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

Shanghai Mental Health Center

Status and phase: Completed; Phase 3

Conditions: Schizophrenia

Treatments: Drug: Phase 2: Olanzapine; Drug: Phase 2: Clozapine; Drug: Phase 2: Amisulpride; Drug: Phase 1: Perphenazine; Drug: Phase 1: Aripiprazole; Drug: Phase 1: Risperidone; Other: Phase 3A: Clozapine extended treatment or Combined clozapine-MECT therapy; Drug: Phase 1: Olanzapine; Drug: Phase 1: Amisulpride; Drug: Phase 3B: Clozapine or another SGAs

Study type: Interventional

Funder types: Other

Identifiers

NCT03510325

CRC2017ZD03

Details and patient eligibility

About

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.

Full 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).

Enrollment: 762 patients

Sex: All

Ages: 16 to 45 years old

Volunteers: No Healthy Volunteers

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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Sequential Assignment

Masking: Single Blind

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762 participants in 10 patient groups

【Phase 1】 Olanzapine RCT

Experimental group

Description:

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.

Treatment:

Drug: Phase 1: Olanzapine

【Phase 1】 Risperidone RCT

Experimental group

Description:

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.

Treatment:

Drug: Phase 1: Risperidone

【Phase 1】 Amisulpride RCT

Experimental group

Description:

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.

Treatment:

Drug: Phase 1: Amisulpride

【Phase 1】 Aripiprazole RCT

Experimental group

Description:

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.

Treatment:

Drug: Phase 1: Aripiprazole

【Phase 1】 Perphenazine RCT

Experimental group

Description:

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.

Treatment:

Drug: Phase 1: Perphenazine

【Phase 2】 Olanzapine ESR

Experimental group

Description:

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.

Treatment:

Drug: Phase 2: Olanzapine

【Phase 2】 Amisulpride ESR

Experimental group

Description:

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.

Treatment:

Drug: Phase 2: Amisulpride

【Phase 2】 Clozapine ESR

Experimental group

Description:

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.

Treatment:

Drug: Phase 2: Clozapine

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

Experimental group

Description:

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.

Treatment:

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

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

Experimental group

Description:

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.

Treatment:

Drug: Phase 3B: Clozapine or another SGAs