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  5. Drug Trials Snapshot: SAVAYSA (edoxaban) for Treatment of Venous Thromboembolism (VTE)
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Drug Trials Snapshot: SAVAYSA (edoxaban) for Treatment of Venous Thromboembolism (VTE)

HOW TO USE THIS SNAPSHOT
The information provided in Snapshots highlights who participated in the clinical trials that supported the FDA approval of this drug, and whether there were differences among sex, race and age groups. The “MORE INFO” bar shows more detailed, technical content for each section. The Snapshot is intended as one tool for consumers to use when discussing the risks and benefits of the drugs.

LIMITATIONS OF THIS SNAPSHOT:
Do not rely on Snapshots to make decisions regarding medical care. Always speak to your health provider about the risks and benefits of a drug. Refer to the SAVAYSA Package Insert for complete information.

SAVAYSA (edoxaban)

For Treatment of Venous Thromboembolism (VTE)
Sa-VAYE-sah
Daiichi Sankyo, Inc.
Approval date: January 8, 2015


DRUG TRIALS SUMMARY:

What is the drug for?

Deep vein thrombosis (DVT) is the formation of a blood clot in a deep vein, often a vein in the leg. The most serious complication of a DVT is that the clot breaks off and travels to the lung, forming a pulmonary embolism (PE), which can be fatal. Venous thromboembolism, or VTE, is a condition that includes (DVT) and pulmonary embolism (PE). Patients who have had a VTE are at a greater risk for developing another one. SAVAYSA is a drug known as a “blood thinner” that lowers the risk. 

How do I use this drug?

SAVAYSA is a pill taken once a day. It is started only after a patient is first treated with an injectable blood thinner.

What are the benefits of this drug?

The clinical trial that supported FDA’s approval of SAVAYSA compared SAVAYSA to warfarin, a drug that is used for the treatment of VTE. The trial showed that SAVAYSA was as effective as warfarin in lowering the chance of another VTE.

What are the benefits of this drug (results of trials used to assess efficacy)?

In the trial, SAVAYSA was shown to be non-inferior to warfarin in the treatment of patients with acute symptomatic VTE. The table below summarizes these overall results in the clinical trial using pre-specified primary efficacy endpoints in the mITT population.

Table 3. Primary Efficacy Analysis Results, mITT Population


Primary efficacy endpoint

SAVAYSA
(N=4118)

Warfarin
(N=4122)

Subjects with recurrent VTE or VTE-related death, n (%)

130 (3.2)

146 (3.5)

PE with/without DVT, n (%)

73 (1.8)

83 (2.0)

Fatal PE, n (%)

24 (0.6)

24 (0.6)

DVT only, n (%)

57 (1.4)

63 (1.5)

Un-stratified Hazard Ratio@ (95% CI*)

0.89 (0.70, 1.13)

0.89 (0.70, 1.13)

Nominal P value for non-inferiority#

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@ Hazard ratio is from un-stratified proportional hazard model. Hazard ratio < 1="" favors="" edoxaban="">
* CI: confidence interval.
# P value from asymptotic normal test
Source: FDA Statistical Review, Table 7

Were there any differences in how well the drug worked in clinical trials among sex, race and age?
Subgroup analyses were conducted for sex, race and age.

  • Sex:  SAVAYSA was similarly effective in men and women.
  • Race:  SAVAYSA was similarly effective in Whites and Asians.  Because the number of non-White, non-Asian patients in the trial was limited, it was not possible to determine whether there were clinically meaningful differences.
  • Age:  SAVAYSA was similarly effective in patients above and below age 65.

Were there any differences in how well the drug worked in clinical trials among sex, race, and age?

Table 4. Subgroup Analyses of Primary Efficacy Endpoint by Subgroup


Subgroup

SAVAYSA
Event/N (%)

Warfarin
Event/N (%)

HR@ (95% CI*)

Sex

Male

82/2360 (3.5)

87/2356 (3.7)

0.94 (0.69, 1.27)

Female

48/1758 (2.7)

59/1766 (3.3)

0.82 (0.56, 1.20)

Age

< 65="">

84/2784 (3.0)

83/2752 (3.0)

1.00 (0.74, 1.36)

≥ 65 yrs

46/1334 (3.5)

63/1370 (4.6)

0.75 (0.51, 1.10)

Race

White

91/2867 (3.2)

98/2895 (3.4)

0.94 (0.70, 1.25)

Asian

27/866 (3.1)

34/861 (4.0)

0.79 (0.48, 1.31)

Other

12/385 (3.1)

14/366 (3.8)

0.83 (0.38, 1.79)

@ HR: hazard ratio; * CI: confidence interval
Source: FDA Statistical Review, Table 12

Figure 3: Forest Plot of Primary Endpoint (Recurrent VTE) by Subgroup, mITT Analysis Set – Overall Study Period

Savaysa Forest Plot VET

What are the possible side effects? 

The most common side effect of SAVAYSA during clinical trials was bleeding, which can be serious. This is because SAVAYSA is a medicine that works by interfering with the process of blood clotting in the body, making bleeding more likely.

What are the possible side effects (results of trials used to assess safety)?

The primary safety endpoint of the clinical trial was time to clinically relevant bleeding, defined as the composite of major or clinically relevant non-major (CRNM) bleeding that occurred during administration of edoxaban or warfarin and for 3 days following its discontinuation. SAVAYSA was superior to warfarin in the primary safety endpoint of clinically relevant bleeding (major or CRNM bleeding).

Table 5. Primary Safety Analysis of Adjudicated Bleeding Events, (Safety Analysis) On-Treatment

Adjudicated BleedingSAVAYSA
N= 4118
Warfarin
N= 4122
Major/CRNM Bleeding, n (%)349 (8.5)423 (10.3)
HR Edoxaban vs. Warfarin (95% CI)
p-value
0.81 (0.71, 0.94)
P value=0.004
0.81 (0.71, 0.94)
P value=0.004
- Major Bleeding, n (%)56 (1.4)66 (1.6)
HR Edoxaban vs. Warfarin (95% CI)
p-value
0.84 (0.59, 1.21)
P value=0.35
0.84 (0.59, 1.21)
P value=0.35
Fatal, n (%)3 (0.1)10 (0.3)
- CRNM Bleeding, n (%)298 (7.2)368 (8.9)
Nuisance Bleeding, n (%)663 (16.1)787 (19.1)
All bleeding events, n (%)895 (21.7)1056 (25.6)

Source: FDA Clinical Review, Table 30

The most common bleeding adverse reactions reported in ≥1% of patients treated with SAVAYSA or warfarin are shown in Table 6 below.

Table 6. Bleeding Events Occurring in ≥ 1% of Subjects, Safety Analysis Set – On-Treatment Study Period

 SAVAYSA 60 mg
N=4118
n (%)
Warfarin N=4122
n (%)
Bleeding adverse events, n (%)895 (21.7)1056 (25.6)
Vaginal158 (9.0)126 (7.1)
Cutaneous Soft Tissue, n (%)245 (5.9)414 (10)
Epistaxis, n (%)195 (4.7)237 (5.7)
Gastrointestinal Tract, n (%)171 (4.2)150 (3.6)
Oral/Pharyngeal, n (%)138 (3.4)162 (3.9)
Macroscopic Hematuria/Urethral, n (%)91 (2.2)117 (2.8)
Puncture site, n (%)56 (1.4)91 (2.4)

* M is number of female patients (M=1758 in SAVAYSA arm and M=1766 in warfarin arm)
Source: SAVAYSA Package Insert, Table 6.4

Were there any differences in side effects among sex, race and age?

Subgroup analyses were conducted for sex, race and age.

  • Sex:  The overall incidence of bleeding was greater in women, primarily due to an increase in vaginal bleeding.
  • Race:  There were no clinically meaningful differences in bleeding between whites and Asians. Because the number of few non-White, non-Asian patients in the trial was limited, it was not possible to determine whether there were clinically meaningful differences in bleeding.
  • Age:  Subgroup analyses for major bleeding were conducted for age below and above 65. The risk of major bleeding increased with age for SAVAYSA .

Were there any differences in side effects among sex, race and age?

Figure 4. Forest Plot of Subgroup Analysis of Adjudicated Major or Clinically Relevant Non-Major Bleeding Events on Treatment, Safety Analysis Set

results of subgroup analysis of adjudicated major or CRNM bleeding events, safety analysis set – on-treatment period.

Source: Sponsor’s NDA Review Submission, Clinical Study Report, Figure 12.2


WHO WAS IN THE STUDIES?

Who participated in the clinical trials?

The FDA approved SAVAYSA based on evidence from a clinical trial in which 8,240 patients who were diagnosed with and had symptoms of VTE received treatment with either SAVAYSA or warfarin. The studies were conducted at 439 sites in 37 different countries, including those from North America, South America, Europe, Asia, Australia, New Zealand, and South Africa.

Figure 1 summarizes how many men and women were enrolled in the clinical trial.

Figure 1. Baseline Demographics by Sex

summarizing how many men and women were enrolled in the clinical trials used to evaluate efficacy of the drug SAYVAYSA.  In total, 4716 men (57%) and 3524 women (43%) participated in the clinical trials used to evaluate efficacy of the drug SAYVAYSA

Source: Adapted from FDA Statistical Review, Table 3

Figure 2. Baseline Demographics by Race

summarizing the percentage of patients by race enrolled in the clinical trials used to evaluate efficacy of the drug SAYVAYSA. In total, 5762 White (69.9%), 300 Black (3.6%), 1727 Asian (21.0%), and 451 identified as Other (5.5%), participated in the clinical trials used to evaluate efficacy of the drug SAYVAYSA.

Source: Adapted from FDA Statistical Review, Table 3
Note: Race information was missing for 20 subjects (9 in SAVAYSA arm and 11 in Warfarin arm), and these subjects were included in “Other” group.

Table 1. Demographics of Efficacy Trials by Race

RaceNumber of PatientsPercentage
White576269.9%
Black3003.6%
Asian172721.0%
Other4515.5%

Source: Adapted from FDA Statistical Review, Table 3

Who participated in the trial?

SAVAYSA was evaluated in one clinical trial for the treatment of symptomatic deep venous thrombosis (DVT) or pulmonary embolism (PE), collectively referred to as venous thromboembolism (VTE).  The trial population included 8,240 patients with VTE, of whom 4,118 patients were randomized to the SAVAYSA treatment arm and 4,122 patients were randomized to the warfarin treatment arm (an active comparator). The trial was conducted in 439 sites in 37 countries, including those from North America, South America, Europe, Asia, Australia, New Zealand, and South Africa.

Table 2. Baseline Demographic Characteristics

 SAVAYSA
(N=4118)
Warfarin
(N=4122)
Age (years)
Mean (SD)55.7 (16.3)55.9 (16.2)
Median57.057.0
Range(18.0, 106.0)(18.0, 95.0)
Category, n (%)
<>2784 (67.6)2752 (66.8)
≥ 651334 (32.4)1370 (33.2)
≥ 75560 (13.6)544 (13.2)
Sex, n (%)
Male2360 (57.3)2356 (57.2)
Female1758 (42.7)1766 (42.8)
Race, n (%)
White2867 (69.6)2895 (70.2)
Black156 (3.8)144 (3.5)
Asian866 (21.0)861 (20.9)
Other*229 (5.6)222 (5.4)

SD=standard deviation
*Race information was missing for 20 subjects (9 in SAVAYSA arm and 11 in Warfarin arm), these subjects were included in race “Other” group.

Extracted from FDA Statistical Review, Table 3

Population used was the modified intent-to-treat (mITT)  population, which was the study population identified by the FDA statistician as the primary analysis population for all efficacy analyses. For this study, mITT was defined as all randomized patients who received at least one dose of study treatment (in the edoxaban or warfarin arm).

How was the study designed?

The trial that compared SAVAYSA to warfarin enrolled 8,240 patients with a VTE that was causing symptoms (referred to as symptomatic VTE). Half the patients were randomly assigned to SAVAYSA and half were assigned to warfarin. Neither the patients nor the health care professionals knew which patients were taking SAVAYSA and which ones were taking warfarin until after the drug trial was complete. Patients were treated for up to one year.

How was the study designed?

Efficacy of SAVAYSA was evaluated in one randomized, double-blind, active (warfarin)-controlled Phase 3 clinical trial. The trial compared SAVAYSA to warfarin for the primary efficacy endpoint, which was symptomatic VTE, defined as the composite of recurrent DVT, new nonfatal symptomatic PE, and fatal PE during the 12 month study period. Patients with a creatinine clearance of 15 to 50 mL/min, patients who weighed less than or equal to 60 kilograms, or patients who were taking certain concomitant medications (known as P gp inhibitors) received either SAVAYSA 30 mg or warfarin. All other patients treated with SAVAYSA received the 60 mg dose.

SAVAYSA was evaluated for safety in the safety analysis set, which is the same population used to assess efficacy.

What are the results of the efficacy study?

The trial showed that SAVAYSA was as effective as warfarin in treating VTE.

What are the results of the trials used to assess safety?

Patients who took SAVAYSA had significantly fewer problems with bleeding than those who took warfarin. 

GLOSSARY

CLINICAL TRIAL: Voluntary research studies conducted in people and designed to answer specific questions about the safety or effectiveness of drugs, vaccines, other therapies, or new ways of using existing treatments.
COMPARATOR: A previously available treatment or placebo used in clinical trials that is compared to the actual drug being tested.
EFFICACY: How well the drug achieves the desired response when it is taken as described in a controlled clinical setting, such as during a clinical trial.
PLACEBO: An inactive substance or “sugar pill” that looks the same as, and is given the same way as, an active drug or treatment being tested. The effects of the active drug or treatment are compared to the effects of the placebo.
SUBGROUP: A subset of the population studied in a clinical trial. Demographic subsets include sex, race, and age groups.

PACKAGE INSERT

MEDICAL REVIEW

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