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Effects of Adjunctive Metformin on Metabolic Profiles in Clozapine-treated Schizophrenic Patients

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ClinicalTrials.gov Identifier: NCT01300637
Recruitment Status : Unknown
Verified February 2011 by Taipei Medical University WanFang Hospital.
Recruitment status was:  Recruiting
First Posted : February 21, 2011
Last Update Posted : February 21, 2011
Sponsor:
Collaborator:
National Science Council, Taiwan
Information provided by:
Taipei Medical University WanFang Hospital

Tracking Information
First Submitted Date  ICMJE February 17, 2011
First Posted Date  ICMJE February 21, 2011
Last Update Posted Date February 21, 2011
Study Start Date  ICMJE November 2008
Estimated Primary Completion Date April 2009   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 18, 2011)
body weight change [ Time Frame: 24 weeks ]
We measure body weight before and after intervention, at week 2, 4, 8, 16, 24
Original Primary Outcome Measures  ICMJE Same as current
Change History No Changes Posted
Current Secondary Outcome Measures  ICMJE
 (submitted: February 18, 2011)
metabolic features [ Time Frame: 24 weeks ]
Our secondary outcomes included waist circumference, blood pressure, triglyceride, HDL-C, fasting glucose and insulin.
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 Effects of Adjunctive Metformin on Metabolic Profiles in Clozapine-treated Schizophrenic Patients
Official Title  ICMJE Prevalence of Metabolic Syndrome and Effects of Adjunctive Metformin on Metabolic Profiles in Clozapine-treated Schizophrenic Patients
Brief Summary

Background: Several studies have suggested that clozapine has the greatest propensity of all available atypical antipsychotics to induce weight gain and metabolic dysregulation. So it is necessary to conduct some interventions to prevent or treat metabolic dysregulation induced by clozapine.

Metformin has been reported to achieve weight loss in several groups of patients characterized by insulin resistance. Several studies evaluated the effects of metformin on antipsychotics-induced weight gain and study period lasted from 8 to 16 weeks. Long-term metformin use had more robust effect on metabolic dysregulation and body weight in non-psychiatric field.

Goals: The study goals are two-fold. The first goal is to estimate the prevalence of metabolic dysregulation among clozapine-treated schizophrenic patients in Taiwan. The second goal is to assess the reversal effect of metformin on metabolic disturbance among clozapine-treated schizophrenic patients in a 24-week double-blind, placebo-control trial. The investigators will use metformin 1500 mg/d or placebo in the second phase trial.

Methods: This study will be divided into two phases. The first phase is to estimate the prevalence of metabolic disturbances among clozapine-treated patients. The second will be a randomized, double-blind, and placebo-controlled study of adjunctive metformin for non-DM clozapine-treated patients.

The clozapine dosage was maintained unchanged during the study period. The eligible patients will be randomly assigned to either metformin or identical placebo pills. Metformin will be titrated to 1500 mg/day in 4 weeks. Patients' blood pressure (BP), waist circumference, body weight, fasting plasma glucose (FPG), triglyceride (TG), high-density lipoprotein cholesterol (HDL), insulin, and leptin will be measured at 2, 4, 8, 16, and 24 weeks after the start of metformin.

In a 3-year period, the investigators estimate to recruit 150 clozapine-treated patients in the first phase and 75 fulfill the second phase criteria. The investigators estimate 60 patients complete the second phase intervention (staying in second phase at least 4 weeks).

From this study, the investigators would like to know the prevalence of metabolic dysregulation among clozapine-treated schizophrenic patients and to know the effect of metformin on metabolic profile among non-DM clozapine treated patients.

Detailed Description

Background: Several studies have suggested that clozapine has the greatest propensity of all available atypical antipsychotics to induce weight gain and metabolic dysregulation. So it is necessary to conduct some interventions to prevent or treat metabolic dysregulation induced by clozapine.

Metformin has been reported to achieve weight loss in several groups of patients characterized by insulin resistance. Several studies evaluated the effects of metformin on antipsychotics-induced weight gain and study period lasted from 8 to 16 weeks. Long-term metformin use had more robust effect on metabolic dysregulation and body weight in non-psychiatric field. In our recent study data showed that after 8 weeks treatment with metformin 1500 mg/day in 24 olanzapine-treated patients, the body weight, fasting levels of glucose, triglyceride, and insulin significantly decreased. Insulin secretion and insulin resistance also decreased significantly. Half of subjects with metabolic syndrome obtained improvement after metformin trial.

Goals: The study goals are two-fold. The first goal is to estimate the prevalence of metabolic dysregulation among clozapine-treated schizophrenic patients in Taiwan. The second goal is to assess the reversal effect of metformin on metabolic disturbance among clozapine-treated schizophrenic patients in a 24-week double-blind, placebo-control trial. We will use metformin 1500 mg/d or placebo in the second phase trial.

Methods: This study will be divided into two phases. The first phase is to estimate the prevalence of metabolic disturbances among clozapine-treated patients. The second will be a randomized, double-blind, and placebo-controlled study of adjunctive metformin for non-DM clozapine-treated patients.

Patients are recruited in the first phase if they meet the following criteria (1) fulfilled DSM-IV criteria of schizophrenia or schizoaffective disorder; (2) 18-65 year of age (3) receiving clozapine for at least 6 months. We will check patients' blood pressure (BP), waist circumference, body weight, fasting plasma glucose (FPG), triglyceride (TG), high-density lipoprotein cholesterol (HDL), insulin, and leptin will be measured. In this study, we use the modified ATP III criteria for Asians to evaluate subjects for a diagnosis of metabolic syndrome.

The inclusion criteria of second phase intervention will be first-phase participants who are (1) overweight and obese (BMI ≧ 24) or (2) one or more metabolic dysregulation, such as abdominal obesity (waist circumference > 90 cm, in men and > 80 cm, in women; fasting hypertriglyceridemia, (≥ 150 mg/dL); low fasting HDL levels (< 40 mg/dL in men and < 50 mg/dL in women); high blood pressure (≥ 130/ ≥ 85 mm Hg or current treatment with antihypertensive medication). The exclusion criteria are the following: (1) current use of hypoglycemic or hypolipidemic agents (2) FPG levels ≥ 126 mg/dL; (3) women who are pregnant; (4) known allergy or contraindicated to metformin (including Creatine>1.4 ng/dl; abnormal liver function test; chronic cardiopulmonary insufficiency).

The clozapine dosage was maintained unchanged during the study period. The eligible patients will be randomly assigned to either metformin or identical placebo pills. Metformin will be titrated to 1500 mg/day in 4 weeks. Patients' blood pressure (BP), waist circumference, body weight, fasting plasma glucose (FPG), triglyceride (TG), high-density lipoprotein cholesterol (HDL), insulin, and leptin will be measured at 2, 4, 8, 16, and 24 weeks after the start of metformin.

In a 3-year period, we estimate to recruit 150 clozapine-treated patients in the first phase and 75 fulfill the second phase criteria. We estimate 60 patients complete the second phase intervention (staying in second phase at least 4 weeks).

From this study, we would like to know the prevalence of metabolic dysregulation among clozapine-treated schizophrenic patients and to know the effect of metformin on metabolic profile among non-DM clozapine treated patients.

Key words: schizophrenia, clozapine, metabolic dysregulation, metformin

Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE
  • Obesity
  • Metabolic Syndrome
  • Schizophrenia
Intervention  ICMJE
  • Drug: Metformin
    metformin 500 mg/pill; target dose 1500 mg/day for 24 weeks
    Other Name: Diaformin 500 mg/pill
  • Drug: placebo
    identical-appearing pill of placebo
    Other Name: Diaformin 500 mg/pill identical-appearing placebo
Study Arms  ICMJE
  • Active Comparator: metformin
    metformin intervention group
    Intervention: Drug: Metformin
  • Placebo Comparator: placebo
    placebo-controlled
    Intervention: Drug: placebo
Publications * Chen CH, Huang MC, Kao CF, Lin SK, Kuo PH, Chiu CC, Lu ML. Effects of adjunctive metformin on metabolic traits in nondiabetic clozapine-treated patients with schizophrenia and the effect of metformin discontinuation on body weight: a 24-week, randomized, double-blind, placebo-controlled study. J Clin Psychiatry. 2013 May;74(5):e424-30. doi: 10.4088/JCP.12m08186.

*   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 Unknown status
Estimated Enrollment  ICMJE
 (submitted: February 18, 2011)
60
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE July 2011
Estimated Primary Completion Date April 2009   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

phase 1

  • fulfilled DSM-IV criteria of schizophrenia or schizoaffective disorder
  • 18-65 year of age
  • receiving clozapine for at least 6 months.

phase 2 are those in phase 1 and met the following

  • overweight and obese (BMI ≧ 24)
  • one or more metabolic dysregulation, such as abdominal obesity (waist circumference > 90 cm, in men and > 80 cm, in women
  • fasting hypertriglyceridemia, (≥ 150 mg/dL)
  • low fasting HDL levels (< 40 mg/dL in men and < 50 mg/dL in women)
  • high blood pressure (≥ 130/ ≥ 85 mm Hg or current treatment with antihypertensive medication).

The exclusion criteria are the following:

  • current use of hypoglycemic or hypolipidemic agents
  • FPG levels ≥ 126 mg/dL
  • women who are pregnant
  • known allergy or contraindicated to metformin (including Creatine>1.4 ng/dl abnormal liver function test; chronic cardiopulmonary insufficiency).

Exclusion Criteria:

phase 2

  • current use of hypoglycemic or hypolipidemic agents
  • FPG levels ≥ 126 mg/dL
  • women who are pregnant
  • known allergy or contraindicated to metformin (including Creatine>1.4 ng/dl abnormal liver function test
  • 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 Taiwan
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01300637
Other Study ID Numbers  ICMJE 96064
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Chun-Hsin Chen, Taipei Medical University-WanFang Hospital
Study Sponsor  ICMJE Taipei Medical University WanFang Hospital
Collaborators  ICMJE National Science Council, Taiwan
Investigators  ICMJE
Principal Investigator: Chun-Hsin Chen, MD Taipei Medical University-WanFang Hospital, Taipei, Taiwan
PRS Account Taipei Medical University WanFang Hospital
Verification Date February 2011

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