Trial Outcomes & Findings for Long-term Safety and Tolerability of Cariprazine as an Adjunctive Treatment to Antidepressant Therapy in Patients With Major Depressive Disorder (NCT NCT01838876)

NCT ID: NCT01838876

Last Updated: 2019-08-21

Results Overview

An adverse event (AE) is any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An adverse event can therefore be any unfavorable and unintended sign (i.e. laboratory value), symptom, or disease temporally associated with the use of a medicinal product, whether or not related to the medicinal product. A TEAE is an AE that occurs or worsens after receiving study drug.

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 442 participants
• Primary outcome timeframe: First dose of study drug to last dose of study drug in the 26-week Treatment Period and within 30 days of last dose of study drug for participants who did not participate in the 2-week Safety Follow-up Period (Up to 30 weeks)
• Results posted on: 2019-08-21

Participant Flow

Rollover participants from Study RGH-MD-72 [NCT01715805] were eligible for this study if they had completed either the double-blind treatment or the continued-treatment periods. New patients were eligible if they had an ongoing inadequate response to a protocol-allowed antidepressant therapy (ADT).

Participant milestones

Measure	Cariprazine + ADT Cariprazine, flexible dose (titrated to a dose of 3.0milligrams (mg) adjusted to 1.5 mg or 4.5 mg based on investigator's judgment of response and tolerability), oral administration, once daily plus antidepressant drug therapy (ADT) for 26 weeks.
Overall Study STARTED	442
Overall Study Safety Population; Received Study Drug	345
Overall Study Entered Safety Follow-up Period	287
Overall Study COMPLETED	209
Overall Study NOT COMPLETED	233

Reasons for withdrawal

Measure	Cariprazine + ADT Cariprazine, flexible dose (titrated to a dose of 3.0milligrams (mg) adjusted to 1.5 mg or 4.5 mg based on investigator's judgment of response and tolerability), oral administration, once daily plus antidepressant drug therapy (ADT) for 26 weeks.
Overall Study Adverse Event	49
Overall Study Insufficient Therapeutic Response	10
Overall Study Protocol Violation	34
Overall Study Withdrawal of Consent	33
Overall Study Lost to Follow-up	21
Overall Study Study or Site Terminated by Sponsor	1
Overall Study Reason not Specified	7
Overall Study Did not meet eligibility criteria	78

Baseline Characteristics

Long-term Safety and Tolerability of Cariprazine as an Adjunctive Treatment to Antidepressant Therapy in Patients With Major Depressive Disorder

Baseline characteristics by cohort

Measure	Cariprazine + ADT n=345 Participants Cariprazine, flexible dose (titrated to a dose of 3.0 mg adjusted to 1.5 mg or 4.5 mg based on investigator's judgment of response and tolerability), oral administration, once daily plus antidepressant drug therapy (ADT) for 26 weeks.
Age, Continuous	46.7 years STANDARD_DEVIATION 10.5 • n=5 Participants
Sex: Female, Male Female	249 Participants n=5 Participants
Sex: Female, Male Male	96 Participants n=5 Participants
Race/Ethnicity, Customized Race · White	280 Participants n=5 Participants
Race/Ethnicity, Customized Race · Black or African American	54 Participants n=5 Participants
Race/Ethnicity, Customized Race · Asian	6 Participants n=5 Participants
Race/Ethnicity, Customized Race · American Indian or Alaska Native	1 Participants n=5 Participants
Race/Ethnicity, Customized Race · Native Hawaiian or Other Pacific Islander	1 Participants n=5 Participants
Race/Ethnicity, Customized Race · Other	3 Participants n=5 Participants
Race/Ethnicity, Customized Ethnicity · Hispanic or Latino	75 Participants n=5 Participants
Race/Ethnicity, Customized Ethnicity · Non-Hispanic or Latino	270 Participants n=5 Participants

PRIMARY outcome

Timeframe: First dose of study drug to last dose of study drug in the 26-week Treatment Period and within 30 days of last dose of study drug for participants who did not participate in the 2-week Safety Follow-up Period (Up to 30 weeks)

Population: Safety Population included all participants in the enrolled population who took at least 1 dose of cariprazine in this study.

An adverse event (AE) is any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An adverse event can therefore be any unfavorable and unintended sign (i.e. laboratory value), symptom, or disease temporally associated with the use of a medicinal product, whether or not related to the medicinal product. A TEAE is an AE that occurs or worsens after receiving study drug.

Outcome measures

Measure	Cariprazine + ADT n=345 Participants Cariprazine, flexible dose (titrated to a dose of 3.0 mg adjusted to 1.5 mg or 4.5 mg based on investigator's judgment of response and tolerability), oral administration, once daily plus antidepressant drug therapy (ADT) for 26 weeks.	Cariprazine + ADT (Male) Cariprazine, flexible dose (titrated to a dose of 3.0 mg adjusted to 1.5 mg or 4.5 mg based on investigators judgment of response and tolerability), oral administration, once daily plus antidepressant drug therapy (ADT) for 26 weeks for male participants.
Number of Participants With Treatment-emergent Adverse Events (TEAEs) in the Treatment Period	274 Participants	—

PRIMARY outcome

Timeframe: 2 weeks following the 26-week Treatment Period

Population: Participants in the Safety Population, all participants in the enrolled population who took at least 1 dose of cariprazine in this study, who entered the Safety Follow-up period.

An AE is any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An adverse event can therefore be any unfavorable and unintended sign (i.e. laboratory value), symptom, or disease temporally associated with the use of a medicinal product, whether or not related to the medicinal product. A NEAE is a new AE that occurred during the 2-week Safety Follow-up Period.

Outcome measures

Measure	Cariprazine + ADT n=287 Participants Cariprazine, flexible dose (titrated to a dose of 3.0 mg adjusted to 1.5 mg or 4.5 mg based on investigator's judgment of response and tolerability), oral administration, once daily plus antidepressant drug therapy (ADT) for 26 weeks.	Cariprazine + ADT (Male) Cariprazine, flexible dose (titrated to a dose of 3.0 mg adjusted to 1.5 mg or 4.5 mg based on investigators judgment of response and tolerability), oral administration, once daily plus antidepressant drug therapy (ADT) for 26 weeks for male participants.
Number of Participants With Newly Emergent Adverse Events (NEAEs) in the Safety Follow-up Period	20 Participants	—

PRIMARY outcome

Timeframe: Baseline (Week 0) to up to 26 weeks in the Treatment Period

Population: Safety Population included all participants in the enrolled population who took at least 1 dose of cariprazine in this study.

Clinical laboratory parameters included tests of hematology, chemistry, urinalysis and prolactin. The investigator assessed the results for clinical significance.

Outcome measures

Measure	Cariprazine + ADT n=345 Participants Cariprazine, flexible dose (titrated to a dose of 3.0 mg adjusted to 1.5 mg or 4.5 mg based on investigator's judgment of response and tolerability), oral administration, once daily plus antidepressant drug therapy (ADT) for 26 weeks.	Cariprazine + ADT (Male) Cariprazine, flexible dose (titrated to a dose of 3.0 mg adjusted to 1.5 mg or 4.5 mg based on investigators judgment of response and tolerability), oral administration, once daily plus antidepressant drug therapy (ADT) for 26 weeks for male participants.
Number of Participants With Clinically Significant Changes From Baseline in Clinical Laboratory Parameters	0 Participants	—

PRIMARY outcome

Timeframe: Baseline (Week 0) to up to 26 weeks in the Treatment Period plus a 2-week Safety Follow-up Period (Up to 28 weeks)

Population: Safety Population included all participants in the enrolled population who took at least 1 dose of cariprazine in this study.

Vital sign parameters included blood pressure, pulse rate, body mass index (BMI), weight, and waist circumference. The investigator assessed the results for clinical significance.

Outcome measures

Measure	Cariprazine + ADT n=345 Participants Cariprazine, flexible dose (titrated to a dose of 3.0 mg adjusted to 1.5 mg or 4.5 mg based on investigator's judgment of response and tolerability), oral administration, once daily plus antidepressant drug therapy (ADT) for 26 weeks.	Cariprazine + ADT (Male) Cariprazine, flexible dose (titrated to a dose of 3.0 mg adjusted to 1.5 mg or 4.5 mg based on investigators judgment of response and tolerability), oral administration, once daily plus antidepressant drug therapy (ADT) for 26 weeks for male participants.
Number of Participants With Clinically Significant Changes From Baseline in Vital Sign Parameters	0 Participants	—

PRIMARY outcome

Timeframe: Baseline (Week 0) to up to 26 weeks

Population: Safety Population included all participants in the enrolled population who took at least 1 dose of cariprazine in this study.

A standard 12-lead ECG was performed. The investigator determined the clinical significance of the ECG findings using the central ECG interpretation laboratory report.

Outcome measures

Measure	Cariprazine + ADT n=345 Participants Cariprazine, flexible dose (titrated to a dose of 3.0 mg adjusted to 1.5 mg or 4.5 mg based on investigator's judgment of response and tolerability), oral administration, once daily plus antidepressant drug therapy (ADT) for 26 weeks.	Cariprazine + ADT (Male) Cariprazine, flexible dose (titrated to a dose of 3.0 mg adjusted to 1.5 mg or 4.5 mg based on investigators judgment of response and tolerability), oral administration, once daily plus antidepressant drug therapy (ADT) for 26 weeks for male participants.
Number of Participants With Clinically Significant Changes From Baseline in Electrocardiograms (ECG)	1 Participants	—

PRIMARY outcome

Timeframe: First dose of study drug to last dose of study drug in the 26-week Treatment Period plus a 2-week Safety Follow-up Period or within 30 days of last dose of study drug for participants who did not participate in the Safety Follow-up Period (Up to 30 weeks)

Population: Safety Population included all participants in the enrolled population who took at least 1 dose of cariprazine in this study.

Extrapyramidal symptoms are drug-induced movement disorders such as dystonia, akathisia, parkinsonism, bradykinesia, tremor, and tardive dyskinesia.

Outcome measures

Measure	Cariprazine + ADT n=345 Participants Cariprazine, flexible dose (titrated to a dose of 3.0 mg adjusted to 1.5 mg or 4.5 mg based on investigator's judgment of response and tolerability), oral administration, once daily plus antidepressant drug therapy (ADT) for 26 weeks.	Cariprazine + ADT (Male) Cariprazine, flexible dose (titrated to a dose of 3.0 mg adjusted to 1.5 mg or 4.5 mg based on investigators judgment of response and tolerability), oral administration, once daily plus antidepressant drug therapy (ADT) for 26 weeks for male participants.
Number of Participants With Extrapyramidal Symptom (EPS)-Related TEAEs	98 Participants	—

PRIMARY outcome

Timeframe: Baseline (Lead-in study Baseline for roll-over participants and prior to first dose in this study for new participants) to Week 26 in this study

Population: Safety Population included all participants in the enrolled population who took at least 1 dose of cariprazine in this study.

The Columbia-Suicide Severity Rating Scale (C-SSRS) is a clinician-rated instrument that reports the severity of both suicidal ideation and behavior. Suicidal ideation is classified on a 5-item scale: 1 (wish to be dead) to 5 (active suicidal ideation with specific plan and intent). The C-SSRS also captures information about the intensity of ideation, specifically the frequency, duration, controllability, deterrents, and reasons for the most severe types of ideation. Suicidal behavior is classified on a 5-item scale: 0 (no suicidal behavior to 4 (actual attempt). More than 1 classification can be selected provided they represent separate episodes.

Outcome measures

Measure	Cariprazine + ADT n=345 Participants Cariprazine, flexible dose (titrated to a dose of 3.0 mg adjusted to 1.5 mg or 4.5 mg based on investigator's judgment of response and tolerability), oral administration, once daily plus antidepressant drug therapy (ADT) for 26 weeks.	Cariprazine + ADT (Male) Cariprazine, flexible dose (titrated to a dose of 3.0 mg adjusted to 1.5 mg or 4.5 mg based on investigators judgment of response and tolerability), oral administration, once daily plus antidepressant drug therapy (ADT) for 26 weeks for male participants.
Number of Participants in the Most Severe Suicidal Ideation and Suicidal Behavior Recorded on the C-SSRS During the Treatment Period No Suicidal Ideation	308 participants	—
Number of Participants in the Most Severe Suicidal Ideation and Suicidal Behavior Recorded on the C-SSRS During the Treatment Period Suicidal Ideation	37 participants	—
Number of Participants in the Most Severe Suicidal Ideation and Suicidal Behavior Recorded on the C-SSRS During the Treatment Period Suicidal Ideation with Specific Plan and Intent	1 participants	—
Number of Participants in the Most Severe Suicidal Ideation and Suicidal Behavior Recorded on the C-SSRS During the Treatment Period Ideation,Some Intent to Act,without Specific Plan	0 participants	—
Number of Participants in the Most Severe Suicidal Ideation and Suicidal Behavior Recorded on the C-SSRS During the Treatment Period Ideation,any Methods,without Intent to Act	6 participants	—
Number of Participants in the Most Severe Suicidal Ideation and Suicidal Behavior Recorded on the C-SSRS During the Treatment Period Non-specific Active Suicidal Thoughts	3 participants	—
Number of Participants in the Most Severe Suicidal Ideation and Suicidal Behavior Recorded on the C-SSRS During the Treatment Period Wish to be Dead	27 participants	—
Number of Participants in the Most Severe Suicidal Ideation and Suicidal Behavior Recorded on the C-SSRS During the Treatment Period No Suicidal Behavior	344 participants	—
Number of Participants in the Most Severe Suicidal Ideation and Suicidal Behavior Recorded on the C-SSRS During the Treatment Period Suicidal Behavior	1 participants	—
Number of Participants in the Most Severe Suicidal Ideation and Suicidal Behavior Recorded on the C-SSRS During the Treatment Period Completed Suicide	0 participants	—
Number of Participants in the Most Severe Suicidal Ideation and Suicidal Behavior Recorded on the C-SSRS During the Treatment Period Actual Suicide Attempt	1 participants	—

PRIMARY outcome

Timeframe: First dose of study drug to last dose of study drug in the 26-week Treatment Period plus a 2-week Safety Follow-up Period or within 30 days of last dose of study drug for participants who did not participate in the Safety Follow-up Period (Up to 30 weeks)

Population: Safety Population included all participants in the enrolled population who took at least 1 dose of cariprazine in this study.

A TEAE is an AE that occurs or worsens after receiving study drug. Ocular events are adverse events related to the eye.

Outcome measures

Measure	Cariprazine + ADT n=345 Participants Cariprazine, flexible dose (titrated to a dose of 3.0 mg adjusted to 1.5 mg or 4.5 mg based on investigator's judgment of response and tolerability), oral administration, once daily plus antidepressant drug therapy (ADT) for 26 weeks.	Cariprazine + ADT (Male) Cariprazine, flexible dose (titrated to a dose of 3.0 mg adjusted to 1.5 mg or 4.5 mg based on investigators judgment of response and tolerability), oral administration, once daily plus antidepressant drug therapy (ADT) for 26 weeks for male participants.
Number of Participants With Treatment-Emergent Ocular Events	1 Participants	—

PRIMARY outcome

Timeframe: Baseline (Lead-in study Baseline for roll-over participants and prior to first dose of this study for new participants) to End of Treatment (Up to Week 26) in this study

Population: Participants from the Safety Population, all participants in the enrolled population who took at least 1 dose of cariprazine in this study, with data available for analysis at the given time-point.

The ASEX is a participant-completed scale to evaluate overall sexual experiences over the previous 7 days consisting of 5 questions answered on a scale of 1 (best) to 6 (worst) for a total possible score of 3 to 30 (2 questions were only answered if the participant was sexually active in the past week), higher score indicates greater sexual dysfunction. There are different forms for males and females. A negative change from Baseline indicates improvement.

Outcome measures

Measure	Cariprazine + ADT n=229 Participants Cariprazine, flexible dose (titrated to a dose of 3.0 mg adjusted to 1.5 mg or 4.5 mg based on investigator's judgment of response and tolerability), oral administration, once daily plus antidepressant drug therapy (ADT) for 26 weeks.	Cariprazine + ADT (Male) n=88 Participants Cariprazine, flexible dose (titrated to a dose of 3.0 mg adjusted to 1.5 mg or 4.5 mg based on investigators judgment of response and tolerability), oral administration, once daily plus antidepressant drug therapy (ADT) for 26 weeks for male participants.
Change From Baseline in the Arizona Sexual Experiences Scale (ASEX) Score Baseline	20.1 score on a scale Standard Deviation 5.9	17.2 score on a scale Standard Deviation 5.5
Change From Baseline in the Arizona Sexual Experiences Scale (ASEX) Score Change from Baseline to the End of Treatment	-0.9 score on a scale Standard Deviation 4.4	-0.1 score on a scale Standard Deviation 4.6

Adverse Events

Cariprazine + ADT

Serious events: 7 serious events

Other events: 274 other events

Deaths: 2 deaths

Serious adverse events

Measure	Cariprazine + ADT n=345 participants at risk Cariprazine, flexible dose (titrated to a dose of 3.0 mg adjusted to 1.5 mg or 4.5 mg based on investigator's judgment of response and tolerability), oral administration, once daily plus antidepressant drug therapy (ADT) for 26 weeks.
Investigations Blood creatine phosphokinase increased	0.29% 1/345 • First dose of study drug to last dose of study drug in the 26-week Treatment Period plus a 2-week Safety Follow-up Period or within 30 days of last dose of study drug for participants who did not participate in the Safety Follow-up Period (Up to 30 weeks)
Psychiatric disorders Completed suicide	0.29% 1/345 • First dose of study drug to last dose of study drug in the 26-week Treatment Period plus a 2-week Safety Follow-up Period or within 30 days of last dose of study drug for participants who did not participate in the Safety Follow-up Period (Up to 30 weeks)
Injury, poisoning and procedural complications Fall	0.29% 1/345 • First dose of study drug to last dose of study drug in the 26-week Treatment Period plus a 2-week Safety Follow-up Period or within 30 days of last dose of study drug for participants who did not participate in the Safety Follow-up Period (Up to 30 weeks)
Infections and infestations Pneumonia	0.29% 1/345 • First dose of study drug to last dose of study drug in the 26-week Treatment Period plus a 2-week Safety Follow-up Period or within 30 days of last dose of study drug for participants who did not participate in the Safety Follow-up Period (Up to 30 weeks)
Injury, poisoning and procedural complications Road traffic accident	0.29% 1/345 • First dose of study drug to last dose of study drug in the 26-week Treatment Period plus a 2-week Safety Follow-up Period or within 30 days of last dose of study drug for participants who did not participate in the Safety Follow-up Period (Up to 30 weeks)
Injury, poisoning and procedural complications Spinal cord injury	0.29% 1/345 • First dose of study drug to last dose of study drug in the 26-week Treatment Period plus a 2-week Safety Follow-up Period or within 30 days of last dose of study drug for participants who did not participate in the Safety Follow-up Period (Up to 30 weeks)
Psychiatric disorders Substance-induced psychotic disorder	0.29% 1/345 • First dose of study drug to last dose of study drug in the 26-week Treatment Period plus a 2-week Safety Follow-up Period or within 30 days of last dose of study drug for participants who did not participate in the Safety Follow-up Period (Up to 30 weeks)
Psychiatric disorders Suicide attempt	0.29% 1/345 • First dose of study drug to last dose of study drug in the 26-week Treatment Period plus a 2-week Safety Follow-up Period or within 30 days of last dose of study drug for participants who did not participate in the Safety Follow-up Period (Up to 30 weeks)

Other adverse events

Measure	Cariprazine + ADT n=345 participants at risk Cariprazine, flexible dose (titrated to a dose of 3.0 mg adjusted to 1.5 mg or 4.5 mg based on investigator's judgment of response and tolerability), oral administration, once daily plus antidepressant drug therapy (ADT) for 26 weeks.
Gastrointestinal disorders Nausea	6.1% 21/345 • First dose of study drug to last dose of study drug in the 26-week Treatment Period plus a 2-week Safety Follow-up Period or within 30 days of last dose of study drug for participants who did not participate in the Safety Follow-up Period (Up to 30 weeks)
General disorders Fatigue	8.7% 30/345 • First dose of study drug to last dose of study drug in the 26-week Treatment Period plus a 2-week Safety Follow-up Period or within 30 days of last dose of study drug for participants who did not participate in the Safety Follow-up Period (Up to 30 weeks)
Infections and infestations Nasopharyngitis	8.7% 30/345 • First dose of study drug to last dose of study drug in the 26-week Treatment Period plus a 2-week Safety Follow-up Period or within 30 days of last dose of study drug for participants who did not participate in the Safety Follow-up Period (Up to 30 weeks)
Investigations Weight increased	9.9% 34/345 • First dose of study drug to last dose of study drug in the 26-week Treatment Period plus a 2-week Safety Follow-up Period or within 30 days of last dose of study drug for participants who did not participate in the Safety Follow-up Period (Up to 30 weeks)
Nervous system disorders Akathisia	15.9% 55/345 • First dose of study drug to last dose of study drug in the 26-week Treatment Period plus a 2-week Safety Follow-up Period or within 30 days of last dose of study drug for participants who did not participate in the Safety Follow-up Period (Up to 30 weeks)
Nervous system disorders Headache	11.6% 40/345 • First dose of study drug to last dose of study drug in the 26-week Treatment Period plus a 2-week Safety Follow-up Period or within 30 days of last dose of study drug for participants who did not participate in the Safety Follow-up Period (Up to 30 weeks)
Nervous system disorders Dizziness	5.8% 20/345 • First dose of study drug to last dose of study drug in the 26-week Treatment Period plus a 2-week Safety Follow-up Period or within 30 days of last dose of study drug for participants who did not participate in the Safety Follow-up Period (Up to 30 weeks)
Nervous system disorders Sedation	5.5% 19/345 • First dose of study drug to last dose of study drug in the 26-week Treatment Period plus a 2-week Safety Follow-up Period or within 30 days of last dose of study drug for participants who did not participate in the Safety Follow-up Period (Up to 30 weeks)
Psychiatric disorders Anxiety	9.9% 34/345 • First dose of study drug to last dose of study drug in the 26-week Treatment Period plus a 2-week Safety Follow-up Period or within 30 days of last dose of study drug for participants who did not participate in the Safety Follow-up Period (Up to 30 weeks)
Psychiatric disorders Insomnia	9.9% 34/345 • First dose of study drug to last dose of study drug in the 26-week Treatment Period plus a 2-week Safety Follow-up Period or within 30 days of last dose of study drug for participants who did not participate in the Safety Follow-up Period (Up to 30 weeks)
Psychiatric disorders Restlessness	9.9% 34/345 • First dose of study drug to last dose of study drug in the 26-week Treatment Period plus a 2-week Safety Follow-up Period or within 30 days of last dose of study drug for participants who did not participate in the Safety Follow-up Period (Up to 30 weeks)

Additional Information

Therapeutic Area, Head

Allergan

Phone: 714-246-4500

Email: clinicaltrials@allergan.com

Results disclosure agreements

• Principal investigator is a sponsor employee A disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 90 days from the time submitted to the sponsor for review. The sponsor cannot require changes to the communication and cannot extend the embargo.
• Publication restrictions are in place

Restriction type: OTHER