Atomoxetine in Melanocortin Obesity Syndrome

Phase 2

Not yet recruiting

• Conditions: Melanocortin Obesity Syndrome; MCOS
• Interventions: Drug: Atomoxetine; Drug: Placebo

• Registration Number: NCT06899178
• Lead Sponsor: Icahn School of Medicine at Mount Sinai

Brief Summary

This is a phase 2 randomized placebo-controlled crossover trial to determine the safety and efficacy of atomoxetine for treating obesity caused by loss-of-function variants in the melanocortin-4 receptor (MC4R), the most common cause of genetic obesity disorders. Atomoxetine was selected for this pilot trial because it has been shown to increase brain-derived neurotrophic factor (BDNF) within the central nervous system and in peripheral circulation. Targeting BDNF is a specific strategy for treating MC4R abnormalities because BDNF functions as a downstream mediator of MC4R signaling.

Detailed Description

Targeted therapies for the treatment of monogenetic obesity are essential because typical lifestyle interventions and standard anti-obesity medications are largely ineffective as they do not correct the specific genetic defect causing abnormal energy balance. The leptin pathway is the key regulator of body weight through control of appetite and energy expenditure. In particular, the severe insatiable hunger experienced by patients with leptin pathway disorders leads not only to extreme obesity, but the unrelenting drive to seek food also causes substantial distress for patients and caregivers. While therapies have been developed for treating genetic disorders affecting the proximal portion of the leptin pathway (LEP, LEPR, POMC, PCSK1, and BBS1-22), there are no treatments for loss-of-function LOF) variants of the melanocortin-4 receptor gene (MC4R), which cause melanocortin obesity syndrome (MCOS). In various population and cohort studies, 1-6% of patients with severe, early onset obesity are found to have MC4R LOF variants, making MCOS the most common cause of genetic obesity. Brain-derived neurotrophic factor (BDNF) is a downstream mediator of MC4R signaling and, therefore, may serve as a specific target for MCOS treatment. The researchers propose repurposing a well-understood and commercially available attention-deficit hyperactive disorder (ADHD) medication, atomoxetine (FDA-approved for the treatment of ADHD in persons ages 6 years and older), for the treatment of MCOS because of animal and human studies show that this drug induces endogenous BDNF levels. Atomoxetine could potentially increase hypothalamic BDNF levels, leading to weight loss through improved anorectic signaling downstream of the abnormally functioning MC4R. A phase 2 randomized, placebo-controlled crossover trial in 20 patients with MCOS will be conducted to test this hypothesis. The study will begin in adult patients and if safety and efficacy are shown, then pediatric patients age ≥ 6 years will be studied. The primary outcome measure will be change in BMI (expressed as the percentage of the 95th percentile BMI for age/sex). Additional measures will include percent body fat and visceral fat area by bioelectrical impedance analysis, resting energy expenditure by indirect calorimetry, dietary intake by food frequency questionnaire and 24-hour recall, hyperphagia score, hunger level, satiety level, hemoglobin A1c, lipid panel, liver function tests, blood pressure, heart rate, and ADHD symptoms. Serum and plasma BDNF and genetic variants in atomoxetine metabolism enzymes will be assessed and correlated with weight changes. This pilot clinical trial will provide valuable data on the safety and efficacy of atomoxetine for treating MCOS, and the data will be used to guide the design of a future phase 3, multicenter, randomized clinical trial.

Study Timeline

• Status Verified: 2025-03
• Study First Submitted: 2025-03-21
• Study First Submitted QC: 2025-03-21
• Last Update Submitted: 2025-03-21
• Study First Posted: 2025-03-27
• Last Update Posted: 2025-03-27
• Study Start: 2025-04
• Primary Completion: 2028-07
• Study Completion: 2028-07

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 20

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Placebo then Atomoxetine	Atomoxetine	Participants receive placebo for 16 weeks (4 weeks titration + 12 weeks at target dose), followed by washout period, then atomoxetine for 16 weeks (4 weeks titration + 12 weeks at target dose).
Placebo then Atomoxetine	Placebo	Participants receive placebo for 16 weeks (4 weeks titration + 12 weeks at target dose), followed by washout period, then atomoxetine for 16 weeks (4 weeks titration + 12 weeks at target dose).
Atomoxetine then Placebo	Atomoxetine	Participants receive atomoxetine for 16 weeks (4 weeks titration + 12 weeks at target dose), followed by washout period, then placebo for 16 weeks (4 weeks titration + 12 weeks at target dose).
Atomoxetine then Placebo	Placebo	Participants receive atomoxetine for 16 weeks (4 weeks titration + 12 weeks at target dose), followed by washout period, then placebo for 16 weeks (4 weeks titration + 12 weeks at target dose).

Primary Outcome Measures

Name	Time	Method
Body Mass Index (BMI)	16 weeks	BMI will be calculated as kg/sq m. The sex appropriate CDC growth chart will be used to calculate BMI as a percent of the 95th percentile (BMI95). For patients \>20 years, the 20-year-old percentiles will be used.

Secondary Outcome Measures

Name	Time	Method
Lipid Panel - Fasting LDL, HDL, Triglycerides	At week 0, week 16 and week 32.	A lipid profile is a blood test to measure different types of lipids: High-density lipoprotein cholesterol (HDL \[good\] cholesterol): HDL helps remove LDL from your blood.; Low-density lipoprotein cholesterol (LDL \[bad\] cholesterol): LDL can build up in your blood vessels and increase your heart disease risk.; Triglycerides: Your body makes some triglycerides. Triglycerides also come from the food you eat. Extra calories are turned into triglycerides and stored in fat cells for later use.; Fasting laboratory studies will be obtained at week 0, week 16 and week 32.
Resting Energy Expenditure (REE)	16 weeks	Resting energy expenditure (REE) will be measured by indirect calorimetry after a minimum 1 hour of rest in the Clinical Research Center. Oxygen consumption and carbon dioxide production will be measured. The first 5-10 minutes of data will be discarded to allow participants to adjust to the metabolic cart.
Healthy Eating Index (HEI)	16 weeks	The VioScreen assessment provides a Healthy Eating Index (HEI) score to measure the quality of a person's diet. The HEI score ranges from 0 to 100, with higher scores indicating better eating habits.
Hyperphagia Questionnaire (HQ)	16 weeks	Hyperphagia will be assessed with the Hyperphagia Questionnaire (HQ); This is a 13-item questionnaire with each question answered on a 5-point scale. Two of the questions are qualitative.; Full range is scored from 11 to 55. Higher score indicates greater hyperphagia.
Hunger and Satiety Score	16 weeks	Full range scored from 0 to 10 with higher score indicating greater hunger/satiety.
Fasting Glucose Level	At week 0, week 16 and week 32.	A blood sugar test measures the amount of a sugar called glucose in a sample of blood.; Fasting laboratory studies will be obtained at week 0, week 16 and week 32.
Alanine Transaminase (ALT) Level	At week 0, week 16 and week 32.	The alanine transaminase (ALT) blood test measures the level of the enzyme ALT in the blood. ALT is an enzyme found in a high level in the liver. An enzyme is a protein that causes a specific chemical change in the body.; Fasting laboratory studies will be obtained at week 0, week 16 and week 32.
Fasting Insulin Level	At week 0, week 16 and week 32.	The insulin level in blood. Insulin is a hormone produced by beta cells in the pancreas.; Fasting laboratory studies will be obtained at week 0, week 16 and week 32.
Hemoglobin A1c	At week 0, week 16 and week 32.	A1C is a lab test that shows the average level of blood sugar (glucose) over the previous 3 months. It shows how well blood sugar is controlled to help prevent complications from diabetes.; Fasting laboratory studies will be obtained at week 0, week 16 and week 32.
High Sensitivity C-Reactive Protein	At week 0, week 16 and week 32.	C-reactive protein (CRP) is produced by the liver. The level of CRP rises when there is inflammation in the body. It is one of a group of proteins, called acute phase reactants that go up in response to inflammation. The levels of acute phase reactants increase in response to certain inflammatory proteins called cytokines. These proteins are produced by white blood cells during inflammation.; The CRP test is a general test to check for inflammation in the body. It is not a specific test. A high-sensitivity C-reactive protein (hs-CRP) is a more A more sensitive CRP test; Fasting laboratory studies will be obtained at week 0, week 16 and week 32.
The ASEBA Brief Problem Monitor	16 weeks	The ASEBA Brief Problem Monitor (BPM) is a quick assessment tool designed to monitor and track a child's behavioral and emotional problems over time, particularly focusing on internalizing, externalizing, and attention issues.; Range is 0 to 99.9th percentile
Adult ADHD Self-Report Scale (ASRS-v1.1) Symptom Checklist.	16 weeks	This is an 18-item self-report questionnaire designed for individuals to assess their own symptoms of Attention Deficit Hyperactivity Disorder (ADHD) focusing on daily experiences related to attention, impulsivity, and hyperactivity. Total scale is scored 0-72 with higher score indicating more predictive of an ADHD diagnosis.

Trial Locations

Locations (2)

Mount Sinai Hospital; 🇺🇸 New York, New York, United States

Vanderbilt University Medical Center; 🇺🇸 Nashville, Tennessee, United States