A Follow-on Study of the Long-Term Safety of Aripiprazole in Patients With Chronic Schizophrenia

Phase 3

Terminated

• Conditions: Schizophrenia
• Interventions: Drug: Aripiprazole

• Registration Number: NCT02435836
• Lead Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc.

Brief Summary

The primary objective of the study was to determine the safety of aripiprazole administered long-term in doses ranging from 10 to 30 mg per day as a maintenance therapy in subjects with chronic or first episode of schizophrenia. Information on the continued efficacy of aripiprazole was also gathered in this long-term trial (until 31 Dec 2012 or until aripiprazole was otherwise available through marketed means and/or reimbursed).

Detailed Description

Not available

Study Timeline

• Study Start: 1998-04
• Primary Completion: 2012-12
• Study Completion: 2012-12
• Study First Submitted: 2015-04-15
• Study First Submitted QC: 2015-05-01
• Study First Posted: 2015-05-06
• Results First Submitted: 2015-07-01
• Status Verified: 2015-08
• Results First Submitted QC: 2015-08-18
• Last Update Submitted: 2015-08-18
• Results First Posted: 2015-09-21
• Last Update Posted: 2015-09-21

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 631

Inclusion Criteria

1. Complete a Prior Study: each patient must meet one of the following conditions for completion of the prior study:

   • A patient who has completed 52 weeks of post-randomization treatment in the prior double blind study (31-97-301 or 31-98-304-01) is eligible, with no further qualifications.

   • A patient who was early-terminated from the study 31-97-301 or 31-98- 304-01 for either of the following two reasons is eligible to enter this open label study with no minimal required duration of prior double-blind participation:

     • Early termination was due to a marked deterioration of clinical status and no serious adverse events (SAE) other than hospitalization has occurred. The marked clinical deterioration must be documented by at least a one-point increase in CGI-Severity score from the baseline and a score of 6 (much worse) or 7 (very much worse) in CGI-Global Improvement at the time of termination, or
     • Early termination was due to a non-serious AE requiring discontinuation of the study drug

   • A patient who was early terminated after a minimum of 4 weeks' participation in the double-blind treatment in study 31-97-301 or 31-98- 304-01 and the reason for early termination was withdrawal of consent due to lack of effect but not marked deterioration. This must be documented by no change from baseline in the CGI-Severity score and a score of 4 (no change) or 5 (minimally worse) on the CGI-Global Improvement scale.

2. Signing of Informed Consent Form: Prior to any procedure or drug administration, each patient must sign an informed consent form. In addition, if required by the Ethical Committee, each patient's next-of-kin or responsible caregiver will co-sign the patient's consent form or a separate consent form.

Exclusion Criteria

1. Patients suffering from any significant somatic disease or medical problem that would obscure the results of treatment, or that might require frequent changes of concomitant medication.
2. Patients with any acute or unstable medical condition requiring pharmacotherapy, other than schizophrenia.
3. Patients with an abnormal laboratory test value in the most recent analysis (from the study 31-97-301 or 31-98-304-01) which is considered by the investigator as presenting a significant risk to the patient for continuing treatment with aripiprazole.
4. Patients who were early-terminated from the prior double-blind studies (31-97-301 or 31-98-304-01) due to a serious adverse event (SAE) other than worsening of psychosis or hospitalization.
5. Female patients of child bearing potential with a positive serum pregnancy test at the baseline (last visit of prior study) of this open-label follow-on study.
6. Patients who have positive result in the urine screen for drugs of abuse (except for cannabis or medically-prescribed analgesics or benzodiazepines.)

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Aripiprazole	Aripiprazole	All subjects began open-label treatment with 30 mg aripiprazole on the first day of participation in the current trial. Once a subject stabilized at the 30 mg per day dose, the investigator could adjust the dose within the range of 10 to 30 mg per day as needed (throughout this long-term trial), to manage AEs.

Primary Outcome Measures

Name	Time	Method
Mean Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Total Score by Week	Baseline, Weeks 1, 2, 4, 6, 8, 12, 16, 24, 36, 48, 60, 72, 84, 96, 108 continuing every 12 weeks, Last Visit	The PANSS consisted of three subscales: a total of 30 symptom constructs. For each symptom construct, severity was rated on a 7-point scale, with a score of 1 (absence of symptoms) and a score of 7 (extremely severe symptoms). The PANSS total score was the sum of the rating scores for 7 positive scale items, 7 negative scale items, and 16 general psychopathology scale items from the PANSS panel. The PANSS total score ranged from 30 (best possible outcome) to 210 (worst possible outcome).
Mean Clinical Global Impression of Improvement (CGI-I) by Week	Baseline, Weeks 1, 2, 4, 6, 8, 12, 16, 24, 36, 48, 60, 72, 84, 96, 108 continuing every 12 weeks, Last Visit	The efficacy of trial medication were rated for each participant using the CGI-I scale. The study physician must rate the participant's total improvement whether or not it is due entirely to drug treatment. All responses were compared to the participant's condition at baseline. Response choices include: 0 = not assessed; 1 =very much improved; 2 = much improved; 3 = minimally improved; 4 = no change; 5; =minimally worse; 6 = much worse; and 7 = very much worse.
Mean Change From Baseline in PANSS Positive Sub-scale Score by Week	Baseline, Weeks 1, 2, 4, 6, 8, 12, 16, 24, 36, 48, 60, 72, 84, 96, 108 continuing every 12 weeks, Last Visit	The PANSS consisted of three subscales: a total of 30 symptom constructs. For each symptom construct, severity was rated on a 7-point scale, with a score of 1 (absence of symptoms) and a score of 7 (extremely severe symptoms). The PANSS positive subscale score was the sum of the rating scores for the 7 positive scale items from the PANSS panel. The 7 positive symptom constructs are delusions, conceptual disorganization, hallucinatory behavior, excitement, grandiosity, suspiciousness/persecution, and hostility. The PANSS Positive Subscale ranges from 7 (absence of symptoms) to 49 (extremely severe symptoms).
Mean Change From Baseline in PANSS Negative Sub-scale Score by Week	Baseline, Weeks 1, 2, 4, 6, 8, 12, 16, 24, 36, 48, 60, 72, 84, 96, 108 continuing every 12 weeks, Last Visit	The PANSS consisted of three subscales: a total of 30 symptom constructs. For each symptom construct, severity was rated on a 7-point scale, with a score of 1 (absence of symptoms) and a score of 7 (extremely severe symptoms). The PANSS negative subscale score was the sum of the rating scores for the 7 negative scale items from the PANSS panel. The 7 negative symptom constructs: blunted affect, emotional withdrawal, poor rapport, passive apathetic withdrawal, difficulty in abstract thinking, lack of spontaneity and flow of conversation, stereotyped thinking. The PANSS Negative Subscale ranges from 7 (absence of symptoms) to 49 (extremely severe symptoms).
Mean Change From Baseline in Clinical Global Impression of Severity (CGI-S) by Week	Baseline, Weeks 1, 2, 4, 6, 8, 12, 16, 24, 36, 48, 60, 72, 84, 96, 108 continuing every 12 weeks, Last Visit	The severity of illness for each participant was rated using the CGI-S scale. To assess CGI-S, the study physician answered the following question: "Considering your total clinical experience with this particular population, how mentally ill is the participant at this time?" Response choices included: 0 = not assessed; 1 = normal, not ill at all; 2 = borderline mentally ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; and 7 = among the most extremely ill participants.
Mean Change From Baseline in Montgomery and Asberg Depression Rating Scale (MADRS) Total Score	Baseline, Weeks 1, 2, 4, 6, 8, 12, 16, 24, 36, 48, 60, 72, 84, 96, 108 continuing every 12 weeks, Last Visit	The MADRS is a ten-item diagnostic questionnaire which psychiatrists use to measure the severity of depressive episodes in participants with mood disorders. The questionnaire includes questions on the following symptoms. 1. Apparent sadness 2. Reported sadness 3. Inner tension 4. Reduced sleep 5. Reduced appetite 6. Concentration difficulties 7. Lassitude 8. Inability to feel 9. Pessimistic thoughts 10. Suicidal thoughts. Higher MADRS score indicates more severe depression, and each item yields a score of 0 to 6. The overall score ranges from 0 to 60. The usual cut-off points are: 0 to 6 = normal/ symptom absent, 7 to 19 = mild depression, 20 to 34 = moderate depression, \>34 = severe depression.
Mean Change From Baseline in Simpson-Angus Scale (SAS) Total Score by Week	Baseline, Weeks 1, 2, 4, 6, 8, 12, 16, 24, 36, 48, 60, 72, 84, 96, 108 continuing every 12 weeks, Last Visit	The SAS is composed of 10 items. This scale contains 10 items: Gait, Arm dropping, Shoulder shaking, Elbow rigidity, Wrist rigidity, Head rotation, Glabella Tap, Tremor, Salivation, Akathisia. Grade of severity of each item is rated using a 5-point scale, 1 (normal) and 5 (most severe). The total score ranges from 10 to 50. Negative changes from baseline indicate an improvement, with higher negative values indicating better improvement.
Mean Change From Baseline in Barnes Akathisia Rating Scale Score (BARS) Total Score by Week	Baseline, Weeks 1, 2, 4, 6, 8, 12, 16, 24, 36, 48, 60, 72, 84, 96, 108 continuing every 12 weeks, Last Visit	BARS consisted of 4 items: objective observation of akathisia by study physician, subjective feelings of restlessness by participant, participant distress due to akathisia, global evaluation of akathisia. The first 3 items were rated on a 4-point scale: 0 = absence of symptoms to 3 = severe condition. The global clinical evaluation were made on a 6-point scale, (0=absent, 1=questionable, 2=mild, 3=moderate, 4=marked, 5=severe). Participants were observed while they were seated and then stood for a minimum of 2 minutes in each position. Symptoms observed in other situations (e.g., while engaged in neutral conversation or engaged in activity on the ward) may also be rated. Subjective phenomena were elicited by direct questioning. The BARS Global Score was derived from the global clinical assessment of akathisia from the BARS panel. Total score ranges from 0 to 14. Negative changes from baseline indicate improvement, with higher negative values indicating better improvement.
Mean Change From Baseline in Abnormal Involuntary Movement Scale Score (AIMS) Total Score by Week	Baseline, Weeks 1, 2, 4, 6, 8, 12, 16, 24, 36, 48, 60, 72, 84, 96, 108 continuing every 12 weeks, Last Visit	The AIMS assessment consisted of 10 items describing symptoms of dyskinesia. Facial and oral movements (items 1 through 4), extremity movements (items 5 and 6), and trunk movements (item 7) were observed unobtrusively while the participant was at rest (e.g., in the waiting room), and the study physician would make global judgments on the participant's dyskinesia's (items 8 through 10). For this scale, the participant was seated on a hard, firm chair. These items are rated on a five-point scale: 0 (none), 1 (minimal), 2 (mild), 3 (moderate), 4 (severe). The total score ranges from 0 to 40. Negative changes from baseline indicate an improvement, with higher negative values indicating better improvement.
Number of Participants With Adverse Events (AEs)	Baseline to Last Visit	The AEs were one of the primary parameters to measure the safety and tolerability of individual participants. The AEs were captured for all participants from the time the ICF was signed until the end of the trial.
Percentage of Participants With Vital Signs of Potential Clinical Relevance	Baseline, Weeks 1, 2, 4, 6, 8, 12, 16, 24, 36, 48, 60, 72, 84, 96, 108 continuing every 12 weeks, Last Visit	The vital signs were one of the primary parameters to measure the safety and tolerability of individual participants. Incidence of TEAEs of potential clinical relevance included abnormal values in heart rate, systolic and diastolic blood pressure, respiratory rate and weight that were identified based on pre-defined criteria.
Percentage of Participants With ECG Measurements of Potential Clinical Relevance	Baseline, Weeks 1, 2, 4, 6, 8, 12, 16, 24, 36, 48, 60, 72, 84, 96, 108 continuing every 12 weeks, Last Visit	The measurement of ECG was one of the primary parameters to measure the safety and tolerability of individual participants. Incidence of TEAEs of potential clinical relevance include abnormal changes in heart rate and ECG intervals of PR, QRS, QT, QTcB, and QTcF that were identified based on pre-defined criteria.
Percentage of Participants With Laboratory Values of Potential Clinical Relevance	Baseline, Weeks 1, 2, 4, 6, 8, 12, 16, 24, 36, 48, 60, 72, 84, 96, 108 continuing every 12 weeks, Last Visit	The laboratory values were one of the primary parameters to measure the safety and tolerability of individual participants. Incidence of TEAEs of potential clinical relevance include abnormal values in serum chemistry, hematology, urinalyses and prolactin tests that were identified based on pre-defined criteria.