A Phase 2, Double Blind, Randomized, Placebo-controlled Crossover Trial to Evaluate the Efficacy and Safety of Atomoxetine in Adults With Melanocortin Obesity Syndrome
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 20
- 试验地点
- 3
- 主要终点
- Body Mass Index (BMI)
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 6 Years 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
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).
干预措施: Placebo (Drug)
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).
干预措施: Placebo (Drug)
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).
干预措施: Atomoxetine (Drug)
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).
干预措施: Atomoxetine (Drug)
结局指标
主要结局
Body Mass Index (BMI)
时间窗: 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.
次要结局
- Lipid Panel - Fasting LDL, HDL, Triglycerides(At week 0, week 16 and week 32.)
- Resting Energy Expenditure (REE)(16 weeks)
- Healthy Eating Index (HEI)(16 weeks)
- Hyperphagia Questionnaire (HQ)(16 weeks)
- Hunger and Satiety Score(16 weeks)
- Fasting Glucose Level(At week 0, week 16 and week 32.)
- Alanine Transaminase (ALT) Level(At week 0, week 16 and week 32.)
- Fasting Insulin Level(At week 0, week 16 and week 32.)
- Hemoglobin A1c(At week 0, week 16 and week 32.)
- High Sensitivity C-Reactive Protein(At week 0, week 16 and week 32.)
- The ASEBA Brief Problem Monitor(16 weeks)
- Adult ADHD Self-Report Scale (ASRS-v1.1) Symptom Checklist.(16 weeks)
研究者
Joan Han
Professor of Pediatrics
Icahn School of Medicine at Mount Sinai