Amisulpride Augmentation Therapy for Clozapine-resistant Schizophrenic Patients (M1106)

Amisulpride Augmentation Therapy for Clozapine-resistant Schizophrenic Patients: A 14-week Randomized, Double-blind and Placebo-controlled Trial

This study includes two main components: the first screening phase and the second clinical intervention phase. During the screening phase, subjects with poor response to clozapine are carefully evaluated by chart-review and clinical assessment. Via chart-review, clinical data of diagnosis, disease course and previous treatment outcome, and concomitant psychotropic agents are obtained. Clinical phenomenology, including psychopathology, psychotic and mood symptoms severity and side effect of psychotropic medication are assessed by clinical interview and observation, which are conducted by experienced clinicians. Blood sample will be also obtained from the subjects for measuring the baseline clozapine drug level and extracting DNA for further analysis. Subjects fulfilling the criteria of treatment-resistant schizophrenia with poor response to adequate dose and duration of clozapine treatment are eligible for the clinical trial phase of 14-week randomized, placebo-controlled amisulpride add-on study. In this phase, subjects are randomly allocated to amisulpride augmentation treatment group and placebo treatment group. Subjects in the former group will receive clozapine and amisulpride combination treatment, while in the latter group will receive clozapine and placebo. Outcomes of clinical efficacy and safety are carefully evaluated by experienced and well-trained research stuffs in the 14 weeks of clinical study period.

All of the above studies will be conducted in four hospitals, including DOH Bali Psychiatric Hospital, DOH Tao-yan Psychiatric hospital, and the Ju-Shang Psychiatric Hospital. Subjects will be recruited from the chronic in-patient settings from these three hospitals.

Study Overview

• Status: Completed
• Conditions: Treatment-resistant Schizophrenia
• Intervention / Treatment: Drug: Amisulpride add-on; Drug: Placebo add-on

• Study Type: Interventional
• Enrollment (Actual): 273
• Phase: Phase 4

Contacts and Locations

Study Locations

• Taiwan
  • Taipei County, Taiwan
    • Bali Psychiatric Center
  • Tao-Yuan, Taiwan
    • Departments of Psychiatry, Tao-yuan Psychiatric Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• DSM-IV diagnosed schizophrenic patients;
• Age between 18 and 60;
• Before treatment with clozapine, documented treatment failure of two antipsychotics for an adequate duration of 6 weeks and in a sufficient dose of 600 mg/day of chlorpromazine equivalents;
• Documented failure to show a satisfactory clinical response to an adequate clozapine treatment, defined as at least clozapine 300 mg/day for 3 months or a plasma drug level of 350ng/ml;
• At least moderately ill, defined as with a Clinical Global Impression (CGI) greater than 4 or PANSS total score greater than 75;
• Persistent positive psychotic symptoms, with rating scores of moderate or worse on at least two of four positive symptom items (delusion, conceptual disorganization, hallucinatory behavior, and suspiciousness/persecution) on Positive and Negative Syndrome Scale (PANSS);

Exclusion Criteria:

• Patients with concomitant treatment with lithium, anti-convulsants, antidepressants and other antipsychotic medication ;
• Patients with underlying severe medical illness, such as cardiovascular disease, cerebrovascular disease, bone marrow suppression or epilepsy;
• Patients with comorbid diagnosis of substance dependence;

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: TRIPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: amisulpride add-on	Drug: Amisulpride add-on; At the beginning of the treatment phase (day 1), subjects in the combination treatment group will be started with adjunctive amisulpride, with a starting dose of 200 mg per day. Amisulpride is planned to increase to 400 mg/day on day 8, 600mg/day on day 15 and 800 mg/day on day 22, according to the subjects' responses and tolerability. All of the add-on amisulpride will be provided to subjects at night. To permit dose adjustment and ensure double-blind procedure, 200mg amisulpride is packed in capsules identical to those used for the placebo.
PLACEBO_COMPARATOR: placebo add-on	Drug: Placebo add-on; For subjects randomly allocated to the placebo treatment group, they will be added with one capsule of placebo from Day 1. On Day 8, Day 15 and Day 22, the placebo will be increased to 2, 3 and 4 capsules, respectively. and adjunctive amisulpride, with a starting dose of 200 mg per day. Amisulpride is planned to increase to 400 mg/day on day 8, 600mg/day on day 15 and 800 mg/day on day 22, according to the subjects' responses and tolerability. To permit dose adjustment and ensure double-blind procedure, 200mg amisulpride is packed in capsules identical to those used for the placebo.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Positive and Negative Symptom Scale(PANSS) total score change	The change from baseline of the Positive and Negative Symptom Scale (PANSS) total score.	12 wks after treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Positive and Negative Symptom Scale (PANSS) positive-symptom subscale score	The change from baseline of the Positive and Negative Symptom Scale (PANSS) positive-symptom subscale score (sum of item P1 to P7)	12 wks after treatment
Positive and Negative Symptom Scale (PANSS) negative-symptom subscale score	The change from baseline of the Positive and Negative Symptom Scale (PANSS) negative-symptom subscale score (sum of item N1 to N7)	12 wks after treatment
Positive and Negative Symptom Scale (PANSS) general psychopathology score	The change from baseline of the Positive and Negative Symptom Scale (PANSS) general psychopathology subscale score (sum of item G1 to G14)	12 wks after treatment
Clinical Global Impressions (CGI) scale score	The change from baseline of the Clinical Global Impressions (CGI) scale score	12 wks after treatment
Brief Psychotic Rating Scale (BPRS) total score	The change from baseline of the Brief Psychotic Rating Scale (BPRS) score	12 wks after treatment

Collaborators and Investigators

• Sponsor: National Health Research Institutes, Taiwan

Study record dates

Study Major Dates

• Study Start: May 1, 2006
• Primary Completion (ACTUAL): March 1, 2008
• Study Completion (ACTUAL): June 1, 2008

Study Registration Dates

• First Submitted: March 31, 2010
• First Submitted That Met QC Criteria: April 14, 2010
• First Posted (ESTIMATE): April 16, 2010

Study Record Updates

• Last Update Posted (ESTIMATE): April 16, 2010
• Last Update Submitted That Met QC Criteria: April 14, 2010
• Last Verified: April 1, 2010

More Information

Terms related to this study

• Keywords: clozapine; amisulpride; treatment-resistant schizophrenia
• Additional Relevant MeSH Terms: Mental Disorders; Schizophrenia Spectrum and Other Psychotic Disorders; Schizophrenia; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Antipsychotic Agents; Tranquilizing Agents; Psychotropic Drugs; Antidepressive Agents; Dopamine Agents; Dopamine Antagonists; Antidepressive Agents, Second-Generation; Amisulpride
• Other Study ID Numbers: M1106