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  1. Development & Approval Process | Drugs

Drug Trials Snapshots: INGREZZA

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 INGREZZA Prescribing Information for complete information.

INGREZZA (valbenazine)
(in greh' zah)
Neurocrine Biosciences
Approval date: April 11, 2017


DRUG TRIALS SNAPSHOT SUMMARY:

What is the drug for?

INGREZZA is a drug for the treatment of tardive dyskinesia.

Tardive dyskinesia is a condition characterized by uncontrolled, repetitive, involuntary movements of the face, tongue, arms, legs, and other body parts often caused by long-term use of some psychiatric drugs, such as antipsychotics.

How is this drug used?

INGREZZA is a capsule taken by mouth once a day.

What are the benefits of this drug?

Patients who received INGREZZA had improvement in the severity of tardive dyskinesia compared to those who received placebo.

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

The table below summarizes the mean change from baseline in the Abnormal Involuntary Movement Scale (AIMS) dyskinesia total score at the end of Week 6. AIMS is a 12-item scale; items 1 to 7 assess the severity of involuntary movements across body regions and these items were used in this trial. The AIMS dyskinesia total score (sum of items 1 to 7) could range from 0 to 28, with a decrease in score indicating improvement.

Table 2. Primary Efficacy Endpoint – Severity of Tardive Dyskinesia at Baseline and the End of Week 6

EndpointTreatment GroupMean Baseline Score (SD)LS Mean Change from Baseline (SEM)⁑Placebo-subtracted Difference (95% CI)
AIMS Dyskinesia Total ScoreINGREZZA 40 mg9.8 (4.1)-1.9 (0.4)-1.8 (-3.0, -0.7)
INGREZZA 80 mg*10.4 (3.6)-3.2 (0.4)-3.1 (-4.2, -2.0)
Placebo9.9 (4.3)-0.1 (0.4) 

LS Mean=least-squares mean; SD=standard deviation; SEM=standard error of the mean; CI=2-sided 95% confidence interval
*Dose that was statistically significantly different from placebo after adjusting for multiplicity.
⁑ A negative change from baseline indicates improvement.

INGREZZA Prescribing Information

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

  • Sex: INGREZZA worked similarly in men and women.
  • Race: INGREZZA worked similarly in White and Black or African American patients. Differences among other races could not be determined because of the small number of patients.
  • Age: INGREZZA worked similarly in patients below and above 65 years of age.

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 INGREZZA by sex, race and age subgroups for the study used to establish efficacy. Because of the small sample sizes, these exploratory analyses should be interpreted with caution.

Table 3. Efficacy Subgroup Analysis by Sex

Treatment Group (n)Efficacy Measure: Change from Baseline in AIMS
Dyskinesia Total Score at Week 6
 Mean Baseline Score (SD)LS Mean Change from Baseline (SE)Placebo-subtracted Differencea
(95% CI)
INGREZZA (40 mg/day)
Women (30)
10.2 (4.3)-2.6 (0.7)-1.8 (-3.6, -0.1)
Men (40)9.6 (4.0)-1.3 (0.6)-1.9 (-3.5, -0.4)
INGREZZA (80 mg/day)
Women (40)
10.3 (3.7)-3.3 (0.6)-2.5 (-4.1, -0.9)
Men (39)10.4 (3.4)-3.0 (0.6)-3.6 (-5.1, -2.0)
Placebo
Women (34)
10.4 (3.8)-0.8 (0.6)--
Men (42)9.5 (4.6)0.6 (0.6)--

SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: confidence interval.
a Difference (drug minus placebo) in least-squares mean change from baseline.

Table 4. Efficacy Subgroup Analysis by Race

Treatment Group (n)Efficacy Measure: Change from Baseline in AIMS
Dyskinesia Total Score at Week 6
 Mean Baseline Score (SD)LS Mean Change from Baseline (SE)Placebo- subtracted Differencea (95% CI)
INGREZZA (40 mg/day)
African American (25)
9.5 (4.8)-1.0 (0.7)-0.1 (-2.1, 1.8)
White (41)10.1 (3.7)-2.4 (0.6)-2.6 (-4.2, -1.1)
INGREZZA (80 mg/day)
African American (32)
9.6 (3.5)-3.4 (0.7)-2.5 (-4.3, -0.6)
White (44)11.0 (3.6)-2.9 (0.5)-3.2 (-4.7, -1.7)
Placebo
African American (29)
9.7 (4.0)-0.9 (0.7)--
White (43)10.2 (4.3)0.2 (0.5)--

SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: confidence interval.
a Difference (drug minus placebo) in least-squares mean change from baseline.

Table 5. Efficacy Subgroup Analysis by Age

Treatment Group (n)Efficacy Measure: Change from Baseline in AIMS
Dyskinesia Total Score at Week 6
 Mean Baseline Score (SD)LS Mean Change from Baseline (SE)Placebo- subtracted Differencea (95% CI)
INGREZZA (40 mg/day)
< 65="">
9.9 (4.2)-1.9 (0.5)-1.7 (-3.0, -0.5)
≥ 65 (8)9.3 (3.2)-1.7 (1.3)-2.1 (-5.1, 1.0)
INGREZZA (80 mg/day)
< 65="">
10.3 (3.5)-3.3 (0.4)-3.2 (-4.4, -1.9)
≥ 65 (12)10.5 (4.1)-2.1 (1.1)-2.5 (-5.2, 0.2)
Placebo
< 65="">
9.5 (4.1)-0.2 (0.5)--
≥ 65 (16)11.6 (4.7)0.4 (0.9)--

SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: confidence interval.
a Difference (drug minus placebo) in least-squares mean change from baseline.

FDA Statistical review

What are the possible side effects?

The most common side effect of INGREZZA is sleepiness, which can sometimes impair the ability to drive a car.

INGREZZA may cause serious heart rhythm problems (QT prolongation).

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

The table below summarizes selected adverse reactions that occurred in the three trials.

Table 6. Adverse Reactions in 3 Placebo-Controlled Trials of 6-Week Treatment Duration Reported in ≥2% and >Placebo

Adverse Reaction1Placebo
(n=183) (%)
INGREZZA
(n=262) (%)
General Disorders
Somnolence (somnolence, fatigue, sedation)4.2%10.9%
Nervous System Disorders
Anticholinergic effects (dry mouth, constipation, disturbance in attention, vision blurred, urinary retention)4.9%5.4%
Balance disorders/fall (fall, gait disturbance, dizziness, balance disorder)2.2%4.1%
Headache2.7%3.4%
Akathisia (akathisia, restlessness)0.5%2.7%
Gastrointestinal Disorders
Vomiting0.6%2.6%
Nausea2.1%2.3%
Musculoskeletal Disorders
Arthralgia0.5%2.3%

1 Within each adverse reaction category, the observed adverse reactions are listed in order of decreasing frequency.

INGREZZA Prescribing Information

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

  • Sex: The occurrence of side effects was similar in women and men.
  • Race: The occurrence of side effects was similar in White and Blacks or African American patients. Differences among other races could not be determined because of the small number of patients.
  • Age: The occurrence of side effects was similar in patients below and above 65 years of age.

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

The table below summarizes the occurrence of somnolence, the most common adverse reaction, by subgroup in the three studies. Here, somnolence includes reports of somnolence, fatigue, or sedation.

Table 7. Subgroup Analysis of Somnolence

SubgroupPlacebo
(N=183)
n (%)
INGREZZA
(N=262)
n (%)
Odds Ratio95% CI
x (%)Total, nx (%)Total, nLLUL
Any somnolence7 (3.8%)18323 (8.8%)2622.421.025.76
Sex
Male5 (4.7%)10614 (9.2%)1531.950.637.18
Female2 (2.6%)779 (8.3%)1094.000.7441.30
Age Group
<65>7 (4.8%)14820 (9.2%)2182.150.836.32
>=65 years0 (0.0%)353 (6.8%)443.100.33Infinity
Race*
White3 (3.0%)9916 (10.1%)1583.711.0120.7
Black or African American2 (2.6%)776 (6.2%)972.360.3925.2
Asian000 (0.0%)1NANANA
American Indian or Alaska Native1 (33.3%)30 (0.0%)50.60-23.40
Native Hawaiian or Other Pacific Islander0 (0.0%)200NANANA
Other1 (25.0%)41 (25.0%)41.00-39.00
Ethnicity
Hispanic or Latino0 (0.0%)511 (1.3%)730.670.02Infinity
Not Hispanic or Latino7 (5.3%)13222 (11.8%)1892.490.967.32

* Total includes who patients who identified themselves as both Black and American Indian and three that identified themselves as White and American Indian.

Clinical trial data

WHO WAS IN THE CLINICAL TRIALS?

Who participated in the clinical trials?

The FDA approved INGREZZA based primarily on evidence from three clinical trials that included 445 patients with tardive dyskinesia. These patients represent the population that was used to assess the side effects of INGREZZA (safety population) and will be presented below. One of the three trials provided evidence for the benefits of INGREZZA at the approved dosage, and information from this trial is presented under MORE INFO in Table 8.

The trials were conducted in USA, Canada and Puerto Rico.

The figure below summarizes how many men and women were in all three clinical trials together.

Figure 1. Baseline Demographics by Sex (safety population)

Pie chart summarizing how many men and women were in the clinical trials of the drug INGREZZA. In total, 259 men (42%) and 186 women (58%) participated in the clinical trials.

FDA Clinical review

Figure 2 and Table 1 below summarize the percentage of patients by race in all three clinical trials together.

Figure 2. Baseline Demographics by Race (safety population)

Pie chart summarizing the percentage of patients by race enrolled in the INGREZZA clinical trial. In total, 254 Whites (57%), 172 Blacks (39%), 5 mixed race (1%) and 14 all others (3%) participated in the clinical trials.

FDA Clinical review

Table 1. Baseline Demographics by Race (safety population)

RaceNumber of PatientsPercentage
White25457
Black or African American17239
Asian1less than 1
American Indian or Alaska Native31
Native Hawaiian or Other Pacific Islander2less than 1
Mixed51
Other82

FDA Clinical review

Figure 3 summarizes the percentage of patients by age group in all three clinical trials together.

Figure 3. Baseline Demographics by Age (safety population)

Pie chart summarizing how many individuals of certain age groups were enrolled in the clinical trial.  In total, 366 patients were below 65 years old (82%) and 79 were 65 and older (18%).

Clinical trial data

Who participated in the trials?

The tables below summarize the demographics of patients in the clinical trial used to establish the efficacy of INGREZZA at the recommended dosage and in all three trials used to establish the safety of INGREZZA, respectively.

Table 8. Baseline Demographics of Patients, Efficacy population

ParameterPlacebo
(N=76)
n (%)
INGREZZA
(N=149)
Total
(N=225)
n (%)
INGREZZA
40 mg daily
(N=70)
n (%)
INGREZZA
80 mg daily
(N=79)
n (%)
Sex
Men42 (55.3%)40 (57.1%)39 (49.4%)121 (53.8%)
Women34 (44.7%)30 (42.9%)40 (50.6%)104 (46.2%)
Age
Mean years (SD)57.0 (10.5)55.3 (8.6)56.0 (10.0)56.1 (9.8)
Median (years)58565757
Min, max (years)30, 8426, 7432, 8326, 84
Age Group
< 65="">60 (78.9%)62 (88.6%)67 (84.8%)189 (84.0%)
≥ 65 years16 (21.1%)8 (11.4%)12 (15.2%)36 (16.0%)
Race
White43 (56.6%)41 (58.6%)44 (55.7%)128 (56.9%)
Black or African American29 (38.2%)25 (35.7%)32 (40.5%)86 (38.2%)
Asian0000
American Indian or Alaska Native01 (1.4%)1 (1.3%)2 (0.9%)
Native Hawaiian or Other Pacific Islander1 (1.3%)001 (0.4%)
Other3 (3.9%)3 (4.3%)2 (2.5%)8 (3.6%)
Ethnicity
Hispanic or Latino23 (30.3%)22 (31.4%)14 (17.7%)59 (26.2%)
Not Hispanic or Latino53 (69.7%)48 (68.6%)65 (82.3%)166 (73.8%)

Adapted from FDA Clinical Review

Table 9. Baseline Demographics of Patients, Safety population

ParameterPlacebo
(N=183)
n (%)
INGREZZA
(N=262)
n (%)
Total
(N=445)
n (%)
Sex
Men106 (57.9)153 (58.4)259 (58.2)
Women77 (42.1)109 (41.6)186 (41.8)
Age Group
< 65="">148 (80.9)218 (83.2)366 (82.2)
≥ 65 years35 (19.1)44(16.8)79 (17.8)
Race
White98 (53.6)156 (59.5)254 (57.1)
Black or African American76 (41.5)96 (36.6)172 (38.7)
Asian01(0.4)1(0.2)
American Indian or Alaska Native1 (0.5)2(0.8)3 (0.7)
Native Hawaiian or Other Pacific Islander2 (1/1)02 (0.4)
Other4 (2.2)4 (1.5)8 (1.8)
Mixed*2 (1.1)3 (1.1)5 (1.1)
Ethnicity
Hispanic or Latino51(27.9)73 (27.9)124 (27.9)
Not Hispanic or Latino132 (72.1)189 (72.1)321(72.1)

*Two patients identified themselves as both Black and American Indian. Three patients identified themselves as White and American Indian.

Adapted from FDA Clinical review

How were the trials designed?

There were three trials that evaluated the side effects of INGREZZA. In all three trials patients were randomly assigned to receive either INGREZZA or placebo once daily for 6 weeks. Neither the patients nor the health care providers knew which treatment was being given until after the trials were completed.

One of these three trials was used to evaluate benefits of INGREZZA at the recommended dosage. The benefit of INGREZZA was evaluated by measuring the change in severity of tardive dyskinesia from baseline to the end of week 6 using the Abnormal Involuntary Movement Scale (AIMS). Using this scale, the total score could range from 0 to 28, with a decrease in score indicating improvement.

How were the trials designed?

The assessment of efficacy of INGREZZA was primary evaluated in a single, randomized (1:1:1 to INGREZZA 40 mg, INGREZZA 80 or placebo), parallel-group trial of patients with moderate to severe tardive dyskinesia as determined by clinical observation. Patients had underlying schizophrenia, schizoaffective disorder, or a mood disorder, and 84% of them were receiving antipsychotics. The change from baseline for two fixed doses of INGREZZA (40 mg or 80 mg) was compared to placebo.

The primary efficacy endpoint was the mean change from baseline in the AIMS dyskinesia total score at the end of Week 6. The AIMS is a 12-item scale; items 1 to 7 assess the severity of involuntary movements across body regions and these items were used in this trial. The AIMS dyskinesia total score (sum of items 1 to 7) could range from 0 to 28.

The safety of INGREZZA was evaluated in three randomized, placebo controlled, parallel-group trials that include the trial described above.

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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