Evaluation of Levothyroxine and Liothyronine Combination Therapy Versus Levothyroxine Monotherapy in Autoimmune Hypothyroidism with Persistent Fatigue

The primary objective of this study is to evaluate the effects of **LT4/LT3 combination therapy** compared to **LT4 monotherapy** on tiredness in patients with **autoimmune hypothyroidism** who experience persistent tiredness despite LT4 monotherapy, after one year of treatment. This objective is clinically relevant as it aims to address the unmet need for effective management of fatigue in this patient population. Additionally, the study seeks to determine if the effect sizes are greater in patients with genetic variations in the type 2 deiodinase (DIO2-rs225014) and the monocarboxylate transporter 10 (MCT10-rs17606253).

Secondary objectives include: - Investigating other determinants of the effects of LT4/LT3 combination therapy compared to LT4 therapy alone on tiredness. - Assessing the effects on other thyroid-related complaints and quality of life. - Exploring the effects on cardiovascular, metabolic, and bone outcomes. - Evaluating the impact on neurocognitive function. - Conducting an economic evaluation, including cost-effectiveness analysis, comparing LT4/LT3 combination therapy and LT4 monotherapy. - Comparing the number of adverse events during LT4/LT3 combination therapy versus LT4 therapy alone.

The clinical trial involves participants diagnosed with **hypothyroidism**, specifically those experiencing persistent tiredness despite ongoing treatment with levothyroxine (LT4) monotherapy. The study population includes both male and female subjects aged 18 years and older. Participants are required to have been on LT4 monotherapy for a minimum of six months, with a dosage ranging from 75 to 225 micrograms, and must have thyroid-stimulating hormone (TSH) levels within the assay-specific reference ranges for at least three months. The trial does not include a vulnerable population. Participants must report severe tiredness that significantly impacts daily life for at least six months, based on their own experience. Additionally, they must be sufficiently fluent in Dutch. The sponsor has not provided information regarding the total number of participants or specific lifestyle considerations such as diet or physical activity.

The clinical trial is designed as a **randomized**, **double-blind**, placebo-controlled study to evaluate the effects of **levothyroxine** (LT4) and **liothyronine** (LT3) combination therapy compared to LT4 monotherapy in patients with autoimmune **hypothyroidism**. The primary objective is to assess the impact on tiredness after one year of treatment. The trial will involve participants who are 18 years or older, have been on LT4 monotherapy for at least six months, and experience severe tiredness impacting daily life. The study will span approximately 52 weeks, with the estimated recruitment start date being September 1, 2021, and the estimated end date being May 1, 2025.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on the principal inclusion criteria. This will be followed by regular follow-up visits to monitor progress and collect data on primary and secondary endpoints, including changes in the ThyPRO tiredness subscale scores and other thyroid-related complaints. The end-of-study visit will conclude the trial, where final assessments will be conducted to evaluate the overall effects of the treatment.

The expected length of participant involvement is one year, during which they will receive either the combination therapy or a placebo. Conditions that may lead to early termination from the study include non-compliance with the study protocol, withdrawal of consent, or any adverse events that compromise participant safety. The trial aims to provide valuable insights into the efficacy of LT4/LT3 combination therapy in improving quality of life for patients with persistent complaints of tiredness due to autoimmune hypothyroidism.

The clinical trial involves the administration of **Levothyroxine Sodium**, a synthetic form of the thyroid hormone thyroxine, used in the treatment of **autoimmune hypothyroidism**. The pharmaceutical form of Levothyroxine Sodium is coded as PHF00245MIG, and it is administered orally. The maximum daily dose is 100 micrograms, with a total maximum dose of 200 micrograms over a treatment period of up to 52 weeks. The medication is classified under the ATC code H03AA01. Compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed regimen.

In addition to Levothyroxine Sodium, the trial also includes the administration of **Liothyronine Sodium**, another thyroid hormone, which is also provided in the pharmaceutical form coded as PHF00245MIG. This medication is administered orally, with a maximum daily dose of 100 micrograms and a total maximum dose of 200 micrograms over a 52-week period. Liothyronine Sodium is classified under the ATC code H03AA02. The trial aims to evaluate the effects of the combination therapy of Levothyroxine and Liothyronine on patients with persistent tiredness despite Levothyroxine monotherapy.

A placebo is used as a comparator in this trial. The placebo tablets are white, round, and biconvex, containing no active pharmaceutical ingredient. They are manufactured following the same process as the Liothyronine tablets, ensuring consistency in appearance and administration. The placebo serves as a control to assess the efficacy of the active treatments in a double-blind manner, ensuring that neither the participants nor the investigators are aware of the treatment allocations.

Efficacy in the clinical trial titled "A national randomized placebo-controlled double-blind multicenter trial of LT4/LT3 combination therapy in patients with autoimmune hypothyroidism: the T3-4-Hypo trial" will be assessed using specific endpoints. The primary endpoint is the mean change from baseline to 52 weeks in the ThyPRO tiredness subscale scores. Secondary endpoints include the mean change from baseline to 52 weeks in the ThyPRO-39 composite scale scores, improvement in the ThyPRO tiredness subscale scores by at least the minimal important difference of 14.3, and mean change in the ThyPRO tiredness subscale scores in participants with a baseline score greater than 57. Additional secondary endpoints involve assessing the effects of LT4/LT3 combination therapy on other thyroid-related complaints, quality of life, cardiovascular, metabolic, and bone outcomes, neurocognitive function, and conducting an economic evaluation including cost-effectiveness analysis. The number of adverse events in the LT4/LT3 combination therapy compared to the LT4 monotherapy groups will also be evaluated.