Tests levothyroxine alongside a diet for adults with obesity

Trial details

Who runs it

Fundación Pública Andaluza para la Investigación de Málaga en Biomedicina y Salud

Trial code

NCT07332273

Record updated

12 January 2026

Original description

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.Read full original descriptionShow less

Effect of Levothyroxine as Adjuvant Therapy to a Hypocaloric Diet in the Treatment of Obesity: a Randomized Placebo-controlled Trial.

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.

Inclusion: 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).

Exclusion: Any prior thyroid disease (hyperthyroidism, overt hypothyroidism) or prior LT4 treatment; Drug/alcohol abuse, life expectancy <12 months, inability to follow the recommended diet or attend visits; Hypersensitivity to any component of the investigational product; Active cancer or cancer within the last 5 years (except basal-cell carcinoma); 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); 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; Diabetes mellitus (HbA1c ≥6.5%, fasting glucose ≥126 mg/dL, or 2-h OGTT ≥200 mg/dL); Chronic liver disease with total bilirubin ≥2.0 mg/dL or AST >3× ULN; Any heart failure; resting HR >85 bpm; eGFR <60 mL/min; Current or recent (≤3 months) use of levothyroxine, hypoglycaemic agents, antibiotics, or regular probiotics/prebiotics; Positive pregnancy test, pregnant, expecting pregnancy, or breastfeeding; Inability or unwillingness to provide informed consent.

ClinicalTrials.gov NCT07332273