Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability

Phase 4

Recruiting

• Conditions: Developmental Disability; Obesity; Intellectual Disability
• Interventions: Drug: Placebo; Drug: Metformin; Behavioral: Lifestyle Intervention

• Registration Number: NCT05744479
• Lead Sponsor: Centre for Addiction and Mental Health

Brief Summary

People with IDD (intellectual and developmental disability) have very high rates of obesity and die prematurely from cardiometabolic disease. While antipsychotics contribute to this problem, their use is necessary and appropriate in a significant subgroup of individuals with IDD. Exercise and diet interventions have limitations and may not be sufficient, requiring effective adjunctive pharmacological approaches to target obesity and related comorbidities in IDD. However, persons with IDD treated with antipsychotics are systematically excluded from clinical trials hindering development of evidence to help guide safe and effective treatment of these comorbidities. Moreover, evidence from other disorders cannot be extrapolated to IDD given inherent biological differences between disorders. This trial will address the identified gaps, which extend beyond cardiovascular morbidity and negatively impact psychosocial outcomes, in a hugely underserviced population.This is the the first RCT (randomized control trial) to examine the efficacy of metformin in overweight or obese adults with IDD who have experienced antipsychotic-induced weight gain. By generating efficacy data for a very accessible and scalable intervention, allows for guideline and implementation strategies to address a recalcitrant health problem.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2023-01-13
• Study First Submitted QC: 2023-02-15
• Study First Posted: 2023-02-27
• Study Start: 2023-02-28
• Status Verified: 2024-08
• Last Update Submitted: 2024-08-19
• Last Update Posted: 2024-08-20
• Primary Completion: 2025-12-01
• Study Completion: 2026-12-01

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 100

Inclusion Criteria

• Stable outpatients

• Age 18-65 years

• Diagnosed with IDD

• On maintenance treatment with an antipsychotic (stable dose for ≥3 months).

• BMI must be ≥30 kg/m2, or ≥27 kg/m2 with at least one weight-related comorbidity (treated or untreated) such as: hypertension, dyslipidaemia, obstructive sleep apnea, or impaired fasting glucose.

• Females of child-bearing age must be on one of the following regular contraceptives:

  1. Agree to abstain from sex for the duration of the trial or
  2. A barrier method of a diaphragm with spermicide and/or Latex condom or
  3. An oral contraceptive agent, implantable contraceptive or an injectable contraceptive for at least six months prior to entering the study and will continue its use throughout the study, or
  4. An intrauterine device, or
  5. Partner has had a vasectomy at least 3 months prior to study start

Exclusion Criteria

• Females who are nursing, currently pregnant, or have a positive pregnancy test
• Clinical or laboratory evidence of uncompensated cardiovascular, endocrine, haematological, hepatic, renal, or pulmonary disease
• Previous treatment and lack of efficacy or tolerability with metformin
• History or diagnosis of Type 1 Diabetes (T1D) or Type 2 Diabetes (TD2) or fasting blood work, HbA1c > 6.5%
• History of metabolic acidosis or lactic acidosis
• Treatment with weight-lowering agents
• Medications with significant renal impact
• Major medical or surgical event in the preceding 3 months
• Acute suicidal risk.
• Moderate to severe substance use disorder, other than caffein or nicotine use disorder

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	50 participants will be administered an identical oral placebo for 24 weeks.
Metformin (Oral)	Metformin	50 participants will be administered oral metformin titrated to a maximum dose of 2000mg/day for 24 weeks.
Metformin (Oral)	Lifestyle Intervention	50 participants will be administered oral metformin titrated to a maximum dose of 2000mg/day for 24 weeks.
Placebo	Lifestyle Intervention	50 participants will be administered an identical oral placebo for 24 weeks.

Primary Outcome Measures

Name	Time	Method
Individual's percentage change in body weight	Weeks 0, 4, 8, 12, 16, 10, 24	Percentage change in body weight measured in percentage change of pounds (lbs)

Secondary Outcome Measures

Name	Time	Method
Proportion of participants who achieve body weight reduction ≥5%, and ≥10% in each arm	Week 0 and week 24	Percentage change in body weight measured in percentage change of pounds (lbs), expressed as a percentage
Between group (metformin vs placebo) absolute change in weight	Week 24	Absolute change in body weight between metformin and placebo groups measured in pounds (lbs). Calculated by the mean change in weight between the metformin and placebo groups.
Between group absolute change in waist circumference	Week 24	Absolute change in waist circumstance measured in centimetres (cm) between metformin and placebo groups. Calculated by the mean change in waist circumstance between the metformin and placebo groups.
Between group absolute change in BMI	Week 24	Absolute change in BMI between metformin and placebo groups. Calculated by the mean change in BMI between the metformin and placebo groups.
Change in whole body insulin sensitivity calculated with Matsuda Index	Week 0 and Week 24	With the results of the oral glucose tolerance test at Week 0 and Week 24, insulin sensitivity was calculated with the Matsuda index.; Insulin sensitivity was calculated with Matsuda index: \[10,000 / √glucose minute 0 x insulin minute 0) (mean glucose (OGTT) x mean insulin OGTT)\]. A higher result is better.; In the formula OGTT: oral glucose tolerance test.
Change in visceral and liver fat content	Week 0 and Week 24	Change in visceral and liver fat content assessed via MRI scans at week 0 and week 24.
Medication Adherence	Week 0 to Week 24	Measured through returning of blister pill packs, and assessing number of pills taken.
Change in beta-cell function, measured using the Insulin Secretion-Sensitivity Index-2 (ISSI-2)	Week 0 and Week 24	ISSI-2 is defined as the product of (i) insulin secretion measured by the ratio of the area-under-the-insulin-curve to the area-under-the-glucose curve and (ii) insulin sensitivity measured by the Matsuda index.
Proportion in each group converting to impaired glucose tolerance, prediabetes, or type 2 diabetes	Week 0 and Week 24	Measured through the change in HOMA-IR (Homeostatic Model Assessment for Insulin Resistance) derived from the Oral Glucose Tolerance Test (OGTT).
Change in cardiovascular risk factors assessed by change in C-reactive protein	Week 0 and Week 24	Measured through the change in C-reactive protein (CRP) assessed at week 0 and week 24.; Healthy levels: CRP: Less than 0.3 mg/dL
Change in cardiovascular risk factor assessed by change in fasting lipids profile	Week 0 and Week 24	Change in fasting lipid profile (low-density lipoprotein cholesterol (LDL), high-density lipoprotein cholesterol (HDL), and triglycerides) assessed at week 0 and week 24.; Healthy levels: LDL: less than 100mg/dL HDL: 40mg/dL or higher Triglycerides: less than 150mg/dL
Change in cardiovascular risk factor assessed by change in blood pressure	Week 0 and Week 24	Measured through the change in blood pressure (systolic/diastolic) assessed at week 0 and week 24. A blood pressure range of 110/70 to 120/80 is considered normal.

Trial Locations

Locations (1)

Centre for Addiction and Mental Health; 🇨🇦 Toronto, Ontario, Canada