## Protocol Section
### Identification Module
**NCT ID:** NCT05744479

**Acronym:** METIDD

**Brief Title:** Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability

**Official Title:** Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability: A Double-Blind Randomized Control Trial

#### Organization Study ID Info
**ID:** 024/2022
#### Organization
**Class:** OTHER
**Full Name:** Centre for Addiction and Mental Health
### Status Module
#### Completion Date
**Date:** 2026-12-01

**Type:** ESTIMATED

#### Expanded Access Info
#### Last Update Post Date
**Date:** 2024-01-16

**Type:** ACTUAL

**Last Update Submit Date:** 2024-01-11

**Overall Status:** RECRUITING

#### Primary Completion Date
**Date:** 2025-12-01

**Type:** ESTIMATED

#### Start Date
**Date:** 2023-02-28

**Type:** ACTUAL

**Status Verified Date:** 2023-02

#### Study First Post Date
**Date:** 2023-02-27
**Type:** ACTUAL
**Study First Submit Date:** 2023-01-13
**Study First Submit QC Date:** 2023-02-15
### Sponsor Collaborators Module

#### Lead Sponsor

**Class:** OTHER

**Name:** Centre for Addiction and Mental Health

#### Responsible Party

**Type:** SPONSOR

### Oversight Module

**Is FDA Regulated Device:** False

**Is FDA Regulated Drug:** False

**Oversight Has DMC:** False

### Description Module

**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.

### Conditions Module

**Conditions:**

- Intellectual Disability

- Developmental Disability

- Obesity

**Keywords:**

- Intellectual Disability

- Developmental Disability

- Obesity

- Metformin

### Design Module

#### Design Info

**Allocation:** RANDOMIZED

**Intervention Model:** PARALLEL

**Intervention Model Description:** Metformin vs Placebo

##### Masking Info

**Masking:** QUADRUPLE

**Masking Description:** Double Blinded RCT

**Who Masked:**

- PARTICIPANT

- CARE_PROVIDER

- INVESTIGATOR

- OUTCOMES_ASSESSOR

**Primary Purpose:** TREATMENT

#### Enrollment Info

**Count:** 100

**Type:** ESTIMATED

**Phases:**

- PHASE4

**Study Type:** INTERVENTIONAL

### Arms Interventions Module

#### Arm Group 1

**Description:** 50 participants will be administered oral metformin titrated to a maximum dose of 2000mg/day for 24 weeks.

**Intervention Names:**

- Drug: Metformin

- Behavioral: Lifestyle Intervention

**Label:** Metformin (Oral)

**Type:** EXPERIMENTAL

#### Arm Group 2

**Description:** 50 participants will be administered an identical oral placebo for 24 weeks.

**Intervention Names:**

- Drug: Placebo

- Behavioral: Lifestyle Intervention

**Label:** Placebo

**Type:** PLACEBO_COMPARATOR

### Interventions

#### Intervention 1

**Arm Group Labels:**

- Metformin (Oral)

**Description:** Metformin oral, 2000mg/day, for 24 weeks.

**Name:** Metformin

**Type:** DRUG

#### Intervention 2

**Arm Group Labels:**

- Placebo

**Description:** Oral placebo for 24 weeks

**Name:** Placebo

**Type:** DRUG

#### Intervention 3

**Arm Group Labels:**

- Metformin (Oral)

- Placebo

**Description:** Participants from both groups will meet a dietician and a diabetes educator at the study start to obtain advice regarding healthy diet, portion size, and meal planning to improve physical health. All participants will be invited to monthly group meetings to learn skills which will help them in a variety of wellness areas such as physical exercises and diet. Attendance in these sessions will be encouraged but not mandatory, and attendance will be recorded. Fidelity with these interventions will be captured using diet and physical activity questionnaires at RCT start, midpoint and end, and end of open label phase.

**Name:** Lifestyle Intervention

**Type:** BEHAVIORAL

### Outcomes Module

#### Primary Outcomes

**Description:** Percentage change in body weight measured in percentage change of pounds (lbs)

**Measure:** Individual's percentage change in body weight

**Time Frame:** Weeks 0, 4, 8, 12, 16, 10, 24

#### Secondary Outcomes

**Description:** Percentage change in body weight measured in percentage change of pounds (lbs), expressed as a percentage

**Measure:** Proportion of participants who achieve body weight reduction ≥5%, and ≥10% in each arm

**Time Frame:** Week 0 and week 24

**Description:** 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.

**Measure:** Between group (metformin vs placebo) absolute change in weight

**Time Frame:** Week 24

**Description:** 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.

**Measure:** Between group absolute change in waist circumference

**Time Frame:** Week 24

**Description:** Absolute change in BMI between metformin and placebo groups. Calculated by the mean change in BMI between the metformin and placebo groups.

**Measure:** Between group absolute change in BMI

**Time Frame:** Week 24

**Description:** 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.

**Measure:** Change in whole body insulin sensitivity calculated with Matsuda Index

**Time Frame:** Week 0 and Week 24

**Description:** 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.

**Measure:** Change in beta-cell function, measured using the Insulin Secretion-Sensitivity Index-2 (ISSI-2)

**Time Frame:** Week 0 and Week 24

**Description:** Measured through the change in HOMA-IR (Homeostatic Model Assessment for Insulin Resistance) derived from the Oral Glucose Tolerance Test (OGTT).

**Measure:** Proportion in each group converting to impaired glucose tolerance, prediabetes, or type 2 diabetes

**Time Frame:** Week 0 and Week 24

**Description:** 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

**Measure:** Change in cardiovascular risk factors assessed by change in C-reactive protein

**Time Frame:** Week 0 and Week 24

**Description:** 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

**Measure:** Change in cardiovascular risk factor assessed by change in fasting lipids profile

**Time Frame:** Week 0 and Week 24

**Description:** 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.

**Measure:** Change in cardiovascular risk factor assessed by change in blood pressure

**Time Frame:** Week 0 and Week 24

**Description:** Change in visceral and liver fat content assessed via MRI scans at week 0 and week 24.

**Measure:** Change in visceral and liver fat content

**Time Frame:** Week 0 and Week 24

**Description:** Measured through returning of blister pill packs, and assessing number of pills taken.

**Measure:** Medication Adherence

**Time Frame:** Week 0 to Week 24

### Eligibility Module

**Eligibility Criteria:** 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

**Maximum Age:** 65 Years

**Minimum Age:** 18 Years

**Sex:** ALL

**Standard Ages:**

- ADULT

- OLDER_ADULT

### Contacts Locations Module

#### Central Contacts

**Contact 1:**

**Email:** mahavir.agarwal@camh.ca

**Name:** Mahavir Agarwal, MD, PhD

**Phone:** 4165358501

**Phone Ext:** 30546

**Role:** CONTACT

**Contact 2:**

**Email:** maria.papoulias@camh.ca

**Name:** Maria Papoulias

**Phone:** 4165358501

**Phone Ext:** 39365

**Role:** CONTACT

#### Locations

**Location 1:**

**City:** Toronto

**Contacts:**

***Contact 1:***

- **Email:** maria.papoulias@camh.ca

- **Name:** Maria Papoulias, MSc

- **Phone:** 416-535-8501

- **Role:** CONTACT

***Contact 2:***

- **Name:** Mahavir Agarwal, PhD, MBBS, MD

- **Role:** PRINCIPAL_INVESTIGATOR

**Country:** Canada

**Facility:** Centre for Addiction and Mental Health

**State:** Ontario

**Status:** RECRUITING

**Zip:** M6J1H3

## Derived Section

### Condition Browse Module - Ancestors

- ID: D000001835

- Term: Body Weight

- ID: D000009461

- Term: Neurologic Manifestations

- ID: D000009422

- Term: Nervous System Diseases

- ID: D000001836

- Term: Body Weight Changes

- ID: D000019954

- Term: Neurobehavioral Manifestations

- ID: D000065886

- Term: Neurodevelopmental Disorders

- ID: D000001523

- Term: Mental Disorders

### Condition Browse Module - Browse Branches

- Abbrev: BC23

- Name: Symptoms and General Pathology

- Abbrev: All

- Name: All Conditions

- Abbrev: BC18

- Name: Nutritional and Metabolic Diseases

- Abbrev: BXM

- Name: Behaviors and Mental Disorders

- Abbrev: BC10

- Name: Nervous System Diseases

### Condition Browse Module - Browse Leaves

- ID: M5114

- Name: Body Weight

- Relevance: LOW

- As Found: Unknown

- ID: M12701

- Name: Obesity

- Relevance: LOW

- As Found: Unknown

- ID: M5902

- Name: Developmental Disabilities

- Relevance: HIGH

- As Found: Developmental Disabilities

- ID: M11589

- Name: Intellectual Disability

- Relevance: HIGH

- As Found: Intellectual Disability

- ID: M18101

- Name: Weight Gain

- Relevance: HIGH

- As Found: Weight Gain

- ID: M12404

- Name: Neurologic Manifestations

- Relevance: LOW

- As Found: Unknown

- ID: M5115

- Name: Body Weight Changes

- Relevance: LOW

- As Found: Unknown

- ID: M21826

- Name: Neurobehavioral Manifestations

- Relevance: LOW

- As Found: Unknown

- ID: M30644

- Name: Neurodevelopmental Disorders

- Relevance: LOW

- As Found: Unknown

- ID: M4815

- Name: Mental Disorders

- Relevance: LOW

- As Found: Unknown

- ID: M14473

- Name: Psychotic Disorders

- Relevance: LOW

- As Found: Unknown

### Condition Browse Module - Meshes

- ID: D000008607

- Term: Intellectual Disability

- ID: D000015430

- Term: Weight Gain

- ID: D000002658

- Term: Developmental Disabilities

### Intervention Browse Module - Ancestors

- ID: D000007004

- Term: Hypoglycemic Agents

- ID: D000045505

- Term: Physiological Effects of Drugs

### Intervention Browse Module - Browse Branches

- Abbrev: Hypo

- Name: Hypoglycemic Agents

- Abbrev: All

- Name: All Drugs and Chemicals

- Abbrev: CNSDep

- Name: Central Nervous System Depressants

- Abbrev: PsychDr

- Name: Psychotropic Drugs

### Intervention Browse Module - Browse Leaves

- ID: M11667

- Name: Metformin

- Relevance: HIGH

- As Found: Assessment

- ID: M16904

- Name: Antipsychotic Agents

- Relevance: LOW

- As Found: Unknown

- ID: M10054

- Name: Hypoglycemic Agents

- Relevance: LOW

- As Found: Unknown

### Intervention Browse Module - Meshes

- ID: D000008687

- Term: Metformin

### Misc Info Module

- Version Holder: 2024-05-24
