Sequential Multiple-Assignment Randomized Trials to Compare Antipsychotic Treatments(SMART-CAT)

NCT ID: NCT03510325

Last Updated: 2025-04-08

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 762 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-02-12
• Study Completion Date: 2023-09-27

Brief Summary

This study is a sequential multiple-assignment randomized trial (RCT) of antipsychotic medication treatment in first-episode schizophrenia patients in the real-world settings.Through analysis of treatment efficacy rate and adverse reactions and pharmacoeconomic evaluation, this project intends to provide evidence for the selection of antipsychotics in FES patients as well as the efficacy and safety of using clozapine in the early phase of schizophrenia treatment by comparing with other SGAs.

Detailed Description

A total of 720 first-episode schizophrenia (FES) patients will be enrolled and followed up for 12 months in this study. The trial includes three treatment phases (each phase lasting for 8 weeks) and a naturalistic follow-up phase. Phase 1 is a 8-week randomized controlled trial; patients will be randomly assigned to one of the treatments with oral olanzapine, risperidone, amisulpride, aripiprazole or perphenazine. Patients who had an acceptable response to the randomly assigned drug therapy will remain on that treatment for a 12-month treatment period. Subjects who fail to respond in phase 1 will switch to phase 2, an equipoise-stratified randomization trial, in which patients will be randomly assigned to oral olanzapine, amisulpride or clozapine for another 8 weeks. No-responders in phase 2 will further enter an open label trial (phase 3). Patients who receive clozapine in phase 2 will be assigned to an extended clozapine treatment or modified electroconvulsive therapy add-on therapy (Phase 3A). Patients who were not assigned to clozapine in phase 2 will be assigned to treatment with clozapine or another SGAs not previously used in phase 1 and 2 (Phase 3B).

Conditions

Schizophrenia

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: SEQUENTIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: SINGLE

Study Groups

【Phase 1】 Olanzapine RCT

Phase 1 of the trial is a 8-week randomized controlled trial (RCT); patients will be randomly assigned to one of five treatment arms with different oral antipsychotics, one of which is 'Olanzapine RCT'. Non-responders or patients with intolerable side effects in phase 1 will switch to phase 2.

Group Type: EXPERIMENTAL

Phase 1: Olanzapine

Intervention Type: DRUG

Initial dosage: 5-10 mg; recommended dosage: 5-20 mg/d; dosage form: po. duration: 8 weeks

【Phase 1】 Risperidone RCT

Phase 1 of the trial is a 8-week randomized controlled trial (RCT); patients will be randomly assigned to one of five treatment arms with different oral antipsychotics, one of which is 'Risperidone RCT'. Non-responders or patients with intolerable side effects in phase 1 will switch to phase 2.

Group Type: EXPERIMENTAL

Phase 1: Risperidone

Intervention Type: DRUG

Initial dosage: 1-2 mg; recommended dosage: 2-6 mg/d; dosage form: po. duration: 8 weeks

【Phase 1】 Amisulpride RCT

Phase 1 of the trial is a 8-week randomized controlled trial (RCT); patients will be randomly assigned to one of five treatment arms with different oral antipsychotics, one of which is 'Amisulpride RCT'. Non-responders or patients with intolerable side effects in phase 1 will switch to phase 2.

Group Type: EXPERIMENTAL

Phase 1: Amisulpride

Intervention Type: DRUG

Initial dosage: 200-400 mg; recommended dosage: 400-1200 mg/d; dosage form: po. duration: 8 weeks

【Phase 1】 Aripiprazole RCT

Phase 1 of the trial is a 8-week randomized controlled trial (RCT); patients will be randomly assigned to one of five 8-week treatment arms with different oral antipsychotics, one of which is 'Aripiprazole RCT'. Non-responders or patients with intolerable side effects in phase 1 will switch to phase 2.

Group Type: EXPERIMENTAL

Phase 1: Aripiprazole

Intervention Type: DRUG

Initial dosage: 5-10 mg; recommended dosage: 10-30 mg/d; dosage form: po. duration: 8 weeks

【Phase 1】 Perphenazine RCT

Phase 1 of the trial is a 8-week randomized controlled trial (RCT); patients will be randomly assigned to one of five treatment arms with different oral antipsychotics, one of which is 'Perphenazine RCT'. Non-responders or patients with intolerable side effects in phase 1 will switch to phase 2.

Group Type: EXPERIMENTAL

Phase 1: Perphenazine

Intervention Type: DRUG

Initial dosage: 2-4 mg; recommended dosage: 6-36 mg/d; dosage form: po. duration: 8 weeks

【Phase 2】 Olanzapine ESR

Non-responders or patients with intolerable side effects in phase 1 will switch to phase 2, a 8-week equipoise-stratified randomization (ESR) trial; patients treated with risperidone, amisulpride, aripiprazole or perphenazine in phase 1 will be randomly assigned to one of three treatment arms, one of which is 'Olanzapine ESR'. Non-responders or patients with intolerable side effects in phase 2 will switch to phase 3.

Group Type: EXPERIMENTAL

Phase 2: Olanzapine

Intervention Type: DRUG

Initial dosage: 5-10 mg; recommended dosage: 5-20 mg/d; dosage form: po. duration: 8 weeks

【Phase 2】 Amisulpride ESR

Non-responders or patients with intolerable side effects in phase 1 will switch to phase 2, a 8-week equipoise-stratified randomization (ESR) trial; patients treated with olanzapine, risperidone, aripiprazole or perphenazine in phase 1 will be randomly assigned to one of three treatment arms, one of which is 'Amisulpride ESR'. Non-responders or patients with intolerable side effects in phase 2 will switch to phase 3.

Group Type: EXPERIMENTAL

Phase 2: Amisulpride

Intervention Type: DRUG

Initial dosage: 200-400 mg; recommended dosage: 400-1200 mg/d; dosage form: po. duration: 8 weeks

【Phase 2】 Clozapine ESR

Non-responders or patients with intolerable side effects in phase 1 will switch to phase 2, a 8-week equipoise-stratified randomization (ESR) trial; patients in phase 1 will be randomly assigned to one of three treatment arms, one of which is 'Clozapine ESR'. Non-responders or patients with intolerable side effects in phase 2 will switch to phase 3.

Group Type: EXPERIMENTAL

Phase 2: Clozapine

Intervention Type: DRUG

Initial dosage: 25-50 mg; recommended dosage: 200-400 mg/d; dosage form: po. duration: 8 weeks

【Phase 3】 Clozapine extended treatment or MECT add-on therapy

If a patient received clozapine in phase 2 failed to response, the individual will be assigned to the clozapine extended treatment or modified electroconvulsive therapy (MECT) add-on therapy.

Group Type: EXPERIMENTAL

Phase 3A: Clozapine extended treatment or Combined clozapine-MECT therapy

Intervention Type: OTHER

Clozapine extended treatment:

dosage: 200-600 mg/d; dosage form: po.

Combined clozapine-MECT therapy:

Dosage of clozapine: 200-600 mg/d; The modified electroconvulsive therapy (MECT) will be administered three times per week for the first 2 weeks, then twice a week for the next 2 weeks. The total treatment duration is about one month.

【Phase 3】 Clozapine or another SGAs (olanzapine, amisulpride, risperidone, or aripiprazole)

Non-clozapine users in phase 2 will be assigned to clozapine or another Second generation antipsychotics (SGAs) not previously used in phase 1 and 2.

Group Type: EXPERIMENTAL

Phase 3B: Clozapine or another SGAs

Intervention Type: DRUG

Clozapine:

Initial dosage: 25-50 mg; recommended dosage: 200-600 mg/d; duration: 8 weeks

Another Second generation antipsychotics (SGAs) (not previously used in phase 1 and 2): Olanzapine, risperidone, amisulpride, or aripiprazole The dosage of each drug is the same as that of phase 1 and phase 2.

Interventions

Phase 1: Olanzapine

Initial dosage: 5-10 mg; recommended dosage: 5-20 mg/d; dosage form: po. duration: 8 weeks

Intervention Type: DRUG

Phase 1: Risperidone

Initial dosage: 1-2 mg; recommended dosage: 2-6 mg/d; dosage form: po. duration: 8 weeks

Intervention Type: DRUG

Phase 1: Amisulpride

Initial dosage: 200-400 mg; recommended dosage: 400-1200 mg/d; dosage form: po. duration: 8 weeks

Intervention Type: DRUG

Phase 1: Aripiprazole

Initial dosage: 5-10 mg; recommended dosage: 10-30 mg/d; dosage form: po. duration: 8 weeks

Intervention Type: DRUG

Phase 1: Perphenazine

Initial dosage: 2-4 mg; recommended dosage: 6-36 mg/d; dosage form: po. duration: 8 weeks

Intervention Type: DRUG

Phase 2: Olanzapine

Initial dosage: 5-10 mg; recommended dosage: 5-20 mg/d; dosage form: po. duration: 8 weeks

Intervention Type: DRUG

Phase 2: Amisulpride

Initial dosage: 200-400 mg; recommended dosage: 400-1200 mg/d; dosage form: po. duration: 8 weeks

Intervention Type: DRUG

Phase 2: Clozapine

Initial dosage: 25-50 mg; recommended dosage: 200-400 mg/d; dosage form: po. duration: 8 weeks

Intervention Type: DRUG

Phase 3A: Clozapine extended treatment or Combined clozapine-MECT therapy

Clozapine extended treatment:

dosage: 200-600 mg/d; dosage form: po.

Combined clozapine-MECT therapy:

Dosage of clozapine: 200-600 mg/d; The modified electroconvulsive therapy (MECT) will be administered three times per week for the first 2 weeks, then twice a week for the next 2 weeks. The total treatment duration is about one month.

Intervention Type: OTHER

Phase 3B: Clozapine or another SGAs

Clozapine:

Initial dosage: 25-50 mg; recommended dosage: 200-600 mg/d; duration: 8 weeks

Another Second generation antipsychotics (SGAs) (not previously used in phase 1 and 2): Olanzapine, risperidone, amisulpride, or aripiprazole The dosage of each drug is the same as that of phase 1 and phase 2.

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

1. Patients must meet the DSM-5 diagnostic criteria for schizophrenia , schizophreniform disorder or schizoaffective disorder, based upon the structured clinical interview by research psychiatrist using Mini International Neuropsychiatric Interview 7.0 (M.I.N.I. 7.0), review of their clinical records, and input from available informants.

2. Inpatients or outpatients.

3. 16-45 years of age.

4. First episode, and the course no more than 3 years.

5. Drug-naïve, or any antipsychotic medication had been used no more than 2 weeks, and the cumulative antipsychotic drug exposure time no more than 6 weeks in lifetime.

6. The severity of psychotic symptoms is moderate or above, and the specific criteria including: have a score ≥4 on at least one item of Positive and Negative Syndrome Scale (PANSS) (delusions, conceptual disorganization, hallucinatory behavior, grandiosity, or suspiciousness/persecution), and PANSS total score >70.

7. Patients must demonstrate adequate decisional capacity to make a choice about participating in this research study and must provide informed consent to participate.

Exclusion Criteria

1. Patients were excluded if more than 3 years had passed since the onset of psychosis;

2. They met any of the contraindications for any of the study drugs;

3. Mental symptoms were caused by organic disease, severe physical illness, psychoactive substance dependence, mental retardation;

4. They were pregnancy or breast-feeding; they were extreme agitation, stupor or negative suicide.

• Minimum Eligible Age: 16 Years
• Maximum Eligible Age: 45 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Shanghai Mental Health Center

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

Beijing Anding Hospital of Capital Medical University

Beijing, Beijing Municipality, China

Renmin Hospital of Wuhan University

Wuhan, Hubei, China

Nanjing Brain Hospital Affiliated to Nanjing Medical University

Nanjing, Jiangsu, China

Dalian Seventh People's Hospital

Dalian, Liaoning, China

Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine

Shanghai, Shanghai Municipality, China

First Affiliated Hospital of Kunming Medical University

Kunming, Yunnan, China

Hangzhou Seventh People's Hospital

Hangzhou, Zhejiang, China

Countries

China

References

Li X, Guo X, Fan X, Feng T, Wang C, Yao Z, Xu X, Chen Z, Wang H, Xie S, He J, Zhuo K, Xiang Q, Cen H, Wang J, Smith RC, Jin H, Keshavan MS, Marder SR, Davis JM, Jiang K, Xu Y, Liu D. Sequential Multiple-Assignment Randomized Trials to Compare Antipsychotic Treatments (SMART-CAT) in first-episode schizophrenia patients: Rationale and trial design. Schizophr Res. 2021 Apr;230:87-94. doi: 10.1016/j.schres.2020.11.010. Epub 2020 Dec 2.

Reference Type: DERIVED

PMID: 33279374 (View on PubMed)

Other Identifiers

CRC2017ZD03

Identifier Type: -

Identifier Source: org_study_id