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

Shanghai Mental Health Center762 enrolled

Overview

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.

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

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

SINGLE

Enrollment

762

Conditions

Schizophrenia

Interventions

Phase 1: OlanzapineDRUG

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

Phase 1: RisperidoneDRUG

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

Phase 1: AmisulprideDRUG

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

Eligibility

Sex: ALLMin age: 16 YearsMax age: 45 Years

Medical Language ↔ Plain English

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.

Locations (7)

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

Outcomes

Primary Outcomes

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).

Time frame: 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.

Time frame: baseline,0.5 months,1 months, 2 months,4 months , 6 months , 8 months and 12 months

Secondary Outcomes

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).

Time frame: 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.

Time frame: 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).

Data from ClinicalTrials.gov

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

Phase 1: PerphenazineDRUG

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

Phase 2: OlanzapineDRUG

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

Phase 2: AmisulprideDRUG

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

Phase 2: ClozapineDRUG

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

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

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 3B: Clozapine or another SGAsDRUG

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.

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

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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)

Time frame: baseline,2 months,4 months and 6 months and 12 months

Safety index: Blood pressure

Blood pressure in mmHg

Time frame: baseline,2 months,4 months and 6 months and 12 months

Safety index: Heart rate

Heart rate

Time frame: baseline,2 months,4 months and 6 months and 12 months

Safety index: Respiratory rate

respiratory rate

Time frame: baseline,2 months,4 months and 6 months and 12 months

Safety index: Vital signs

body temperature in celsius

Time frame: baseline,2 months,4 months and 6 months and 12 months

Safety index: Blood count

Blood count

Time frame: baseline,2 months,4 months and 6 months and 12 months

Safety index: Liver function

\*Concentration of ALT, AST, GGT, ALP, TB, and DB.

Time frame: 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.

Time frame: 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.

Time frame: baseline,2 months,4 months and 6 months and 12 months

Safety index: prolactin

Serum prolactin level

Time frame: baseline,2 months,4 months and 6 months and 12 months

Safety index: QTc interval

QTc interval

Time frame: baseline,2 months,4 months and 6 months and 12 months

Metabolic side effects: body weight

Weight in kilograms

Time frame: baseline,2 months,4 months and 6 months and 12 months

Metabolic side effects: BMI

BMI in kg/m\^2

Time frame: baseline,2 months,4 months and 6 months and 12 months

Metabolic side effects: waist circumstance

Waist circumstance in centimeter

Time frame: baseline,2 months,4 months and 6 months and 12 months

Metabolic side effects: fasting blood-glucose

Fasting blood-glucose

Time frame: 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).

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: baseline,2 months,4 months and 6 months and 12 months

Metabolic side effects: Physical Activity Evaluation

Physical Activity Evaluation

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: baseline,2 months,4 months