Effect of Levothyroxine as Adjuvant Therapy to a Hypocaloric Diet in the Treatment of Obesity: a Randomized Placebo-controlled Trial.
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 发起方
- 入组人数
- 286
- 试验地点
- 5
- 主要终点
- Change in body weight (kg) from baseline to Month 3
研究概览
简要总结
Obesity is a chronic disease with high relapse rates after initial weight loss. Thyroid hormones modulate energy expenditure, body composition, and thermogenesis; higher TSH within the reference range and subclinical hypothyroidism have been associated with adverse metabolic profiles and weight gain. These signals suggest the thyroid axis could influence weight-loss response and subsequent regain. Levothyroxine (LT4) is widely used for hypothyroidism; evaluating its adjuvant role in obesity management is clinically relevant.
This is a phase III, randomized, double-blind, placebo-controlled, multicentre clinical trial conducted in five Spanish hospitals. A total of 286 adults (25-60 years) with grade I-II obesity will be enrolled if they have subclinical hypothyroidism (TSH 5-10 mIU/L with normal peripheral hormones) or are euthyroid with TSH in the highest tertile of the reference range. Participants are randomized 1:1, stratified by age, sex, and BMI.
Intervention: LT4 88 µg once daily or matching placebo for 9 months. During months 0-3, all participants receive a structured hypocaloric Mediterranean diet (≈600 kcal/day deficit; macronutrients 45% carbohydrates, 35% fats, 20% proteins) plus standardized physical-activity advice. From months 3-9, lifestyle support continues with a normocaloric Mediterranean diet. Physical-activity guidance targets ≥150 min/week of moderate-to-vigorous activity (spread over ≥3 days) and 2-3 resistance sessions/week.
Primary endpoint (3 months): change in body weight (kg and %) and body composition (BMI, waist/hip circumferences, fat mass, fat-free mass, total body water by bioimpedance) comparing LT4 versus placebo under the same lifestyle program. The study is powered for n=286.
Key secondary endpoints (up to 9 months): prevention of weight regain; changes in obesity stage; cardiometabolic markers (lipids, glucose/HbA1c, HOMA-IR, adipokines, inflammation, blood-pressure patterns); resting energy expenditure by indirect calorimetry; objectively measured physical activity by accelerometry; cardiac parameters (ECG) and safety; quality of life (EuroQol-5D). Mechanistic substudies assess adipose-tissue metabolic activity (gene/protein expression, browning markers, mitochondrial DNA) and explore gut microbiota, epigenetic signatures, nitrogen balance, and sex-specific differences in response.
Assessments are performed at baseline and follow-up visits through 9 months and include anthropometry, bioimpedance, laboratory panels, indirect calorimetry, ambulatory blood-pressure monitoring, ECG, diet/physical-activity questionnaires, and biobanking of blood, urine, and stool; an adipose-tissue biopsy is obtained in a subsample.
The trial uses intention-to-treat analyses with mixed linear models and is designed with 90% power to detect a clinically meaningful between-group difference in 3-month weight loss; total sample size is 286 (143 per arm). Overall study duration is 21 months (12 months of recruitment plus 9 months of treatment/follow-up); each participant remains in the study for 9 months.
In summary, this trial tests whether adding LT4 88 µg/day to a structured Mediterranean-diet and exercise program enhances early weight loss and helps prevent regain versus placebo in adults with obesity and high-normal TSH or subclinical hypothyroidism, while characterizing metabolic mechanisms and biomarkers of response.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 25 Years 至 60 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Adults 25-60 years of age.
- •Obesity grade I-II: BMI 30.0-39.9 kg/m².
- •Either subclinical hypothyroidism (TSH 5-10 mIU/L with normal peripheral hormones) or euthyroid with TSH in the highest tertile of the population reference range (no known thyroid disease).
- •Able and willing to provide written informed consent.
- •Women of childbearing potential: not pregnant or breastfeeding and using a highly effective contraception method (failure rate <1%) per CTCG guidance (e.g., hormonal methods, IUD/IUS, sterilization, or dual barrier with spermicide).
排除标准
- •Diabetes mellitus (HbA1c ≥6.5%, fasting glucose ≥126 mg/dL, or 2-h OGTT ≥200 mg/dL).
- •Any prior thyroid disease (hyperthyroidism, overt hypothyroidism) or prior LT4 treatment.
- •Current or recent (≤3 months) use of levothyroxine, hypoglycaemic agents, antibiotics, or regular probiotics/prebiotics.
- •Active cancer or cancer within the last 5 years (except basal-cell carcinoma).
- •Chronic liver disease with total bilirubin ≥2.0 mg/dL or AST >3× ULN.
- •Established cardiovascular disease (e.g., stroke, ischemic heart disease, peripheral artery disease).
- •Atrial fibrillation or any arrhythmia history.
- •Uncontrolled hypertension (>160/100 mmHg) despite therapy (assessed by ABPM at screening).
- •Any heart failure; resting HR >85 bpm; eGFR <60 mL/min.
- •Known HIV, HBV, or HCV infection.
- •Acute inflammatory disease or inflammatory bowel disease.
- •Serious underlying disease that, in the investigator's judgment, could affect participation.
- •Drug/alcohol abuse, life expectancy <12 months, inability to follow the recommended diet or attend visits.
- •Positive pregnancy test, pregnant, expecting pregnancy, or breastfeeding.
- •Hypersensitivity to any component of the investigational product.
- •Inability or unwillingness to provide informed consent.
研究组 & 干预措施
Levothyroxine 88mcg
干预措施: Levothyroxine (Drug)
Placebo
干预措施: Placebo (Drug)
结局指标
主要结局
Change in body weight (kg) from baseline to Month 3
时间窗: Baseline to Month 3 (12 weeks ±2)
Change in fat mass (kg) by bioimpedance from baseline to Month 3
时间窗: Baseline to Month 3 (12 weeks ±2)
次要结局
- Weight-regain (kg) from Month 3 to Month 9(Month 3 to Month 9 (36 weeks ±2))
- Change in BMI (kg/m²) from baseline to Month 9(Baseline to Month 9)
- Change in waist circumference (cm) from baseline to Month 9(Baseline to Month 9)
- Change in fasting LDL-cholesterol (mg/dL) from baseline to Month 9(Baseline to Month 9)
- Change in glycaemic control (HbA1c, %) from baseline to Month 9(Baseline to Month 9)
- Change in insulin resistance (HOMA-IR) from baseline to Month 9(Baseline to Month 9)
- Change in resting energy expenditure (kcal/day) by indirect calorimetry from baseline to Month 9(Baseline to Month 9)
- Change in physical activity level measured by accelerometry(Baseline to Month 9)
- Change in blood pressure parameters assessed by ambulatory blood pressure monitoring (ABPM) from baseline to Month 9(Baseline to Month 9)
- Change in heart rate measured by electrocardiogram (ECG) from baseline to Month 9(Baseline to Month 9)
- Change in number of ventricular extrasystoles measured by electrocardiogram (ECG) from baseline to Month 9(Baseline to Month 9)
- Change in QT interval measured by electrocardiogram (ECG) from baseline to Month 9(Baseline to Month 9)
- Incidence of adverse events (AEs) and serious adverse events (SAEs)(From first dose to Month 9)
- Change in quality of life measured by EuroQol-5D index from baseline to Month 9(Baseline to Month 9)
- Change in quality of life measured by EuroQol-5D visual analogue scale (VAS) from baseline to Month 9(Baseline to Month 9)
- Change in gene expression related to metabolic activity in adipose tissue (subsample)(Baseline to Month 3)
- Change in protein abundance related to metabolic activity in adipose tissue (subsample)(Baseline to Month 3)
- Change in mitochondrial DNA in adipose tissue (subsample)(Baseline to Month 3)
- Change in gut microbiota diversity determined by 16S rRNA gene sequencing from baseline to Month 9(Baseline to Month 9)
- Change in relative abundance of gut microbiota taxa determined by 16S rRNA gene sequencing from baseline to Month 9(Baseline to Month 9)
- Change in nitrogen balance (g/day) from baseline to Month 9(Baseline to Month 9)