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

Sequential Multiple-Assignment Randomized Trials to Compare Antipsychotic Treatments

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.

Study Overview

• Status: Completed
• Conditions: Schizophrenia
• Intervention / Treatment: Drug: Phase 1: Olanzapine; Drug: Phase 1: Risperidone; Drug: Phase 1: Amisulpride; Drug: Phase 1: Aripiprazole; Drug: Phase 1: Perphenazine; Drug: Phase 2: Olanzapine; Drug: Phase 2: Amisulpride; Drug: Phase 2: Clozapine; Other: Phase 3A: Clozapine extended treatment or Combined clozapine-MECT therapy; Drug: Phase 3B: Clozapine or another 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).

• Study Type: Interventional
• Enrollment (Actual): 762
• Phase: Phase 3

Contacts and Locations

Study Locations

• China
  • Beijing
    • Beijing, Beijing, China, 100000
      • Beijing Anding Hospital of Capital Medical University
  • Hubei
    • Wuhan, Hubei, China, 430000
      • Renmin Hospital of Wuhan University
  • Jiangsu
    • Nanjing, Jiangsu, China, 210000
      • Nanjing Brain Hospital Affiliated to Nanjing Medical University
  • Liaoning
    • Dalian, Liaoning, China, 116000
      • Dalian Seventh People's Hospital
  • Shanghai
    • Shanghai, Shanghai, China, 200030
      • Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine
  • Yunnan
    • Kunming, Yunnan, China, 650000
      • First Affiliated Hospital of Kunming Medical University
  • Zhejiang
    • Hangzhou, Zhejiang, China, 310000
      • Hangzhou Seventh People's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 36 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: Single

Number of Arms

10

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 【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.	Drug: Phase 1: Olanzapine; Initial dosage: 5-10 mg; recommended dosage: 5-20 mg/d; dosage form: po. duration: 8 weeks
Experimental: 【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.	Drug: Phase 1: Risperidone; Initial dosage: 1-2 mg; recommended dosage: 2-6 mg/d; dosage form: po. duration: 8 weeks
Experimental: 【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.	Drug: Phase 1: Amisulpride; Initial dosage: 200-400 mg; recommended dosage: 400-1200 mg/d; dosage form: po. duration: 8 weeks
Experimental: 【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.	Drug: Phase 1: Aripiprazole; Initial dosage: 5-10 mg; recommended dosage: 10-30 mg/d; dosage form: po. duration: 8 weeks
Experimental: 【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.	Drug: Phase 1: Perphenazine; Initial dosage: 2-4 mg; recommended dosage: 6-36 mg/d; dosage form: po. duration: 8 weeks
Experimental: 【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.	Drug: Phase 2: Olanzapine; Initial dosage: 5-10 mg; recommended dosage: 5-20 mg/d; dosage form: po. duration: 8 weeks
Experimental: 【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.	Drug: Phase 2: Amisulpride; Initial dosage: 200-400 mg; recommended dosage: 400-1200 mg/d; dosage form: po. duration: 8 weeks
Experimental: 【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.	Drug: Phase 2: Clozapine; Initial dosage: 25-50 mg; recommended dosage: 200-400 mg/d; dosage form: po. duration: 8 weeks
Experimental: 【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.	Other: 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.
Experimental: 【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.	Drug: 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Treatment efficacy rate	A 40% reduction or more of the total score in the Positive and Negative Syndrome Scale (PANSS). The PANSS scale consists of 30 items, and each item is rated on a 7-point scale, ranging from 1 (no symptoms) to 7 (extremely severe).	baseline,0.5 months,1 months, 2 months,4 months , 6 months , 8 months and 12 months
All-cause dropout rate	Marked by the treatment discontinuation for any reasons, including poor efficacy, intolerance of adverse reactions, poor compliance and other reasons.	baseline,0.5 months,1 months, 2 months,4 months , 6 months , 8 months and 12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from baseline in Clinician-Rated Dimensions of Psychosis Symptom severity (CRDPS)	Clinician-Rated Dimensions of Psychosis Symptom severity (CRDPS). The CRDPS scale evaluates eight symptom dimensions of psychosis. Each symptom domain is rated for the past 7 days on a 5-point scale ranging from 0 (absent) to 4 (present and severe).	baseline,0.5 months,1 months, 2 months,4 months , 6 months , 8 months and 12 months
Cost inventory	Direct medical costs (for example, antipsychotics costs, medical examinations costs, health care and service costs and adverse events costs) and indirect costs (such as traffic, nursing, and losing of labor) of the treatments.	baseline,2 months,4 months, 6 months and 12 months
Change from baseline in Clinical Global Impression Scale-Severity (CGI-S)	Clinical Global Impression Scale-Severity (CGI-S), including assessment of disease severity and overall efficacy. The severity of the disease was scored on an eight-point scale ranging from 0 (not rated) to 7 (extremely severe). The overall efficacy was assessed on an 8-point scale ranging from 0 (not assessed) to 7 (significant deterioration).	baseline,0.5 months,1 months, 2 months,4 months , 6 months , 8 months and 12 months
Change from baseline in Calgary Depression Scale for Schizophrenia (CDSS)	The Calgary Depression Scale for Schizophrenia (CDSS) consists of nine items, each scored from 0 to 3. A total score greater than 6 is considered depression.	baseline,0.5 months,1 months, 2 months,4 months , 6 months , 8 months and 12 months
Social function	Chinese version of UPSA-B, the UCSD (University of California,San Diego) Performance-based Skills Assessment-Brief, consists of two parts: financial skill (A and B) and communication skill. The score of financial skill A range from 0 to 5. The score of financial skill B range from 0 to 6. The score of communication skill range from 0 to 9. The higher scores mean a better outcome.	baseline,2 months,4 months and 6 months and 12 months
Life quality: The Heinirich Quality of life Scale (HRQOL)	The Heinirich Quality of life Scale (HRQOL) consists of 21 items, each scored from 0 to 6. The higher scores mean a better outcome.	baseline,2 months,4 months and 6 months and 12 months
Life quality: Medication Satisfaction Questionnaire (MSN)	Medication Satisfaction Questionnaire (MSN) has one item, scored from 1 to 7. The higher scores indicate higher satisfaction with the medication.	baseline,2 months,4 months and 6 months and 12 months
Life quality: Subjective Well-being under Neuroleptics (SWN)	Subjective Well-being under Neuroleptics (SWN) consists of 20 items, each scored from 1-6.	baseline,2 months,4 months and 6 months and 12 months
Extrapyramidal adverse effects: The Barnes Akathisia Scale (BAS)	The Barnes Akathisia Scale (BAS) will be used to evaluate objective performance and subjective experience of akathisia, scored from 0 to 3, and the overall clinical evaluation of akathisia is scored from 0 to 5. The higher scores mean a more serious side effect.	baseline,0.5 months,1 months, 2 months,4 months , 6 months , 8 months and 12 months
Extrapyramidal adverse effects: Simpson-Angus Extrapyramidal Side Effects Scale (SAS)	Simpson-Angus Extrapyramidal Side Effects Scale (SAS) consists of 10 items, each scored from 0 to 4. The higher scores mean a more serious side effect.	baseline,0.5 months,1 months, 2 months,4 months , 6 months , 8 months and 12 months
Extrapyramidal adverse effects: Abnormal Involuntary Movement Scale (AIMS)	Abnormal Involuntary Movement Scale (AIMS) consists of 12 items. The first 10 of 12 items is scored from 0 to 4, and the last 2 is scored from 0 to 1. The higher scores mean the more obvious abnormal involuntary movement.	baseline,0.5 months,1 months, 2 months,4 months , 6 months , 8 months and 12 months
Sexual dysfunction	Arizona Sexual Experiences Scale (ASEX) includes 5 items, each scored from 1-6. A total score greater than or equal to 19 and any item greater than or equal to 5, or any 3 items greater than or equal to 4, can help clinical diagnosis of sexual dysfunction.	baseline,0.5 months,1 months, 2 months,4 months , 6 months , 8 months and 12 months
Change from baseline in cognitive function: MCCB	MATRICS consensus cognitive battery (MCCB) consists of 10 tests that assess cognitive performance in 7 domains, including processing speed, attention/vigilance, working memory, verbal memory, visual learning, reasoning and problem solving, and social cognition.	baseline,2 months,4 months and 6 months and 12 months
Change from baseline in cognitive function: NBSC	New cognitive battery for patients with schizophrenia in China(NBSC). NBSC includes 4 tests from MCCB and 5 new tests (Trial making A, BACS, HVLT-R learning and recall, CPTIP, dominant hand Grooved Pegboard, Color Trails I and II, PASAT)	baseline,2 months,4 months and 6 months and 12 months
Safety index: Blood pressure	Blood pressure in mmHg	baseline,2 months,4 months and 6 months and 12 months
Safety index: Heart rate	Heart rate	baseline,2 months,4 months and 6 months and 12 months
Safety index: Respiratory rate	respiratory rate	baseline,2 months,4 months and 6 months and 12 months
Safety index: Vital signs	body temperature in celsius	baseline,2 months,4 months and 6 months and 12 months
Safety index: Blood count	Blood count	baseline,2 months,4 months and 6 months and 12 months
Safety index: Liver function	*Concentration of ALT, AST, GGT, ALP, TB, and DB.	baseline,2 months,4 months and 6 months and 12 months
Safety index: renal function	*Concentration of serum creatinine, blood urea nitrogen, uric acid, serum cystatin C, homocysteine.	baseline,2 months,4 months and 6 months and 12 months
Safety index: thyroid function	Thyroid function related hormone levels will be tested, including FT3, FT4, T3, TSH, and T4.	baseline,2 months,4 months and 6 months and 12 months
Safety index: prolactin	Serum prolactin level	baseline,2 months,4 months and 6 months and 12 months
Safety index: QTc interval	QTc interval	baseline,2 months,4 months and 6 months and 12 months
Metabolic side effects: body weight	Weight in kilograms	baseline,2 months,4 months and 6 months and 12 months
Metabolic side effects: BMI	BMI in kg/m^2	baseline,2 months,4 months and 6 months and 12 months
Metabolic side effects: waist circumstance	Waist circumstance in centimeter	baseline,2 months,4 months and 6 months and 12 months
Metabolic side effects: fasting blood-glucose	Fasting blood-glucose	baseline,2 months,4 months and 6 months and 12 months
Metabolic side effects: insulin index	Insulin resistance was assessed using homeostasis model assessment (HOMA-IR).	baseline,2 months,4 months and 6 months and 12 months
Metabolic side effects: serum lipid level	Concentration of serum triglyceride, LDL-C(low density lipoprotein cholesterol), HDL-C(high density lipoprotein cholesterol) and apolipoprotein.	baseline,2 months,4 months and 6 months and 12 months
Metabolic side effects: assessment of feeding behavior	Three-Factor Eating Questionnaire (TFEQ-21) consists of 21 items, including 3 dimensions (non-controlled eating, cognitively restricted eating, and emotional eating). Each item is scored from 1 to 4, and the first 16 item requires reverse scoring before calculating dimension scores. The higher scores mean a higher tendency for non-controlled eating, cognitively restricted eating, and emotional eating.	baseline,2 months,4 months and 6 months and 12 months
Metabolic side effects: Visual Analogue Scale (VAS)	Visual Analogue Scale (VAS) was used to evaluate the desire to eat, hunger sensation and willingness to eat. The scale consists of 3 items, each scored from 0 to 10. The higher scores mean a stronger desire to eat, hunger sensation and willingness to eat.	baseline,2 months,4 months and 6 months and 12 months
Metabolic side effects: Physical Activity Evaluation	Physical Activity Evaluation	baseline,2 months,4 months and 6 months and 12 months
MRI examinaitons	Change of grey matter volume and functional connectivity in certain brain region was focused in the MRI examinations, to evaluate the ability of MRI examinaitons (structural MRI, functional MRI and Magnetic Resonance Spectroscopy) to predict response to antipsychotic treatment in first-episode schizophrenia.	baseline,2 months and 4 months
Pharmacogenomics	*Blood sample was collected and genes related to drug efficacy and adverse reaction were tested to evaluate the ability of pharmacogenomics to predict response to antipsychotic treatment in first-episode schizophrenia.	baseline,2 months,4 months
Lipidomics	*Serum sample was collected for lipidomic analysis to investigate correlation between serum lipids and rapid weight gain in first-episode schizophrenia.	baseline,2 months,4 months

Collaborators and Investigators

• Sponsor: Shanghai Mental Health Center

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): February 12, 2019
• Primary Completion (Actual): September 27, 2023
• Study Completion (Actual): September 27, 2023

Study Registration Dates

• First Submitted: February 12, 2018
• First Submitted That Met QC Criteria: April 17, 2018
• First Posted (Actual): April 27, 2018

Study Record Updates

• Last Update Posted (Actual): April 8, 2025
• Last Update Submitted That Met QC Criteria: April 6, 2025
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Keywords: switch; Schizophrenia;; Antipsychotics；; first-episode
• Additional Relevant MeSH Terms: Schizophrenia Spectrum and Other Psychotic Disorders; Mental Disorders; Schizophrenia; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antiemetics; Autonomic Agents; Peripheral Nervous System Agents; Gastrointestinal Agents; Central Nervous System Depressants; Neurotransmitter Agents; Membrane Transport Modulators; Tranquilizing Agents; Psychotropic Drugs; GABA Agents; Neurotransmitter Uptake Inhibitors; Dopamine Agents; Dopamine Agonists; Antidepressive Agents; Serotonin Antagonists; Serotonin Agents; Selective Serotonin Reuptake Inhibitors; Antidepressive Agents, Second-Generation; Antipsychotic Agents; Serotonin 5-HT2 Receptor Antagonists; Dopamine Antagonists; Serotonin Receptor Agonists; Serotonin 5-HT1 Receptor Agonists; Dopamine D2 Receptor Antagonists; GABA Antagonists; Olanzapine; Aripiprazole; Amisulpride; Risperidone; Clozapine; Perphenazine
• Other Study ID Numbers: CRC2017ZD03

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No