FDA Briefing Package

 

Anti-Infective Drugs Advisory Committee

 

April 26th, 2001

 

 

 

 

 


 

 

 

 


New Drug Application (NDA) 21-144

KetekTM (telithromycin)

 

 

 


Executive Summary 

This FDA briefing document contains a summary of New Drug Application (NDA) 21-144 for  telithromycin tablets (KetekÔ, Aventis Pharmaceuticals; development name HMR 3647).  Telithromycin is the first in a new class of antimicrobials, ketolides, within the macrolide-lincosamide streptogramin (MLSB) family. The FDA has reviewed the primary data provided to support the safety and efficacy of telithromycin.  Concerns regarding telithromycin will focus on the following specific areas:

·         cardiac repolarization effect (QT interval prolongation);

·         hepatotoxicity;

·         pharmacokinetic variability and drug-drug interactions;

·         resistance claims for S. pneumoniae (penicillin and macrolides).

Safety:

Recently, approvals of non-cardiac drugs with a documented effect on QT interval have come under considerable scrutiny within the FDA. Assessment of risk/benefit must be considered in the decision to approve such drugs.

Telithromycin elicited delayed repolarization in in vitro models of cardiac repolarization, and in vivo in animals. In phase I studies, telithromycin caused concentration-dependent increases in the QTc interval. In phase III studies, telithromycin caused a consistent effect on mean QTc duration in humans, with evidence that interactions with drugs metabolized by CYP 3A4 may further prolong QTc duration.

Telithromycin’s effect on QTc is concentration-dependent; thus, understanding sources of pharmacokinetic variability is important. Telithromycin concentrations in human plasma are highly variable (1.99 mg/L after a single dose in phase I, up to 9.9 mg/L after multiple doses in phase III), with a significant increase in Cmax in elderly subjects.  Telithromycin is a CYP 3A4 substrate, and is primarily metabolized and eliminated by the liver.  Co-administration of a 3A4 inhibitor significantly increases telithromycin concentrations. In hepatically impaired subjects, the t˝ of telithromycin was significantly increased.

Telithromycin has significant toxicologic effects on liver and heart in mice, rats, dogs and monkeys.  These include increased liver-associated enzymes, increased total bilirubin, hepatic necrosis and associated inflammation, and phospholipidosis. Toxicologic comparisons between telithromycin and clarithromycin are discussed in the briefing package.

Efficacy:

The applicant has requested approval for telithromycin in adults for the following indications:

·         tonsillitis/pharyngitis (T/P);

·         acute exacerbation of chronic bronchitis (AECB);

·         acute sinusitis;

·         community-acquired pneumonia (CAP)

Included among the requested pathogens are S. pneumoniae resistant to penicillin and erythromycin in CAP, AECB, and sinusitis.

Requests to the FDA regarding marketing claims for infections due to resistant S. pneumoniae are increasing. Levofloxacin is currently approved for the treatment of pneumonia caused by S. pneumoniae resistant to penicillin.  No agents are approved for the treatment of S. pneumoniae resistant to erythromycin.

Summary: 

Given the concerns raised regarding the safety of telithromycin, we ask the Advisory Committee to focus on the risk-benefit ratio of this new agent. This is the first time the Anti-Infectives Advisory Committee is to discuss a possible erythromycin resistance claim.  Important considerations in this discussion, in addition to safety considerations, include: in vitro evidence; potential for cross-resistance; clinical efficacy; overall weight of evidence; and public health benefit.


Table of Contents

Executive Summary............................................................................................................ 2

I.    Summary of Selected Microbiologic Information........................................................ 4

II.    Pre-clinical Pharmacology /Toxicology....................................................................... 5

III.  Clinical Pharmacology................................................................................................. 6

IV.  Clinical/Statistical Efficacy Analysis of Phase III trials............................................... 8

A.   Community Acquired Pneumonia........................................................................... 12

B.   Acute Bacterial Exacerbation of Chronic Bronchitis............................................. 20

C.   Acute Sinusitis........................................................................................................ 22

D.   Tonsillitis / Pharyngitis........................................................................................... 25

E.   Streptococcus pneumoniae: resistance claims and FDA regulatory history........... 27

V.  Safety Analysis............................................................................................................. 30

A.   Overview of FDA Integrated Summary of Safety Review...................................... 30

1.    Extent of Exposure.................................................................................................. 30

2.    Deaths.................................................................................................................... 30

3.    Nonfatal serious adverse events............................................................................... 30

4.    Discontinuations...................................................................................................... 33

B.   Cardiovascular Safety.............................................................................................. 34

1.    In vitro and preclinical data..................................................................................... 34

2.    Phase I data QTc prolongation and pharmacokinetics in normal subjects...................... 35

a)    Dose-response relationship................................................................................... 35

b)    Population concentration response......................................................................... 37

3.    QTc prolongation and pharmacokinetics in patients with cardiac disease...................... 37

4.    QTc prolongation in drug-interaction studies (Study 1041 - cisapride)........................... 38

5.    Pharmacokinetic variability in special populations....................................................... 38

6.    Potential for drug interactions with 3A4 inhibitors...................................................... 39

7.    Summary: Pharmacokinetics.................................................................................... 39

8.    Phase III  Studies: Cardiac Safety............................................................................ 43

a)    Deaths and adverse events related to the cardiovascular system............................. 43

b)    Cardiovascular serious adverse events (SAEs)...................................................... 43

c)    Cardiovascular adverse events (AEs).................................................................... 44

d)    Electrocardiographic data..................................................................................... 44

e)    Summary: Cardiac Safety..................................................................................... 48

 C. Hepatic Safety.............................................................................................................. 51

1.   Preclinical liver abnormalities.................................................................................... 51

       2.   Phase I liver abnormalities........................................................................................ 52

3.   Phase III liver abnormalities and clinical outcome....................................................... 54

4.   Summary: Hepatic Safety......................................................................................... 61

VI. Appendices.................................................................................................................. 63

A.   FDA Cardio-Renal Consult......................................................................................... 63

B.   Patient Narratives: Efficacy Section............................................................................. 72

C.   Patient Narratives: Serious Hepatic Adverse Events..................................................... 74

D.   Review and Evaluation of Pharmacology and Toxicology Data...................................... 80

 


 

I.                   Summary of Selected Microbiologic Information

Chemistry

·        Semisynthetic

·        Belongs to the ketolide family of antimicrobials within the macrolide-lincosamide streptogramin (MLSB) class.

Mechanism of Action

·         Inhibition of bacterial protein synthesis by action at the 23S ribosomal RNA.

Spectrum of Activity

·        In vitro activity against Gram-positive bacteria, fastidious Gram-negative bacteria, some anaerobes, and atypical pathogens (Legionella pneumophilia, Mycoplasma pneumoniae, and Chlamydiae pneumoniae).

·        MIC90 (μg/ml) range for target pathogens:  

·        S. pneumoniae (including penicillin- and erythromycin-resistant strains): 0.25

·        H. influenzae: β-lactamase-negative – 2 ; β-lactamase-positive – 4

·        M. catarrhalis (including β-lactamase-positive strains) – 0.5

·        S. pyogenes: erythromycin-susceptible – 0.06; erythromycin-resistant – 8

·        Bacteriostatic against S. pyogenes, S. aureus

·        Bactericidal against penicillin- or erythromycin-susceptible and resistant S. pneumoniae, H. influenzae and M. catarrhalis.

·        None to minimal activity against methicillin-resistant S. aureus or methicillin- resistant coagulase-negative staphylococci.

Resistance

·        In vitro activity against some strains of S. pneumoniae that carry the mefE and ermB genes.

·        In vitro activity against S. pyogenes that do not carry ermB gene. Increased MIC90s in S. pyogenes that carry ermB.

Other microbiologic characteristics of telithromycin

·        Synergism: no data available

·        Antagonism: no data available

·        Post-Antibiotic effect: Telithromycin has been shown to have a PAE ranging from approximately 1 h to 8 h at 10x MIC against the pathogens of interest.

·        pH effect: A decrease in pH from 7 to 5.5 increases the telithromycin  MIC for S. pneumoniae by approximately 15-fold.

·        Inoculum effect: Increasing inoculum size from 104 to 106 cfu/mL does not affect the MIC. If the inoculum size is 107 or greater, the telithromycin MIC for S. pneumoniae goes up approximately 2 to 4-fold.

 

 

II.                Pre-clinical Pharmacology /Toxicology

The pre-clinical pharmacology/toxicology review of the telithromycin NDA submission included a side-by-side comparison with pre-clinical data for clarithromycin.  (See Appendix D of this briefing document for the complete report.) The review evaluated the original source data submitted to the FDA in support of all clarithromycin applications, since the NDA for telithromycin compares its hepatic and cardiac effects to those of clarithromycin.  Summary comments are listed below, and additional data regarding potential he­patic and cardiac toxicity are included in the Safety section (section V) of this briefing package.

            Dr. John Koerner of the Division of Cardio-Renal Drug Products has reviewed the preclinical electrophysiologic data for telithromycin. He concluded that “[Telithromycin] demonstrated a potential to affect ventricular repolarization . . . The absence of an effect on absolute QT interval in the presence of a heart rate increase strongly supports the con­clusion of a drug-related effect on ventricular repolarization since, in the absence of drug, a heart rate increase should shorten the QT.  All of the above mentioned effects were concentration- or dose-related.”

As the applicant has suggested that telithromycin has a risk profile no worse than that of clarithromycin, it is critical to consider the effects of each drug in each species evaluated.  The applicant for clarithromycin considered the monkey the most appropriate animal model for toxicologic studies.  After 2 weeks of dosing with telithromycin or clarithromycin, increased LFTs were seen with both compounds.  In addition, telithromy­cin elicited renal tubular atrophy and increased total bilirubin levels.  After 4 weeks of dosing in the monkey, both compounds elicited increased LFTs, but more significant in­creases were seen with telithromycin.  Telithromycin-treated monkey showed increased total bilirubin levels during this entire dosing period.

In the rat, after 4 weeks of dosing, although both drugs increased LFTs (clarithromycin 2-3x; telithromycin 2-15x), the qualitative and quantitative effects were quite different.  Clarithromycin primarily affected multinucleated hepatocytes (significance to humans unknown) with minimal to mild hepatic necrosis at >50 mg/kg/d.  Telithromycin caused moderate to severe hepatic necrosis with steatosis/phospholipidosis at >50 mg/kg/d (lowest dose tested).  After 13 weeks of dosing, multinucleated hepatocytes were reported for clarithromycin while telithromycin elicited increased LFTs, increased N-acetyl-ß-glucosamidase (3x) in urine, and phospholipidosis.

In dogs, LFTs were increased with both compounds (clarithromycin 4-5x; telithromycin 6x) but telithromycin elicited one premature decedent with acute liver and renal failure, and phospholipidosis in mid- and high-dose groups.  EKGs showed no drug-related differences from controls/baseline with clarithromycin, while telithromycin caused a markedly increased heart rate and increased QTc interval (27-30 msec).  In the only comparative study performed, clarithromycin and erythromycin each increased the QTc interval by 17 msec while telithromycin increased it by 30 msec. 

The applicant for clarithromycin stated that dogs are exquisitely sensitive to the toxicologic effects of clarithromycin. Of note, it appears that the incidence and severity of significant changes in LFTs, histopathology, and QT intervals were increased in telithromycin-treated dogs when compared to clarithromycin-treated dogs.  In addition, more species appeared to be adversely affected by telithromycin treatment than by clarithromycin treatment.


III.             Clinical Pharmacology

Standard pharmacokinetic parameters for oral telithromycin are given in Table 1.  Clinical pharmacology concerns of particular importance include:

·        Pharmacokinetic variability: drug exposure may be significantly increased in the elderly and hepatically impaired patients.

·        Drug-drug interactions: telithromycin exposure may be significantly increased by co-administration of a CYP 3A4 inhibitor such as ketoconazole.

·        Cardiac repolarization effects: telithromycin prolongs the QT interval in a concentration-dependent fashion.

·        The potential for these factors to act in an additive or synergistic fashion, leading to an increased risk of torsades de pointes.

            Specific details are discussed in the Safety section (section V) of this document.


 

Table 1.  Summary of oral telithromycin pharmacokinetics

PK Assessments in Healthy

Subjects

PK Parameters After 800 mg QD (Unless Noted)

Expressed as Mean (CV)

Absorption and Systemic Bioavailability

(Study 1044)

Absolute Bioavailability: Young: 57.3% (31); Elderly 56.6% (20)

Tmax: 2.5–3 hours

Food Effects (Study 1003)

None

Distribution

Protein Binding: 60% – 70% Bound

Vss (L): Young subjects:210 (27); elderly subjects: 226 (21)

Penetration into tissues:

Blister fluid/tonsil secretion/pulmonary tissue/saliva

Metabolism (Study 1009)

Mainly metabolized (22% and 12% unchanged in feces and urine)

CYP3A substrate

Four metabolites have been identified.

Excretion

(Study 1009)

Urine: 12% Unchanged telithromycin

Feces: 22% Unchanged telithromycin

 

Single dose:

    Cmax (mg/L)= 1.90 (42); range:0.964-3.252

    AUC0-Ą(mg·h/L)= 8.25 (31)

    t1/2 (h): 7.16 (19)

    CL/F (L/h): 102.3 (31)  range: 53.5-184.8

    CLr/F0-24: (L/h): 12.32 (17)

Multiple doses:

    Cmax (mg/L)= 2.27(31); range:1.40-3.77 mg/L

    AUC0-Ą(mg·h/L)= 12.5 (43); range: 7.08-31.53

    t1/2 (h): 9.81 (20)

    CL/F (L/h): 71.1 (29)  range: 25.4-85.2

    CLr/F: (L/h): 12.5 (34)

Disposition Kinetics

Nonlinear pharmacokinetics

Slightly more than dose proportional Increases in AUC and Cmax after 400 mg, 800 mg and 1600 mg.

Accumulation factor was about 1.5 after multiple doses.

Significant Interactions

CYP3A4 inhibitor: ­ telithromycin by ketoconazole/itraconazole

                               « telithromycin by grapefruit juice

CYP3A4 substrate: ­ cisapride /­ simvastatin

CYP2D6 substrate: «paroxetine

CYP1A2 substrate: ­ theophylline

CYP2C9 substrate: « warfarin

Others: ­ digoxin / « oral contraceptive (ethinylestradiol)

Gastric pH: telithromycin not changed by ranitidine and Maalox

Renal impairment

AUC and Cmax not significantly changed after single dose.

No dose adjustment recommended by sponsor.

Hepatic Impairment

AUC and Cmax are comparable but t1/2 ­ significantly. No dose adjustment recommended by sponsor.

Effects of Age on PK

AUC and Cmax increased by 100% in elderly after multiple doses but no dose adjustment recommended by sponsor.

Effects of Gender on PK

None


IV.       Clinical/Statistical Efficacy Analysis of Phase III trials

This section summarizes the FDA analyses of pivotal and supportive phase III trials contained in the NDA.  The applicant has requested labeling of oral telithromycin for the treatment of the following infections (indications) in adults:

 

·        Community-acquired pneumonia due to S. pneumoniae, including strains resistant to penicillin and erythromycin, H. influenzae, H. parainfluenzae, M. catarrhalis, C. pneumoniae, L. pneumophila, and/or M. pneumoniae.

 

·        Acute bacterial exacerbation of chronic bronchitis due to S. pneumoniae, H. influenzae, H. parainfluenzae, M. catarrhalis, S. aureus, C. pneumoniae, and/or M. pneumoniae.

 

·        Acute sinusitis due to S. pneumoniae, including strains resistant to penicillin and erythromycin, H. influenzae, H. parainfluenzae, M. catarrhalis, and/or S. aureus.

 

·        Tonsillitis/pharyngitis due to S. pyogenes in patients 13 years old and above.


The NDA for telithromycin presents efficacy and safety data from 9 phase III pivotal trials and 4 phase III supportive trials. While some studies included patients from the US, there were no studies that enrolled US patients only. Phase III studies were conducted between 1997 and 2000. There were a total of 6113 patients enrolled, 5193 randomized and 5169 actually treated. There were 3390 subjects exposed to telithromycin and 1779 to comparators as shown by study protocol and indication in Table 2.

Table 2. Subject disposition by indication for all phase III studies

 

 

Indication/

Protocol #

 

Randomized

Treated

 

Enrolled

Ketek

Comparator b

Total

Ketek

Comparator b

Total

CAPa

 

 

 

 

 

 

 

 

  3006

493

224

225

449

224

224

448

 

  3009

312

124

124

248

124

124

248

 

  3001

405

199

205

405

199

205

404

 

  3000*

240

240

-

240

240

-

240

 

  3009OL*

221

221

-

221

221

-

221

 

  3010*

442

432

-

432

432

-

432

 

Total CAP

2133

1440

554

1994

1440

553

1993

 

AECBa

 

 

 

 

 

 

 

 

  3007

571

244

254

498

243

253

496

 

  3003

325

163

161

324

161

160

321

 

Total AECB

896

407

415

822

404

413

817

 

Sinusitis

 

 

 

 

 

 

 

 

  3005

1244

528

263

791

528

262

790

 

  3002 c

343

341

-

341

336

-

336

 

  3011

593

260

125

385

252

122

374

 

Total SINUSITIS

2180

1129

388

1517

1116

384

1500

 

Tonsillitis/

Pharyngitis

 

 

 

 

 

 

 

 

  3008

526

232

231

463

232

231

463

 

  3004

398

198

199

397

198

198

396

 

Total

TONS/PHARa

924

430

430

860

430

429

859

 

GRAND TOTAL

6113

3406

1787

5193

3390

1779

5169

 

* Open label studies

 

a CAP =Community acquired pneumonia, AECB = Acute exacerbation of chronic bronchitis,  TONS/PHAR = Tonsillitis/pharyngitis

b Comparators included:  CAP [clarithromycin (3006), trovafloxacin (3009), amoxicillin (3001)], AECB [cefuroxime axetil (3007), amoxicillin/clavulanic acid (3003)], SINUSITIS [amoxicillin/clavulanic acid (3005), cefuroxime axetil (3011)], TONS/PHAR [penicillin VK (3004), clarithromycin (3008)]

c A double-blind, trial comparing two telithromycin regimens (5-Days vs. 10-Days)

 

Study populations

Table 3 shows the definitions of the various study populations used in the analysis of efficacy; Table 4 shows the sizes of the populations for the various indications. The definition of the mITT is different from the classic definition of intent-to-treat (ITT, i.e., all randomized patients). The purpose behind analyzing mITT rather than ITT populations was to exclude subjects with a clear misdiagnosis and to provide a more conservative approach to establish statistical and clinical equivalence between telithromycin and the comparators under study. The difference between the ITT and mITT populations was largely explained by subjects who did not meet the predefined radiologic criteria as specified for the various infections.

 

Table 3.  Definitions of the various populations used in the FDA efficacy analysis

Population

Definition

mITT

All randomized subjects, as treated, with a confirmed diagnosis of the infection, as defined in the respective study protocol, who received at least one dose of study medication. A confirmed diagnosis was defined by clinical signs and symptoms and radiologic findings supportive of the diagnosis, as defined in the protocols. This definition was intended to exclude subjects with a clear misdiagnosis, in whom study medication was not expected to demonstrate the desire therapeutic effect.

 

 

 

PPc

All mITT subjects except those with major protocol violations and/or indeterminate responses.

bmITT

All mITT subjects with a pathogen at pretherapy/entry considered by the investigator to be responsible for infection.

PPb

All PPc subjects with isolation of a causative pathogen from an adequate culture at pretherapy/entry.

 

Table 4.  Populations used for efficacy analysis by indication, excluding subjects from censored sites

 

Efficacy Populations

Indication

Randomized

Treated

mITT

PPc/PP

bmITT

PPb

CAPa

 

 

 

 

 

 

      Telithromycin

1440

1427

1373

1132

562

344

      Comparator

554

553

521

394

142

90

AECBa

 

 

 

 

 

 

     Telithromycin

407

404

343

255

82

64

     Comparator

413

413

353

254

79

58

Sinusitis

 

 

 

 

 

 

    Telithromycin

1129

1116

980

731

345

253

    Comparator

388

384

318

226

71

57

Tonsillitis/pharyngitis

 

 

 

 

 

 

    Telithromycin

430

430

430

302

325

265

     Comparator

430

429

428

254

323

424

a CAP =Community acquired pneumonia, AECB = Acute exacerbation of chronic bronchitis

Seven clinical trial sites were inspected at random by the FDA’s Division of Scientific Investigation. Six of these sites failed to meet good clinical practice guidelines and were therefore censored by the Agency due to data integrity issues. A total of 186 subjects from these sites were excluded from all analyses for efficacy and safety. Table 5 summarizes the number of subjects censored by the FDA.


 

Table 5. Number of subjects censored by the agency from applicant’s original submission 

 

Indication

 

Study Protocol

Number of subjects

Telithromycin

Comparator

Total

CAP

3009

13

12

25

AECB

3007

62

62

124

Sinusitis1

3005

26

11

37

Total

 

 

 

186

1 11 additional subjects were censored prior to submission of the major amendment because two sites were associated with investigators who were previously censored by the agency.

The following outcome definitions were applied in all studies:

·        Clinical Cure: all infection-related signs and symptoms had disappeared or had returned to the pre-infection state and (for CAP) Chest X-ray findings showed improvement or lack of progression; OR

Infection-related signs and symptoms had improved,  (for CAP) chest X-ray findings showed improvement or lack of progression and NO subsequent antibiotic therapy was started for the treatment of the disease under investigation.

·        Bacteriologic Eradication was defined as either of the following:

1.) proven eradication (the causative pathogen was absent in a culture obtained during the post therapy/TOC time window and no subsequent antibiotic therapy was started prior to the culture being obtained, AND

2.) presumed eradication (the subject had improved clinically to such an extent that a proper follow-up culture could not be obtained and no subsequent antibiotic therapy had been started up to the end of the post therapy/TOC time window.


 

A.      Community Acquired Pneumonia

The applicant submitted five clinical studies in support of community-acquired pneumonia indication for KetekÔ (telithromycin) tablets in the original NDA submission on February 28, 2000. Three of the clinical studies were pivotal (3001, 3006, 3009OL and two studies were supportive (3000 and 3009OL).  The applicant submitted an additional clinical study (3010) on March 1, 2001, primarily to supplement the efficacy data on resistance claims. Table 6 summarizes all submitted studies of CAP.

Table 6.  Community-Acquired Pneumonia: Pivotal and Supportive Studies

STUDY

DESIGN

TREATMENT

DAYS

N

GEOGRAPHIC REGION

Pivotal Comparative Studies

3001

Multicenter,double-blind,randomized, active-controlled,

comparative,2-arm parallel group

 

Telithromycin 800 mg po qd

 

Amoxicillin 1000 mg po tid

 

 

 

7 - 10 d

 

7 - 10 d

 

 

 

404

 

 

 

 

 

Argentina, Australia, Austria, Finland, France, Germany, Hungary, New Zealand, South Africa, Spain, Sweden, UK, Uruguay

3006

Multicenter,double-blind,randomized,

active-controlled,

comparative

Telithromycin 800 mg po qd

 

Clarithromycin 500 mg po bid

7 - 10 d

 

7 - 10 d

449

USA, Canada, Argentina, Chile

3009*

Multicenter,double-blind,ranndomized,

active-controlled,

comparative

Telithromycin 800 mg  po qd

Trovafloxacin 200 mg  po qd

7 - 10 d

 

7 - 10 d

204

USA, Canada, South Africa

Supportive Non-Comparative Studies

3000

Multicenter,open-label,non-comparative

 

Telithromycin 800 mg po qd

7 - 10 d

240

Argentina, Australia, Austria, Belgium, Finland, France, Germany, Hungary, Israel, New Zealand, Norway, South Africa, Sweden

3009OL

Multicenter,open-label,Non-comparative

Telithromycin 800 mg po qd

7 - 10 d

221

South Africa

 

3010

 

 

 

Open-label, non-

comparative

 

 

Telithromycin 800 mg po qd

 

 

 7 d

 

 

 

432

 

 

 

USA, South America, South Africa, Canada

 

 

* This study was terminated prematurely because of safety concerns with the comparator, trovafloxacin.

The primary efficacy variable was clinical response (cure, failure or indeterminate) assessed by the investigator at the posttherapy/TOC visit, 7 to 10 days after the end of therapy. The primary analysis study population was the per protocol population (PPc). The PPc population was defined as all protocol-compliant subjects who received study medication and remained in the study. Clinical outcome was also analyzed for the modified-intent-to treat population (mITT) who were all subjects treated with a confirmed diagnosis of CAP (as defined in the protocol) and received at least one dose of study drug.  Clinical cures include patients who had complete resolution of symptoms and those who had improved.

Tables 7A-7C summarize the clinical and bacteriologic efficacy data for all studies of CAP at the TOC visit in both per-protocol and mITT populations.

Table 7A. Clinical cure rates for telithromycin versus comparators at the test-of-cure visit - CAP

 

Telithromycin

Comparators1

2-sided

95% Confidence Interval

 

 

N

 

n

 

%

 

 

N

 

n

 

%

PPc Population

 

 

 

 

 

 

 

 

 

 Study 3001

TEL     10 d

149

141

94.6

AMX 10 d

152

137

90.1

 ( -2.1% , 1.1%)2

 Study 3006

TEL     10 d

150

129

86.0

CLA 10 d

143

121

84.6

( -7.4% , 10.2%)2

 Study 3009

TEL 7-10 d

80

72

90.0

TVA 7-10d

86

81

94.2

( -13.6% , 5.2%)2

 Study 3000*

TEL 7-10 d

197

183

92.9

-

-

-

-

[88.1% , 95.9%]3

 Study 3009OL*

TEL    10-d

187

175

93.6

-

-

-

-

[88.8%, 96.5%]3

 Study 3010*

TEL      7 d

357

332

93.0

-

-

-

-

[89.7% , 95.3%]3

mITT Population

 

 

 

 

 

 

 

 

 

 Study 3001

TEL     10 d

199

171

85.9

AMX  10 d

205

161

78.5

(- 0.5% , 15.3%)2

 Study 3006

TEL     10 d

204

156

76.5

CLA 10 d

212

171

80.7

(- 9.9% , 6.5%)2

 Study 3009

TEL 7-10 d

100

82

82.0

TVA 7-10d

104

89

85.6

(-14.7%, 7.5%)2

 Study 3000*

TEL 7-10 d

240

191

79.6

-

-

-

-

[73.8%, 84.4%]3

 Study 3009OL*

TEL    10-d

212

182

85.8

-

-

-

-

[80.3%, 90.1%]3

 Study 3010*

TEL      7 d

418

357

85.4

-

-

-

-

[81.6%, 88.6%]3

* Studies which did not include an active control arm

1 TEL 10-d = telithromycin 10-Days, AMX = amoxicillin, CLA= clarithromycin, TVA = trovafloxacin,

2Confidence interval for the difference of the two cure rates.

3Confidence interval for the cure rate observed in the open label trial.

 


 

Table 7B. Bacteriologic response by subject for telithromycin versus comparators at the test-of-cure visit - CAP

 

 

Telithromycin

 

Comparators1

 

2-sided 95% Confidence Interval 2

 

 

N

 

n

 

%

 

 

N

 

n

 

%

PPb Population

 

 

 

 

 

 

 

 

 

 Study 3001

TEL     10 d

40

36

90.0

AMX  10  d

40

35

87.5

(- 13.8%, 18.9%)2

 Study 3006

TEL     10 d

28

25

89.3

CLA    10 d

28

27

96.4

(- 3.3%, 10.4%)2

 Study 3009

TEL 7-10 d

14

13

92.9

TVA  7-10 d

22

22

100

(- 26.5%, 12.2%)2

 Study 3000*

TEL 7-10 d

45

40

88.9

-

-

-

 

[ 75.2%, 95.8%]3

 Study 3009OL*

TEL    10-d

68

61

89.7

-

-

-

 

[ 79.3%, 95.4%]3

 Study 3010*

TEL      7 d

149

137

91.9

-

-

-

 

[ 86.0%, 95.6%]3

bmITT Population

 

 

 

 

 

 

 

 

 

 Study 3001

TEL     10 d

56

49

87.5

AMX  10  d

54

46

85.2

(- 12.3%, 17.0%)2

 Study 3006

TEL     10 d

40

36

90.0

CLA    10 d

39

37

94.9

(- 14.4%, 22.7%)2

 Study 3009

TEL 7-10 d

29

27

93.1

TVA  7-10 d

32

30

93.8

(- 19.0%, 9.3%)2

 Study 3000*

TEL 7-10 d

54

49

90.7

-

-

-

 

[ 78.9%, 96.5%]3

 Study 3099OL*

TEL    10-d

88

80

90.9

-

-

-

 

[ 82.3%, 95.7%]3

 Study 3010*

TEL      7 d

255

215

84.3

-

-

-

 

[ 79.1%, 88.4%]3

* Studies which did not include an active control comparator arm

1 TEL 10-D = telithromycin 10-Days, AMX = amoxicillin, CLA= clarithromycin, TVA = trovafloxacin,

2Confidence interval for the difference of the two cure rates.

3Confidence interval for the cure rate observed in the open label trial.

 

 

Table 7C.  Overall eradication rates of Baseline Pathogens Pooled from all CAP Studies at posttherapy/TOC- PPb population

All Combined Studies

Telithromycin

Comparator

Pathogen

N          n              %

N          n              %

S. pneumoniae

174     166          95.4

50       44            88.0

H. influenzae

105       94          89.5

28       26            92.8

M. catarrhalis

 30        27          90.0

  6         6           100.0

H. parainfluenzae

 60        53          88.3

10         9             90.0

S. aureus

19         15          79.0

  3         3           100.0

Other

46         37          80.4

16       13              81.2

 


Penicillin-resistant S. pneumoniae (PRSP)/Erythromycin-resistant S. pneumoniae (ERSP)

The applicant is requesting the indication of community-acquired pneumonia due to S. pneumoniae, including penicillin- and erythromycin-resistant strains.  Table 8 summarizes the efficacy of telithromycin across the five CAP studies in the PPb population that contained resistant organism.  The definition of the breakpoints for S. pneumoniae is as follows:

Penicillin                                                         Erythromycin

            Sensitive           < 0.6 µg/ml                               Sensitive           < 0.25 µg/ml

            Intermediate     0.12 < MIC < 1 µg/ml              Intermediate     0.25 < MIC < 1 µg/ml

            Resistant           ≥ 2 µg/ml                                  Resistant           > 1 µg/ml

It should be noted that the majority of subjects were treated as outpatients with oral therapy, and were classified as having mild to moderate pneumonia upon entry into the studies.

Table 8.  Summary of Outcomes by Resistance patterns for Streptococcus pneumoniae (single and mixed cultures) – Telithromycin (PPb population, 5 studies combined*)

 

Outcome- Cured

 

Pen-S

PRSP

Ery-S

Ery-R

PRSP+EryR

TOTAL

125/128 (97.6%)

14/17 (82%)

135/137 (99%)

14/17 (82%)

6/9 (66.6%)

Blood

27/29 (93%)

4/6 (66.7%)

32/34 (94%)

4/6 (66.7%)

1/3 (33.3%)

Sputum

98/99 (98.9%)

10/11 (91%)

103/103 (100%)

10/11 (91%)

5/6 (83.3%)

Mixed**

33/34 (97.1%)

5/7 (71.4%)

33/34 (97.1%)

5/7 (71.4%)

3/5 (60%)

* Studies 3000, 3001, 3006, 3009OL, 3010

** mixed = cultures which contained bacterial pathogens in addition to S. pneumoniae

Overall, the cure rate in telithromycin-treated patients was 97.6% for those with S. pneumoniae penicillin-sensitive isolates compared to 82% for those with PRSP isolates.  PRSP was isolated from 17 telithromycin-treated patients; six of these had documented S. pneumoniae bacteremia.  Of the six patients with PRSP bacteremia, the cure rate was 66.7%.  There was only one PRSP isolated from the sputum in a comparator-treated patient, who was reported as cured.

Erythromycin resistance was seen in 17 telithromycin-treated patients.  The cure rate for telithromycin-treated patients with erythromycin-sensitive isolates was 99%, compared to 82% for patients with erythromycin-resistant isolates.  Only 6 telithromycin-treated patients had ERSP isolated from the blood.  The cure rate in patients with ERSP bacteremia was 66.7%.

ERSP was isolated from 3 patients among the comparator-treated patients, all of whom were cured. Of note, 5 of these patients had telithromycin MICs greater than the suggested FDA resistance breakpoint for telithromycin (0.25 µg/mL).

Outcomes in patients with erythromycin-resistant isolates of different genotypes were examined.   There were 9 ermB isolates with MICs ranging from 4.0 to 32.0 ug/mL.  The cure rate was 77.8% (7/9). The two patients who failed had severe pneumonia, were hospitalized and had penicillin-resistant S. pneumoniae.  Ten patients had S. pneumoniae isolates with the mefE genotype (two of the 17 patients had both genes).  Only one patient, who was bacteremic, was a clinical failure.  The telithromycin MICs of these isolates ranged from 0.3 to 1.0 µg/mL.  Using the FDA breakpoint for telithromycin, 5 of these patients’ isolates were resistant to telithromycin.

Of PRSP isolates, 52.9% (9/17) were also resistant to erythromycin.  Although these are small numbers, patients with a PRSP+EryR isolate were more likely to have poorer clinical outcomes that those with either a PSRP or Ery-R phenotype alone.  All of these isolates were sensitive to telithromycin with a MIC or < 0.5 µg/ml.  All of the MICs reported for the isolates classified as PRSP were < 2.0 µg/ml (final MICs are pending). 

Tables 9A and 9B display details regarding the individual patients with PRSP isolates.  It should be noted that the bmITT patients were listed in order to give the reader an understanding of the types of outcomes that were recorded.  It is particularly interesting to note that of the 5 patients who were in the bmITT group and were not included in the PPb subgroup, 3 were classified as having Indeterminate outcomes. One patient died due to aspiration pneumonia on day 5 after showing improvement on a chest X-ray on day 4.


Table 9A. Subjects with S. pneumoniae penicillin resistant (PRSP)[ MIC ł2 mg/mL)]–bmITT+PPb Populations:   ALL CAP  Studies – Telithromycin group

Study Number/

Investigator No./

Subject Number/

Location

Fine Score/

Severity

Pathogen/

(Single or

Mixed)/

Genotype

Source

MIC to

Pen G

(ug/ml)

MIC to

Ery A

(ug/ml)

MIC to

Ketek

(ug/ml)

Clinical Outcome

Bacteriological Outcome

bmITT

3000/101/1365

Argentina

3001/0111/010

Argentina/

3001/0902/002

New Zealand

3010/0473/009

USA

3010/0526/002

South America

 Total = 5

 

       I

 

      III

 

      III

 

      V

 

      II

 

S. pneumoniae/

(Single)/ NA

S. pneumoniae/

(Single)/ NA

S. pneumoniae/

(Single)/ NA

S. pneumoniae/

(Mixed)/mefE

S. pneumoniae/

(Single)

 

 

BLOOD

 

BLOOD

 

SPUTUM

 

SPUTUM

 

SPUTUM

 

2.000

 

2.000

 

2.000

 

2.000

 

2.000

 

0.030

 

0.060

 

0.060

 

8.000

 

0.250

 

0.015

 

0.015

 

0.015

 

2.000

 

0.030

 

Indeterminate

 

Indeterminate

 

Failure

 

Indeterminated

 

Cure

 

Indeterminate

 

Indeterminate

 

Eradication

 

Indeterminate

 

Presumed eradication

PPb

3000/603/1081

France

3000/605/1091

France

3000/610/1110

France

3001/1002/027

South Africa

3001/1401/002

Australia

3006/0008/031

USA

3006/0008/039

USA

3006/0012/019

USA

3009OL/0355/104

South Africa

3009OL/0368/105

South Africa

3009OL/0369/105

South Africa

3010/0483/008

USA

3010/0494/036

USA

3010/0503/001

USA

3010/0526/001

South America

3010/0533/007

South Africa

3010/0534/059

South Africa

Total = 17

 

      II

 

      III

 

      I

 

      IV

 

 Moderate  

    

      I

 

      I

 

      I

 

      II

 

      I

 

      II

 

      I

 

     III

 

      II

 

     III

 

      I

 

      I

 

S. pneumoniae/

(Single)/ NA

S. pneumoniae/

(Mixed)/ermB

S. pneumoniae/

(Single) /NA

S. pneumoniae/

(Mixed)/ermB

S. pneumoniae/

(Single)/ NA

S. pneumoniae/

(Single) /NA

S. pneumoniae/

(Single)/mefE

S. pneumoniae/

(Mixed)/ NA

S. pneumoniae/

(Single)/mefE

S. pneumoniae/

(Single)/ NA

S. pneumoniae/

(Single)/mefE

S. pneumoniae/

(Mixed)/mefE

S. pneumoniae/

(Mixed)/ermB

S. pneumoniae/

(Mixed)/ NA

S. pneumoniae/

(Single)/ NA

S. pneumoniae/

(Single)/ermB/mefE

S. pneumoniae/

Mixed)/ermB/mefE

 

BLOOD

 

BLOOD

 

SPUTUM

 

SPUTUM

 

SPUTUM

 

BLOOD

 

SPUTUM

 

SPUTUM

 

BLOOD

 

BLOOD

 

BLOOD

 

SPUTUM

 

SPUTUM

 

SPUTUM

 

SPUTUM

 

SPUTUM

 

SPUTUM

 

 

2.000

 

2.000

 

2.000

 

2.000

 

ND*

 

2.000

 

2.000

 

2.000

 

2.000

 

2.000

 

2.000

 

2.000

 

2.000

 

2.000

 

2.000

 

2.000

 

2.000

 

0.030

 

32.000

 

0.030

 

32.000

 

ND

 

0.060

 

4.000

 

0.060

 

4.000

 

0.060

 

4.000

 

4.000

 

8.000

 

0.060

 

0.250

 

8.000

 

8.000

 

 

 

0.015

 

0.030

 

0.015

 

0.030

 

ND

 

0.008

 

0.030

 

0.008

 

0.060

 

0.030

 

0.120

 

0.060

 

0.250

 

0.030

 

0.030

 

0.500

 

0.500

 

Cure

 

Failure

 

Cure

 

Failure

 

Cure

 

Cure

 

Cure

 

Cure

 

Cure

 

Cure

 

Failure

 

Cure

 

Cure

 

Cure

 

Cure

 

Cure

 

Cure

 

Eradication

 

Pres.persistence

 

Pres. eradication

 

Pres.persistence

 

Pres. eradication

 

Eradication

 

Pres. eradication

 

Pres. eradication

 

Pres. eradication

 

Pres. eradication

 

Pres. persistence

 

Pres. eradication

 

Pres. eradication

 

Pres. eradication

 

Pres. eradication

 

Pres. eradication

 

Pres. eradication

d - death due to aspiration pneumonia.

* ND – not done

 

 

 

 

Table 9B.  Subjects with S. pneumoniae erythromycin-resistant (ERSP) [MIC ł1 mg/mL], alone and combination with PRSP–bmITT+PPb Populations: All CAP Studies –Telithromycin Group

Study Number/

Investigator No./Subject Number/Location

Fine Score/

Severity

Pathogen/

(Single or

 Mixed)/

Genotype

Source

MIC to Pen G

(mg/mL)

MIC to

Ery A

(ug/ml)

 

MIC to

Ketek

(ug/ml)

Clinical Outcome

Bacteriologic Outcome

BmITT

3000/605/1090/France

 

3010/0473/009/USA

 

3010/0494/026/USA

 

Total = 3

 

    III

   

    V

   

     I

     

 

S. pneumoniae/

(Single)/ermB

S. pneumoniae/

(Mixed)/mefE

S. pneumoniae/

(Mixed)/ermB

 

 

SPUTUM

 

SPUTUM

 

SPUTUM

 

 

 

0.120

 

2.000

 

0.500

 

 

 

0.030

 

8.000

 

8.000

 

 

 

0.030

 

2.000

 

0.030

 

 

 

Cure

 

Indeterminate

 

Cure

 

 

 

Pres. eradication

 

Indeterminate

 

Pres. eradication

 

 

PPb

3000/605/1091/

France

3001/1002/027

South Africa

3001/1401/002/*

Australia

3001/1101/005/

Sweden

3006/0008/039

USA

3006/0425/008

Argentina

3009OL/0355/104

South Africa

3009OL/055/154

South Africa

3009OL/055/157

South Africa

3009OL/0369/105

South Africa

3010/0483/008/

USA

3010/0494/036/

USA

3010/0523/001/

South America

3010/0533/007/

South Africa

3010/0523//059

South Africa

3010/0536/014/

South Africa

3010/0536/031/

South Africa

Total = 17

 

      III

 

       IV

 

 Moderate  

    

      IV

 

      I

 

      I

 

      II

 

      II 

    

      I

 

      II

 

      I

 

     III

 

       I

 

      I

 

      I

 

      I

 

      1

 

S. pneumoniae/

(Mixed)/ermB

S. pneumoniae/

(Mixed)/ermB

S. pneumoniae/

(Mixed)/ermB

S. pneumoniae/

(Single)/ ermB

S. pneumoniae/

(Single) /mefE

S. pneumoniae/

(Single)/mefE

S. pneumoniae/

(Single)/mefE

S. pneumoniae/

(Single)/ermB

S. pneumoniae/

(Single)/ mefE

S. pneumoniae/

(Single)/mefE

S. pneumoniae/

(Mixed)/mefE

S. pneumoniae/

(Mixed)/ermB

S. pneumoniae/

(Single)/ ermB

S. pneumoniae/

(Single)/ermB/mefE

S. pneumoniae/

(Mixed)/ermB/mefE

S. pneumoniae/

(Mixed)/mefE

S. pneumoniae/

(Mixed)/mefE

 

 

BLOOD

 

SPUTUM

 

SPUTUM

 

blood

 

SPUTUM

 

SPUTUM

 

BLOOD

 

SPUTUM

 

SPUTUM

 

BLOOD

 

SPUTUM

 

SPUTUM

 

SPUTUM

 

SPUTUM

 

SPUTUM

 

BLOOD

 

BLOOD

 

 

2.000

 

2.000

 

ND**

 

0.008

 

2.000

 

0.500

 

2.000

 

0.250

 

0.030

 

2.000

 

2.000

 

2.000

 

2.000

 

0.030

 

2.000

 

0.250

 

0.500

 

32.000

 

32.000

 

ND**

 

32.000

 

4.000

 

8.000