Levothyroxine as Adjuvant to a Hypocaloric Diet for the Treatment of Obesity.

Official title

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

Overview

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.

Interventions

• Drug Levothyroxine
  Film-coated oral tablets containing levothyroxine 88 mcg, taken once daily for 9 months. All participants receive a structured lifestyle program: months 0-3 hypocaloric Mediterranean diet (\~600 kcal/day deficit) with physical-activity advice; months 3-9 normocaloric Mediterranean diet with continued advice. The IMP is purchased from authorized manufacturers, then reconditioned and relabeled per GMP and supplied blinded for the full study period. Dispensing follows the randomization code; emerge
• Drug Placebo
  (white, plain, circular), oral once daily for 9 months, no active ingredient. Administered alongside the same lifestyle program as the active arm (months 0-3 hypocaloric Mediterranean diet; months 3-9 normocaloric Mediterranean diet). Placebo is reconditioned and relabeled per GMP to be indistinguishable from levothyroxine; supply is blinded and dispensed per randomization code. Emergency unblinding is performed only by the pharmacy service when medically necessary.

Primary outcome measures

• Change in body weight (kg) from baseline to Month 3 [Time frame: Baseline to Month 3 (12 weeks ±2)]
• Change in fat mass (kg) by bioimpedance from baseline to Month 3 [Time frame: Baseline to Month 3 (12 weeks ±2)]

Secondary outcome measures (12)

• Weight-regain (kg) from Month 3 to Month 9 [Time frame: Month 3 to Month 9 (36 weeks ±2)]
• Change in BMI (kg/m²) from baseline to Month 9 [Time frame: Baseline to Month 9]
• Change in waist circumference (cm) from baseline to Month 9 [Time frame: Baseline to Month 9]
• Change in fasting LDL-cholesterol (mg/dL) from baseline to Month 9 [Time frame: Baseline to Month 9]
• Change in glycaemic control (HbA1c, %) from baseline to Month 9 [Time frame: Baseline to Month 9]
• Change in insulin resistance (HOMA-IR) from baseline to Month 9 [Time frame: Baseline to Month 9]
• Change in resting energy expenditure (kcal/day) by indirect calorimetry from baseline to Month 9 [Time frame: Baseline to Month 9]
• Change in physical activity level measured by accelerometry [Time frame: Baseline to Month 9]
• Change in blood pressure parameters assessed by ambulatory blood pressure monitoring (ABPM) from baseline to Month 9 [Time frame: Baseline to Month 9]
• Change in heart rate measured by electrocardiogram (ECG) from baseline to Month 9 [Time frame: Baseline to Month 9]
• Change in number of ventricular extrasystoles measured by electrocardiogram (ECG) from baseline to Month 9 [Time frame: Baseline to Month 9]
• Change in QT interval measured by electrocardiogram (ECG) from baseline to Month 9 [Time frame: Baseline to Month 9]

Eligibility criteria

Inclusion criteria

• 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 criteria

• 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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Double blind

Primary purpose

Treatment

Study locations

Spain · 5 centers

• Hospital Puerta del Mar — Cadiz
• Hospital Reina Sofía — Córdoba
• Hospital Universitario de Jaén — Jaén
• Hospital Universitario Virgen de la Victoria — Málaga
• Hospital Clínico Universitario de Valladolid — Valladolid

Identifiers

NCT: NCT07332273 · LEVOBESITY

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗