Atomoxetine in Melanocortin Obesity Syndrome (MCOS)

A Phase 2, Double Blind, Randomized, Placebo-controlled Crossover Trial to Evaluate the Efficacy and Safety of Atomoxetine in Adults with Melanocortin Obesity Syndrome

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Melanocortin Obesity Syndrome; MCOS
• Intervention / Treatment: Drug: Placebo; Drug: Atomoxetine

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 Type: Interventional
• Enrollment (Estimated): 20
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Joan C Han, MD; Phone Number: 301-312-7 212-241-3744; Email: joan.han@mountsinai.org

Study Locations

• United States
  • New York
    • New York, New York, United States, 10029
      • Mount Sinai Hospital
      • Contact: Joan Han, MD; Phone Number: 212-241-3744; Email: joan.han@mountsinai.org
      • Contact: Joan Han
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Center
      • Contact: Jenny Leshko, RN; Phone Number: 615-343-8116; Email: jenny.leshko@vumc.org
      • Contact: Ashley Shoemaker, MD, MSCI; Phone Number: 615-343-8116; Email: ashley.h.shoemaker@vumc.org
      • Contact: Ashley Shoemaker

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion criteria:

• Age 6 years and above
• Documented MC4R variant classified as pathogenic, likely pathogenic, or variant of uncertain significance per ACMG criteria. If testing was done in a research lab, it will be confirmed by a CLIA-approved lab prior to randomization.
• Obesity defined as BMI ≥30 kg/m2 in adults or ≥95th percentile for age and sex in children

Exclusion criteria:

• Use of atomoxetine, viloxazine (another selective norepinephrine-reuptake inhibitor), methylphenidate, amphetamine, dextroamphetamine, lisdexamfetamine, phentermine, or any other stimulant medication in the past 30 days. If on other ADHD medications, such as guanfacine and clonidine, must be on a stable dose for >3 months.
• Weight loss >5% in the past 3 months.
• Initiation of new weight loss program, including diet or medications. If on weight loss medications, must be on a stable dose for >3 months.
• Inability to swallow capsules.
• History of hypersensitivity to atomoxetine.
• Narrow angle glaucoma.
• History of pheochromocytoma.
• Uncontrolled Stage 2 hypertension (≥95th percentile + 12 mmHg or >140/90, whichever is lower) at screening. If on antihypertensive medication, must be on stable dose for >3 months.
• Hepatic insufficiency including cirrhosis and acute hepatitis (AST or ALT >3x upper limit of normal)
• Uncontrolled asthma requiring albuterol more than once weekly over the past 3 months
• History of a cardiac arrhythmia (not including bradycardia)
• Current use of monoamine oxidase inhibitors
• Pregnancy or intention to become pregnant during the next year
• History of Major Depressive Disorder in the past 2 years, lifetime history of suicide attempt, history of any suicidal behavior in the past month, history of other severe psychiatric disorders (e.g. schizophrenia, bipolar disorder)
• PHQ-9 score is ≥15 or suicidal ideation of type 4 or 5 (C-SSR) in the past month
• Unable to comply with study procedures in the opinion of the investigator

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo then 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).	Drug: Placebo; Matching placebo oral capsule; Drug: Atomoxetine; Initial dose 40 mg, day 7 dose 60 mg, day 14 dose 80 mg, day 21 dose 100 mg (target dose)
Active Comparator: Atomoxetine then 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).	Drug: Placebo; Matching placebo oral capsule; Drug: Atomoxetine; Initial dose 40 mg, day 7 dose 60 mg, day 14 dose 80 mg, day 21 dose 100 mg (target dose)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Body Mass Index (BMI)	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.	16 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Resting Energy Expenditure (REE)	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.	16 weeks
Healthy Eating Index (HEI)	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.	16 weeks
Hyperphagia Questionnaire (HQ)	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.	16 weeks
Hunger and Satiety Score	Full range scored from 0 to 10 with higher score indicating greater hunger/satiety.	16 weeks
Fasting Glucose Level	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.	At week 0, week 16 and week 32.
Alanine Transaminase (ALT) Level	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.	At week 0, week 16 and week 32.
Fasting Insulin Level	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.	At week 0, week 16 and week 32.
Hemoglobin A1c	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.	At week 0, week 16 and week 32.
Lipid Panel - Fasting LDL, HDL, Triglycerides	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.	At week 0, week 16 and week 32.
High Sensitivity C-Reactive Protein	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.	At week 0, week 16 and week 32.
The ASEBA Brief Problem Monitor	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	16 weeks
Adult ADHD Self-Report Scale (ASRS-v1.1) Symptom Checklist.	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.	16 weeks

Collaborators and Investigators

• Sponsor: Icahn School of Medicine at Mount Sinai
• Collaborators: Vanderbilt University Medical Center
• Investigators: Principal Investigator: Joan C Han, MD, Mount Sinai Kravis Children's Hospital; Principal Investigator: Ashley H Shoemaker, MD, MSCI, Vanderbilt University Medical Center

Study record dates

Study Major Dates

• Study Start (Estimated): April 1, 2025
• Primary Completion (Estimated): July 1, 2028
• Study Completion (Estimated): July 1, 2028

Study Registration Dates

• First Submitted: March 21, 2025
• First Submitted That Met QC Criteria: March 21, 2025
• First Posted (Actual): March 27, 2025

Study Record Updates

• Last Update Posted (Actual): March 27, 2025
• Last Update Submitted That Met QC Criteria: March 21, 2025
• Last Verified: March 1, 2025

More Information

Terms related to this study

• Keywords: Obesity; Weight loss; BDNF; Energy balance; MC4R; Atomoxetine
• Additional Relevant MeSH Terms: Pathologic Processes; Nutrition Disorders; Overnutrition; Body Weight; Disease; Overweight; Obesity; Syndrome; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Neurotransmitter Agents; Membrane Transport Modulators; Adrenergic Agents; Neurotransmitter Uptake Inhibitors; Adrenergic Uptake Inhibitors; Atomoxetine Hydrochloride
• Other Study ID Numbers: GCO 24-0669

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Individual participant data that underlie the results reported in this article, after deidentification (text, tables, figures, and appendices).
• IPD Sharing Time Frame: Beginning 9 months and ending 36 months following article publication.
• IPD Sharing Access Criteria: Researchers who provide a methodologically sound proposal. To achieve aims in the approved proposal. Proposals may be submitted up to 36 months following article publication. After 36 months the data will be available in our University's data warehouse but without investigator support other than deposited metadata. Information regarding submitting proposals and accessing data may be found at (Link to be included in the URL field below).
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No