Trial Outcomes & Findings for Relapse Prevention Study in Patients With Schizophrenia (NCT NCT01291511)

Last Updated: 2023-07-17

Results Overview

Relapse or impending relapse was defined as any of the following: hospitalization due to worsening of schizophrenia; increase (worsening) of the PANSS total score of greater than or equal to 30% from randomization, PANSS total score confirmed at a second visit conducted within 1-7 days; clinically significant emergent or worsening suicidal, homicidal, or aggressive behavior; a CGI-Improvement (CGI-I) score of 6 (much worse) or 7 (very much worse) after randomization; a dose increase in study medication or a need for additional open-label antipsychotic treatment.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

635 participants

Primary outcome timeframe

Up to 26 weeks post-randomization

Results posted on

2023-07-17

Participant Flow

A total of 635 patients were enrolled and received iloperidone in the Cross-Titration Phase and entered Stabilization Phase. A total of 303 were randomized and received either iloperidone (n=153) or placebo (n=150) in the Double-Blind Relapse Prevention Phase.

Participant milestones

Participant milestones
Measure	Iloperidone After meeting all entry criteria, completing a 1-week open-label iloperidone titration period (up to 12 mg/day), followed by a 14-24 week open-label iloperidone flexible dose-stabilization period (up to 24 mg/day), patients in this arm were randomized to iloperidone (flexible dosing 8-24 mg/day). Post-randomization double-blind study medication was administered orally twice daily for up to 26 weeks to evaluate relapse prevention. Subsequently, during the extension period, after a 1-week mock double-blind titration, open-label iloperidone (8-24 mg/day) was administered for up to 51 weeks to evaluate long-term safety.	Placebo After meeting all entry criteria, completing a 1-week open-label iloperidone titration period (up to 12 mg/day), followed by a 14-24 week open-label iloperidone flexible dose-stabilization period (up to 24 mg/day), patients in this arm were randomized to matching placebo. Post-randomization double-blind study medication was administered orally twice daily for up to 26 weeks to evaluate relapse prevention.
Cross-Titration and Stabilization Phase STARTED	635	0
Cross-Titration and Stabilization Phase COMPLETED	309	0
Cross-Titration and Stabilization Phase NOT COMPLETED	326	0
Double-blind Relapse Prevention Phase STARTED	153	150
Double-blind Relapse Prevention Phase COMPLETED	76	102
Double-blind Relapse Prevention Phase NOT COMPLETED	77	48

Reasons for withdrawal

Reasons for withdrawal
Measure	Iloperidone After meeting all entry criteria, completing a 1-week open-label iloperidone titration period (up to 12 mg/day), followed by a 14-24 week open-label iloperidone flexible dose-stabilization period (up to 24 mg/day), patients in this arm were randomized to iloperidone (flexible dosing 8-24 mg/day). Post-randomization double-blind study medication was administered orally twice daily for up to 26 weeks to evaluate relapse prevention. Subsequently, during the extension period, after a 1-week mock double-blind titration, open-label iloperidone (8-24 mg/day) was administered for up to 51 weeks to evaluate long-term safety.	Placebo After meeting all entry criteria, completing a 1-week open-label iloperidone titration period (up to 12 mg/day), followed by a 14-24 week open-label iloperidone flexible dose-stabilization period (up to 24 mg/day), patients in this arm were randomized to matching placebo. Post-randomization double-blind study medication was administered orally twice daily for up to 26 weeks to evaluate relapse prevention.
Cross-Titration and Stabilization Phase Withdrawal by Subject	107	0
Cross-Titration and Stabilization Phase Adverse Event	92	0
Cross-Titration and Stabilization Phase Administrative problems	30	0
Cross-Titration and Stabilization Phase Lack of Efficacy	28	0
Cross-Titration and Stabilization Phase Abnormal Laboratory Value	25	0
Cross-Titration and Stabilization Phase Lost to Follow-up	24	0
Cross-Titration and Stabilization Phase Protocol Violation	13	0
Cross-Titration and Stabilization Phase Abnormal test	6	0
Cross-Titration and Stabilization Phase Death	1	0
Double-blind Relapse Prevention Phase Administrative problems	45	29
Double-blind Relapse Prevention Phase Withdrawal by Subject	14	10
Double-blind Relapse Prevention Phase Lost to Follow-up	6	4
Double-blind Relapse Prevention Phase Adverse Event	5	0
Double-blind Relapse Prevention Phase Abnormal Laboratory Value	4	2
Double-blind Relapse Prevention Phase Protocol Violation	1	1
Double-blind Relapse Prevention Phase Lack of Efficacy	0	2
Double-blind Relapse Prevention Phase Abnormal test	1	0
Double-blind Relapse Prevention Phase Death	1	0

Baseline Characteristics

Relapse Prevention Study in Patients With Schizophrenia

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Iloperidone n=153 Participants oral, open-label titration up to 12 mg for 1-week followed by open-label flexible dosing (8-24 mg/day), followed by double-blind 8-24 mg/day dosing for 26 weeks	Placebo n=150 Participants oral, matching placebo administered during double-blind phase for up to 26 weeks	Total n=303 Participants Total of all reporting groups
Age, Continuous	38.4 years STANDARD_DEVIATION 11.3 • n=5 Participants	38.2 years STANDARD_DEVIATION 11.1 • n=7 Participants	38.3 years STANDARD_DEVIATION 11.2 • n=5 Participants
Sex: Female, Male Female	57 Participants n=5 Participants	68 Participants n=7 Participants	125 Participants n=5 Participants
Sex: Female, Male Male	96 Participants n=5 Participants	82 Participants n=7 Participants	178 Participants n=5 Participants
Race/Ethnicity, Customized Caucasian	74 Participants n=5 Participants	77 Participants n=7 Participants	151 Participants n=5 Participants
Race/Ethnicity, Customized Black	31 Participants n=5 Participants	28 Participants n=7 Participants	59 Participants n=5 Participants
Race/Ethnicity, Customized Asian	38 Participants n=5 Participants	40 Participants n=7 Participants	78 Participants n=5 Participants
Race/Ethnicity, Customized Pacific Islander	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Race/Ethnicity, Customized Other	9 Participants n=5 Participants	5 Participants n=7 Participants	14 Participants n=5 Participants

PRIMARY outcome

Timeframe: Up to 26 weeks post-randomization

Population: Two subjects lost to follow-up after randomization were excluded from the analysis population.

Outcome measures

Outcome measures
Measure	Iloperidone n=151 Participants oral, flexible dosing 8-24 mg/day given bid	Placebo n=150 Participants oral, matching placebo given bid
Time to Relapse or Impending Relapse	NA Days The median relapse free time could not be estimated as the Kaplan-Meier probability estimate of relapse over the 26-week double-blind period did not exceed 50% (i.e. the median, lower and upper limit of 95% CI was not estimable due to low number of participants with events).	99 Days Interval 57.0 to 122.0

SECONDARY outcome

Timeframe: Up to 26 weeks post-randomization

Population: Data presented are FAS (Full Analysis set) LOCF (last observation carried forward) Change From DBRP (Double-Blind Relapse Prevention) Baseline to RP Completion. RP Completion visit includes observations from last visit during DBRP period for patients who completed the study or RP Completion visit for patients who discontinued the DBRP phase and not included in previous scheduled visit.

The 30-item Positive and Negative Syndrome Scale (PANSS) was developed to assess the severity of symptoms of schizophrenia. The PANSS items are divided into positive, negative, and general psychopathology factors. All items were rated on a scale of 1 (absent) to 7 (extremely severe). The PANSS total score (or rating) is the sum of all 30 PANSS items taken together (the sum of its 3 subscales), with a maximum score of 210. Change from baseline is calculated as post value minus baseline value. A negative change indicates improvement.

Outcome measures

Outcome measures
Measure	Iloperidone n=150 Participants oral, flexible dosing 8-24 mg/day given bid	Placebo n=149 Participants oral, matching placebo given bid
PANSS Total Score, Change From Baseline to Last Visit	1.1 units on a scale Standard Error 1.12	12.4 units on a scale Standard Error 1.15

SECONDARY outcome

Timeframe: Up to 26 weeks post-randomization

Population: Data presented are FAS (Full Analysis set) OC (observed cases), as this measure does not include a baseline assessment; RP Completion visit includes observations from last visit during DBRP period for patients who completed the study and RP Completion visit that could not be remapped to a previous scheduled visit for patients who discontinued the DBRP phase.

The 7-item Clinical Global Impression of Severity (CGI-S) scale was developed to assess the overall, absolute degree of illness at any point in time. A rating of 1 is equivalent to "normal, not at all ill," and a rating of 7 is equivalent to "among the most extremely ill patients."

Outcome measures

Outcome measures
Measure	Iloperidone n=112 Participants oral, flexible dosing 8-24 mg/day given bid	Placebo n=105 Participants oral, matching placebo given bid
CGI-S, Last Visit	3.0 units on a scale Standard Deviation 0.89	3.6 units on a scale Standard Deviation 1.11

SECONDARY outcome

Timeframe: Up to 26 weeks post-randomization

The Sheehan Disability Scale (SDS) a self-reported measure that was developed to assess functional impairment in 3 inter-related domains (i.e., work/school, social, and family life). It is a 10-point visual analog scale with 0 being not impaired at all and 10 extremely impaired. Change from baseline is calculated as post value minus baseline value. A negative change indicates improvement.

Outcome measures

Outcome measures
Measure	Iloperidone n=142 Participants oral, flexible dosing 8-24 mg/day given bid	Placebo n=128 Participants oral, matching placebo given bid
SDS Total Score, Change From Baseline to Last Visit	-0.2 units on a scale Standard Error 0.54	1.8 units on a scale Standard Error 0.61

Adverse Events

Iloperidone (Cross-titration and Stabilization Phase)

Serious events: 21 serious events

Other events: 244 other events

Deaths: 1 deaths

Iloperidone (Relapse-prevention Phase)

Serious events: 6 serious events

Other events: 16 other events

Deaths: 1 deaths

Placebo (Relapse-prevention Phase)

Serious events: 4 serious events

Other events: 30 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	Iloperidone (Cross-titration and Stabilization Phase) n=629 participants at risk During the 1 week Cross-titration phase, patients were titrated up to 12 mg/d open-label iloperidone orally twice a day. The prior antipsychotic was discontinued by day 4. During the 14 to 24 week Stabilization Phase, the dose could be modified within a permitted range of a total daily dose of 8-24 mg/d.	Iloperidone (Relapse-prevention Phase) n=151 participants at risk Patients received 8 to 24 mg/d iloperidone orally twice a day for up to 26 weeks.	Placebo (Relapse-prevention Phase) n=150 participants at risk Patients received placebo orally twice a day for up to 26 weeks.
Psychiatric disorders Schizophrenia	1.3% 8/629 • Cross-Titration Phase (1 week) and Stabilization Phase (14-24 weeks); Relapse-prevention phase (up to 26 weeks) For each phase, i.e. Cross-titration/Stabilization Phase and Relapse-prevention Phase, the safety population included all enrolled or randomized patients who received at least 1 dose of study drug during the corresponding phase. For the Relapse-prevention Phase, in case of a treatment error, patients were analyzed according to the treatment received.	0.66% 1/151 • Cross-Titration Phase (1 week) and Stabilization Phase (14-24 weeks); Relapse-prevention phase (up to 26 weeks) For each phase, i.e. Cross-titration/Stabilization Phase and Relapse-prevention Phase, the safety population included all enrolled or randomized patients who received at least 1 dose of study drug during the corresponding phase. For the Relapse-prevention Phase, in case of a treatment error, patients were analyzed according to the treatment received.	8.7% 13/150 • Cross-Titration Phase (1 week) and Stabilization Phase (14-24 weeks); Relapse-prevention phase (up to 26 weeks) For each phase, i.e. Cross-titration/Stabilization Phase and Relapse-prevention Phase, the safety population included all enrolled or randomized patients who received at least 1 dose of study drug during the corresponding phase. For the Relapse-prevention Phase, in case of a treatment error, patients were analyzed according to the treatment received.
Psychiatric disorders Insomnia	5.6% 35/629 • Cross-Titration Phase (1 week) and Stabilization Phase (14-24 weeks); Relapse-prevention phase (up to 26 weeks) For each phase, i.e. Cross-titration/Stabilization Phase and Relapse-prevention Phase, the safety population included all enrolled or randomized patients who received at least 1 dose of study drug during the corresponding phase. For the Relapse-prevention Phase, in case of a treatment error, patients were analyzed according to the treatment received.	2.0% 3/151 • Cross-Titration Phase (1 week) and Stabilization Phase (14-24 weeks); Relapse-prevention phase (up to 26 weeks) For each phase, i.e. Cross-titration/Stabilization Phase and Relapse-prevention Phase, the safety population included all enrolled or randomized patients who received at least 1 dose of study drug during the corresponding phase. For the Relapse-prevention Phase, in case of a treatment error, patients were analyzed according to the treatment received.	4.7% 7/150 • Cross-Titration Phase (1 week) and Stabilization Phase (14-24 weeks); Relapse-prevention phase (up to 26 weeks) For each phase, i.e. Cross-titration/Stabilization Phase and Relapse-prevention Phase, the safety population included all enrolled or randomized patients who received at least 1 dose of study drug during the corresponding phase. For the Relapse-prevention Phase, in case of a treatment error, patients were analyzed according to the treatment received.
Nervous system disorders Dizziness	11.6% 73/629 • Cross-Titration Phase (1 week) and Stabilization Phase (14-24 weeks); Relapse-prevention phase (up to 26 weeks) For each phase, i.e. Cross-titration/Stabilization Phase and Relapse-prevention Phase, the safety population included all enrolled or randomized patients who received at least 1 dose of study drug during the corresponding phase. For the Relapse-prevention Phase, in case of a treatment error, patients were analyzed according to the treatment received.	2.6% 4/151 • Cross-Titration Phase (1 week) and Stabilization Phase (14-24 weeks); Relapse-prevention phase (up to 26 weeks) For each phase, i.e. Cross-titration/Stabilization Phase and Relapse-prevention Phase, the safety population included all enrolled or randomized patients who received at least 1 dose of study drug during the corresponding phase. For the Relapse-prevention Phase, in case of a treatment error, patients were analyzed according to the treatment received.	2.7% 4/150 • Cross-Titration Phase (1 week) and Stabilization Phase (14-24 weeks); Relapse-prevention phase (up to 26 weeks) For each phase, i.e. Cross-titration/Stabilization Phase and Relapse-prevention Phase, the safety population included all enrolled or randomized patients who received at least 1 dose of study drug during the corresponding phase. For the Relapse-prevention Phase, in case of a treatment error, patients were analyzed according to the treatment received.
Nervous system disorders Headache	6.4% 40/629 • Cross-Titration Phase (1 week) and Stabilization Phase (14-24 weeks); Relapse-prevention phase (up to 26 weeks) For each phase, i.e. Cross-titration/Stabilization Phase and Relapse-prevention Phase, the safety population included all enrolled or randomized patients who received at least 1 dose of study drug during the corresponding phase. For the Relapse-prevention Phase, in case of a treatment error, patients were analyzed according to the treatment received.	2.0% 3/151 • Cross-Titration Phase (1 week) and Stabilization Phase (14-24 weeks); Relapse-prevention phase (up to 26 weeks) For each phase, i.e. Cross-titration/Stabilization Phase and Relapse-prevention Phase, the safety population included all enrolled or randomized patients who received at least 1 dose of study drug during the corresponding phase. For the Relapse-prevention Phase, in case of a treatment error, patients were analyzed according to the treatment received.	3.3% 5/150 • Cross-Titration Phase (1 week) and Stabilization Phase (14-24 weeks); Relapse-prevention phase (up to 26 weeks) For each phase, i.e. Cross-titration/Stabilization Phase and Relapse-prevention Phase, the safety population included all enrolled or randomized patients who received at least 1 dose of study drug during the corresponding phase. For the Relapse-prevention Phase, in case of a treatment error, patients were analyzed according to the treatment received.
Investigations Weight Increased	5.4% 34/629 • Cross-Titration Phase (1 week) and Stabilization Phase (14-24 weeks); Relapse-prevention phase (up to 26 weeks) For each phase, i.e. Cross-titration/Stabilization Phase and Relapse-prevention Phase, the safety population included all enrolled or randomized patients who received at least 1 dose of study drug during the corresponding phase. For the Relapse-prevention Phase, in case of a treatment error, patients were analyzed according to the treatment received.	1.3% 2/151 • Cross-Titration Phase (1 week) and Stabilization Phase (14-24 weeks); Relapse-prevention phase (up to 26 weeks) For each phase, i.e. Cross-titration/Stabilization Phase and Relapse-prevention Phase, the safety population included all enrolled or randomized patients who received at least 1 dose of study drug during the corresponding phase. For the Relapse-prevention Phase, in case of a treatment error, patients were analyzed according to the treatment received.	2.7% 4/150 • Cross-Titration Phase (1 week) and Stabilization Phase (14-24 weeks); Relapse-prevention phase (up to 26 weeks) For each phase, i.e. Cross-titration/Stabilization Phase and Relapse-prevention Phase, the safety population included all enrolled or randomized patients who received at least 1 dose of study drug during the corresponding phase. For the Relapse-prevention Phase, in case of a treatment error, patients were analyzed according to the treatment received.
Gastrointestinal disorders Nausea	5.1% 32/629 • Cross-Titration Phase (1 week) and Stabilization Phase (14-24 weeks); Relapse-prevention phase (up to 26 weeks) For each phase, i.e. Cross-titration/Stabilization Phase and Relapse-prevention Phase, the safety population included all enrolled or randomized patients who received at least 1 dose of study drug during the corresponding phase. For the Relapse-prevention Phase, in case of a treatment error, patients were analyzed according to the treatment received.	1.3% 2/151 • Cross-Titration Phase (1 week) and Stabilization Phase (14-24 weeks); Relapse-prevention phase (up to 26 weeks) For each phase, i.e. Cross-titration/Stabilization Phase and Relapse-prevention Phase, the safety population included all enrolled or randomized patients who received at least 1 dose of study drug during the corresponding phase. For the Relapse-prevention Phase, in case of a treatment error, patients were analyzed according to the treatment received.	0.00% 0/150 • Cross-Titration Phase (1 week) and Stabilization Phase (14-24 weeks); Relapse-prevention phase (up to 26 weeks) For each phase, i.e. Cross-titration/Stabilization Phase and Relapse-prevention Phase, the safety population included all enrolled or randomized patients who received at least 1 dose of study drug during the corresponding phase. For the Relapse-prevention Phase, in case of a treatment error, patients were analyzed according to the treatment received.
Nervous system disorders Somnolence	8.3% 52/629 • Cross-Titration Phase (1 week) and Stabilization Phase (14-24 weeks); Relapse-prevention phase (up to 26 weeks) For each phase, i.e. Cross-titration/Stabilization Phase and Relapse-prevention Phase, the safety population included all enrolled or randomized patients who received at least 1 dose of study drug during the corresponding phase. For the Relapse-prevention Phase, in case of a treatment error, patients were analyzed according to the treatment received.	1.3% 2/151 • Cross-Titration Phase (1 week) and Stabilization Phase (14-24 weeks); Relapse-prevention phase (up to 26 weeks) For each phase, i.e. Cross-titration/Stabilization Phase and Relapse-prevention Phase, the safety population included all enrolled or randomized patients who received at least 1 dose of study drug during the corresponding phase. For the Relapse-prevention Phase, in case of a treatment error, patients were analyzed according to the treatment received.	0.00% 0/150 • Cross-Titration Phase (1 week) and Stabilization Phase (14-24 weeks); Relapse-prevention phase (up to 26 weeks) For each phase, i.e. Cross-titration/Stabilization Phase and Relapse-prevention Phase, the safety population included all enrolled or randomized patients who received at least 1 dose of study drug during the corresponding phase. For the Relapse-prevention Phase, in case of a treatment error, patients were analyzed according to the treatment received.
Gastrointestinal disorders Dry mouth	6.8% 43/629 • Cross-Titration Phase (1 week) and Stabilization Phase (14-24 weeks); Relapse-prevention phase (up to 26 weeks) For each phase, i.e. Cross-titration/Stabilization Phase and Relapse-prevention Phase, the safety population included all enrolled or randomized patients who received at least 1 dose of study drug during the corresponding phase. For the Relapse-prevention Phase, in case of a treatment error, patients were analyzed according to the treatment received.	0.00% 0/151 • Cross-Titration Phase (1 week) and Stabilization Phase (14-24 weeks); Relapse-prevention phase (up to 26 weeks) For each phase, i.e. Cross-titration/Stabilization Phase and Relapse-prevention Phase, the safety population included all enrolled or randomized patients who received at least 1 dose of study drug during the corresponding phase. For the Relapse-prevention Phase, in case of a treatment error, patients were analyzed according to the treatment received.	0.00% 0/150 • Cross-Titration Phase (1 week) and Stabilization Phase (14-24 weeks); Relapse-prevention phase (up to 26 weeks) For each phase, i.e. Cross-titration/Stabilization Phase and Relapse-prevention Phase, the safety population included all enrolled or randomized patients who received at least 1 dose of study drug during the corresponding phase. For the Relapse-prevention Phase, in case of a treatment error, patients were analyzed according to the treatment received.

Additional Information

Vanda Pharmaceuticals

Phone: 202-734-3400

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Pooled site data analysis is restricted to publication by consent of steering committee. PI is restricted from presenting or publishing independently on their own site data until the expiration of eighteen (18) months from the completion of the Clinical Trial or as otherwise noted in the Investigator's clinical trial agreement.
Publication restrictions are in place

Restriction type: OTHER