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  1. Development & Approval Process (Drugs)

Drug Trials Snapshots: VRAYLAR for the treatment of bipolar disorder with a manic/mixed episode

Drug Trials Snapshots: VRAYLAR for the treatment of bipolar disorder with a manic/mixed episode

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 VRAYLAR Prescribing Information for complete information.

VRAYLAR (cariprazine)
pronunciation
(vrāy-lar)
Approval date: September 17, 2015


DRUG TRIALS SNAPSHOT SUMMARY:

What is the drug for?

VRAYLAR is used for bipolar disorder, also known as manic-depressive illness. It is a brain disorder that causes unusual shifts in mood, energy, activity levels and the ability to carry out day-to-day tasks.

How is this drug used?

VRAYLAR is a capsule that is taken by mouth once a day.

What are the benefits of this drug?

VRAYLAR reduced symptoms of bipolar disorder.

What are the benefits of this drug?

The table below summarizes the primary efficacy endpoints. This was based on the mean change in the Young Mania Rating Scale (YMRS) total score after 3 weeks.

Table 2. Summary of Efficacy Results (ITT population)

Trial NumberTreatment GroupPrimary Efficacy Endpoint: YMRS Total
Mean Baseline Score (SD)LS Mean Change from Baseline (SE)Placebo-subtracted Differencea (95% CI)
Trial 1VRAYLAR (3-6 mg/day)*33.2 (5.6)-18.6 (0.8)-6.1 (-8.4, -3.8)
VRAYLAR (6-12 mg/day)*32.9 (4.7)-18.5 (0.8)-5.9 (-8.2, -3.6)
Placebo32.6 (5.8)-12.5 (0.8)--
Trial 2VRAYLAR (3-12 mg/day)*30.6 (5.0)-15.0 (1.1)-6.1 (-8.9, -3.3)
Placebo30.2 (5.2)-8.9 (1.1)--
Trial 3VRAYLAR (3-12 mg/day)*†32.3 (5.8)-19.6 (0.9)-4.3 (-6.7, -1.9)
Placebo32.1 (5.6)-15.3 (0.9)--

SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: confidence interval, not adjusted for multiple comparisons.
aDifference (drug minus placebo) in least-squares mean change from baseline.
*Doses that are statistically significantly superior to placebo
The maximum approved dose is 6 mg/day
Source: Prescribing Information, Section 14, Table 14

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

Subgroup analyses were conducted for sex and race. Analysis for different age groups was not done because all patients were between 18 and 65 years of age.

  • Sex: VRAYLAR worked similarly in men and women.
  • Race: VRAYLAR worked similarly in all races studied.
  • Age: All patients were between 18 and 65 years of age. Differences in how well VRAYLAR worked in patients below and above 65 years of age could not be determined.

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

The tables below summarize the responses to VRAYLAR by sex and race subgroups for the Intent to Treat population.

Table 3. Subgroup Analysis of Primary Endpoint-YMRS (by sex)

  SexTrial 1Trial 2Trial 3
VRAYLAR
3-6 mg
VRAYLAR
6-12 mg
VRAYLAR
3-12mg
VRAYLAR
3-12 mg
Male
Placebo-subtracted difference,  Mean (SE)
-5.1 (1.7)-4.2 (1.6)-5.7 (1.9)-5.3 (1.8)
Female
Placebo-subtracted difference,  Mean (SE)
-7.5 (1.9)-6.7 (1.9)-7.3 (2.5)-2.9 (2.1)

The maximum approved dose is 6 mg/day
Source: Company Trial Data

Table 4. Subgroup Analysis of Primary Endpoint-YMRS (by race)

RaceTrial 1Trial 2Trial 3
VRAYLAR
3-6 mg
VRAYLAR
6-12 mg
VRAYLAR
3-12 mg
VRAYLAR
3-12 mg
White
Placebo-subtracted difference,  Mean (SE)
-7.4 (1.5)-6.8 (1.5)-5.2 (2.0)0.8 (2.5)
All other races
Placebo-subtracted difference,  Mean (SE)
-3.4 (2.4)-2.4 (2.2)-6.9 (2.3)-5.9 (1.6)

The maximum approved dose is 6 mg/day
Source: Company Trial Data

What are the possible side effects?

The most common side effects of VRAYLAR are unintentional trembling or shaking movements in one or more parts of your body (called a tremor), slurred speech, and involuntary muscle movements. Other common side effects are the urge to move (called akathisia), indigestion, vomiting, drowsiness, and restlessness.

What are the possible side effects?

The table below summarizes adverse reactions for the Safety population.

Table 5. Adverse Reactions that Occurred in 2% or more of VRAYLAR-Treated Patients and at Greater Incidence than in the Placebo-Treated Patients

System Organ Class /
Preferred Term
Placebo
(N= 442)
(%)
VRAYLAR*
3-6 mg
(N=263)
(%)
9-12 mg
(N=360)
(%)
Eye Disorders
Vision blurred144
Gastrointestinal Disorders
Nausea81311
Constipation5611
Vomiting4108
Dyspepsia479
Abdominal paina568
Diarrheab556
Toothache243
General Disorders/Administration Site Conditions
Fatiguec245
Investigations
Blood creatine phosphokinase increased223
Hepatic enzymes increasedd113
Metabolism and Nutrition Disorders
Decreased appetite334
Musculoskeletal and Connective Tissue Disorders
Pain in extremity242
Back pain113
Nervous System Disorders
Akathisia52021
Extrapyramidal Symptomse122629
Dizziness476
Somnolencef478
Psychiatric Disorders
Insomniag798
Restlessness277
Vascular Disorders
Hypertensionh154

Note: Figures rounded to the nearest integer
* Data shown by modal daily dose, defined as most frequently administered dose per patient
a Abdominal pain terms: abdominal discomfort, abdominal pain, abdominal pain upper, abdominal tenderness,
b Diarrhea: diarrhea, frequent bowel movements
c Fatigue terms: asthenia, fatigue
d Hepatic enzymes increased terms: alanine aminotransferase increased, aspartate aminotransferase increased, hepatic enzyme increased, transaminases increased
e Extrapyramidal Symptoms terms: bradykinesia, drooling, dyskinesia, dystonia, extrapyramidal disorder, hypokinesia, muscle rigidity, muscle tightness, musculoskeletal stiffness, oromandibular dystonia, parkinsonism, salivary hypersecretion, tremor
f Somnolence terms: hypersomnia, sedation, somnolence
g Insomnia terms: initial insomnia, insomnia, middle insomnia
h Hypertension terms: blood pressure diastolic increased, blood pressure increased, hypertension
The maximum approved dose is 6 mg/day
Source: Prescribing Information, Section 6, Table 8

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

Subgroup analyses were conducted for sex and race. Analysis for different age groups was not done because all patients were between 18 and 65 years of age.

  • Sex: The risk of side effects appeared to be similar in men and women.
  • Race: The risk of side effects appeared to be similar among different races.
  • Age: Most patients were between 18 and 65 years of age. Differences in side effects in patients below and above 65 years of age could not be determined.

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

The table below summarizes extrapyramidal adverse events in the Safety population.

Table 6. Subgroup Analysis of Extrapyramidal Symptoms

Demographic ParametersPlacebo 


 n/N (%)
VRAYLAR
3-6 mg

n/N (%)
VRAYLAR
9-12 mg

n/N (%)
Any EPS TAES*78/442 (18)109/263 (41)161/360 (45)
Sex  
  Male41/268 (15)61/148 (41)97/217 (45)
  Female37/174 (21)48/115 (42)64/143 (45)
Race  
  White39/203 (19)68/158 (43)70/158 (44)
  All other races39/239 (16)41/105 (39)91/203 (45)

*Extrapyramidal symptoms treatment emergent adverse events
The maximum approved dose is 6 mg/day
Source: Company Trial Data

WHO WAS IN THE STUDIES?

Who participated in the clinical trials?

The FDA approved VRAYLAR based on evidence from three clinical trials of 1065 patients with manic or mixed episode associated with bipolar disorder. The trials were conducted in the United States, Europe, and Asia.

The figure below summarizes how many men and women participated in the clinical trials. The population represents any patient who received study treatment (also known as the safety population).

Figure 1. Baseline Demographics by Sex

Pie chart summarizing how many men and women were enrolled in the clinical trials used to evaluate efficacy of the drug VRAYLAR.  In total, 633 men (59%) and 432 women (41%) participated in the clinical trials used to evaluate efficacy of the drug VRAYLAR.

Source: Company Trial Data

The figure and table below summarize the percentage of patients by race who participated in the clinical trials.

Figure 2. Baseline Demographics by Race

Pie chart summarizing the percentage of patients by race enrolled in the VRAYLAR clinical trial. In total, 519 White (49%), 271 Black (25%), 253 Asian (24%), 7 American Indian or Alaska Native (1%), 2 Native Hawaiian or Other Pacific Islander (<1%), and 13 identified as Other (1%).

<1%=less than="">
Source: Company Trial Data

Table 1. Baseline Demographics by Race

RaceNumber of PatientsPercentage  of Patients
White51949%
Black or African American27125%
Asian25324%
American Indian or Alaska Native71%
Native Hawaiian or Other Pacific Islander2less than 1%
Other131%

Source: Company Trial Data

The figure below summarizes the percentage of patients by age group enrolled in the clinical trials.

Figure 3. Baseline Demographics by Age

Pie chart summarizing how many individuals of certain age groups were enrolled in the VRAYLAR clinical trial.  In total, 1063 were between 18 and 64 years (100%) and 2 were 65 years and older (<1%).

<1%=less than="">
Source: Company Trial Data

Who participated in the trials?

The table below summarizes baseline demographics for the Safety population. The demographics for the efficacy population were similar.

Table 7. Baseline Demographics for the Trials

Demographic ParametersVRAYLAR
3-6 mg
(N=263)
n (%)
VRAYLAR
9-12 mg
(N=360)
n (%)
Placebo

(N=442)
n(%)
Total

(N=1065)
n (%)
Sex  
  Male148 (56)217 (60)268 (61)633 (59)
  Female115 (44)143 (40)174 (39)432 (41)
Age  
  Mean years (SD)41 (12)39 (12)38.9 (12)39.4 (12)
  Median (years)41393940
  Min, Max (years)18, 6518, 6418, 6518, 65
Age Group
=18 - <65>262 (100)360 (100)441 (100)1063 (100)
>=65 years1(<>01 (<>2(<>
Race  
  White158 (60)158 (44)203 (46)519 (49)
  Black or African American67 (26)98 (27)106 (24)271 (25)
  Asian34 (13)96 (27)123 (28)253 (24)
  American Indian or Alaska Native1(<>1 (<>5 (1)7 (1)
  Native Hawaiian or Other Pacific Islander1(<>1 (<>02 (<>
  Other2 (1)6 (2)5 (1)13 (1)
Ethnicity  
  Hispanic or Latino13 (5)15 (4)19 (4)47 (4)
  Not Hispanic or Latino250 (95)345 (96)423 (96)1018 (96)
Region   
    United States147 (56)179 (50)231 (52)557 (52)
    Europe85 (32)82 (23)85 (19)252 (24)
    Asia31 (12)99 (27)126 (28)256 (24)

The maximum approved dose is 6 mg/day
Source: Company Trial Data

How were the trials designed?

There were three trials that evaluated the benefits of VRAYLAR, and two of them evaluated side effects.

In the trials, patients were randomly assigned to receive either VRAYLAR or placebo. Neither the patients nor the health care providers knew which treatment was being given until after the trials were completed. The trials measured overall improvement in the symptoms of mania. nt

How were the trials designed?

VRAYLAR was studied in three 3-week, randomized, double-blind, placebo controlled, trials in adult patients who met Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision, (DSM IV TR) criteria for bipolar 1 disorder with manic or mixed episodes with or without psychotic features.

VRAYLAR or placebo drug was administered daily.

The primary endpoint was the change from baseline to week 3 in Young Mania Rating Scale (YMRS) total score.

The YMRS is an 11-item clinician rated scale traditionally used to assess the degree of manic symptomatology. The total score ranges from 0 to 60.

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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