Materials.............................................................................................. 95

1.       SPORTIF II............................................................................................................ 95

2.       SPORTIF IV.......................................................................................................... 96

B.       Individual More Detailed Study Reviews (if performed)................................................. 97

 


List of Tables

 

Table I: Cumulative risk of major bleeding with increasing exposure of study drug in SPORTIF III/V. 13

Table II: Cumulative risk of ALAT >3x ULN with increasing exposure of study drug in SPORTIF III/V 14

Table III: Important milestones in Product development.................................................................... 15

Table IV: Effects of renal impairment on the pharmacokinetics of melagatran, the active metabolite of ximelagatran.  Values represent the ratio of subjects with renal impairment to patients with normal renal function......... 18

Table V: Summary of the clinical trials submitted in support of the atrial fibrillation indication.............. 23

Table VI: Summary of randomized controlled trials of warfarin in patients with atrial fibrillation........... 26

Table VII: Summary of the issue dates of the original protocol and protocol amendments to Study 0005 34

Table VIII: Table summarizing the primary reason for discontinuing study drug (ITT population)a....... 46

Table IX: Comparison of total study drug discontinuation rates including and excluding patients with ALAT > 3x ULNa  46

Table X: Summary of inclusion/exclusion criteria violations by treatment groups (Please refer to inclusion/exclusion criteria section of this review to match the number with the description of the criteria)a.......................... 47

Table XI: Number (%) of patients by total days of treatment interruption, and treatment groupa......... 48

Table XII: INR measurements for warfarin patients in SPORTIF V.................................................. 48

Table XIII: Patient characteristics at screening: number (%) of patients by treatment group (ITT population)a      49

Table XIV: Mean (+SD) of patient characteristics at screening (ITT population)a.............................. 50

Table XV: Number (%) of patients with the presence of the listed risk factor at study entry............... 50

Table XVI: Number (%) of patients with concomitant medication use at study entry by treatment group (ITT population)a............................................................................................................................................... 51

Table XVII: Proportion of time patients took concomitant ASA between the first and last dose of study drug (ITT population)a............................................................................................................................. 51

Table XVIII: Number (%) of patients using other cardiovascular medications between the first and last dose of study drug, by treatment group (ITT population)a....................................................................................... 52

Table XIX: Number of patients with stroke and/or SEE by treatment group (primary prespecified endpoint)a      52

Table XX: Breakdown of primary endpoint by type of event and whether fatal or non-fatala.............. 53

Table XXI: Number of patients with all cause mortality/stroke/ SEE/AMI by treatment group (secondary prespecified endpoint based on OT analysis)a.............................................................................................. 55

Table XXII: Number of patients with ischemic stroke/TIA/SEE by treatment group (secondary prespecified endpoint based on OT analysis)a...................................................................................................................... 55

Table XXIII: Number of patients with strokes with a poor outcome by treatment group (tertiary prespecified endpoint based on ITT analysis)a...................................................................................................................... 55

Table XXIV: Number of patients with stroke or SEE as a function of age (<, > 75 years of age) (tertiary prespecified endpoint based on ITT analysis)a.............................................................................................. 56

Table XXV:  Original Protocol and Protocol Amendment Issue dates for SPORTIF III.................... 57

Table XXVI: Summary of the reasons for discontinuing study drug (ITT population)a......................... 62

Table XXVII:  Comparison of total study drug discontinuation rates including and excluding patients with ALAT > 3x ULNa............................................................................................................................................... 62

Table XXVIII: Number of patients that discontinued the study and had missing vital status or primary event data at time of study closure procedures but were asked to re-consent to provide follow-up information.......... 62

Table XXIX: Inclusion/exclusion criteria violations by treatment group.............................................. 63

Table XXX: Number (%) of patients by total days of treatment interruption, and treatment groupa..... 63

Table XXXI: Patient characteristics at screening: number (%) of patients by treatment group (ITT population)a   64

Table XXXII: Mean (+SD) of patient characteristics at screening (ITT population)a.......................... 65

Table XXXIII: Number (%) of patients with presence of the listed risk factor at study entrya............. 65

Table XXXIV: Number (%) of patients with concomitant medication use at study entry by treatment group (ITT population)a............................................................................................................................................... 66

Table XXXV: Proportion of time patients took concomitant ASA between the first and last dose of study drug (ITT population)a............................................................................................................................. 66

Table XXXVI: Number (%) of patients using other cardiovascular medications between the first and last dose of study drug, by treatment group (ITT population)a....................................................................................... 67

Table XXXVII: Number of patients with stroke and/or SEE by treatment group (primary prespecified endpoint)a           67

Table XXXVIII: Listing of the individual components of the primary endpoint in SPORTIF IIIa......... 67

Table XXXIX: Number of patients with all cause mortality/stroke/ SEE/AMI by treatment group (secondary prespecified endpoint based on OT analysis)a.............................................................................................. 69

Table XL: Number of patients with ischemic stroke/TIA/SEE by treatment group (secondary prespecified endpoint based on OT analysis)a........................................................................................................................... 70

Table XLI: Number of patients with strokes with a poor outcome by treatment group (tertiary prespecified endpoint based on ITT analysis)a...................................................................................................................... 70

Table XLII: Number of patients with stroke or SEE as a function of age (<, > 75 years of age) (tertiary prespecified endpoint based on ITT analysis)a.............................................................................................. 70

Table XLIII:  Demographic description of Safety population............................................................. 73

Table XLIV: Summary of Exposure Data......................................................................................... 74

Table XLV: Listing of the most common adverse events leading to deatha(PLEASE NOTE THAT NUMBER OF EVENTS  RATHER THAN PERCENTAGES ARE REPORTED)......................................................... 75

Table XLVI: Listing of serious adverse events not leading to deatha, b, c, d, e (PLEASE NOTE THAT NUMBER OF EVENTS RATHER THAN PERCENTAGES ARE REPORTED).......................................... 76

Table XLVII: Listing of study drug discontinuations due to adverse events.  Listed are the total number of AE’s occurring at a frequency of > 1% in the ximelagatran group or were > 2x fold higher in the ximelagatran arm relative to the warfarin arma (PLEASE NOTE THAT NUMBER OF EVENTS RATHER THAN PERCENTAGES ARE REPORTED) 78

Table XLVIII: Summary Table of Major bleeding events (Based on On Treatment – OT Analysis)a.. 79

Table XLIX: Number of patients with major bleeding events according to the CEAC, by criteria for judgment according to local criteria assessed and by treatment group (OT analysis)a.................................................... 82

Table L: Locations/subtypes of major bleedsa................................................................................... 82

Table LI: Frequency of patients with elevated ALAT, ASAT, ALP, and Bilirubin (ITT population)a (PLEASE NOTE THAT NUMBER OF EVENTS  RATHER THAN PERCENTAGES ARE REPORTED)................. 84

Table LII: Number of Patients with ALAT > 3x ULN followed by a bilirubin level > 2x ULN within one month of the elevated ALAT (PLEASE NOTE THAT NUMBER OF EVENTS  RATHER THAN PERCENTAGES ARE REPORTED) ......................................................................................................................... 85

Table LIII: Pattern of liver enzyme progression for Patient 7259....................................................... 88

Table LIV: Pattern of liver enzyme progression for patient 7859....................................................... 89

Table LV: Most common AE’s with an absolute frequency > 5% (based on the ximelagatran arm) or were > 2 fold higher than on the control group (warfarin)a........................................................................................ 90

Table LVI: Summary of pancreatic adverse events in SPORTIF III and SPORTIF V....................... 91

Table LVII: Comparison of cholecystokinin plasma concentrations at month 3 in a subset of patients in the SPORTIF V studya...................................................................................................................................... 91

Table LVIII: Pancreatic volume obtained via CT scan: mean change from screening to last available value.  (SPORTIF V study)a..................................................................................................................................... 92

Table LIX: Summary of safety findings from SPORTIF II study (shown are the numbers of patients with events) 96

Table LX: Summary of findings from the SPORTIF IV study............................................................ 97

Table LXI: Pattern of liver enzyme progression in patient 3174......................................................... 98

Table LXII: Pattern of liver enzyme progression for patient 1967...................................................... 99

Table LXIII: Pattern of liver enzyme progression for patient 7986................................................... 100

Table LXIV: Pattern of liver enzyme progression for patient 5402................................................... 101

Table LXV: Pattern of liver enzyme progression for patient 8387.................................................... 101

 


List of Figures

 

Figure 1: The metabolic pathways of ximelagatran for the formation of melagatran (Figure taken from Figure 1 of Summary of Clinical Pharmacology Studies)............................................................................................ 17

Figure 2: Mean CrCL (ml/min) versus CL/F (l/h) after oral ximelagatran administration (This figure taken from Figure 11:9 of Sponsor’s Clinical Pharmacology Study Report for study SH-TP1-0026)................................. 19

Figure 3: Relationship between aPTT levels and plasma concentrations of melagatran (obtained from Figure 18 of the Sponsor’s Summary of Clinical Pharmacology Studies)............................................................ 20

Figure 4: Relationship between the PK time course of melagatran and the PD time course of aPTT (obtained from Figure 19 of the Sponsor’s Summary of Clinical Pharmacology Studies)................................................... 21

Figure 5:  INR values plotted versus plasma melagatran concentration (Figure obtained from Figure 27 of Summary of Clinical Pharmacology Studies)................................................................................................ 22

Figure 6: Study Schema for SPORTIF V (Figure taken from Figure 1 of SPORTIF V CSR)............ 36

Figure 7: Patient disposition in SPORTIF V (Figure taken from Figure 4 of SPORTIF V CSR)......... 45

Figure 8: Cumulative proportion of patients with stroke and/or SEE over time-estimated Kaplan-Meier curves (Figure taken from Figure 12 of SPORTIF V CSR)...................................................................................... 53

Figure 9: Event rate difference (ximelagatran – warfarin) for the primary endpoint (stroke and/or SEE) according to prognostic factors (Figure taken from Figure 16 of SPORTIF V CSR)..................................... 54

Figure 10: Adequacy of anticoagulation as assessed by INR in patients assigned to warfarin (OT population); (Figure taken from Figure 23 of SPORTIF V CSR)...................................................................................... 56

Figure 11: Study Schema for SPORTIF III (Figure obtained from Figure 1 of SPORTIF III CSR).... 59

Figure 12: Patient disposition in SPORTIF III (Figure obtained from Figure 4 of SPORTIF III CSR) 61

Figure 13: Cumulative proportion of patients with stroke and/or SEE (primary endpoint) over time – estimated Kaplan-Meier curves (This figure obtained from Figure 12 of SPORTIF III CSR)................................. 68

Figure 14: Event rate difference (ximelagatran – warfarin) for the primary endpoint (stroke and/or SEE) according to prognostic factors (This figure obtained from Figure 13 of SPORTIF III CSR)......................... 69

Figure 15: Adequacy of anticoagulation as assessed by INR in patients assigned to warfarin (OT population)  (This figure was obtained from Figure 25 of SPORTIF III CSR)................................................................ 71

Figure 16: Cumulative percentage of patients with major bleeding events over time – Estimated Kaplan-Meir Curves (OT analysis) for SPORTIF III study (Obtained from Figure 32 of Sponsor’s SPORTIF III Clinical Study report)         81

Figure 17: Cumulative percentage of patients with major bleeding events over time; estimated Kaplan-Meier curves (OT Analysis). (Obtained from Figure 25 of Sponsor’s SPORTIF V Clinical Study report).............. 81

Figure 18: Summary of safety comparison: ximelagatran vs. warfarin (difference in percent events, with 95% CI) for major bleed events, according to prognostic factors (OT analysis) (SPORTIF III) (Obtained from Figure 33 of SPORTIF III CSR)...................................................................................................................................... 83

Figure 19: Summary of safety comparison: ximelagatran vs. warfarin (difference in percent events, with 95% CI) for major bleed events, according to prognostic factors (OT analysis) (SPORTIF V) (Obtained from Figure 26 of SPORTIF V CSR)...................................................................................................................................... 84

Figure 20: Cumulative risk of ALAT > 3x ULN versus time after randomization (ITT population) (Figure obtained from Figure 36 of SPORTIF III CSR)............................................................................................. 86

Figure 21: Cumulative risk of ALAT > 3x ULN versus time after randomization (ITT population) (Figure obtained from Figure 33 of SPORTIF V CSR).............................................................................................. 86

Figure 22: Summary of patients on ximelagatran with an ALAT > 3x ULN in SPORTIF III............... 87

Figure 23: Estimated within-group ratios relative to baseline (each patient’s mean of all measurements post-randomization divided by baseline) with 95% CI. Between-group comparisons for those ratios made with unpaired t-test (OT analysis) (Figure taken from Figure 41 of SPORTIF V CSR)................................................... 92

 
Executive Summary

 

I.                    Recommendations

 

A.                 Recommendation on Approvability

 

The sponsor of NDA 21-686 is currently seeking approval of ximelagatran (H376/95) for 3 different indications.  The indication that is the focus of this review is the prevention of stroke and other thromboembolic complications associated with atrial fibrillation.  Two pivotal phase 3 studies (SPORTIF III and SPORTIF V) have been submitted in support of the stated indication.   The two studies are active controlled studies designed to show that ximelagatran is non-inferior or “as efficacious as” treatment with warfarin, the current standard of care.  The active controlled, non-inferiority design of the SPORTIF studies makes interpretation of efficacy relatively more complicated compared to a design involving a placebo control.  An important step in interpreting the effectiveness of ximelagatran in the SPORTIF studies is to understand the benefit of warfarin relative to placebo.  The benefit of warfarin relative to placebo was derived from several placebo controlled trials conducted approximately 10 to 15 years ago and published in the peer reviewed medical literature.  A summary of these studies is discussed in detail elsewhere in this review.    Based on these studies, the relative risk reduction for stroke appears to be approximately 64% (95% CI à 47%, 75%). 

The 2 SPORTIF studies compared the effectiveness of a fixed dose of ximelagatran, 36 mg administered twice a day, to warfarin, targeting an INR of 2 – 3 in patients with nonvalvular atrial fibrillation and at least one additional risk factor for stroke.  SPORTIF III and SPORTIF V were similar in design except that the former was open-label while the latter was blinded.  The primary endpoint was a composite of all strokes (ischemic and hemorrhagic) and systemic embolic events.  The sponsor pre-specified a non-inferiority margin of 2% in the event rate.  Ximelagatran would be called non-inferior if an excess of 2% per year in the event rate relative to warfarin could be confidently excluded.  A margin of this magnitude could leave open the possibility that ximelagatran was only half as effective as warfarin and still be considered non-inferior to warfarin.  The magnitude of this non-inferiority margin was not formally agreed upon by the reviewing division within the Agency and marked as a point of future review/discussion.

The two SPORTIF studies produced divergent results despite similar designs.  In SPORTIF III, the primary event rate was numerically higher in the warfarin arm compared to the ximelagatran arm.  In SPORTIF V, the primary event rate was numerically higher in the ximelagatran arm compared to the warfarin arm.  Comparing the event rates in the common arm of both SPORTIF studies,  the rate in the ximelagatran arm was practically the same in both studies while the event rate in the warfarin arm varied by nearly two-fold.  The variable event rate on warfarin in the two studies could potentially be attributed to the fact that patients in the two studies were slightly different at baseline.  Patients in SPORTIF V were slightly older, had lower blood pressures on average, had fewer patients with histories of transient ischemic attacks (TIA’s) or strokes, and had greater consumption of HMG CoA reductase inhibitors than did patients enrolled in SPORTIF III.  It is puzzling why differences in patient populations of both studies would lead to differences in event rates in the warfarin arms while leaving the event rate in the ximelagatran arms unaffected.  In such a setting where two similarly designed studies produce divergent results, I would favor the results from a double-blind study.       

In terms of safety, liver toxicity as assessed by serum aminotransferase abnormalities occurred approximately 6 times more often on ximelagatran compared to warfarin and was consistent across both trials.  There was one well documented case (and most probably a second case) of drug induced liver failure leading to coagulopathy and death among the approximately 3700 patients randomized to ximelagatran.  Intense protocol mandated liver enzyme monitoring did not prevent serious liver toxicity in these two cases although in some other cases it did prevent serious adverse outcomes.  These two cases highlight the possibility that liver enzyme monitoring as a risk management strategy may not be entirely fool proof.  In terms of major bleeding events, the total number of bleeds was numerically lower in the ximelagatran arm of both studies.  In neither of the studies did the difference achieve statistical significance.  The majority of major bleeds in both studies were due to bleeding with a fall in the hemoglobin level of > 2g/dL or due to overt bleeding requiring > 2 units of whole blood.  Bleeding events leading to death were relatively few in both studies and similar in the two treatment arms. 

With respect to dosing, there is a strong correlation between the oral clearance of melagatran (the active metabolite of ximelagatran) and creatinine clearance.  Thus exposure to melagatran will be affected by renal impairment.  Varying degrees of renal impairment are expected in the patient population for which this therapy is targeted and will potentially be a significant factor affecting exposure to melagatran.  There is a clear relationship between higher exposures to melagatran and increased risk of major bleeds and elevations in aminotransferases.  A strategy of fixed dosing as is being proposed for ximelagatran is concerning.                            

           

  

B.                 Recommendation on Phase 4 Studies and/or Risk Management Steps

 

The sponsor has proposed a risk management program that is intended to minimize the risk of severe hepatic injury that could occur in the setting ximelagatran use.  One of the key features of this program involves liver enzyme (ALAT) monitoring.  The method of monitoring proposed in the risk management plan is similar in intensity to the monitoring that was conducted in the pivotal clinical trials.  Unfortunately, the relatively intense liver enzyme monitoring in the clinical trials did not prevent two cases of drug induced liver failure/death in the SPORTIF V study. 

The experience of the FDA in using liver enzyme monitoring as a risk management tool has been disappointing particularly in the case of troglitazone.  Troglitazone was an antidiabetic agent that was approved in 1997 but taken off the market in 2000 because of numerous cases of liver failure reported post marketing.  Despite labeling changes, Dear doctor letters and other risk management strategies, baseline testing of liver enzymes was conducted in less than one-half of the patients that were started on troglitazone (Graham et al JAMA 2001;286:831-833).    

II.                 Summary of Clinical Findings

 

A.                 Brief Overview of Clinical Program

 

One of the indications that ximelagatran is being developed for is the prevention of stroke and other thromboembolic complications associated with atrial fibrillation.  Two pivotal phase 3 studies have been submitted in support of the stated indication.  In the atrial fibrillation development program a total of approximately 7,300 patients were followed for an average of 1.4 years.  The two studies were active controlled studies designed to show that ximelagatran is “non-inferior” to treatment with warfarin, the current standard of care.  The 2 SPORTIF studies compared the effectiveness of fixed doses of ximelagatran 36 mg administered twice a day versus warfarin, targeting an INR of 2 – 3 in patients with nonvalvular atrial fibrillation and at least one additional risk factor for stroke. 

 

B.                 Efficacy

 

SPORTIF III and SPORTIF V are two Phase III, active control, non-inferiority studies that were provided in support of NDA21-686.  Both studies compared the effectiveness of a fixed dose of ximelagatran, 36 mg administered twice a day to warfarin targeting an INR of 2 to 3 in patients with nonvalvular atrial fibrillation and at least one additional risk factor for stroke.  The studies were very similar in design except that SPORTIF III was open label while SPORTIF V was double-blind.  The primary endpoint was the composite of all strokes (fatal and non-fatal) and systemic embolic events.  The sponsor pre-specified a non-inferiority margin of 2% points in the event rate in both studies.  A margin of that size could leave open the possibility that ximelagatran is only half as effective as warfarin and still be considered “non-inferior.”     

In both studies, the efficacy of ximelagatran was within the sponsor’s pre-specified non-inferiority margin of 2% and it was concluded by the sponsor that ximelagatran was as efficacious as warfarin.  While the two studies could be considered “successes” based on the sponsor’s pre-specified margin, the margin chosen was too liberal. 

The two SPORTIF studies produced divergent results despite their similar designs and patient populations studied.  In SPORTIF V, the event rate was higher in the ximelagatran arm compared to the warfarin arm while in SPORTIF III, the event rate was higher in the warfarin arm compared to the ximelagatran arm.  Comparing the event rates in common arm of both studies, the event rate in the ximelagatran arm of both SPORTIF studies were similar at approximately 1.6%.  However, the event rate in the warfarin arm varied by almost two-fold: 1.2% in SPORTIF V versus 2.3% in SPORTIF III.  Differences in the patient populations in the two studies at baseline could be a possible explanation of the differences in the event rate in the treatment arms.  However, it is difficult to explain why such differences would lead to differences in event rates in the warfarin arm while leaving the event rate in the ximelagatran arm unaffected.  In a setting where two similarly designed studies produce divergent results, I would favor the results from a double-blind study.  It is important to note that the event rate in both studies was primarily driven by the occurrence of ischemic strokes.  More than 80% of the events in both studies were ischemic strokes. 

 

C.                 Safety

 

In SPORTIF III, there were a total of 145 deaths that occurred on drug or during the follow-up period: 75 Ximelagatran, 70 Warfarin.  In SPORTIF V, there were a total of 237 deaths occurring on drug or during the follow-up period: 116 Ximelagatran, 121 Warfarin.  The etiologies of deaths were consistent with what is to be expected from an elderly population with co-morbidities.  The most common etiologies of death included sudden death, heart rate and rhythm disorders, myocardial infarctions, and congestive heart failure. 

In terms of serious adverse events (SAE’s) not leading to death, the reporting rate was lower in SPORTIF III compared to SPORTIF V.  The etiologies of the SAE’s not leading to death were also consistent with what would be expected in an elderly population.  The most common etiologies of SAE’s included congestive heart failure, cerebrovascular disorders, myocardial infarctions, GI hemorrhage, pneumonia, and angina pectoris.         

Discontinuations due to adverse events were numerically greater in the ximelagatran arms of both SPORTIF studies.  The most common reason for study drug discontinuation from ximelagatran was liver and biliary system disorders.  The frequency of aminotransferase abnormalities was significantly higher on ximelagatran compared to warfarin regardless of the criteria used to define abnormal (e.g. ALAT or ASAT > 3x ULN, > 5x ULN, or > 10 x ULN).  The majority of patients that developed liver enzyme abnormalities did so beginning 2 to 4 months after starting ximelagatran therapy.  There was one case of a biopsy documented drug induced liver failure leading to death.  There was a second probable case of drug induced liver failure leading to coagulopathy and subsequently death.  In addition there were multiple cases of aminotransferase abnormalities greater than 3 times the upper limit of normal temporally associated with a bilirubin increase of greater than 2 times the upper limit of normal.  The cases fitting the description of “Hy’s Law” and their associated narratives are listed in the Appendix of this review.  In most of these cases the patients were asymptomatic.  Liver enzyme abnormalities returned to normal after drug discontinuation in these patients. 

In terms of major bleeding events, the total number of bleeds was numerically lower in the ximelagatran arm of both SPORTIF studies.  In neither of the studies did this difference achieve statistical significance.  The majority of major bleeds in both studies was due to bleeding with a fall in the hemoglobin level of greater than or equal to 2 g/dL or due to overt bleeding requiring > 2 units of whole blood.

 

D.                 Dosing

 

A fixed dose of ximelagatran 36mg bid was studied in the SPORTIF trials.  The sponsor’s preliminary labeling proposes for the use of fixed doses of ximelagatran without recommending dose adjustment.    

There is a strong correlation between creatinine clearance and the apparent oral clearance of melagatran, the active metabolite of ximelagatran.  As creatinine clearance decreases, there is a proportional decrease in melagatran clearance.  In the sponsor’s proposed labeling there are no provisions for dose adjustment in patients with varying degrees of renal impairment.  The proposed labeling would only contradict the use of ximelagatran in patients with a creatinine clearance less than 30 ml/min.  Not allowing for dose adjustment in renal impairment may compromise safety because the risk of serious adverse events increases as the exposure to drug increases as shown in Table I and Table II below.  

Table I below shows that as the exposure to melagatran increases as measured by the area under the plasma concentration time curve increases, the cumulative risk of major bleeding increases by a factor of about 4 fold.   

 

Table I: Cumulative risk of major bleeding with increasing exposure of study drug in SPORTIF III/V

Study

(SPORTIF III/V)

 

AUC value

Cumulative Risk (%)

95%CI

 

Lower (%)

Upper (%)

 

Lowest 5%

2.06

1.00

.64

1.37

 

Lowest 25%

2.77

1.29

0.89

1.70

 

Median

3.46

1.65

1.21

2.10

 

Highest 75%

4.38

2.29

1.74

2.85

 

Highest 95%

6.19

4.37

3.05

5.69

Obtained from Table 27 of Summary of Clinical Pharmacology Studies Study Report

 

Similar to the previous table, Table II below shows that as the exposure to melagatran increases, the cumulative risk of hepatotoxicity (as measured by an ALAT > 3x ULN) increases.  The increased risk of toxicity with increased exposures to melagatran appears to be slightly less pronounced for hepatotoxicity than that for major bleeding.   

Table II: Cumulative risk of ALAT >3x ULN with increasing exposure of study drug in SPORTIF III/V

Study

(SPORTIF III/V)

 

AUC value

Cumulative Risk (%)

95%CI

 

Lower (%)

Upper (%)

 

Lowest 5%

2.06

5.13

4.02

6.23

 

Lowest 25%

2.77

5.59

4.64

6.55

 

Median

3.46

6.08

5.22

6.94

 

Highest 75%

4.38

6.80

5.83

7.77

 

Highest 95%

6.19

8.47

6.38

10.6

Obtained from Table 27 of Summary of Clinical Pharmacology Studies Study Report

 

 

E.                  Special Population

 

Just under 1/3 of the patients randomized in the SPORTIF studies were females.  The direction and magnitude of the ximelagatran effect with respect to the primary efficacy endpoint was similar in males and females. 

Less than 5% of the study population in the SPORTIF studies was Black and thus limited conclusions can be made of efficacy or safety of ximelagatran in that population. 

It was not unexpected that both SPORTIF studies randomized predominantly a geriatric population with a mean age of just over 70 years as the prevalence of atrial fibrillation increases with increasing age.   

Melagatran, the active metabolite of ximelagatran is predominantly excreted in the urine unchanged.  Thus, patients with severe renal impairment can have up to 5 times the exposure compared to those with normal renal function.

There are no adequate and well controlled studies of ximelagatran use in pregnant women.  Reproductive toxicity studies with ximelagatran in pregnant rats, rabbits, and minipigs have been conducted and have not shown any risk of harm to the fetus at doses that do not produce maternal bleeding.   Please refer to the Pharmacology/Toxicology review for further details.         

 

 

 

 

Clinical Review

 

III.               Introduction and Background

 

A.                 Drug Established and Proposed Trade Name, Drug Class, Sponsor’s Proposed Indication(s), Dose Regimens, Age Groups

 

Proposed trade name: EXANTAÒ

Drug Class:  Reversible, oral thrombin inhibitor

Proposed indications: The sponsor is seeking a total of 3 indications.  Two of the indications are related to the prevention and treatment of venous thromboembolism.  The third indication that is the purpose of this review is “prevention of stroke and other thromboembolic complications associated with atrial fibrillation.”

Dose/Regimen: Fixed dose of 36 mg orally twice daily

Age groups:  Older adults will be the primary recipients of this therapy.  The prevalence of atrial fibrillation is much higher in older adults than in younger adults.  Chronic ximelagatran therapy has not been studied in pediatric populations because atrial fibrillation is a rare, atypical arrhythmia in children.      

 

B.                 State of Armamentarium for Indication(s)

 

EXANTA is the first in a new class of oral anticoagulants.  The primary mechanism of action involves reversible inhibition of thrombin.  The most commonly used oral anticoagulants worldwide are the vitamin K antagonists.   Warfarin is an approved Vitamin K antagonist that is available in the U.S.  Warfarin is generally recognized as a very effective oral anticoagulant.  Its main side effect is risk of bleeding that is predictable from its pharmacologic action.  One drawback of using warfarin is that it requires therapeutic drug monitoring to ensure that efficacy is being maximized while minimizing bleeding risk.       

 

C.                 Important Milestones in Product Development

Table III: Important milestones in Product development

January 16, 1998

Patent issue date

August 14, 1998

IND filed for the oral tablet formulation of ximelagatran

June 16, 2000

End of Phase 2 meeting to discuss SPORTIF protocols

July 14, 2003

Pre-NDA meeting

October 9, 2003

Meeting to discuss risk management strategies

December 23, 2003

NDA filed to Division of GI/Coagulation Drug Products

 

IV.              Clinically Relevant Findings from From Chemistry, Animal Pharmacology and Toxicology, Microbiology, Biopharmaceutics, Statistics and/or Other Consultant Reviews

 

Please refer to the Medical Officer Review by Dr. Ruyi He (Primary Medical Officer in Division of GI/Coagulation Drug Products) for further details. 

 

V.                 Human Pharmacokinetics and Pharmacodynamics

 

Please refer to the Clinical Pharmacology, Biopharmaceutics Review for details. 

Melagatran is a potent, competitive and reversible direct inhibitor of the serine protease a-thrombin.  Thrombin converts fibrinogen to fibrin in the coagulation cascade.  In addition thrombin also produces platelet aggregation.  Inhibition of thrombin by ximelagatran prevents thrombus development and reduces platelet aggregation.  Melagatran inhibits both free and fibrin-bound thrombin and thrombin-induced aggregation of platelets.

A.                 Pharmacokinetics

 

Ximelagatran is a prodrug, which after oral administration yields melagatran as the dominant metabolite.  As shown in Figure 1 below, there are two intermediate metabolites in the pathway from the prodrug to melagatran:  ethyl-melagatran and OH-melagatran.  Ximelagatran and OH-melagatran are essentially inactive as thrombin inhibitors while melagatran and ethyl-melagatran are both active inhibitors of thrombin.  The formation of melagatran primarily occurs via formation of the OH-melagatran intermediate metabolite.  The formation of melagatran via ethyl-melagatran is a relatively minor pathway.     


 

Figure 1: The metabolic pathways of ximelagatran for the formation of melagatran (Figure taken from Figure 1 of Summary of Clinical Pharmacology Studies). 

 

 

The conversion (hydrolysis) from ximelagatran to OH-melagatran is rapid and mediated primarily by esterases.  The reduction reaction from OH-melagatran to melagatran is a reduction reaction through a yet unidentified metabolic pathway.    No cytochrome P450 enzymes have been identified in the reduction of OH-melagatran to melagatran.

Ximelagatran, melagatran, ethyl-melagatran, or OH-melagatran has not been shown shown to inhibit human drug metabolizing enzymes in various in vitro studies (e.g. human liver microsomes).   In vivo studies in rats showed that ximelagatran did not induce P450 enzymes that were studied.  

Melagatran is eliminated primarily by excretion in urine with a renal clearance that corresponds to the glomerular filtration rate. 

 

Summary of key pharmacokinetic (PK) findings in healthy subjects

·        The pharmacokinetics are dose proportional

·        The bioavailability is approximately 20%

·        The half-life of melagatran is approximately 3 hours

·        Inter-individual variability in exposure:  CV = 20%,  while intra-individual variability in exposure: CV = 10%

·        Melagatran is main excreted unchanged in urine

Summary of key PK findings in patients

  • The pharmacokinetics are dose proportional
  • The half-life of melagatran is approximately 5 hours
  • Inter-individual variability in exposure:  CV = 50%,  Intra-individual variability in exposure: CV = 25%

 

Effects of renal impairment on PK of melagatran

The effects of renal impairment on ximelagatran PK were evaluated in an open-label, randomized, single dose study.  Subjects enrolled in this study were given single oral doses of Ximelagatran 24 mg.  Plasma concentrations and amount of melagatran, the active metabolite of ximelagatran, excreted in urine were measured up to 24 hours post dose.     

 

Study subjects were between the ages of 20 to 80 yeas old and were enrolled into 3 groups.  Note that the creatinine clearance (CrCL) was calculated according to the Cockcroft & Gault formula. 

 

Group 1 CrCL > 50 ml/min/1.73m2

Group 2 CrCL 20-30 ml/min/1.73m2

Group 3 CrCL 10-19 ml/min/1.73m2

 

12 subjects were enrolled into Group 1 and this group was considered as having normal renal function.   Groups 2 and 3 were lumped together as one group and were considered as having renal impairment.  There were a total of 12 subjects in these 2 groups.  In Group 1, the mean Cr CL (using Cockcroft Gault) was 107.7 + 24.3 ml/min (min 63.9 ml/min and max 151.1 ml/min).  In groups 2 and 3, the mean CrCL was 27.1 + 9.7 ml/min (min 13.9 ml/min and max 43.1 ml/min). 

 

The effects of renal impairment on melagatran PK are summarized in

Table IV below.  As shown in the table, the exposure to melagatran in terms of AUC is approximately 5 fold higher in patients with renal impairment compared to “Normals.”  Similarly Cmax is about 2 fold higher.  

 

Table IV: Effects of renal impairment on the pharmacokinetics of melagatran, the active metabolite of ximelagatran.  Values represent the ratio of subjects with renal impairment to patients with normal renal function.

Variable

Group comparison

Estimate

 

95% CI

 

 

 

 

Lower

 

Upper

AUC

Renally impaired/normal

5.33

3.76

 

7.56

Cmax

Renally impaired/normal

1.83

1.42

 

2.37

t1/2

Renally impaired/normal

2.60

2.07

 

3.26

Frel

Renally impaired/normal

1.32

1.04

 

1.67

CL/F

Renally impaired/normal

0.188

0.132

 

0.266

CLR

Renally impaired/normal

0.106

0.065

 

0.173

Data in this table obtained from synopsis report of study SH-TP1-0026

 

The oral clearance (CL/F) of melagatran correlates very well with CrCL calculated using Cockcroft Gault as shown in Figure 2 below.  This type of relationship makes justification of a fixed dose of ximelagatran for all patients rather problematic particularly in the setting of increased risk of serious adverse events with increasing exposure to drug.      

Figure 2: Mean CrCL (ml/min) versus CL/F (l/h) after oral ximelagatran administration (This figure taken from Figure 11:9 of Sponsor’s Clinical Pharmacology Study Report for study SH-TP1-0026)

 

Effect of hepatic impairment on PK of melagatran

 

An open-label, single dose study was conducted in patients with hepatic impairment and controls matched in terms of age, sex, and weight.  A total of 12 liver patients and 12 controls were studied.  The subjects ranged in age from 45-69 years.  Among the patients with hepatic impairment, 7 had mild impairment (Child Pugh A) while 5 had moderate impairment (Child Pugh B).  The results of this study showed that the pharmacokinetics of melagatran were similar in patients with or without hepatic impairment. 

 

  

 

B.                 Pharmacodynamics

 

Melagatran, the active metabolite of ximelagatran, prolongs the activated partial thromboplastin time (aPTT) and INR ratio.  Melagatran is an inhibitor of thrombin which happens to be Factor II in the coagulation cascade.  aPTT is prolonged by abnormalities in factors involved in the intrinsic coagulation cascade (e.g. FVIII, FIX, XI, XII, etc), fibrinogen, and also factors in the common pathway (e.g. FII, V, X).  Prolongation of aPTT occurs in a concentration dependent manner and is non-linear.  The relationship between melagatran concentrations and aPTT prolongation is illustrated in Figure 3 and  Figure 4 below.  It is important to note that the pharmacodynamic data in the figures below has been generated from healthy subjects.   

Figure 3: Relationship between aPTT levels and plasma concentrations of melagatran (obtained from Figure 18 of the Sponsor’s Summary of Clinical Pharmacology Studies).

 

 

As shown in Figure 4 below, after oral dosing with ximelagatran, the aPTT starts to prolong within 20 minutes of dosing and peak prolongations are observed 2 hours post dosing.  The effect of ximelagatran on aPTT at the end of 12 hours is approximately at the same level seen pre-dose.  Based on this figure it appears as though a once a day dosing strategy would be sub-optimal.  It can not be determined from this trial whether a more than twice a day dosing regimen would result in greater efficacy compared to twice a day dosing.   

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Figure 4: Relationship between the PK time course of melagatran and the PD time course of aPTT (obtained from Figure 19 of the Sponsor’s Summary of Clinical Pharmacology Studies)

 

In addition to effects on aPTT, ximelagatran can also affect the prothrombin time (PT) and INR.  In vitro studies in human plasma have demonstrated that the PT was prolonged by melagatran but that the corresponding INR varied considerably depending on the ISI of the thromboplastin.    It is predicted that INR’s of approximately 1.2 to 1.8 are expected at steady-state trough and peak plasma concentrations of melagatran in atrial fibrillation receiving 36 mg bid.  At very high plasma melagatran concentrations the INR ranged from approximately 2.8 to 6 depending on the ISI of the thromboplastin used.  Figure 5 below summarizes the relationship between melagatran plasma concentrations and INR based on an in vitro study using two different thromboplastins with differing ISI levels.  

 

 

 

 

 

 

 

 

 

 

   Figure 5:  INR values plotted versus plasma melagatran concentration (Figure obtained from Figure 27 of Summary of Clinical Pharmacology Studies)

 

VI.              Description of Clinical Data and Sources

 

A.                 Overall Data

 

The sources of data used in generating this review include:

·        Electronic NDA submission for N21686

·        Sponsor’s reply to an Information Request dated March 23, 2004, June 3, 2004 

·        NDA21686 4-month Safety Update Report

 

 

 

 

 

 

 

 

 

 

 

B.                 Tables Listing the Clinical Trials

 

Table V: Summary of the clinical trials submitted in support of the atrial fibrillation indication

SPORTIF V

 “Efficacy and Safety of the Oral Direct Thrombin Inhibitor H376/95 Compared with Dose-Adjusted Warfarin (Coumadin) in the Prevention of Stroke and Systemic Embolic Events in Patients with Atrial Fibrillation.”

  • Pivotal Phase 3 study
  • Randomized, Double-blind

·         U.S. and Canada

·         Active control (warfarin INR 2 – 3)

·         Fixed dose ximelagatran 36 mg bid

·         Patients with nonvalvular atrial fibrillation + at least one additional risk factor for stroke

SPORTIF III

“Efficacy and Safety of the Oral Direct Thrombin Inhibitor H376/95 Compared with Dose-Adjusted Warfarin (Coumadin) in the Prevention of Stroke and Systemic Embolic Events in Patients with Atrial Fibrillation.”

  • Pivotal Phase 3 study

·         randomized, Unblind

·         Europe and Asia

·         Active control (warfarin INR 2 – 3)

·         Fixed dose of ximelagatran 36 mg bid

·         Population of patients with nonvalvular atrial fibrillation + at least one additional risk factor for stroke

SPORTIF II, SPORTIF IV

  • Non-pivotal, phase 2 studies

·         Unblind with respect warfarin arm

·         Dose ranging (20 mg, 40mg, 60mg)

·         Active control (warfarin INR 2 – 3)

·         Primarily designed to assess long term safety of ximelagatran

 

 

C.                 Postmarketing Experience

 

No post-marketing safety data are available.  Marketing authorization was received in France in December 2003 for the prevention of venous thromboembolism (VTE) in patients undergoing hip or knee replacement surgery.  However, ximelagatran has not yet obtained full approval by the European Union and thus is not commercially available as of April 2004. 

 

D.                 Literature Review

 

The studies in support of the efficacy of ximelagatran (H376/95) are active control, non-inferiority trials.  The active control chosen for both studies was warfarin titrated to an INR of 2 to 3.  One aspect in trying to understand whether ximelagatran is non-inferior to warfarin is to understand the efficacy of warfarin over placebo.     

Table VI below summarizes a total of 6 randomized controlled trials of warfarin in patients with chronic, non-rheumatic atrial fibrillation.  The 6 studies (or portions of them) listed in the table were used to derive the benefit of warfarin relative to placebo.  Please refer to Dr. John Lawrence’s Statistical Review for further details regarding the benefit of warfarin over placebo to use in the non-inferiority analysis. 

Similarities and differences in terms of study design

In terms of study design, 2 of the listed studies were blinded while 4 were unblind.  One of the SPORTIF trials was blinded while the other was not.  Also in terms of design, the studies differed significantly from each other and from the SPORTIF studies with respect to the target INR (e.g. BAATAF Target INR 1.5 – 2.7, AFASAK Target INR 2.8 – 4.2).  In the SPORTIF studies the target INR was 2 – 3.  

Lack of blinding may be less problematic for “hard” endpoints such as death or severely disabling stroke.  However, lack of blinding may be more problematic when evaluating “softer” endpoints such as TIA’s.

 

Similarities and differences with respect to patient demographics

Patients in the 6 listed warfarin studies were similar in age and gender to those patients in the SPORTIF studies.  However, in 5/6 listed studies, fewer patients had a prior history of stroke/TIA compared to the SPORTIF studies.  In addition, there were fewer patients with a history of hypertension in the 6 warfarin studies compared to the SPORTIF studies.

Similarities and differences with respect to endpoints

The definitions of stroke varied in some of the studies.  For example in the Veterans Affairs Stroke Prevention study (5th study in Table VI), stroke was defined as a new neurologic deficit that persisted for longer than 12 hours.  Most other studies used a new neurologic deficit lasting > 24 hours to define stroke.  The AFASAK study (1st study in Table VI) defined a “minor stroke” as a focal neurologic deficit lasting more than 24 hours but less than one week.  Most of the other studies did not define such a subgroup of patients.  Also in terms of differences in endpoints, the EAFT study included death from vascular disease and non-fatal MI in its primary endpoint and thus the overall event rate was significantly higher in that study compared to either of the SPORTIF studies.                  

It is important to note that in many of the studies listed in Table VI, intracranial bleed/hemorrhage was not included as part of the primary efficacy endpoint but was rather a secondary endpoint or assessed as a safety endpoint.  On the other hand, in the two SPORTIF studies, the primary endpoint included all strokes both ischemic and hemorrhagic.  In addition, the two SPORTIF studies did not include TIA’s as part of their primary endpoint unlike what was done in the AFASAK study.  Hemorrhagic strokes or TIA’s did not occur in large numbers in any of the studies listed in Table VI.   

In summary, it seems acceptable to use the studies listed in Table VI to define the benefit of warfarin relative to placebo despite differences in study design, endpoints, target INR’s, and patient population.  Based on the 6 studies in this table, the benefit of warfarin over placebo appears to be a rather large 64% (95% CI à 47%, 75%) relative risk reduction.  The studies listed in Table VI clearly suggest that warfarin is an effective oral anti-coagulant in terms of preventing the composite endpoint of stroke and systemic embolic events.                

 

 

 

 


Table VI: Summary of randomized controlled trials of warfarin in patients with atrial fibrillation

Study

Population studied

Design

Endpoints

Results (based on primary endpoint)

AFASAK Studya

 

(n = 335 randomized to warfarin)

Chronic, non-valvular atrial fibrillation;

 

Median age = 72.8 years; 53% male; 6% with previous stroke or TIA; 32% with hypertension

Randomized, Unblinded, placebo- controlled

 

Study duration was 2 years or until “end of trial”

 

Target INR range = 2.8 – 4.2

 

 

1° = Stroke, TIA, embolic complication to viscera and extremities

 

 

There were a total of 5 events in the warfarin arm (incidence rate as reported in the manuscript =  2.0% / year).   The 5 events included 4 “disabling strokes” and 1 “fatal” stroke. 

 

There were a total of 21 events in the control (placebo) arm (incidence rate as reported in the manuscript = 5.5 % / year).  The 21 events included 3 TIA’s, 2 minor strokes, 3 non-disabling strokes, 7 disabling strokes, 4 fatal strokes, 2 visceral emboli.  

 

 

 

INR between 2.8 and 4.2 à 42% of time

INR > 4.2 à 0.6% of time

INR < 2.4 à 26% of time

BAATAF Studyb

 

(n = 212 randomized to warfarin)

Chronic, non-valvular, non-Rheumatic atrial fibrillation;

 

Mean age = 68.5 years; 75% male, 3% with previous stroke; 51% with hypertension

Randomized, Unblinded, controlled (control group consisted of patients that received no treatment or ASA per their choice)

 

Target INR range = 1.5 – 2.7  (INR’s were checked every 3 weeks during study)

 

1° = Ischemic stroke

 

(TIA’s were not counted as endpoints)

 

Major bleeds were also counted and defined in the manuscript

Follow-up in the warfarin arm was 487 patient-years;  There were a total of 2 ischemic strokes during this time (0.41%/ year) that included 1 stroke classified as “severe.” 

 

Follow-up in the control arm was 435 patient-years; There were a total of 13 ischemic strokes during this time (2.98%/year) that included 5 that were classified as “severe.”

 

In terms of “major bleeds”, there were 2 on warfarin (including 1 fatal intracranial bleed) and 1 in the control arm as reported in the text.

 

INR between 1.5 to 2.7  à 83% of time

INR > 2.7 à 9% of time

INR < 1.5 à 8% of time

CAFA Studyc

 

(n = 187 randomized to warfarin)

Chronic atrial fibrillation;

 

Mean age = 68 years; 76% males, 3.2% with previous stroke or TIA; 43.3% with history of hypertension

Randomized,  Double-Blind, Placebo-controlled

 

Target INR range = 2 – 3

 

 

1° = Ischemic strokes (except lacunar), systemic embolism to the gut, legs, kidneys or arm, intracranial or fatal hemorrhage

 

2° = TIA’s, lacunar infarctions, major bleeding, minor bleeding, death

Mean follow-up period was 15.2 months

 

Primary endpoint

A total of 8 events occurred in the warfarin arm = 3.4%/patient-year. Of the 8 events, 5 were nonlacunar strokes, 1 was a non-CNS embolic event, 1 was an intracranial hemorrhage, and 1 was “other” fatal hemorrhage.

 

A total of 11events occurred in the control arm (incidence as reported in the manuscript  = 4.6% / patient-year.  Of the 11 events, 9 were nonlacunar strokes and 2 were non-CNS embolic events. 

 

Secondary endpoint

A total of 13 events occurred in the warfarin arm while a total of 10 occurred in the control arm (excluding bleeding events)

 

A total of 5 major bleeds occurred in patients in the warfarin arm compared to 1 major bleed in a patient in the control arm.   

 

INR between 2 to 3 à 43.7%

INR > 3 à 16.6%

INR < 2 à 39.6%

SPAF Studyd

 

(n = 210 randomized to warfarin)

Nonrheumatic atrial fibrillation;

 

Mean age = 65 years; 74% males; 8% with previous stroke or TIA; 49% with history of hypertension

Randomized, Unblinded, controlled (placebo)

 

Target INR range = 2.0 – 4.5

 

 

1° = Ischemic stroke, systemic embolism

 

2° = Intracerebral hemorrhage, TIA’s, MI’s, mortality

 

 

Primary endpoint

For the primary endpoint, the total patient-years of observation were 260 on warfarin and 244 on placebo. 

 

In the warfarin arm there were a total of 6 events -  event rate is 2.3%/patient-year.  This includes 4 minimally disabling strokes and 2 moderate to severely disabling strokes.  

In the placebo arm there were a total of 18 events on placebo

- event rate is 7.4%/patient-year.  This includes 10 minimally disabling strokes, 7 moderate to severely disabling strokes, and 1 systemic embolic event.  

 

Secondary endpoints

There was one intracerebral hemorrhage on warfarin and none on placebo.  There were 3 TIA’s on warfarin and 4 on placebo.  There were 2 myocardial infarctions on warfarin and 2 on placebo.  There were 6 deaths in the warfarin arm and 8 on placebo. 

 

In terms of “relevant bleeding” there were a total of 3 cases in the warfarin arm and 1 in the placebo arm

 

 

INR 2 to 4.5 à 71% of all values

INR > 4.5 à 5%

INR < 2 à 23%

VA Stroke prevention Studye

 

(n = 260 randomized to warfarin)

Nonrheumatic atrial fibrillation;

 

Mean age = 67 years; 100% males, 0% with history of stroke; 55% with history of hypertension

Randomized, Double-Blind, Placebo-controlled

 

Target INR range = 1.4 – 2.8

 

INR’s were checked monthly

 

 

1° = Cerebral infarction

 

2° = cerebral hemorrhage and death

 

Systemic embolic events were not assessed in this study

 

Major bleeding was defined in the manuscript

Primary endpoint

Mean follow-up in the warfarin arm was 1.8 years while mean follow-up in the control arm was 1.7 years. 

 

There were a total of 4 primary events in the warfarin arm including 3 patients with minor impairment and 1 patient with a fatal stroke.  Incidence = 0.9% /patient-year.

 

There were a total of 19 events in the control (placebo) arm including 9 patients with no impairment post stroke, 7 with minor impairment, 2 with major impairment, and 1 fatal stroke.  Incidence = 4.3%/patient-year.  

 

Secondary endpoint 

Cerebral hemorrhage occurred in 1 patient in the warfarin arm versus 0 patients in the control arm.  The total number of deaths was 15 in the warfarin arm and 22 in the control arm.   

 

 

INR 1.4 to 2.8 à 56% of time

INR > 2.8 à 15% of time

INR < 1.4 à 29% of time

EAFT Studyf

 

(n = 225 randomized to warfarin)

Nonrheumatic atrial fibrillation with  history of TIA or stroke within 3 months of study onset

 

Mean age = 71 years; 59% males, 44% with history of hypertension

Randomized, Unblinded, controlled (placebo)

 

Target INR = 2.5 – 4.0

 

(warfarin was not the anticoagulant necessarily given to all patients)

1° = Death from vascular disease, non-fatal stroke, non-fatal MI, systemic embolism;

 

2° = death from all causes, all strokes and major thromboembolic events

 

“Major bleed” was defined in manuscript.

Primary endpoint

There was a total of 507 patient-years follow up in the anticoagulation arm and 405 patient-years follow up in the control arm.  There were a total of 43 events in the anticoagulation arm and a total of 67 events in the control arm.  The event rate equals 8.5% in the anticoagulation arm and 16.5% in the control arm.  The components of the primary endpoint driving the composite were mainly nonfatal stroke and vascular death. 

 

In terms of major and/or fatal bleeding, there were 13 events in the anticoagulation arm and 3 events in the control arm. 

 

INR 2.5 to 4 à 59 % of time

INR > 4 à 9% of time

INR < 2.5 à 32%

aPetersen P, Boysen G, Godtfredsen J, Andersen ED, Andersen B. Placebo-controlled

randomised trial of warfarin and aspirin for prevention of thromboembolic complications in

chronic atrial fibrillation: the Copenhagen AFASAK study. Lancet 1989;1:175-8.

 

bBoston Area Anticoagulation Trial for Atrial Fibrillation Investigators. The effect of low dose

warfarin on the risk of stroke in patients with nonrheumatic atrial fibrillation. N Engl J Med

1990;323(22):1505-11.

 

cConnolly SJ, Laupacis A, Gent M, Roberts RS, Cairns JA, Joyner C. Canadian atrial

fibrillation anticoagulation (CAFA) study. J Am Coll Cardiol 1991;18:349-55.

 

dStroke Prevention in Atrial Fibrillation Investigators (SPAF). Stroke Prevention in Atrial

Fibrillation Study. Final results. Circulation 1991;84:527-39.

 

eEzekowitz MD, Bridgers SL, James KE, Carliner NH, Colling CL, Gornick CC, et al.

Warfarin in the prevention of stroke associated with nonrheumatic atrial fibrillation. Veteran

Affairs Stroke Prevention in Nonrheumatic Atrial Fibrillation Investigators (SPINAF). N Engl

J Med 1992;327:1406-1412.

 

fEuropean Atrial Fibrillation Trial Study Group. Secondary prevention of vascular events in

patients with non-rheumatic atrial fibrillation and recent transient ischaemic attack or minor

ischaemic stroke. Lancet 1993;342:1255-1262.


VII.            Clinical Review Methods

 

A.                 How the Review was Conducted

 

I spent the majority of time reviewing the two pivotal SPORTIF trials submitted in support of the chronic use of ximelagatran in patients with atrial fibrillation.  Relatively less time was spent in reviewing SPORTIF II/IV, as this was a smaller, non-pivotal, dose ranging study.  Each of the SPORTIF trials was reviewed separately.  The efficacy and safety data from the 2 SPORTIF studies were not pooled as one was a blinded study while the other was not.  In addition, the results particularly with respect to efficacy were different in the two studies. 

            With respect to safety, I spent relatively more time reviewing hepatobiliary adverse events.  Case narratives of all hepatobiliary serious adverse events and discontinuations due to hepatobiliary AE’s in both SPORTIF trials were read in detail by the reviewer.  Line listings of the causes of death from both studies were reviewed and narratives from selected cases of death were read in depth.   

             

 

 

B.                 Overview of Materials Consulted in Review

 

The materials used in this review include the electronic NDA submissions, Sponsor’s responses to Information requests, Literature references, and Sponsor’s 4 month safety update. 

 

C.                 Overview of Methods Used to Evaluate Data Quality and Integrity

 

I evaluated the case narratives for selected AE’s and cross checked the statements in the narratives with Case Report Forms (CRF) for consistency.  It is important to note that in at least one instance the case narrative referred to abnormal or elevated liver enzyme values but no such documentation was reported in the CRF.  The reason was that only liver enzymes obtained at pre-specified time points and measured by the Central Lab were recorded in the CRF.  Local lab tests of liver enzymes were not recorded in the study database regardless of whether they were abnormal or not.

 

One study site in SPORTIF V was evaluated by the Division of Scientific Investigation (DSI) where the source documents were reviewed and compared to the case report forms.  In addition, DSI reviewed inclusion and exclusion criteria, protocol deviations, and also adverse event reporting.  One study site in the SPORTIF III study is also to be inspected by DSI.     

 

The sponsor’s analysis of the primary endpoint in SPORTIF V was re-analyzed and confirmed by the statistical reviewer Dr. John Lawrence.  The primary endpoint in SPORTIF III was not re-analyzed and confirmed by Dr. Lawrence.     

 

  

 

D.                 Were Trials Conducted in Accordance with Accepted Ethical Standards

 

The studies conducted were performed in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with Good Clinical Practice. 

 

E.                  Evaluation of Financial Disclosure

 

The sponsor submitted FDA Form 3454 for each of the two pivotal studies, SPORTIF III and SPORTIF V.  In Form 3454, the sponsor attested that they had not entered into any financial arrangements with investigators whereby the value of compensation to the investigator could be affected by the outcome of the study.  The sponsor also certified that each investigator/sub-investigator in the study was required to disclose to the sponsor whether the investigator had a proprietary interest in the product or a significant equity interest in the sponsor.  Finally the sponsor also certified that no investigator was the recipient of significant payments of other sorts.   

The sponsor received financial disclosure forms in the vast majority of investigators/sub-investigators.  There were 4 sub-investigators that participated in SPORTIF III that did not complete financial disclosure forms.  These 4 sub-investigators had moved from their respective facilities and no forwarding addresses were available.  These 4 sites enrolled 39 (1.1%) of the 3410 patients randomized. There were 5 investigators that did not complete financial disclosure forms despite attempts to contact them by the sponsor.  These 5 investigators enrolled a total of 64 (1.9%) of the 3410 patients randomized. 

Two investigators in SPORTIF III, disclosed that they held “significant equity interest” as defined by 21CFR54.2.  The first of these investigators was Dr. Bertil Olsson, who was co-chair of the Executive Steering Committee and Principal investigator at center 312.  Center 312 randomized 33 patients.  The second investigator was Dr. Jan Hysing, a sub-investigator at site 253.  This center randomized 15 patients.

I do not believe the financial disclosure issues discussed above significantly impacted the study outcomes as the number of patients enrolled at each center was a small fraction of the total number of subjects randomized.        

     

VIII.         Integrated Review of Efficacy

 

A.                 Brief Statement of Conclusions

 

SPORTIF III and SPORTIF V are two Phase III, active control, non-inferiority studies that were provided in support of NDA21-686.  Both studies compared the effectiveness of a fixed dose of ximelagatran 36 mg administered twice a day to warfarin targeting an INR of 2 to 3 in patients with nonvalvular atrial fibrillation and at least one additional risk factor for stroke.  The studies were very similar in design except that SPORTIF III was open label while SPORTIF V was double-blind.  The primary endpoint was the composite of all strokes (fatal and non-fatal) and systemic embolic events.  The sponsor pre-specified a non-inferiority margin of 2% points in the event rate in both studies.  A margin of that size could leave open the possibility that ximelagatran is only half as effective as warfarin and still be considered “non-inferior.”     

The two studies produced divergent results despite their similar designs.  In SPORTIF V, the event rate was higher in the ximelagatran arm compared to the warfarin arm while in SPORTIF III, the event rate was higher in the warfarin arm compared to the ximelagatran arm.  In both studies, the efficacy of ximelagatran was within the sponsor’s pre-specified non-inferiority margin of 2%.  Comparing the event rates in the common arm of both studies, the rate in the ximelagatran arm was approximately the same at 1.6%/year.  However, the event rate in the warfarin arm varied nearly 2-fold between the studies:  1.2% in SPORTIF V and 2.3% in SPORTIF III.  Differences in the patient populations in the two studies at baseline could be a possible explanation of the differences in the event rate in the treatment arms.  Patients in SPORTIF V were slightly older, had lower blood pressures on average, had fewer patients with histories of transient ischemic attacks (TIA’s) or strokes, and had greater consumption of HMG CoA reductase inhibitors than did patients enrolled in SPORTIF III.  However, it is difficult to explain why such differences would lead to differences in event rates in the warfarin arm while leaving the event rate in the ximelagatran arm unaffected.  In a setting where two studies produce divergent results, I would favor the results from the double-blind study.  The event rate in both studies was primarily driven by the occurrence of ischemic strokes.  More than 80% of the events in both studies were ischemic strokes. 

 

         

B.                 General Approach to Review of the Efficacy of the Drug

 

SPORTIF III and SPORTIF V were the two studies submitted in support of efficacy.  Each of these studies was reviewed separately as the former was unblinded while the latter was a blinded study.      

C.                 Detailed Review of Trials by Indication

1.                  SPORTIF V

 

Study Title: “Efficacy and Safety of the Oral Direct Thrombin Inhibitor H376/95 Compared with Dose-Adjusted Warfarin (Coumadin) in the Prevention of Stroke and Systemic Embolic Events in Patients with Atrial Fibrillation”

 

a.                  Study dates

Date first patient enrolled: July 24, 2000

Date enrollment ended: December 7, 2001

Date study closure procedures began: January 13, 2003

Date final patient completed study: June 19, 2003

Date of Clinical Study Report: October 9, 2003

 

b.                  Protocol amendments:

Table VII below summarizes the date at which the original protocol was issued along with the dates of all subsequent amendments to the original protocol.  Below Table VII are listed the summaries of each protocol amendment. 

 

 

 

 

 

 

Table VII: Summary of the issue dates of the original protocol and protocol amendments to Study 0005

Version of Protocol or Protocol Amendment

Date of issue

Original Protocol

May 19, 2000

Approval amendment 1

July 18, 2000

Approval amendment 2

July 11, 2001

Approval amendment 3

October 31, 2001

Approval amendment 4

August 8, 2002

Approval amendment 5

November 7, 2002

 

Amendment 1:

·        Additional pregnancy testing was to be done at 3 month intervals

·        Occult bleeding determined by the laboratory would not be classified as a minor bleed

·        Recommendations for managing patients that may experience ALT elevations were broadened to include all liver enzymes (e.g. ALAT, ASAT, alkaline phosphatase, and bilirubin).  In addition, treatment discontinuation would be considered if there is a rapid increase in liver enzymes to > 5x ULN. 

·        A melagatran PK sample was to be obtained from patients with persistent LFT elevations.

·        The study was to remain open until the sponsor collected a minimum of 2000 patient-years of exposure data per treatment arm.

 

Amendment 2:

·        A sub study to measure pancreas volumes and plasma CCK concentrations was added

·        Definitions of lone atrial fibrillation and prosthetic heart valves were clarified

·        Clarifies the exclusion of a patient with known intracardiac thrombus

·        Clarifies that the intent to treat population (ITT) includes all randomized patients regardless of whether the study medication had been taken. 

·        Clarifies the data to record once a patient had discontinued study medication.  Once a patient prematurely discontinued the study the adverse events (AE’s) that were to be recorded included the primary events of stroke and systemic embolic events in addition to death.  After premature study drug discontinuation, patients were contacted via phone on a monthly basis to ascertain these events.  It was not necessary to record other AE’s. 

·        The timing of the study medication on the day of a point of care INR determination was clarified

·        The limit on the period of study drug interruption was clarified.  There were 30 consecutive days (60 days for cardioversion) during which a patient was allowed to temporarily discontinue study drug.  During the course of the entire study, a patient could be temporarily off study drug for a total of 60 non-consecutive days. 

·        The concomitant medications to be recorded in the 14 day period following a serious adverse event was clarified

 

Amendment 3

·        The total number of patients randomized and the total number of sites was increased.  The Data Safety Monitoring Board (DSMB) noted that the aggregate primary event rate was substantially below what was anticipated.  Based on this information from the DSMB, the Executive Steering Committee (ESC) recommended increasing exposure to 5000 patient-years via increasing both duration of patient exposure and through an increase in the total number of subjects enrolled in the trial. 

·        The time period for enrollment was increased

·        Instructions were revised for management of patients with elevated liver enzymes.  Patients with LFT’s > 2x ULN would undergo weekly LFT testing until the affected entity returns to below the ULN or the baseline measurement.  Patients with an LFT elevation > 3x ULN will have a blood sample drawn for extensive liver function testing.  If the affected entity did not demonstrate a tendency to decrease or an alternative reason for the elevation was found, patients were to be withdrawn from study drug.  Patients with an LFT > 5x ULN were to be withdrawn from study drug. 

 

Amendment 4

·        A new plan for the transition from study medication to open label warfarin at the termination visit was implemented to provide additional protection against too little anticoagulation. 

·        The amendment provided clarity regarding the frequency of measurement of full safety laboratory values and INR’s. 

·        There was also clarification as to when to obtain blinded and unblinded INR’s during interruptions of study medication. 

 

Amendment 5

            The treatment period of “active” patients and the follow-up period of “inactive” patients (those prematurely discontinued) were increased to a maximum of 36 months.  Consequently additional office visits and procedures were added. 

c.                   Study Design:

 

SPORTIF V was a multi-centered, randomized, double-blind, double-dummy, active controlled (warfarin), parallel group study in patients with chronic, non-valvular atrial fibrillation (AF).  This study was conducted primarily in the United States and Canada.

 

The study randomized a total of 3922 patients.  The treatment period ranged between 12 to 36 months.  As shown in Figure 6 below, patients were randomized to either fixed doses of Ximelagatran 36 mg bid or to Warfarin titrated to an INR of 2 to 3 via monthly blood tests. 

 

 

 


Figure 6: Study Schema for SPORTIF V (Figure taken from Figure 1 of SPORTIF V CSR)

 

Patients that prematurely discontinued study medication (e.g. to bleeding or hepatobiliary AE) were not withdrawn from the trial but were followed up via monthly telephone contacts until the end of the study with regard to primary events (e.g. strokes and SEE’s) and death.  Patients that discontinued from study medication and withdrew from study were not followed for primary efficacy endpoints or death.    

 

Patients were stratified based on aspirin use and a previous history of stroke/TIA.

 

The primary analysis consisted of events adjudicated by the CEAC.  Events that were “suspected” by the study site investigator were eligible for adjudication.  If an event was not “suspected” it would not have been forwarded to the CEAC for adjudication. 

 

If an investigator suspected an event, an initial fax describing the event was to be sent to the CEAC committee within 24 hours of the knowledge of the event.  The initial fax was followed up with more complete forms within 14 days of knowledge of the event.  Data that were to be submitted to the CEAC for purposes of adjudication could have included documentation of the patient’s history and physical exam, discharge summary, neurology consultation, CT scans, Angiograms, X-rays, ECG’s, or appropriate enzyme levels.     

 

The CEAC was to work in accordance with the principles described in a written charter.  Pairs of primary reviewers were to independently assess each event and if in agreement, this adjudication would be accepted.  In cases of disagreement, a second, final review would be performed by a third independent reviewer.

 

The trial included a Data Safety Monitoring Board (DSMB), Clinical Events Adjudication Committee (CEAC), and an Executive Steering Committee (ESC).

 

The DSMB was composed of the following members:

 

·        Prof. Robert Hart (Chairman), Department of Medicine (Neurology), University of Texas Health Science Centre, USA.

·        Prof. David DeMets, Department of Biostatistics, University of Wisconsin Medical School, USA.

·        Prof. Gudrun Boysen, Bispebjerg Hospital, Neurologisk Afd, Denmark.

·        Prof. Desmond Julian, London, UK.

 

The CEAC was composed of the following members listed below.  All were based at University Hospital in Dresden, Germany.

 

·        Prof. Rüdiger von Kummer (Chairman) Department of Neuroradiology

·        Dr. Angela Müller, Department of Neuroradiology

·        Dr. Dirk Mucha, Department of Neuroradiology

·        Prof. Heinz Reichmann, Department of Neurology

·        Dr. Georg Gahn, Department of Neurology

·        Dr. Thomas Schwarz, Department of Internal Medicine

·        Dr. Alexander Schmeisser, Department of Cardiology

·        Olaf Wunderlich (Administrator)

 

The Executive steering committee members included:

 

·        Jonathan Halperin, MD (Co-chairman), Mount Sinai Medical Center, New York, USA

·        Bertil Olsson, MD PhD (Co-chairman) University Hospital, Lund, Sweden

·        Gregory Albers, MD,Stanford Stroke Center, Palo Alto, USA

·        Hans Christoph Diener, MD, PhD, University of Essen, Germany

·        Palle Petersen, MD, PhD, University Hospital of Copenhagen, Hvidovre Hospital, Hvidovre, Denmark

·        Alec Vahanian, MD Hospital Tenon, Paris, France

·        Margaretha Grind, MD, PhD, AstraZeneca R&D Charnwood, UK

·        Lars Frison, PhD, AstraZeneca R&D Molndal, Sweden

·        Stephen Partridge, PhD, AstraZeneca R&D Charnwood, UK

·        Mark Nevinson, BPharm (Secretary) AstraZeneca R&D Charnwood, UK

·        Jay Horrow, MD, AstraZeneca LP, Wilmington, DE, USA

 


 

 

 

d.                  Rationale for doses selected

 

Rationale for warfarin dose: 

Warfarin is the most widely used oral anticoagulant worldwide.  Treatment guidelines recommend the use of long-term oral anticoagulant therapy, aiming for an INR of 2 – 3, for all patients who are at high risk of stroke.  Over anticoagulation increases the risk of bleeding events while under anticoagulation increases the risk of ischemic stroke.  Warfarin has proven to be highly effective at preventing strokes and SEE in previous placebo controlled clinical trials. 

 

Please refer to Section VI D “Literature Review” for further details regarding placebo controlled studies involving warfarin. 

 

 

Rationale for ximelagtran dose: 

The sponsor took into consideration an array of data in selecting the fixed dose of 36 mg bid used in both SPORTIF studies.  These include:

·        A phase 2 study (SPORTIF II), suggested that there were fewer minor bleeding events in the 20 and 40 mg bid dose groups relative to a 60 mg bid dose group.  In addition, there was some concern about possible dose related increase in liver enzyme abnormalities based on SPORTIF II. 

·        A phase 2 study conducted in patients for the prevention of venous thromboembolism showed enhanced efficacy of doses of 24 mg bid versus doses of 12 mg bid. 

·        Pre-clinical thrombosis models showing that acceptable antithrombotic effect was achieved at plasma concentrations of 0.05 to 0.5 mmol/L. 

·        Capillary bleeding time study showed that mean plasma levels of 0.31 mmol/L caused a small, non-significant prolongation of bleeding time. 

 

e.                   Blinding/Randomization

A double-dummy technique was used to preserve blinding during this trial.  Real INR values and warfarin doses were entered into a centralized interactive voice response system (IVRS) that would issue a standardized report containing a real INR value if the patient was randomized to warfarin or a sham value if the patient was randomized to ximelagatran (H736/95). 

At the End of Treatment visit, a plan was implemented by the sponsor that retained study blinding while transitioning patients from ximelagatran to warfarin.  This was necessary for patients in the ximelagatran arm because of the risk of reduced anti-coagulation due to the quick offset of ximelagatran and the slow onset of open-label warfarin (details of this plan are in the sponosor’s clinical study report).  

A centralized and automated IVRS was used to manage the randomization process, allowing for stratification factors, and to aid the efficient distribution of study drugs.  

 

 

f.                    Pre-specified Study Objectives

 

Primary objective:

To determine whether H376/95 is non-inferior compared to dose-adjusted warfarin aiming for an INR 2.0 – 3.0 for the prevention of all strokes (fatal and non-fatal) and systemic embolic events in patients with chronic non-valular AF. 

Secondary objectives:

·        To compare the efficacy of H376/95 to that of dose-adjusted warfarin aiming for an INR 2.0 – 3.0 for the combined endpoint of prevention of death, non-fatal strokes, non-fatal systemic embolic events and non-fatal acute myocardial infarction (AMI). 

·        To compare the efficacy of H376/95 to that of dose-adjusted warfarin aiming for an INR 2.0 – 3.0 for the combined endpoint of prevention of ischemic strokes, TIA’s, and systemic embolic events

·        To assess the safety of H376/95 compared to dose-adjusted warfarin aiming for INR 2.0 – 3.0 with an emphasis on major and minor bleeding events and any treatment discontinuations

 

Tertiary objectives

·        To compare the efficacy of H376/95 and dose-adjusted warfarin aiming for an INR 2.0 – 3.0 for the prevention of all strokes with a poor outcome (defined by a Modified Rankin score of > 3 at 3 months post-stroke or a Barthel score of < 60 at 3 months post-stroke). 

·        To compare the efficacy of H376/95 and dose-adjusted warfarin aiming for an INR 2.0 – 3.0 for the prevention of all strokes and systemic embolic events in patients > 75 years of age with AF and to compare this with patients below the age of 75 years. 

 

It is important to note that patients that prematurely discontinued study medication but agreed to remain in the study were followed up for primary events (e.g. strokes and SEE’s) and death via regular telephone contact.    

g.                  Definitions of study endpoints

Definition of stroke and TIA:

Stroke was defined as the abrupt onset over minutes to hours of a focal neurological deficit persisting for more than 24 h and caused by altered cerebral circulation in the distribution of a cervical or cerebral artery. If the focal neurological deficit lasted for less than 24 h, the event was classified as a TIA. Patients that died within 30 days of the onset of the stroke were regarded as having had a fatal stroke. Patients who had a stroke and then died 30 or more days after the onset of the stroke were regarded as having non-stroke death.

 

Definition of stroke with poor outcome:

A stroke was defined as having a poor outcome if it met 1 or more of the following criteria:

• An increased (relative to baseline) Modified Rankin score to ≥3 at 3 months post stroke

• A Barthel score of <60 at 3 months post-stroke

• A fatal stroke. This component was not specified in the protocol, but added in the

statistical analysis plan (SAP) before unblinding of study data;

 

Definition of Systemic embolic events (SEE’s):

SEE was defined as abrupt vascular insufficiency associated with clinical or radiologic evidence of arterial occlusion in the absence of other likely mechanisms, eg, atherosclerosis instrumentation. In the presence of atherosclerotic peripheral vascular disease, diagnosis of embolism to the lower extremities should be made with caution and requires arteriographic demonstration of abrupt arterial occlusion.

 

Definition of acute myocardial infarction:

AMI was defined as the presence of at least 2 of the following:

·        Typical retrosternal chest pain indicating AMI for at least 20 minutes

·        Electrocardiogram showing changes typical of AMI

·        Elevation of the cardiac enzyme creatine phosphokinase, myocardial band (CK-MB) or troponin to more than twice ULN.

 

The occurrence of AMI was documented only in patients that were on study drug at the time

of the event.

 

Definition of Major Bleed:

Major bleed was defined as one or more of the following:

• Fatal bleeding

• Clinically overt bleeding associated with a fall in hemoglobin of 20 g/L (2 g/dL) or

more

• Clinically overt bleeding leading to transfusion of 2 or more units of whole blood or

erythrocytes

• Bleeding in areas of special concern, such as intracranial, intraspinal, intraocular,

retroperitoneal, pericardial or atraumatic intra-articular bleeding.

 

Subdural and epidural bleeds, but not intracerebral bleeds were treated as major bleeds.

Intracerebral bleeding events were handled in the same way as stroke and were not

documented on the “Major Bleed” Form.  Major bleeds were reported only for active patients at

the time of the event.

 

Definition of Minor Bleed:

Any bleeding event other than a major bleed was considered a minor bleed.  Bleeding events initially characterized by the investigator as a major bleed but subsequently rejected by CEAC, as such, were considered minor bleeds.

 

 

h.                  Inclusion/Exclusion Criteria

 

Inclusion Criteria

 

1.  Chronic non-valvular AF (constant or paroxysmal) verified by at least 2 ECG readings in the last year separated by at least one week; the second ECG being carried out within the 2 weeks prior to randomization.  Historical evidence of the first ECG showing AF (i.e. tracing available in patient notes) is required.  In addition one of the items under 2 must be present.

2.  At least one of the following risk factors for stroke:

·        Hypertension requiring anti-hypertensive treatment, and which is below 180/100 mmHg on randomization

·        Age ≥75 years

·        Previous cerebral ischemic attack (stroke or TIA)

·        Previous systemic embolism

·        Left ventricular dysfunction (either LVEF <40% or symptomatic CHF)

·        Age ≥65 years AND coronary artery disease

·        Age ≥65 years AND diabetes mellitus.

3. Aged 18 years or older.

4. Willing and able to give signed informed consent.

 

Exclusion Criteria

 

1. Stroke within the previous 30 days or TIA within the previous 3 days.

2. The following conditions associated with increased risk of bleeding:

·        History of intracranial, intraocular, spinal, retroperitoneal or atraumatic intra-articular bleed

·        Overt gastrointestinal bleed in the previous year

·        Endoscopically verified ulcer disease in the previous 30 days

·        Major surgical procedure or trauma in the previous 30 days

·        Persistent blood pressure ≥180/100 mmHg (with or without antihypertensive therapy)

·        Hemorrhagic disorder.

3. Lone AF (atrial fibrillation in the absence of overt cardiovascular disease or precipitating illness).

4. Transient AF caused by reversible disorders, e.g. current thyrotoxicosis, pulmonary embolism.

5. Rheumatic valve disease, a prosthetic heart valve or valve surgery.

6. Active endocarditis.

7. Diagnosis of current atrial myxoma or left ventricular thrombus.

8. Hospitalization for acute coronary syndromes or percutaneous coronary artery intervention within the last 30 days.

9. Planned cardioversion (electrical or chemical).

10. Concomitant treatment with antiplatelet or fibrinolytic agents (or use of these within 10 and 30 days, respectively, before randomization); other anticoagulant agents or continuous treatment with NSAID drugs.  However, aspirin ≤100 mg/day is allowed during the whole study period.

11. Requirement for chronic anticoagulant treatment other than for atrial fibrillation

(eg repeated deep vein thrombosis, hereditary thrombophilia).

12. Renal impairment defined as a calculated creatinine clearance <30 mL/min

13. Active liver disease or persistent elevation of liver enzymes > 2 times the upper limit of the normal level defined by central laboratories.

14. Anemia (Hb <100 g*L-1) or a platelet count <100 x 109 L-1.

15. Childbearing potential (female patients should be at least 2 years post-menopausal, surgically sterile or using medically accepted contraceptive measures as judged by the investigator).

16. Pregnancy or lactation (see Section 10.2).

17. Drug addiction and/or alcohol abuse in the past 3 years.

18. Participation in any clinical study involving an investigational drug within one month prior to randomization; previous randomization in this study or any other 376/95 study.

19. Other diseases that give an estimated life survival less than 36 months as judged by the treating physician.

20. Inability to complete the study according to the protocol, eg inability to comply with the monitoring required for therapy control, significant mental impairment or geographic inaccessibility to a laboratory.

21. Previous significant disabling stroke (defined as Modified Rankin score ≥3).

22. Planned major surgery.

23. Allergy or intolerance to warfarin.

 

i.                    Statistical considerations (please refer to statistical review for details)

 

Major changes to planned analyses:

Please refer to the statistical review by Dr. John Lawrence for further details regarding amendments to the statistical analysis plan. 

 

The major changes to the planned analyses that were implemented prior to unblinding the database were:

·        The methodology for the analysis of the primary endpoint was changed to a patient-years calculation assuming an exponentially distributed event rate. 

·        The definition of the ITT population was modified to include all randomized patients.  The original protocol and SAP stated that patients needed two baseline ECG’s demonstrating atrial fibrillation to be eligible for study entry. 

 

The major changes to the planned analyses that were implemented after the database was unblinded were:

·        AE’s were counted in all periods where they occurred instead of only in the period when they started. 

·        The analyses of the tertiary objectives and liver function tests were performed for the ITT population instead of the OT analysis set. 

 

Analysis of primary endpoint:

The primary objective of the study was to be addressed with an intention to treat (ITT) approach.  In this approach, all randomized patients were included until the date of each patient’s study closure visit or final contact, irrespective of their protocol adherence.  The primary objective was to be addressed with a life table analysis.  Primary events (e.g. all strokes or SEE’s, and death) were reported for all patients in the trial including patients who had already suffered a study endpoint.  For example, if a patient suffered an MI as a study endpoint (and assuming he/she did not withdraw consent), this patient would continued to be followed for the occurrence of death or a primary endpoint event such as stroke or SEE.  For patients with multiple occurrences of events the time to first event was used.  Each patient was counted once in any composite endpoint that included at least one of the events that the patient had experienced.  In this non-inferiority trial, the margin of non-inferiority chosen was 2% points in the annual event rate of stroke and SEE. 

 

As part of a sensitivity analysis, the primary objective was also analyzed using the On Treatment (OT) approach.  This was done to examine the robustness of the primary analysis using the ITT approach.  While the ITT approach is a conservative approach particularly when dealing with superiority study designs, the OT approach may be a more appropriate when trying to interpret the results of a non-inferiority study.  The OT approach included all patients in the ITT population but only their time on active study drug was used for analysis.  A maximum continuous interruption of up to 30 days without active study drug was allowed.  For patients undergoing cardioversion, a maximum 60 continuous days of study drug interruption was allowed.  A maximum of 60 accumulated days of interruption was also permitted. 

Analyses of the secondary and tertiary endpoints:

Analyses related to the secondary and tertiary objectives, as well as descriptive and exploratory analyses were to be based on an On Treatment approach according to the statistical analysis plan.  In this approach, all patients in the ITT population would be included as long as they remained on study medication.  A maximum continuous interruption of up to 30 days without active study drug was allowed.  For patients undergoing cardioversion, a maximum 60 continuous days of study drug interruption was allowed.  Any patient with a study drug interruption (H376/95 or warfarin) of more than 60 days would not be included in the On Treatment analysis. 

It is important to note that in the clinical study report the sponsor analyzed the tertiary endpoint using the ITT population, a change from what was proposed in the statistical analysis plan.  This change was implemented after the database was unblinded.   

 

Analysis of adverse events(AE’s):

AE’s were actively collected up to the End of Treatment Visit. AE’s that started in 1 time period and continued into a subsequent time period(s) were counted once in each period. This was a difference from the SAP where AE’s were to be counted only in the period of onset. If an ongoing AE worsened in a subsequent period, it was reported as a new AE at the time of worsening and was then counted twice; at the time of initial onset and at the time of worsening onset.

All analyses of liver function tests were performed using the ITT analysis, which utilized the full time pattern for liver function elevations. This is a change from the SAP, which had specified the OT analysis.

 

Other analysis considerations:

No Analyses based on a per protocol approach were performed. 

The sponsor was to make every effort to trace all patients until the very end of the study and to record their status with regard to occurrence of stroke, systemic embolism and mortality. 

 

Determination of Sample Size:

It was estimated that the combined rate of ischemic stroke, hemorrhagic stroke and systemic embolism for patients in this study protocol would be 3.1% per year for both treatment groups.  In order to obtain 90% statistical power, adopting a one sided a = 0.025, approximately 1600 patient years of follow-up per treatment group would be necessary to establish a non-inferiority of H376/95 compared to adjusted-dose warfarin within 2% per year.  Assuming an average follow-up of 16 months about 2400 patients would be required in total.  In the protocol it was stated that if the aggregate event rate (stroke + SEE) was low, follow-up could be extended to ensure a minimum of 80 events. 

 

DSMB Interim safety analysis:

The DSMB was to formally compare the two treatment arms for safety with respect to:

·        All cause mortality

·        All cause mortality, all strokes, and all systemic embolic events

·        All strokes and all systemic embolic events

·        Major bleeding

This was to be done when approximately 12.5%, 25%, 50%, and 75% of the expected total number of patient exposure years have been reached.  Pre-determined stopping rules for a positive or a negative trend were described in a DSMB charter.  No adjustments to the significance levels in the final statistical analyses of the primary, secondary or tertiary endpoints were made.  

j.                    Study patient disposition

 

A total of 4763 patients were enrolled into the study from which 3922 were randomized.  Patients were randomized from a total of 422 centers in the U.S. (n = 361) and Canada (n = 61).  A total of 1960 and 1962 patients were randomized to H376/95 and warfarin respectively.  These patients formed the ITT population. 

The population used for the analysis of the safety data was equal to 3906 patients (3922 – 16).  Of the 16 patients excluded in the safety population, 15 were randomized but never received study drug.   One patient received a dose of study drug but no post-randomization data are available. 

Please refer to Figure 7 below for a summary of patient disposition in SPORTIF V. 

 

Figure 7: Patient disposition in SPORTIF V (Figure taken from Figure 4 of SPORTIF V CSR)

 

As seen in Figure 7 above, 841 patients were enrolled but not randomized.  Approximately 2/3 of these patients were not eligible because they failed to meet inclusion/exclusion criteria.  Sixty three percent of patients remained on ximelagatran at the time of study closure, while 67% remained on warfarin.  A total of 300 patients prematurely withdrew from the ximelagatran arm while 286 did soon the warfarin arm.   

            As shown in Figure 7, there were a total of 586 study withdrawals that were pre-mature in SPORTIF V (300 ximelagatran, 286 warfarin).  It is important to note that these patients were not followed up for primary endpoint events (e.g. stroke or SEE) or death.  Although not shown in this review, the reasons for pre-mature withdrawal were similar in both study arms. 

Unlike patients that pre-maturely withdrew from the study, patients that discontinued study drug were followed up for primary endpoint events or death.  As shown in Figure 7 above, there were 424 study drug discontinuations in the ximelagatran arm and 362 study drug discontinuations in the warfarin arm. 

As shown in Table VIII below, the total number of study drug discontinuations was greater on ximelagatran compared to warfarin by an absolute value of 3.7%.   A large portion of this excess discontinuation on ximelagatran could be attributed to adverse events specifically liver enzyme abnormalities. 

 

Table VIII: Table summarizing the primary reason for discontinuing study drug (ITT population)a

 

Ximelagatran

Warfarin

Total

Reason for study drug discontinuation

N=1960

N=1962

N=3922

Total

720

(36.7%)

646

(33.0%)

1366

(34.8%)

Eligibility criteria not fulfilled

15

(0.8%)

8

(0.4%)

23

(0.6%)

Adverse event

238

(12.1%)

175

(8.9%)

413

(10.5%)

Patient decision (Consent withdrawn from study drug)

207

(10.6%)

197

(10.0%)

404

(10.3%)

 

Endpoint events

 

 

 

 

 

 

   Acute myocardial infarction

10

(0.5%)

12

(0.6%)

22

(0.6%)

   Major bleed

30

(1.5%)

41

(2.1%)

71

(1.8%)

   Stroke

24

(1.2%)

24

(1.2%)

48

(1.2%)

   Systemic embolic event

6

(0.3%)

5

(0.3%)

11

(0.3%)

   Transient ischemic attack

16

(0.8%)

8

(0.4%)

24

(0.6%)

   Death

44

(2.2%)

47

(2.4%)

91

(2.3%)

Other

130

(6.6%)

129

(6.6%)

259

(6.6%)

aThe data in this table obtained from table 18 of SPORTIF V CSR

 

As shown in Table IX below, even after excluding patients with ALAT > 3x ULN, the total study drug discontinuation rate was numerically higher on ximelagatran compared to warfarin.

 

Table IX: Comparison of total study drug discontinuation rates including and excluding patients with ALAT > 3x ULNa 

 

Ximelagatran

Warfarin

Totals

Total discontinuation rate (including patients with ALAT > 3x ULN)

 

720/1960 (36.7%)

646/1962 (33.0%)

1366 (34.8%)

Total discontinuation rate (excluding patients with ALAT > 3x ULN)

640/1843 (34.7%)

635/1947 (32.6%)

1275 (33.6%)

aData in this table obtained from Tables 18 and 19 of SPORTIF V CSR

 

After study closure activities, vital status and primary event status were unknown for a total of 226 subjects: 119 Ximelagatran, 107 warfarin.  Efforts were made to contact these subjects and information related to the primary event or death was obtained on 203/226 subjects.  In 188 of the 203 patients in whom follow-up information was available, the information was obtained prior to unblinding the database.  In 15 of the 203 patient in whom follow-up information was available, the information was obtained after unblinding the database.  Information on these 203 patients was not entered into the database.  In these 203 patients, follow-up information revealed that there was one stroke in a patient that received warfarin.  There were a total of 15 deaths (8 ximelagatran, 7 warfarin).  A total of 23 patients (226 – 203) were lost to follow-up and for whom there is no primary event or vital status information. 

    

k.                  Protocol deviations

In the clinical study report for SPORTIF V the sponsor summarizes 4 different classes of protocol deviations that occurred: Enrollment deviations, Study drug administration deviations, Deviations relating to interruption of study drug, Unblinding deviations.  Each of these is summarized below. 

 

 

Enrollment deviations (violations of inclusion/exclusion criteria):

For Table X below, please refer to Section VII, C, 1, h (“Inclusion/Exclusion Criteria”) for reference to each criteria #. 

Table X: Summary of inclusion/exclusion criteria violations by treatment groups (Please refer to inclusion/exclusion criteria section of this review to match the number with the description of the criteria)a

 

Ximelagatran (n = 1960)

Warfarin (n = 1962)

Total (n = 3922)

Criteria #

Inclusion Criteria violations

1

27

18

45

2

3

1

4

Criteria #

Exclusion Criteria violations

1

0

1

1

2 (bullet 1)

0

3

2

2 (bullet 2)

2

2

4

2 (bullet 5)

0

1

1

3

1

0

1

5

2

2

4

8

1

0

1

9

1

0

1

10

2

0

2

12

5

2

7

13

4

1

5

14

3

4

7

17

0

4

4

21

1

1

2

aData in this table obtained from Table 11.1.20 of SPORTIF V NDA submission

 

Study drug administration deviations:

The sponsor reported a drug shipment error in which a study drug (Coumadin 2.5 mg YY series) from a different AstraZeneca study bearing similar bottle numbers had been shipped to numerous sites.  SPORTIF V and THRIVE V shared common bottle numbers and bottle appearances.  Five patients were affected by this shipping error. 

            Drug dispensing errors resulted in 13 patients receiving a total of 14 bottles of the incorrect active medication.  In 11 instances (8 ximelagatran, 3 warfarin), patients took both active medications together for various durations.  In 2 instances, patients returned the incorrect bottles.  No endpoints occurred during the time of dispensing error.  Endpoints occurred for 3 of the 13 patients 6 months or more after the administration error and are unlikely to be related to the error.   

 

Deviations relating to interruption of study drug:

A greater number of warfarin patients (61.6%) interrupted study drug for any duration compared with ximelagatran patients (41.7%) as shown in Table XI below.  One of the factors that might be responsible for the discrepancy in treatment interruption between the two groups is that patients in the warfarin arm with an INR > 3 would have their treatment interrupted until the INR had returned to less than 3.  It is unclear if this was the only reason in the discrepancy between the two study arms or if there are other reasons.   

 

Table XI: Number (%) of patients by total days of treatment interruption, and treatment groupa

 

Ximelagatran

Warfarin

Total

Treatment interruption

N=1952

N=1952

N=3904

No interruption

1138

(58.3)

749

(38.4)

1887

(48.3)

Any interruption

814

(41.7)

1203

(61.6)

2017

(51.7)

    1 to 7 days

463

(23.7)

660

(33.8)

1123

(28.8)

    8 to 30 days

274

(14.0)

431

(22.1)

705

(18.1)

    31 to 60 days

63

(3.2)

83

(4.3)

146

(3.7)

    >60 days

14

(0.7)

29

(1.5)

43

(1.1)

aData in this table obtained from Table 27 of SPORTIF V CSR. 

 

Unblinding deviations:

Three patients were unblinded during the study.  Two unblindings were intentional and one was unintentional. 

 

Intervals greater than 28 + 3 days between INR measurements:

 

As shown in Table XII below, more than 75% of patients had INR’s measured at an interval of < 31 days as specified in the protocol.  

Table XII: INR measurements for warfarin patients in SPORTIF V

 

Number (%)

INR measurement interval

of INR measurements

Total number of INR measurements

44108 (100)

Number of INR’s with interval <31 days (<1 month)

33758 (77)

Number of INR’s with interval >31 days (at least 1 month)

10350 (23)

Number of INR’s with interval > 31 but <61 days

10099 (23)

(between 1 and 2 months)

 

Number of INR’s with interval  61 days

251 (<1)

(at least 2 months)

 

Data in this table obtained from Table 6 of 5May2004 FDA Information request

 

 

 

 

l.                    Demographics and other patient characteristics

 

The characteristics of the patients enrolled in SPORTIF V are described in the Table XIII below.  The majority of patients were males, Caucasians, and > 65 years old.  Approximately 75% had two or more risk factors for stroke (in addition to non-valvular atrial fibrillation).  In general, the baseline characteristics were similar in the two treatment arms suggesting that randomization in the trial was successful. 

Comparing the population in SPORTIF V to that in SPORTIF III, there were fewer non-smokers and more non-drinkers in the former compared to the latter study.  In addition, the number of patients using aspirin at baseline was greater in SPORTIF V compared to SPORTIF III. 

Table XIII: Patient characteristics at screening: number (%) of patients by treatment group (ITT population)a

 

 

Ximelagatran

Warfarin

Total

Characteristic

 

N=1960

N=1962

N=3922

Sex

Male

1365

(69.9)

1353

(69.0)

2718

(69.3)

 

Female

595

(30.4)

609

(31.0)

1204

(30.7)

Race

Caucasian

1875

(95.7)

1888

(96.2)

3763

(95.9)

 

Black

67

(3.4)

58

(3.0)

125

(3.2)

 

Oriental

15

(0.8)

10

(0.5)

25

(0.6)

 

Other

3

(0.2)

6

(0.3)

9

(0.2)

Age

<65

383

(19.5)

401

(20.4)

784

(20.0)

 

³65 to <75

739

(37.7)

741

(37.8)

1480

(37.7)

 

³75

838

(42.8)

820

(41.8)

1658

(42.3)

Number of unique

0

3

(0.2)

4

(0.2)

7

(0.2)

stroke risk factors

1

490

(25.0)

509

(25.9)

999

(25.5)

(In addition to AF)

2

600

(30.6)

597

(30.4)

1197

(30.5)

 

3

472

(24.1)

459

(23.4)

931

(23.7)

 

4

274

(14.0)

273

(13.9)

547

(13.9)

 

5

100

(5.1)

96

(4.9)

196

(5.0)

 

6

20

(1.0)

21

(1.1)

41

(1.0)

 

7

1

(0.0)

3

(0.2)

4

(0.1)

Smoking

Non-smoker

711

(36.3)

689

(35.1)

1400

(35.7)

 

Previous smoker

1085

(55.4)

1108

(56.5)

2193

(55.9)

 

Occasional

27

(1.4)

31

(1.6)

58

(1.5)

 

smoker

 

 

 

 

 

 

 

Daily smoker

137

(7.0)

134

(6.8)

271

(6.9)

Alcohol use

No

1151

(58.7)

1163

(59.3)

2314

(59.0)

 

Yes

808

(41.2)

799

(40.7)

1607

(41.0)

 

Missing

1

(0.1)

0

(0.0)

1

(0.0)

Drinks per week

None

1151

(58.7)

1163

(59.3)

2314

(59.0)

 

>0 to £5 drinks

450

(23.0)

458

(23.3)

908

(23.2)

 

>5 to £10 drinks

208

(10.6)

200

(10.2)

408

(10.4)

 

>10 to £15 drinks

103

(5.3)

102

(5.2)

205

(5.2)

 

>15 to £20 drinks

5

(0.3)

7

(0.4)

12

(0.3)

 

>20 drinks

39

(2.0)

30

(1.5)

69

(1.8)

 

Missing

4

(0.2)

2

(0.1)

6

(0.2)

Undergone any

No

452

(23.1)

501

(25.5)

953

(24.3)

major surgery

Yes

1506

(76.8)

1458

(74.3)

2964

(75.6)

 

Missing

2

(0.1)

3

(0.2)

5

(0.1)

Current ASA use

No

1398

(71.3)

1393

(71.0)

2791

(71.2)

 

Yes

542

(27.7)

544

(27.7)

1086

(27.7)

 

Missing

20

(1.0)

25

(1.3)

45

(1.1)

Rankin score

0

1481

(75.6)

1479

(75.4)

2960

(75.5)

 

1

310

(15.8)

311

(15.9)

621

(15.8)

 

2

159

(8.1)

165

(8.4)

324

(8.3)

 

3

6

(0.3)

5

(0.3)

11

(0.3)

 

4

2

(0.1)

0

(0.0)

2

(0.1)

 

5

0

(0.0)

0

(0.0)

0

(0.0)

 

Missing

2

(0.1)

2

(0.1)

4

(0.1)

aData in this table obtained from Table 29 of SPORTIF V CSR

Patients in the two treatment arms were also comparable with respect to various demographic factors listed in Table XIV below. 

Patients in SPORTIF V were slightly older compared to patients in SPORTIF III – 71.6 years versus 70.2 years.  In addition, the mean blood pressure at baseline for patients enrolled in SPORTIF V was lower compared to that for patients in SPORTIF III. 

 

Table XIV: Mean (+SD) of patient characteristics at screening (ITT population)a

 

Ximelagatran (N = 1960)

Warfarin (N = 1962)

Total (N = 3922)

Mean Age (years)

71.6 + 9.2

71.6 + 9.0

71.6 + 9.1

Mean Height (cm)

173.0 + 10.8

173.1 + 10.6

173.1 + 10.7

Mean Weight (kg)

90.1 + 21.9

89.1 + 21.3

89.6 + 21.6

Mean BMI ((kg/m2)

30.0 + 6.6

29.6 + 6.2

29.8 + 6.4

Mean estimated CrCL (mL/min)

87.0 + 40.5

86.1 + 38.3

86.6 + 39.4

Mean Sitting SBP (mm Hg)

132.6 + 17.7

132.4 + 17.6

132.5 + 17.7

Mean Sitting DBP (mm Hg)

77.4 + 10.5

77.2 + 10.3

77.3 + 10.4

aData in this table obtained from Table 30 of SPORTIF V CSR. 

 

As shown in Table XV below, hypertension was by far the most prevalent risk factor in SPORTIF V.  Less than 1/5 of the randomized patients had a prior history of stroke or TIA.  The distribution of risk factors was similar between the two treatment arms. 

In SPORTIF V, fewer patients had a history of stroke or TIA compared to patients in SPORTIF III: 18% versus 24%.  

Table XV: Number (%) of patients with the presence of the listed risk factor at study entry. 

 

Ximelagatran (N = 1960)

Warfarin (N = 1962)

Total (N = 3922)

Hypertension

1584 (80.8)

1582 (80.6)

3166 (80.7)

Age > 75 years

838 (42.8)

820 (41.8)

1658 (42.3)

History of stroke or TIA

369 (18.8)

348 (17.7)

717 (18.3)

History of SEE

92 (4.7)

85 (4.3)

177 (4.5)

Left ventricular dysfunction

735 (37.5)

788 (40.2)

1523 (38.8)

Age > 65 and CAD

822 (41.9)

803 (40.9)

1625 (41.4)

Age > 65 and DM

389 (19.8)

373 (19.0)

762 (19.4)

Data in this table obtained from Table 32 of SPORTIF V CSR

 

As shown in Table XVI below, the use of study medications at study entry was similar between the two treatment arms.  Approximately 20% of the randomized patients were on aspirin at study entry and the majority of those were on doses less than 100 mg/day.  In SPORTIF III, just under 30% of the randomized patients were on aspirin at study entry, the majority being on doses less than 100 mg/day.  The use of HMG CoA reductase inhibitors at study entry was more prevalent in SPORTIF V (36.8%) than in SPORTIF III (19%). 


Table XVI: Number (%) of patients with concomitant medication use at study entry by treatment group (ITT population)a

 

Ximelagatran

Warfarin

Total

 

Therapya

N=1960

N=1962

N=3922

 

Vitamin K antagonists

1617

(82.5)

1661

(84.7)

3278

(83.6)

 

Heparin group

15

(0.8)

4

(0.2)

19

(0.5)

 

ASA £100 mg/day

227

(11.6)

251

(12.8)

478

(12.2)

 

ASA >100 mg/day

160

(8.2)

135

(6.9)

295

(7.5)

 

ASA (dose unknown)

31

(1.6)

25

(1.3)

56

(1.4)

 

Digoxin/Digitoxin

1058

(54.0)

1056

(53.8)

2114

(53.9)

Beta blockers

972

(49.6)

937

(47.7)

1909

(48.6)

Calcium antagonists

754

(38.5)

743

(37.8)

1497

(38.1)

Diuretics

1274

(65.0)

1275

(64.9)

2549

(65.1)

ACE inhibitors

937

(47.8)

938

(47.8)

1875

(47.8)

Angiotensin II-antagonists

213

(10.9)

189

(9.6)

402

(10.2)

Acetaminophen

351

(17.9)

299

(15.2)

650

(16.6)

Amiodarone

83

(4.2)

94

(4.8)

177

(4.5)

HMG CoA reductase inhibitors

733

(37.4)

709

(36.1)

1442

(36.8)

aData in this table obtained from Table 39 of SPORTIF V CSR. 

 

Table XVII below shows the proportion of time patients took concomitant aspirin between the first and last dose of study drug.  As discussed earlier in the inclusion/exclusion criteria, patients were permitted to take ASA < 100 mg/day during the trial.  As shown in the table below, the overall percentage of time that patients in the ximelagatran arm were on aspirin during the study was greater than in the warfarin arm. 

Table XVII: Proportion of time patients took concomitant ASA between the first and last dose of study drug (ITT population)a

 

Ximelagatran

Warfarin

Total

Proportion of time

N=512

N=535

N=1047

>0% to 25%

160

(31.3)

178

(33.3)

338

(32.3)

>25% to 50%

22

(4.3)

28

(5.2)

50

(4.8)

>50% to 75%

22

(4.3)

18

(3.4)

40

(3.8)

>75% to 100%

308

(60.2)

311

(58.1)

619

(59.1)

Overall % of time on ASA

64.4

60.4

62.3

aData in this table obtained from Table 40 of SPORTIF V CSR. 

 

As shown in Table XVIII below, the number of patients on the various listed medications between the first and last dose of study drug were similar in the 2 treatment arms. 


Table XVIII: Number (%) of patients using other cardiovascular medications between the first and last dose of study drug, by treatment group (ITT population)a

 

Ximelagatran

Warfarin

Total

Medicationa

N=1960

N=1962

N=3922

Digoxin/Digitoxin

1122

(57.2)

1132

(57.7)

2254

(57.5)

Beta blockers

1149

(58.7)

1187

(60.6)

2336

(59.6)

Calcium antagonists

905

(46.1)

910

(46.5)

1815

(46.2)

Diuretics

1603

(81.9)

1681

(85.9)

3284

(83.8)

ACE inhibitors

1091

(55.7)

1121

(57.2)

2212

(56.4)

Angiotensin II-antagonists

301

(15.4)

296

(15.1)

597

(15.2)

Acetaminophen

654

(33.4)

642

(32.7)

1296

(33.0)

Amiodarone

130

(6.6)

139

(7.1)

269

(6.9)

HMG CoA reductase inhibitors

923

(47.1)

926

(47.2)

1849

(47.1)

aData in this table was obtained from Table 41 SPORTIF V CSR. 

 

 

m.                Primary endpoint results

The results of the primary pre-specified endpoint from SPORTIF V are summarized in Table XIX below.  The results of the sponsor’s primary endpoint analysis was re-analyzed and confirmed by the statistical reviewer Dr. John Lawrence. 

Table XIX: Number of patients with stroke and/or SEE by treatment group (primary prespecified endpoint)a

 

 

 

Event

        95% CI

 

 

 

Patient

Rate

 

 

 

Treatment group

Eventsb,c

Years

(%/year)

Lower

Higher

p-value

Ximelagatran

51

3160

1.61

1.17

2.06

 

Warfarin

37

3186

1.16

0.79

1.54

 

Ximelagatran – warfarin

 

 

0.45

-0.13

1.03

0.133

aData in this table obtained from Table 45 of SPORTIF V CSR

bEvents represent CEAC adjudicated events

cThis table only informs of the number of patients with their first event.  If a patient had more than one event, it is not reflected in this table. 

  

As shown in Table XX below, the most striking finding was a total of 10 fatal strokes on ximelagatran versus 3 fatal strokes on warfarin.  In terms of overall number of events, the majority of strokes were non-fatal and ischemic in nature.  Relatively few were hemorrhagic in nature.  SEE’s were also relatively rare comprising less than 10% of the total number of primary events.


Table XX: Breakdown of primary endpoint by type of event and whether fatal or non-fatala. 

 

Ximelagatran

Warfarin

Total

Endpoint eventb

N=1960

N=1962

N=3922

Fatal stroke

10

(0.5)

3

(0.2)

13

(0.3)

      Ischemic stroke

8

(0.4)

3

(2.0)

11

(0.3)

     Hemorrhagic stroke

2

(0.1)

0

(0.0)

2

(0.1)

Non-fatal stroke

38

(1.9)

34

(1.7)

72

(1.8)

     Ischemic stroke

38

(1.9)

33

(1.7)

71

(1.8)

     Hemorrhagic stroke

0

(0.0)

2

(0.1)

2

(0.1)

Non fatal SEE

6

(0.3)

1

(0.1)

7

(0.2)

Total number of events

57

(2.9)

40

(2.0)

97

(2.5)

Total number of patients with at least 1 event

51

(2.6)

37

(1.9)

88

(2.2)

aData in this table obtained from Table 46 of SPORTIF V CSR. 

bPatients are counted once in each category of event if they had one or more events of that type. 

 

Figure 8: Cumulative proportion of patients with stroke and/or SEE over time-estimated Kaplan-Meier curves (Figure taken from Figure 12 of SPORTIF V CSR). 

 

 

Figure 9 below summarizes the results of the primary endpoint as a function of various prognostic factors.  The point estimates of the event rates were generally consistent across various subgroups and favored warfarin with the exception of patients with a BMI < 25.   


Figure 9: Event rate difference (ximelagatran – warfarin) for the primary endpoint (stroke and/or SEE) according to prognostic factors (Figure taken from Figure 16 of SPORTIF V CSR) 

 

n.                  Secondary and Tertiary endpoint results

The results of the secondary and tertiary endpoints are summarized in Table XXI through Table XXIV.     

 

SECONDARY ENDPOINTS

Table XXI below summarizes the results of the secondary endpoint.  There were a total of 229 patients with at least one event.  However, the total number of events was 261 because of the fact that a patient could have had more than one event.  Of the 229 patients with one event, just under 50% were deaths. 


Table XXI: Number of patients with all cause mortality/stroke/ SEE/AMI by treatment group (secondary prespecified endpoint based on OT analysis)a

 

 

 

Event

        95% CI

 

 

 

Patient

Rate

 

 

 

 

Treatment

Eventsb,c

years

(%/year)

Lower

Higher

p-value

 

Ximelagatran

110

2612

4.21

3.42

5.00

 

 

Warfarin

119

2738

4.35

3.56

5.13

 

 

Ximelagatran – warfarin

 

 

-0.13

-1.24

0.98

0.839

 

aData in this table obtained from Table 58 of SPORTIF V CSR

bEvents represent CEAC adjudicated events

cIf a patient had more than one event, it is not reflected in this table.  The total number of events was 127 and 134 on ximelagatran and warfarin respectively. 

 

Table XXII below shows the results of one of the secondary prespecified endpoints which evaluated the number of patients with stroke/TIA/SEE.  There were numerically more TIA’s in the ximelagatran arm compared to the warfarin arm.  

 

Table XXII: Number of patients with ischemic stroke/TIA/SEE by treatment group (secondary prespecified endpoint based on OT analysis)a

 

 

 

Event

        95% CI

 

 

 

Patient

Rate

 

 

 

 

Treatment

Eventsb,c

Years

(%/year)

Lower

Higher

p-value

 

Ximelagatran

67

2606

2.57

1.96

3.19

 

 

Warfarin

52

2728

1.91

1.39

2.42

 

 

Ximelagatran – warfarin

 

 

0.66

-0.14

1.47

0.115

 

aData in this table obtained from Table 62 of SPORTIF V CSR

bEvents represent CEAC adjudicated events

cIf a patient had more than one event, it is not reflected in this table.  The total number of events was 80 and 57 on ximelagatran and warfarin respectively.   

 

 

TERTIARY ENDPOINTS

It is important to note that the analysis of the tertiary endpoint was changed to include the ITT population after the database was unblinded.  

Table XXIII: Number of patients with strokes with a poor outcome by treatment group (tertiary prespecified endpoint based on ITT analysis)a

 

 

 

Event

        95% CI

 

 

 

Patient

Rate

 

 

 

 

Treatment

Eventsb

years

(%/year)

Lower

Higher

p-value

 

Ximelagatran

16

3190

0.50

0.26

0.75

 

 

Warfarin

10

3207

0.31

0.12

0.51

 

 

Ximelagatran – warfarin

 

 

0.19

-0.12

0.50

0.246

 

aData in this table obtained from Table 64 of SPORTIF V CSR

bEvents represent CEAC adjudicated events

 

 

Table XXIV: Number of patients with stroke or SEE as a function of age (<, > 75 years of age) (tertiary prespecified endpoint based on ITT analysis)a

 

 

 

 

 

      95% CI

 

 

 

 

 

Event

 

 

 

Age

 

 

Patient

rate

 

 

 

group

Treatment

Eventsb

Years

(%/year)

Lower

Higher

p-value

Age ³75

Ximelagatran

23

1322

1.74

1.03

2.45

 

Years

 

 

 

 

 

 

 

 

Warfarin

18

1311

1.37

0.74

2.01

 

 

Ximelagatran - warfarin

 

 

0.37

-0.59

1.32

0.530

Age <75

Ximelagatran

28

1840

1.52

0.96

2.09

 

Years

 

 

 

 

 

 

 

 

Warfarin

19

1875

1.01

0.56

1.47

 

 

Ximelagatran - warfarin

 

 

0.51

-0.22

1.23

0.187

aData in this table obtained from Table 66 of SPORTIF V CSR

bEvents represent CEAC adjudicated events

 

o.                  Adequacy of anticoagulation in the warfarin arm

The adequacy of anticoagulation in the warfarin group was assessed in the OT (on treatment) population.  Overall, the number of patients in the warfarin group with an:

·        INR < 2.0 occurred 20.3% of total time

·        INR 2.0 to 3.0 occurred 68% of the time

·        INR > 3.0 occurred 11.7% of the time

 

Figure 10 below shows the percentage of patients with INR’s < 2.0, between 2.0 and 3.0, and > 3.0 as a function of time since randomization. 

Figure 10: Adequacy of anticoagulation as assessed by INR in patients assigned to warfarin (OT population); (Figure taken from Figure 23 of SPORTIF V CSR). 

 

In general, the adequacy of anticoagulation with warfarin in SPORTIF V was good and comparable to that seen in historical studies of warfarin.  Please refer to Table VI for details of the adequacy of anticoagulation in studies involving warfarin.  Using the AFASAK study as an example of the worst case scenario, the INR was in the “therapeutic” range (2.8 to 4.2) 42% of the time.  In the best case scenario, the BAATAF study showed that the “therapeutic” range (1.5 to 2.7) was achieved 83% of the time.   

 

A total of 172 (8.8%) of patients had intervals between INR measurements of more than 2 months. 

 

2.                  SPORTIF III

 

Study Title:  “Efficacy and Safety of the Oral Direct Thrombin Inhibitor H376/95 Compared with Dose-Adjusted Warfarin in the Prevention of Stroke and Systemic Embolic Events in Patients with Atrial Fibrillation”

 

SPORTIF III (SH-TPA-0003) was the second of the 2 pivotal Phase 3 studies submitted by the sponsor for the indication of prevention of stroke and SEE in patients with atrial fibrillation.    SPORTIF III was very similar in design to SPORTIF V except for the aspect of blinding.  The former was open-label while the latter was double-blind. 

a.                  Study dates

 

Date first patient enrolled: July 25, 2000

Date enrollment ended: September 13, 2001

Date study closure procedures began: July 1, 2002

Date final patient completed study: September 30, 2002

Date of Clinical Study Report: September 26, 2003

b.                  Protocol Amendments

Table XXV below summarizes the date at which the original protocol was issued along with dates at which all subsequent amendments to the original protocol were issued.  Below

Table XXV are listed the summaries of each protocol amendment. 

 

Table XXV:  Original Protocol and Protocol Amendment Issue dates for SPORTIF III

Version of Protocol or Protocol Amendment

Date of issue

Protocol Version 1

March 8, 2000

Protocol amendment 1 to Version 1

May 3, 2000

Protocol Version 2

May 3, 2000

Protocol Amendment 1 to Version 2

October 30, 2001

Protocol Amendment 1 to Version 3

June 12, 2002

 

 

Amendment entitled: “Protocol amendment 1 to Version 1”

 

  • Change in exclusion criteria relating to active liver disease and persistent elevation of liver enzymes has been changed from “more than 3 times the upper limit of normal” to“≥2 times the upper limit of normal”.
  • Additional laboratory assessments, hematology and clinical chemistry, were scheduled at the following time points: 6 weeks, 2 months, 4, 5, 8, 10, 15 and 21 months.  Additional clinic visits were added to accommodate the extra laboratory assessments. 
  • The protocol was amended to include specific instructions for the investigator to follow in the event of liver enzyme abnormalities.  If, at any time during the study, the liver enzyme, S-ALAT (GPT) is ≥3 times the upper limit of normal (ULN) and this is confirmed in a repeat test then the patient will be recalled for a third check-up visit when a 14-15 mL blood sample will be drawn for extended liver function tests evaluating various etiologies for liver enzyme abnormalities.   Once an increase of S-ALAT to > 3x ULN has been confirmed in a repeat test, weekly liver enzyme test check-ups, i.e. S-ASAT, S-ALAT, S-ALP and S-Bilirubin will be performed until S-ALAT is either less than 2x ULN or has returned to normal values.
  • Specific instruction regarding when to discontinue a patient for liver enzyme abnormalities were added.  A patient was to be discontinued from the study if repeated measurements showed that S-ALAT remains elevated 3 to 7x ULN during a 2-month period without any tendency to decrease or other clinical explanation being found.  Any patient with a S-ALAT > 7x ULN at any time was to be discontinued from the study. 
  • The number of patients was increased from 2700 to 3000.
  • The study start date was changed from April 2000 to July 2000.
  • The treatment period was changed from 30 months to 26 months.

 

 

Amendment entitled: “Protocol amendment 1 to Version 2”

 

  • The threshold for discontinuing a patient due to liver enzyme abnormalities was reduced.  Patients with an increase of >5 times the upper limit of normal (ULN) in any liver enzyme test, i.e. S-ASAT, S-ALAT, S-ALP and S-Bilirubin, were to be withdrawn from study treatment, unless it was agreed with the AstraZeneca responsible physician that it is acceptable for the patient to remain on treatment.
  • For any patient that showed a persistent elevation of any LFT (not just restricted to ALAT elevation) >3 times the ULN but < 5 times the ULN for 8 weeks then study treatment must be discontinued. 
  • If an increase of >3 times ULN was seen in any LFT then the patient was to be recalled for a visit where further work-up occurred.  No confirmation or repeat lab test was necessary to confirm the enzyme abnormality – unlike that required in Amendment 1 to Version 1. 

 

Amendment entitled: “Protocol amendment 1 to Version 3”

 

  • The following was added:  “It is important that the final health status of all patients is known at the end of the study. For patients who withdraw from the study due to death, stroke or systemic embolic event, their final health status is considered known. Patients who withdraw completely from the study due to other reasons are considered to have an unknown final health status. These patients will be contacted during the 3-month closeout period and will be asked to consent to provide follow-up information regarding their health status. If consent is provided, the patient will be asked to confirm that they are still alive and whether or not they have suffered a stroke or a systemic embolic event.”
  • With regards to the statistical analysis of the primary endpoint it was decided to analyze the primary endpoint with an Intention to Treat approach using adjudication from the Clinical Events Committee. 

 

c.                   Study Design:

 

SPORTIF III was similar in design to SPORTIF V except that it was open-label.  It was a randomized, active control, parallel group study in patients with non-valvular atrial fibrillation.  SPORTIF III was conducted in Europe and Asia whereas SPORTIF V was conducted in the U.S. and Canada.  Please refer to section VIII, C, 2, j for details of the countries that enrolled patients into this study.  

 

SPORTIF III randomized a total of 3410 patients.  As shown in Figure 11, patients were randomized to either fixed doses of ximelagatran 36 mg bid or to adjusted dose warfarin, titrating to an INR of 2-3 via monthly blood tests. 

 

 

Figure 11: Study Schema for SPORTIF III (Figure obtained from Figure 1 of SPORTIF III CSR)

 

Stratification in SPORTIF III was based on: 

Aspirin Use

Previous stroke/TIA

Country

 

Study duration:  The study is to continue until 4000 patient years are collected and/or at least 80 primary endpoints are achieved. 

 

The study included a DSMB, CEAC, and ESC.  The members of the DSMB, CEAC and ESC were the same as in SPORTIF V and are listed in Section VIII, C, 1, c of this review. 

d.                  Rationale for doses selected

Please refer to Section VIII, C, 1, d of this of this review for details. 

e.                   Blinding/Randomization:

Unlike SPORTIF V, this study was conducted open-label.  All primary events (stroke and systemic embolic events), secondary events (deaths, acute MI’s, TIA’s) and major bleeding events were adjudicated by a CEAC. 

f.                    Pre-specified study objectives

The primary, secondary, and tertiary endpoints were almost identical to those in SPORTIF V.  Please refer to Section VIII, C, 1, f of this review for details. 

g.                  Definitions of study endpoints

Please refer to Section VIII, C, 1, g of this review for details

h.                  Inclusion/Exclusion Criteria:

The inclusion and exclusion criteria were identical to those is SPORTIF V.  Please refer to Section VIII, C, 1, h of this review for details. 

i.                    Statistical Considerations (please refer to the statistical review for details):

 

The general statistical considerations and sample size calculations were very similar for both studies.  Please refer to Section VIII, C, 1, i of this review for further details.

j.                    Study patient disposition

 

Patients were enrolled from a total of 259 centers in 23 countries (Australia, Belgium, Czech