Atomoxetine in Melanocortin Obesity Syndrome

NCT ID: NCT06899178

Last Updated: 2025-03-27

Basic Information

• Recruitment Status: NOT_YET_RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 20 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2025-04-30
• Study Completion Date: 2028-07-31

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.

Conditions

Melanocortin Obesity Syndrome; MCOS

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

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).

Group Type: PLACEBO_COMPARATOR

Atomoxetine

Intervention Type: DRUG

Initial dose 40 mg, day 7 dose 60 mg, day 14 dose 80 mg, day 21 dose 100 mg (target dose)

Placebo

Intervention Type: DRUG

Matching placebo oral capsule

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).

Group Type: ACTIVE_COMPARATOR

Atomoxetine

Intervention Type: DRUG

Initial dose 40 mg, day 7 dose 60 mg, day 14 dose 80 mg, day 21 dose 100 mg (target dose)

Placebo

Intervention Type: DRUG

Matching placebo oral capsule

Interventions

Atomoxetine

Initial dose 40 mg, day 7 dose 60 mg, day 14 dose 80 mg, day 21 dose 100 mg (target dose)

Intervention Type: DRUG

Placebo

Matching placebo oral capsule

Intervention Type: DRUG

Eligibility Criteria

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

• Minimum Eligible Age: 6 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Vanderbilt University Medical Center

OTHER

Sponsor Role: collaborator

Icahn School of Medicine at Mount Sinai

OTHER

Sponsor Role: lead

Responsible Party

Joan Han

Professor of Pediatrics

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Joan C Han, MD

Role: PRINCIPAL_INVESTIGATOR

Mount Sinai Kravis Children's Hospital

Ashley H Shoemaker, MD, MSCI

Role: PRINCIPAL_INVESTIGATOR

Vanderbilt University Medical Center

Locations

Mount Sinai Hospital

New York, New York, United States

Vanderbilt University Medical Center

Nashville, Tennessee, United States

Countries

United States

Central Contacts

Joan C Han, MD

Role: CONTACT

joan.han@mountsinai.org

212-241-3744 ext. 301-312-7

Facility Contacts

Joan Han, MD

Role: primary

joan.han@mountsinai.org

212-241-3744

Jenny Leshko, RN

Role: primary

jenny.leshko@vumc.org

615-343-8116

Ashley Shoemaker, MD, MSCI

Role: backup

ashley.h.shoemaker@vumc.org

615-343-8116

Other Identifiers

GCO 24-0669

Identifier Type: -

Identifier Source: org_study_id