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Adjunctive Low-dose Metformin in Patients With Schizophrenia and Metabolic Abnormalities

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ClinicalTrials.gov Identifier: NCT02751307
Recruitment Status : Completed
First Posted : April 26, 2016
Last Update Posted : April 28, 2016
Sponsor:
Collaborator:
Taipei City Hospital
Information provided by (Responsible Party):
Chun-Hsin Chen, Taipei Medical University WanFang Hospital

Tracking Information
First Submitted Date  ICMJE April 19, 2016
First Posted Date  ICMJE April 26, 2016
Last Update Posted Date April 28, 2016
Study Start Date  ICMJE May 2013
Actual Primary Completion Date January 2015   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 25, 2016)
Changes in body weight [ Time Frame: baseline; week-4; week-8; week-12 ]
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: April 25, 2016)
  • Changes in waist circumference [ Time Frame: baseline; week-4; week-8; week-12 ]
  • Changes in blood pressure [ Time Frame: baseline; week-4; week-8; week-12 ]
  • Changes in fasting triglyceride level [ Time Frame: baseline; week-4; week-8; week-12 ]
  • Changes in fasting high-density lipoprotein cholesterol level [ Time Frame: baseline; week-4; week-8; week-12 ]
  • Changes in fasting glucose level [ Time Frame: baseline; week-4; week-8; week-12 ]
  • Changes in scores of positive and negative syndrome scale (PANSS) [ Time Frame: baseline; week-4; week-8; week-12 ]
    Recruited patients were interviewed by research assistants to get PANSS scores.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Adjunctive Low-dose Metformin in Patients With Schizophrenia and Metabolic Abnormalities
Official Title  ICMJE Treatment of Metabolic Abnormalities in Patients With Schizophrenia: Adjunctive Low-dose Metformin in Patients With Schizophrenia and Metabolic Abnormalities
Brief Summary

Metformin has been used for alleviating metabolic abnormalities in patients with schizophrenia. Until now, the lowest dose of metformin to treat metabolic abnormalities in clozapine-treated patients is 1000 mg/d. The aim of this study was to determine whether a lower dosage of metformin, such as 500 mg/d, is effective for improving metabolic profiles in clozapine-treated patients with pre-existing metabolic abnormalities.

Methods:

In this 12-week, randomized, double-blind, placebo-controlled trial, metformin 500 mg/d or 1000 mg/d or a placebo was prescribed to clozapine-treated patients with schizophrenia having pre-existing metabolic abnormalities. The recruited patients underwent physical and laboratory evaluations at week-4, week-8, and week-12.

Detailed Description

Methods In this 12-week, randomized, double-blind, placebo-controlled trial, metformin 500 mg/d or 1000 mg/d or placebo was prescribed to clozapine-treated patients with schizophrenia having pre-existing metabolic abnormalities. The study was approved by an institutional review board and was conducted at Taipei Medical University-Wan Fang Hospital and Taipei City Psychiatric Center from May 2013 to January 2015. All clinical investigation had been conducted according to the principles expressed in the Declaration of Helsinki. The investigators screened clozapine-treated patients in the first phase and enrolled eligible patients in this clinical trial. Written informed consent was obtained from all patients before the screening.

Patients in the first-phase screening Patients diagnosed with schizophrenia or schizoaffective disorder according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition; aged 20-65 years; and who had taken clozapine for at least 3 months were invited to the first-phase screening. Clinical interviews were conducted, and medical records were evaluated for collecting patient demographics and clinical information, namely diagnosis, age of onset, and dosage of clozapine use.

Measurements The height, BW, waist circumference (WC), and blood pressure (BP) of all patients were measured. The body mass index (BMI) was calculated as the BW in kilograms divided by the square of the height in meters. After overnight fasting, blood was collected for analyzing the fasting plasma glucose (FPG), TG, and high-density lipoprotein cholesterol (HDL-C) levels. Under manufacture's guide, fasting TG, FPG, and HDL-C levels were measured using an automated system (Roche Cobas C501).

Patients in the metformin trial Patients in the first-phase screening were enrolled in the present trial if they had at least one of the following metabolic abnormalities: BMI ≥ 24; WC > 90 cm (men) or 80 cm (women); fasting serum TG level ≥ 150 mg/dL; fasting serum HDL-C level ≤ 40 mg/dL (men) or 50 mg/dL (women); systolic BP ≥ 130 or diastolic BP ≥ 85 mm Hg; current use of antihypertensive agents; and FPG level = 100-126 mg/dL. The exclusion criteria were the following: history of diabetes mellitus (DM); current use of hypoglycemic or hypolipidemic agents; pregnancy; allergy to metformin; a creatinine level > 1.4 ng/dL; an abnormal liver function test result; and chronic cardiopulmonary insufficiency.

Trial procedures Patients recruited in the trial were randomized to three groups, metformin 500 mg/d, metformin 1000 mg/d, or placebo. The randomization was conducted by a research assistant, who was blinded to the patient's status. To ensure the concealment of the randomization, the metformin and placebo were provided in coded containers. The appearance of the placebo was identical to that of metformin tablets. All patients, caregivers, and investigators were masked to the randomization.

In the first week, 500 mg of metformin was administered in the morning to the groups of metformin 500 mg/d and 1000 mg/d, and placebo was administered to the placebo group. In the second week, the dosage was revised to 500 mg of metformin in the morning and the placebo in the evening for the group of metformin 500 mg/d, 500 mg of metformin twice a day for the group of metformin 1000 mg/d, and placebo twice daily for the placebo group. For all patients, the clozapine dosage remained unchanged throughout the intervention. The recruited patients underwent physical and laboratory evaluations at week-4, week-8, and week-12.

Statistical analyses The investigators used descriptive statistics for summarizing the baseline clinical characteristics of patients and analysis of variance for examining the differences in these characteristics among all groups. Patients who continued the intervention for at least 4 weeks were included in the analyses. The investigators adopted the last observation carried forward (LOCF) approach for replacing missing data, assuming no change in the missing values of metabolic indices after an event of dropout. Furthermore, for investigating whether repeated measures collected in a longitudinal manner change over time, the investigators first used the paired t test for examining differences between the baseline and follow-up measures. Repeated measure analyses were conducted using 2-way within-subjects analysis of variance for examining group (df = 2, between groups), time (df = 3, within subjects), and interaction (df = 6, interaction between time and groups) effects on the changes in metabolic profiles over time. The analyses were conducted using SPSS Version 20.0 (IBM, Armonk, NY). P < 0.05 was considered to indicate statistical significance.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Metabolic Syndrome
Intervention  ICMJE
  • Drug: metformin 500 mg
    metformin 500 mg QAM for metformin 500 mg/d group; metformin 500 mg 1 BID for metformin 1000 mg/d
    Other Name: Loditon
  • Drug: clozapine 100 mg
    Clozapine dose remained unchanged during metformin intervention period in recruited patients.
    Other Name: Clozaril
Study Arms  ICMJE
  • Active Comparator: metformin 500 mg/d; clozapine 100 mg
    In the first week, 500 mg of metformin was administered in the morning. In the second week, the dosage was revised to 500 mg of metformin in the morning and the placebo in the evening. During metformin intervention period, the clozapine dose remained unchanged in these recruited clozapine-treated patients.
    Interventions:
    • Drug: metformin 500 mg
    • Drug: clozapine 100 mg
  • Active Comparator: metformin 1000 mg/d; clozapine 100 mg
    In the first week, 500 mg of metformin was administered in the morning. In the second week, 500 mg of metformin twice a day was administered. During metformin intervention period, the clozapine dose remained unchanged in these recruited clozapine-treated patients.
    Interventions:
    • Drug: metformin 500 mg
    • Drug: clozapine 100 mg
  • Placebo Comparator: placebo; clozapine 100 mg
    In the first week, one pill of placebo was given and in the second week, placebo BID was given. During metformin intervention period, the clozapine dose remained unchanged in these recruited clozapine-treated patients.
    Interventions:
    • Drug: metformin 500 mg
    • Drug: clozapine 100 mg
Publications * Chiu CC, Lu ML, Huang MC, Chen PY, Lin YK, Lin SK, Chen CH. Effects of Low Dose Metformin on Metabolic Traits in Clozapine-Treated Schizophrenia Patients: An Exploratory Twelve-Week Randomized, Double-Blind, Placebo-Controlled Study. PLoS One. 2016 Dec 14;11(12):e0168347. doi: 10.1371/journal.pone.0168347. eCollection 2016. Erratum in: PLoS One. 2018 Feb 16;13(2):e0193315.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: April 25, 2016)
55
Original Actual Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE January 2015
Actual Primary Completion Date January 2015   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. patients diagnosed with schizophrenia or schizoaffective disorder according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition
  2. aged 20-65 years
  3. had taken clozapine for at least 3 months
  4. had at least one of the following metabolic abnormalities: BMI ≥ 24; WC > 90 cm (men) or 80 cm (women); fasting serum TG level ≥ 150 mg/dL; fasting serum HDL-C level ≤ 40 mg/dL (men) or 50 mg/dL (women); systolic BP ≥ 130 or diastolic BP ≥ 85 mm Hg; current use of antihypertensive agents; and FPG level = 100-126 mg/dL.

Exclusion Criteria:

  1. history of diabetes mellitus
  2. current use of hypoglycemic or hypolipidemic agents
  3. pregnancy
  4. allergy to metformin
  5. a creatinine level > 1.4 ng/dL
  6. an abnormal liver function test result
  7. chronic cardiopulmonary insufficiency.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 20 Years to 65 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Not Provided
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02751307
Other Study ID Numbers  ICMJE TMU-JIRB 201303005
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Responsible Party Chun-Hsin Chen, Taipei Medical University WanFang Hospital
Study Sponsor  ICMJE Taipei Medical University WanFang Hospital
Collaborators  ICMJE Taipei City Hospital
Investigators  ICMJE
Principal Investigator: Chun-Hsin Chen, MD Department of Psychiatry, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
PRS Account Taipei Medical University WanFang Hospital
Verification Date April 2016

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP