Combination therapy for autoimmune hypothyroidism

A National Randomized Placebo-controlled Double-blind Multicenter Trial of LT4/LT3 Combination Therapy in Patients with Autoimmune Hypothyroidism: the T3-4-Hypo Trial.

This study is testing if adding a medication called liothyronine to the standard treatment for autoimmune hypothyroidism can help people who still feel tired even when their thyroid levels are normal.

Quick facts

• Phase: PHASE3
• Study type: Interventional
• Enrollment: 600 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: Erasmus Medical Center (other)
• Drugs / interventions: immunotherapy
• Locations: 19 sites (Almere Stad and 18 other locations)
• Trial ID: NCT05682482 on ClinicalTrials.gov

What this trial studies

This clinical trial investigates the effectiveness of combining liothyronine (LT3) with levothyroxine (LT4) in patients suffering from autoimmune hypothyroidism who experience persistent tiredness despite normalized thyroid-stimulating hormone (TSH) levels on LT4 monotherapy. Patients will undergo a run-in period where they will switch to a standardized LT4 preparation to ensure stable TSH levels before being randomized to receive either LT3 or a placebo. The study aims to determine if the addition of LT3 can improve quality of life and alleviate symptoms in this patient population. Genetic factors related to thyroid hormone metabolism will also be considered in evaluating treatment responses.

Who should consider this trial

Good fit: Ideal candidates are adults aged 18 and older with autoimmune hypothyroidism who have been on LT4 monotherapy for at least six months and report severe tiredness impacting their daily life.

Not a fit: Patients with congenital or secondary hypothyroidism, or those who have not been on LT4 monotherapy, are unlikely to benefit from this study.

Why it matters

Potential benefit: If successful, this approach could significantly improve the quality of life for patients with autoimmune hypothyroidism who continue to experience fatigue despite standard treatment.

How similar studies have performed: Previous studies have shown mixed results regarding the effectiveness of LT3 addition in similar patient populations, indicating that this approach is still under investigation.

Eligibility criteria

Inclusion Criteria:

* Patients with overt or subclinical primary hypothyroidism 18 years or older.\*
* LT4 monotherapy for at least 6 months.
* LT4 monotherapy dose of 75-225 microg, with at least a dose of 1.2 microg/kg.
* TSH levels within the assay-specific reference ranges for at least 3 months.
* Severe tiredness with a large negative impact on daily life for at least 6 months, with or without other persisting complaints. This is based on the patient's own experience, without judgment of the treating physician.
* Sufficiently fluent in Dutch and able to read Dutch.

  * Thyroid peroxidase (TPO) and/or thyroglobulin (Tg) antibody positivity is not a requirement as these have frequently not been determined. Instead, we ensure that we only include patients with autoimmune hypothyroidism by excluding other causes of hypothyroidism (see exclusion criteria).

Exclusion Criteria:

* Congenital hypothyroidism, hypothyroidism after (sub)acute thyroiditis\*, secondary (central) hypothyroidism
* Thyroid surgery, radioactive iodine treatment, or head and/or neck radiotherapy.
* Use of thyroid interfering drugs (current/past use of amiodarone, immunotherapy, tyrosin kinase inhibitors, interferon, or lithium and current use of oral or iv corticosteroids or dopamine).
* Current psychiatric disease treated at a "gespecialiseerde GGZ instelling"\*\*
* Clinical diagnosis of dementia.
* Pregnancy, breastfeeding or wish to become pregnant within 2 years.
* Women of reproductive age not using adequate contraception, who are not sterilized and do not have a sterilized partner. Adequate contraceptives include the contraceptive pill, patch, injection, implant, intrauterine device or system, vaginal ring, diaphragm or cap, and condom.
* Clinically relevant functional or structural abnormal heart (e.g., cardiomyopathy or valve disease)
* Recent acute coronary syndrome or unstable angina pectoris (\<4 weeks)
* Current/past atrial fibrillation
* Current conduction disorder on ECG (i.e, QRS\>120 ms or prolonged QTc (women≥460 ms and men≥450 ms)).
* Frequent ventricular extrasystole (=doublet, trigeminy, bigeminy or (non-sustained) ventricular tachycardia) in the past or on current ECG.
* Other obvious medical explanation for tiredness (e.g. end-stage renal disease, anemia, COPD stage IV, cancer, etc.)
* Other obvious major life event explanation for tiredness (e.g., mourning, loss of job)

  * Postpartum thyroiditis is not an exclusion criterium.
  * Treatments of mild non-complex psychological/psychiatric complaints are done in the " basis GGZ", e.g. consisting of conversations with a psychologist or psychotherapist, or via internet (e-health). "Gespecialiseerde GGZ" encompasses treatments of more severe psychological/psychiatric complaints. (link: Basis GGZ en gespecialiseerde GGZ \| Geestelijke gezondheidszorg (GGZ) \| Rijksoverheid.nl)

Where this trial is running

Almere Stad and 18 other locations

• Flevoziekenhuis — Almere Stad, Netherlands (RECRUITING)
• Amsterdam UMC - Location AMC — Amsterdam, Netherlands (RECRUITING)
• Gelre ziekenhuizen — Apeldoorn, Netherlands (NOT_YET_RECRUITING)
• Rijnstate — Arnhem, Netherlands (RECRUITING)
• Amphia ziekenhuis — Breda, Netherlands (RECRUITING)
• Van Weel-Bethesda Hospital — Dirksland, Netherlands (RECRUITING)
• Albert Schweitzer Hospital — Dordrecht, Netherlands (RECRUITING)
• Treant — Emmen, Netherlands (NOT_YET_RECRUITING)
• Admiraal de Ruyter Hospital — Goes, Netherlands (RECRUITING)
• University Medical Center Groningen — Groningen, Netherlands (RECRUITING)
• Saxenburgh MC — Hardenberg, Netherlands (RECRUITING)
• Radboudumc — Nijmegen, Netherlands (RECRUITING)
• Erasmus Medical Center — Rotterdam, Netherlands (RECRUITING)
• Maasstad Hospital — Rotterdam, Netherlands (RECRUITING)
• Franciscus Gasthuis & Vlietland — Schiedam, Netherlands (RECRUITING)
• Zuyderland — Sittard, Netherlands (RECRUITING)
• University Medical Center Utrecht — Utrecht, Netherlands (RECRUITING)
• Maxima Medical Center — Veldhoven, Netherlands (RECRUITING)
• Vie Curie MC — Venlo, Netherlands (NOT_YET_RECRUITING)

Study contacts

• Principal investigator: Marco Medici, MD PhD — Erasmus Medical Center
• Study coordinator: Marco Medici, MD PhD

Conditions: Autoimmune Hypothyroidism, Triiodothyronine, Quality of life, Persistent complaints