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  1. Development & Approval Process (Drugs)

Drug Trial Snapshots: Bevyxxa

Drug Trial Snapshots: Bevyxxa


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 BEVYXXA Prescribing Information for complete information.

BEVYXXA (betrixaban)
(be vix’ ah)
Portola Pharmaceuticals, Inc.
Approval date: June 23, 2017


DRUG TRIALS SNAPSHOT SUMMARY:

What is the drug for?

BEVYXXA is a drug known as a “blood thinner” that helps prevent  venous thromboembolism (VTE) in hospitalized adult patients who at risk for developing VTE.

VTE is a condition characterized by  the formation of a blood clot in a deep vein (deep vein thrombosis or DVT) which may be complicated by breaking off  of the clot which can then travel to the lung  and cause serious and sometimes fatal pulmonary embolism (PE). 

How is this drug used?

BAXDELA is a capsule. Two capsules are taken together on the first day of treatment followed by one capsule a day for 35 to 42 days.

What are the benefits of this drug?

The trial showed that patients who received BEVYXXA had fewer VTE events in comparison to patients who received another drug approved for VTE prevention called enoxaparin.

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

The table below summarizes the efficacy results of the trial based on modified intent-to-treat (mITT) population defined as all randomized patients who received at least one dose of trial drug and were evaluated for every component of the primary endpoint.  The primary efficacy endpoint was a composite of asymptomatic proximal deep-vein thrombosis (DVT) between day 32 and day 47, symptomatic proximal or distal deep-vein thrombosis, symptomatic nonfatal pulmonary embolism (PE), or death from venous thromboembolism occurred between day 1 and day 42.

Table 2.  Efficacy Outcomes in Trial 1 (mITT Population)
 

  BEVYXXA
N =3,721
n (%)1
Enoxaparin
N =3,720
n (%)1
Relative Risk
(95% CI)2
Composite Outcome 165 (4.4) 223 (6.0) 0.75 (0.61, 0.91)
Asymptomatic Event 133 (3.6) 176 (4.7)  
Symptomatic DVT 14 (0.4) 22 (0.6)  
Non-fatal PE 9 (0.2) 18 (0.5)  
VTE-related Death 13 (0.3) 17 (0.5)  
Symptomatic Events3 35 (0.9) 54 (1.5) 0.64 (0.42, 0.98)


1 Percentages and event rates are based on the total number of patients and events included in each treatment group.
2 Relative Risk (BEVYXXA arm versus enoxaparin arm) is based on the Mantel-Haenszel test stratified by the dosing strata and D-dimer status from the local laboratory. The analyses are not adjusted for multiplicity.
3 Symptomatic events include symptomatic DVT, non-fatal PE or VTE-related death. 

BEVYXXA Prescribing Information

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

  • Sex:  BEVYXXA worked similarly in men and women.
  • Race:  Most of the patients were White. Differences in how will the drug worked among races could not be determined because of the small number of patients in other races.
  • Age:  BEVYXXA worked similarly 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 groups?
 

 The tables below summarize subgroup differences based on the Primary Efficacy Outcome Population (PEOP) defined  as all patients in the mITT population who have had assessment of all components of the primary efficacy outcome endpoint which are necessary to determine (via the adjudication process) whether or not a primary efficacy outcome event has occurred.

Table 3. Exploratory Analysis of Primary Efficacy Endpoint in Subgroups of Age, Sex, Race and Geographic Region –PEO Population

  BEVYXXA n/N (%) Enoxaparin n/N (%) Relative Risk (95% CI)
Age (years)
<> 12/306 (3.9) 27/334 (8.1) 0.537 (0.284, 1.015)
≥ 65 153/2806 (5.5) 196/2840 (6.9) 0.790 (0.644, 0.970)
<> 50/974 (5.1) 71/1038 (6.8) 0.770 (0.542, 1.093)
≥ 75 115/2138 (5.4) 152/2136 (7.1) 0.754 (0.596, 0.954)
Sex
Men 81/1406 (5.8) 102/1447 (7.0) 0.823 (0.620, 1.090)
Women 84/1706 (4.9) 121/1727 (7.0) 0.704 (0.536, 0.923)
Race
White 150/2915 (5.1) 211/2992 (7.1) 0.737 (0.602, 0.903)
Black or African American 5/53 (9.4) 5/59 (8.5) 0.975 (0.286, 3.321)
Asian 2/7 (28.6) 0/5 (0) NE (NE, NE)
Multiple 0/21 (0) 1/23 (4.4) 0 (NE, NE)
Other 5/54 (9.3) 3/48 (6.3) 0.796 (0.140, 4.540)
Geographic Region
North America 12/186 (6.5) 14/196 (7.1) 0.935 (0.455, 1.922)
Non-North America 153/2926 (5.2) 209/3470 (6.0) 0.743 (0.606, 0.910)

FDA review

What are the possible side effects?

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

People who take a blood thinner medicine like BEVYXXA, and have medicine injected into their spinal and epidural area, or have a spinal puncture have a risk of forming a blood clot that can cause long-term or permanent loss of the ability to move (paralysis). 

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

Below is the summary of the most common adverse reactions observed in ≥ 2% patients treated with BEVYXXA.

Table 4. Adverse Reactions Occurring in ≥ 2% of Patients

Adverse Reaction

BEVYXXA
 N=3,716
n (%)

Enoxaparin
N=3,716
n (%) 
Bleeding-Related (all sources)
Epistaxis 58 (2) 24 (1)
Hematuria 62 (2) 28 (1)
Non Bleeding Adverse Reaction
Urinary Tract Infection 123 (3) 87 (2)
Constipation 110 (3) 102 (3)
Hypokalemia 93 (3) 84 (2)
Hypertension 89 (2) 80 (2)
Headache 74 (2) 59 (2)
Nausea 67 (2) 56 (2)
Diarrhea 64 (2) 61 (2)

BEVYXXA Prescribing Information
 

A summary of major and clinically relevant non-major (CRNM) bleeding events in the overall safety population is shown in Table 5.

Table 5. Bleeding Events in the Trial through 7 Days after Discontinuation of All Trial Drugs (Safety Population)

Parameter BEVYXXA
 (N=3,716)
Enoxaparin
(N=3,716)
BEVYXXA vs. Enoxaparin
RR (95% CI)
Major Bleedinga 25 (0.67) 21 (0.57) 1.19 (0.67, 2.12)
p = 0.554
Gastrointestinal (GI) 19 (0.51) 9 (0.24)  
Intracranial Hemorrhage 2 (0.05) 7 (0.19)  
Intraocular 0 (0) 1 (0.03)  
Fatal Bleeding 1 (0.03) 1 (0.03)  
Clinically Relevant Non-major Bleedingb 91 (2.45) 38 (1.02) 2.39 (1.64, 3.49)
p <>

a Major bleeding event was defined as clinically overt bleeding that met one of the following criteria: a
reduction in hemoglobin of a least 2 g/dL within 48 hours of an overt bleeding event; a transfusion of at least two units of whole blood or packed red blood cells; a critical area; e.g., intraocular, intracranial, intraspinal, intramuscular with compartment syndrome, retroperitoneal, intra-articular, pericardial, or a fatal outcome. Retinal hemorrhages secondary to diabetic retinopathy or conjunctival bleeds did not qualify as a major bleeds.
b CRNM bleeding was defined as overt bleeding not meeting the criteria for major bleeding but associated with medical intervention, unscheduled contact (visit or telephone call) with a physician, (temporary/permanent) cessation of the study treatment, or associated with discomfort for the patient such as pain or impairment of activities of daily life.

BEVYXXA Prescribing Information

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

  • Sex:  The occurrence of bleeding was greater in women.
  • Race: Most of the patients were White. Differences in the occurrence of bleeding among races could not be determined because of the small number of patients in other races.
  • Age:  The occurrence of bleeding was similar in patients above and below age 65.

Were there any differences in side effects of the clinical trials among sex, race, and age groups?

 

Table below summarizes the occurrence of bleeding by subgroups. Race subgroups are not presented because twenty-four of the 25 major bleeding events in the BEVYXXA group and 18 of the 21 major bleeding events in the enoxaparin group occurred in White patients. 

Table 6. Adjudicated Major Bleeding in Demographic Subgroups (Overall Safety Population)

  BEVYXXA
(N=3,716)
Enoxaparin
(N=3,716)
RR (95% CI)
Sex n/N (%)*
Men 6/1691 (0.35) 13/1696 (0.77) 0.39 (0.14, 1.09)
Women 19/2025 (0.94) 8/2020 (0.40) 2.28 (0.98, 5.27)
Age Group n/N (%)*
<75 years="" of=""> 3/1166 (0.26) 71/1226 (0.57) 0.45 (0.11, 1.74)
≥75 years of Age 22/2250 (0.86) 14/2490 (0.56) 1.37 (0.69, 2.72)
<65 years="" of=""> 0/372 (0) 3/395 (0.76) 0 (NE, NE)
≥65 years of Age 25/3344 (0.75) 18/3321 (0.54) 1.26 (0.68, 2.33)

*number of patients with bleeding/number of patients at risk (%)
RR = Relative Risk, NE = Not evaluable
FDA Review
 

WHO WAS IN THE STUDIES?

Who participated in the clinical trials?

The FDA approved BEVYXXA based on evidence from one clinical trial that enrolled 7513 hospitalized patients who were at risk of developing VTE. The trial was conducted in Europe, Latin America, Asia, Australia, South Africa, Canada and United States.

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

Figure 1. Baseline Demographics by Sex

Pie chart summarizing how many men and women were in the clinical trial. In total, 3425 men (46%) and 4088 women (54%) participated in the clinical trial.

Clinical trial data

Figure 2 and Table 1 summarize the percentage of patients by race enrolled in the clinical trial.

Figure 2. Baseline Demographics by Race

Figure 2. Baseline Demographics by Race for BEVYXXA

Clinical trial data

Table 1. Baseline Demographics by Race

Race Number of Patients Percentage
White 7021 93
Black or African American 147 2
Asian 16 less than 1
Multiple 52 1
Other 126 2
Unknown* 151 2

* Data collection prohibited by local regulatory authority

Clinical trial data
 

Figure 3 summarizes the percentage of patients  by age  enrolled in the clinical trial.

Figure 3. Baseline Demographics by Age

Figure 3. Baseline Demographics by Age for BEVYXXA

Clinical trial data

The table below summarizes demographics of all randomized patients in clinical Trial 1.

Table 7. Baseline Demographics (Randomized Population)

  BEVYXXA
(N=3,759)
Enoxaparin
(N=3,754)
Total
(N=7,513)
Age (years)
Mean (SD) 76.6 (8.46) 76.2 (8.31) 76.4 (8.39)
Median 77.0 77.0 77.0
Min, Max 40, 103 40, 102 40, 103
Age Group N (%)
<65> 384 (10.2) 398 (10.6) 782 (10.4)
65-75 years 800 (21.3) 839 (22.3) 1,639 (21.8)
≥ 75 years 2,575 (68.5) 2,517 (67.0) 5,092 (67.8)
Sex N (%)
Men 1,705 (45.4) 1,720 (45.8) 3,425 (45.6)
Women 2,054 (54.6) 2,034 (54.2) 4,088 (54.4)
Race N (%)
White 3,503 (93.2) 3,518 (93.7) 7,021 (93.5)
Black or African American 74 (2.0) 73 (1.9) 147 (2.0)
Asian 9 (0.2) 7 (0.2) 16 (0.2)
American Indian or Alaska Native 4 (0.1) 4 (0.1) 8 (0.1)
Native Hawaiian or Other Pacific Islander 0 1 (<> 1 (<>
Multiple 26 (0.7) 26 (0.7) 52 (0.7)
Other 62 (1.6) 55 (1.5) 117 (1.6)
Data Collection Prohibited by Regulation 81 (2.2) 70 (1.9) 151 (2.0)
Ethnicity N (%)
Hispanic or Latino 405 (10.8) 426 (11.3) 831 (11.1)
Not Hispanic or Latino 3,260 (86.7) 3,246 (86.5) 6,506 (86.6)
Data Collection Prohibited by Regulation 94 (2.5) 82 (2.2) 176 (2.3)
Region N (%)
North America 292 (7.8) 286 (7.6) 578 (7.7)
Europe 3,235 (86.1) 3,231 (86.1) 6,466 (86.1)
Latin America/Asia Pacific 232 (6.1) 237 (6.3) 469 (6.2)

Adapted from FDA review

How were the trials designed?

There was one trial that established the benefit and side effects of BEVYXXA. Trial enrolled patients who were hospitalized for an acute illness and were at risk for developing VTE.

Patients were randomly chosen to receive one of two therapies: one group received once a day placebo injection (for 6 to 14 days) and BEVYXXA tablet (for 35 to 42 days) and, the second group received once a day enoxaparin injection (for 6 to 14 days) and placebo tablets for 35 to 42 days. This way, neither the patients nor the health care providers knew which treatment was being given until after the trial was completed.

The benefit of BEVYXXA was measured by the proportion of patients who developed some form of VTE between day 32 and 47 and compared it to enoxaparin.

How were the trials designed?

There was one randomized, double-blind, multicenter trial comparing extended duration BEVYXXA (35 to 42 days) to standard duration of enoxaparin (6 to 14 days) in the prevention of venous thromboembolic events (VTE) in an acutely medically ill hospitalized population with risk factors for VTE due to moderate or severe immobility, and an additional risk factors for VTE.

A total of 7,513 patients were randomized 1:1 to BEVYXXA arm (BEVYXXA 160 mg orally on Day 1, then 80 mg once daily for 35 to 42 days and subcutaneous placebo injections once daily for 6 to 14 days) or enoxaparin arm (enoxaparin 40 mg subcutaneously once daily for 6 to 14 days and placebo capsule orally once daily for 35 to 42 days.

The efficacy of BEVYXXA was based upon the composite endpoint-the occurrence of any of the following events up to Day 35 visit: asymptomatic proximal DVT detected by ultrasound, symptomatic proximal or distal DVT, non-fatal PE, or VTE-related death.

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.

PRESCRIBING INFORMATION

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