Clinical trial NCT06899178: Atomoxetine in Melanocortin Obesity Syndrome
Official title: A Phase 2, Double Blind, Randomized, Placebo-controlled Crossover Trial to Evaluate the Efficacy and Safety of Atomoxetine in Adults With Melanocortin Obesity Syndrome
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE2
Conditions: Melanocortin Obesity Syndrome
MCOS
Keywords: Obesity
BDNF
MC4R
Atomoxetine
Energy balance
Weight loss
Lead sponsor: Icahn School of Medicine at Mount Sinai
Sponsor class: OTHER
Collaborators: name: Vanderbilt University Medical Center
First posted: 2025-03-27
Enrollment: 20
Sex: ALL
Minimum age (years): 6
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: A randomized, placebo-controlled, crossover study of atomoxetine. The treatment periods will last 16 weeks, separated by a 2-week washout period. Atomoxetine immediate release is approved for treatment of ADHD in children and adults. Enrollment will be based on age groups in batches, beginning with 10 adults, to optimize the protocol and monitor safety/efficacy before treating younger patients. If safety and efficacy are acceptable, the pediatric cohort will be enrolled. The intervention length of 16 weeks per arm was chosen to allow for 4 weeks of dose titration and 12 weeks exposure to target dose. The FDA effectiveness threshold for anti-obesity medication is 5% weight loss after 12 weeks. The half-life of atomoxetine is approximately 5 hours. A two-week washout period will allow for elimination of study drug while minimizing participant burden from frequent study visits.
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Body Mass Index (BMI)
timeFrame: 16 weeks
Secondary outcomes:
measure: Resting Energy Expenditure (REE)
timeFrame: 16 weeks
measure: Healthy Eating Index (HEI)
timeFrame: 16 weeks
measure: Hyperphagia Questionnaire (HQ)
timeFrame: 16 weeks
measure: Hunger and Satiety Score
timeFrame: 16 weeks
measure: Fasting Glucose Level
timeFrame: At week 0, week 16 and week 32.
measure: Alanine Transaminase (ALT) Level
timeFrame: At week 0, week 16 and week 32.
measure: Fasting Insulin Level
timeFrame: At week 0, week 16 and week 32.
measure: Hemoglobin A1c
timeFrame: At week 0, week 16 and week 32.
measure: Lipid Panel - Fasting LDL, HDL, Triglycerides
timeFrame: At week 0, week 16 and week 32.
measure: High Sensitivity C-Reactive Protein
timeFrame: At week 0, week 16 and week 32.
measure: The ASEBA Brief Problem Monitor
timeFrame: 16 weeks
measure: Adult ADHD Self-Report Scale (ASRS-v1.1) Symptom Checklist.
timeFrame: 16 weeks
Other outcomes:
Locations:
city: New York
country: United States
facility: Mount Sinai Hospital
state: New York
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
Study officials:
affiliation: Mount Sinai Kravis Children's Hospital
name: Joan C Han, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Vanderbilt University Medical Center
name: Ashley H Shoemaker, MD, MSCI
role: PRINCIPAL_INVESTIGATOR
References: