Drug Trials Snapshots: VRAYLAR for the treatment of schizophrenia
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)
(vrāy-lar)
Forest Laboratories, LLC
Approval date: September 17, 2015
DRUG TRIALS SNAPSHOT SUMMARY:
What is the drug for?
VRAYLAR is used for the treatment of schizophrenia.
Schizophrenia is a brain disorder characterized by hearing voices, believing other people are reading one’s mind or controlling one’s thoughts, and being suspicious or withdrawn.
How is this drug used?
VRAYLAR is a capsule that is taken once a day.
What are the benefits of this drug?
VRAYLAR reduced symptoms of schizophrenia.
What are the benefits of this drug?
The table below summarizes the primary efficacy endpoints. This was based on the mean change in the Positive and Negative Syndrome Scale (PANSS) total score after 6 weeks. The population represents the Full Analysis Set (FAS) and consists of all randomized patients who received at least one dose of study drug and had at least one post-randomization efficacy evaluation for PANSS total score.
Table 2. Summary of Efficacy Results (FAS population)
Trial Number |
Treatment Group | Primary Efficacy Endpoint: PANSS Total | ||
---|---|---|---|---|
Mean Baseline Score (SD) | LS Mean Change from Baseline (SE) | Placebo-subtracted Differencea (95% CI) | ||
Trial 1 | VRAYLAR (1.5 mg/day)* | 97.1 (9.1) | -19.4 (1.6) | -7.6 (-11.8, -3.3) |
VRAYLAR (3 mg/day)* | 97.2 (8.7) | -20.7 (1.6) | -8.8 (-13.1, -4.6) | |
VRAYLAR (4.5 mg/day)* | 96.7 (9.0) | -22.3 (1.6) | -10.4 (-14.6, -6.2) | |
Placebo | 97.3 (9.2) | -11.8 (1.5) | -- | |
Trial 2 | VRAYLAR (3 mg/day)* | 96.1 (8.7) | -20.2 (1.5) | -6.0 (-10.1, -1.9) |
VRAYLAR (6 mg/day)* | 95.7 (9.4) | -23.0 (1.5) | -8.8 (-12.9, -4.7) | |
Placebo | 96.5 (9.1) | -14.3 (1.5) | -- | |
Trial 3 | VRAYLAR (3-6 mg/day)* | 96.3 (9.3) | -22.8 (1.6) | -6.8 (-11.3, -2.4) |
VRAYLAR (6-9 mg/day)*† | 96.3 (9.0) | -25.9 (1.7) | -9.9 (-14.5, -5.3) | |
Placebo | 96.6 (9.3) | -16.0 (1.6) | -- |
FAS=Full Analysis Set
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 13
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 FAS population which includes all randomized patients who received at least one dose of study drug and had at least one post-randomization efficacy evaluation for PANSS total score.
Table 3. Subgroup Analysis of Primary Endpoint-PANNS (by sex)
Sex | Trial 1 | Trial 2 | Trial 3 | ||||
---|---|---|---|---|---|---|---|
VRAYLAR 1.5 mg |
VRAYLAR 3 mg | VRAYLAR 4.5 mg | VRAYLAR 3 mg | VRAYLAR 6 mg | VRAYLAR 3-6 mg | VRAYLAR 6-9 mg† |
|
Male Placebo-subtracted difference, Mean (SE) |
-7.6 (3.0) | -9.1 (2.9) | -6.5 (2.5) | -8.6 (2.6) | -9.4 (2.8) | -6.9 (2.5) | -8.1 (2.5) |
Female Placebo-subtracted difference, Mean (SE) |
-8.2 (4.0) | -9.2 (4.1) | -3.5 (3.7) | -6.3 (3.5) | -13.8 (3.9) | -6.1 (4.6) | -7.1 (4.7) |
† The maximum approved dose is 6 mg/day
Source: Company Trial Data
Table 4. Subgroup Analysis of Primary Endpoint –PANSS (by race)
Race | Trial 1 | Trial 2 | Trial 3 | ||||
---|---|---|---|---|---|---|---|
VRAYLAR 1.5 mg |
VRAYLAR 3 mg | VRAYLAR 4.5 mg | VRAYLAR 3 mg | VRAYLAR 6 mg | VRAYLAR 3-6 mg | VRAYLAR 6-9 mg† |
|
White Placebo-subtracted difference, Mean (SE) |
-4.5 (3.2) | -6.9 (3.3) | -8.2 (3.0) | -9.1 (2.5) | -9.3 (2.5) | -11.9 (4.6) | -13.4 (4.9) |
All other races Placebo-subtracted difference, Mean (SE) |
-11.5 (3.6) | -11.5 (3.5) | -13.4 (3.4) | 2.2 (4.0) |
-3.7 (4.0) | -5.4 (2.5) | -6.6 (2.5) |
† 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.
What are the possible side effects?
The table below summarizes adverse reactions in the Safety population defined as all patients who receive at least at least one injection dose of study drug.
Table 3. 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= 584) (%) |
VRAYLAR* | ||
---|---|---|---|---|
1.5-3 mg/day (N=539) (%) |
4.5-6 mg/day (N=575) (%) |
9-12† mg/day (N=203) (%) |
||
Cardiac Disorders | ||||
Tachycardiaa | 1 | 2 | 2 | 3 |
Gastrointestinal Disorders | ||||
Constipation | 5 | 6 | 7 | 10 |
Nausea | 5 | 5 | 7 | 8 |
Vomiting | 3 | 4 | 5 | 5 |
General Disorders/Administration Site Conditions | ||||
Fatigueb | 1 | 2 | 3 | 2 |
Investigations | ||||
Weight increased | 1 | 3 | 2 | 3 |
Musculoskeletal and Connective Tissue Disorders | ||||
Back pain | 2 | 3 | 3 | 2 |
Nervous System Disorders | ||||
Akathisia | 4 | 9 | 13 | 14 |
Extrapyramidal Symptomsc | 8 | 15 | 19 | 20 |
Somnolenced | 6 | 5 | 8 | 10 |
Dizziness | 2 | 3 | 5 | 5 |
Psychiatric Disorders | ||||
Insomniae | 11 | 12 | 13 | 11 |
Restlessness | 3 | 4 | 6 | 5 |
Anxiety | 4 | 6 | 5 | 3 |
Vascular Disorders | ||||
Hypertensionf | 1 | 2 | 3 | 6 |
Note: Figures rounded to the nearest integer
* Data shown by modal daily dose, defined as most frequently administered dose per patient
a Tachycardia terms: heart rate increased, sinus tachycardia, tachycardia
b Fatigue terms: asthenia, fatigue
c Extrapyramidal Symptoms terms: bradykinesia, cogwheel rigidity, drooling, dyskinesia, dystonia, extrapyramidal disorder, hypokinesia, masked facies, muscle rigidity, muscle tightness, musculoskeletal stiffness, oculogyric crisis, oromandibular dystonia, parkinsonism, salivary hypersecretion, tardive dyskinesia, tremor, trismus
d Somnolence terms: hypersomnia, sedation, somnolence
e Insomnia terms: initial insomnia, insomnia, middle insomnia, terminal insomnia
† The maximum approved dose is 6 mg/day
Source: Prescribing Information, Section 6 Table 7
Were there any differences in side effects among sex, race and age?
Subgroup analyses were conducted for sex and race.
- 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: All 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 defined as all patients who received at least at least one dose of study drug.
Table 4. Subgroup Analysis of Extrapyramidal Symptoms
Demographic Parameters | Placebo n/N (%) |
VRAYLAR 1.5-3 mg n/N (%) |
VRAYLAR 4.5-6 mg n/N (%) |
VRAYLAR† 9-12 mg n/N (%) |
---|---|---|---|---|
Any EPS TAES* | 79/584 (14) |
128/539 (24) | 182/575 (32) |
66/203 (33) |
Sex | ||||
Male | 56/415 (14) |
84/372 (23) |
135/422 (32) |
49/151 (33) |
Female | 23/169 (14) |
44/167 (26) |
47/153 (31) |
17/52 (33) |
Race | ||||
White | 28/237 (12) |
48/278 (17) |
68/247 (28) |
16/49 (33) |
All other races | 48/335 (14) |
74/244 (30) |
110/311 (35) |
50/154 (33) |
*Extrapyramidal symptoms treatment emergent adverse events
† The maximum approved dose is 6 mg/day
Source: Company Trial Data
WHO WAS IN THE CLINICAL TRIALS?
Who participated in the clinical trials?
The FDA approved VRAYLAR based on evidence from three clinical trials that enrolled a total of 1754 patients with schizophrenia. The trials were conducted in the United States, Europe, Asia, South America, and Africa.
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
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
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* Not collected in some countries per local regulations
Source: Company Trial data
Table 1. Baseline Demographics by Race
Race | Number of Patients | Percentage of Patients |
---|---|---|
White | 811 | 43% |
Black or African American | 655 | 35% |
Asian | 328 | 17% |
American Indian or Alaska Native | 6 | less than 1% |
Native Hawaiian or Other Pacific Islander | 7 | less than 1% |
Other | 48 | 3% |
Not collected* | 46 | 2% |
* Not collected in some countries per local regulations
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
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Source: Company Trial Data
Who participated in the trials?
The table below summarizes baseline demographics for the Safety population. Overall demographics for the efficacy population were similar.
Table 5. Baseline Demographics for the Trials
Demographic Parameters | VRAYLAR 1.5-3 mg (N=539) n (%) |
VRAYLAR 4.5-6 mg (N=575) n (%) |
VRAYLAR 9-12 mg† (N=203) n (%) |
Placebo (N=584) n (%) |
Total (N=1901) n (%) |
---|---|---|---|---|---|
Sex | |||||
Male | 372 (69) | 422 (73) | 151 (74) | 415 (71) | 1360 (72) |
Female | 167 (31) | 153 (27) | 52 (26) | 169 (29) | 541 (28) |
Age | |||||
Mean years (SD) | 37 (10) | 38 (11) | 40 (10) | 37.8 (11) | 37.8 (11) |
Median (years) | 36 | 37 | 41 | 38 | 37 |
Min, Max (years) | 18, 61 | 18, 65 | 18, 63 | 18, 64 | 18, 65 |
Age Group | |||||
18 - <65> | 539 (100) | 574 (100) | 203 (100) | 584 (100) | 1900 (100) |
>=65 years | 0 | 1(<> | 0 | 0 | 1 (<> |
Race | |||||
White | 278 (52) | 247 | 49 (24) | 237 (41) | 811 (43) |
Black or African American | 141 (26) | 191 | 108 (53) | 215 (37) | 655 (35) |
Asian | 90 (17) | 104 | 38 (19) | 96 (16) | 328 (17) |
American Indian or Alaska Native | 3 (1) | 1 | 0 | 2 (<> | 6 (<> |
Native Hawaiian or Other Pacific Islander | 1 (<> | 1 | 1 (1) | 4 (1) | 7 (<> |
Other | 9 (2) | 14 | 7 (3) | 18 (3) | 48 (3) |
Not collected | 17 (3) | 17 | 0 | 12 (2) | 46 (2) |
Ethnicity | |||||
Hispanic or Latino | 33 (6) | 41 (7) | 20 (10) | 42 (7) | 136 (7) |
Not Hispanic or Latino | 487 (90) | 515 (90) | 183 (90) | 529 (91) | 1714 (90) |
Not collected | 19 (4) | 19 (3) | 0 | 13 (2) | 51 (3) |
Region | |||||
United States | 228 (42) | 302 (53) | 162 (80) | 318 (55) | 1010 (53) |
South America | 12 (2) | 13 (2) | 6 (3) | 16 (3) | 47 (2) |
Europe | 212 (39) | 157 (27) | 0 | 155 (26) | 524 (28) |
Asia | 87 (16) | 100 (17) | 35 (17) | 93 (16) | 315 (17) |
Africa | 0 | 3 (1) | 0 | 2 (<> | 5 (<> |
† The maximum approved dose is 6 mg/day
Source: Company Trial Data
How were the trials designed?
Three trials evaluated the benefit of VRAYLAR, and two of them evaluated the 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 symptoms of schizophrenia.
How were the trials designed?
VRAYLAR was studied in three 6-week, randomized, double-blind, placebo controlled, trials in adult patients with schizophrenia who met Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision, (DSM IV TR) criteria. An active control arm (risperidone or aripiprazole) was included in two trials to assess assay sensitivity.
VRAYLAR or placebo was administered daily.
The primary endpoint was the change from baseline to week 6 in Positive and Negative Syndrome Scale (PANSS) total score.
The PANSS is a 30-item scale that measures positive symptoms of schizophrenia (7 items), negative symptoms of schizophrenia (7 items), and general psychopathology (16 items), each rated on a scale of 1 (absent) to 7 (extreme); the total PANSS scores range from 30 to 210.
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.