LT4/LT3 Combination Therapy Versus LT4 Monotherapy in Patients with Autoimmune Hypothyroidism.
T3-4-Hypo
A National Randomized Placebo-controlled Double-blind Multicenter Trial of LT4/LT3 Combination Therapy in Patients with Autoimmune Hypothyroidism: the T3-4-Hypo Trial.
1 other identifier
interventional
600
1 country
19
Brief Summary
Hypothyroidism is common, affecting 5% of the general population, for which levothyroxine (LT4) monotherapy is the standard treatment. Despite normalized serum thyroid hormone levels, 10-15% of LT4 treated patients have various persistent complaints, the most important of which is tiredness. This could be explained by the fact that physiological T4/T3 ratios cannot be reached with LT4 monotherapy, as in a healthy individual T3 is not only derived from T4/T3 conversion but is also directly produced by the thyroid itself. Studies have reported contradicting results as to whether addition of liothyronine (LT4/LT3 combination therapy) in patients with persistent tiredness on LT4 monotherapy is effective or not. Studies have suggested higher effectiveness in patients carrying genetic variation in the type 2 deiodinase (DIO2-rs225014) and monocarboxylate transporter 10 (MCT10-rs17606253) genes. Objective: To investigate whether addition of liothyronine (LT4/LT3 combination therapy) in in patients with persistent tiredness on LT4 monotherapy is effective or not in relieving tiredness.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P75+ for phase_3
Started Oct 2022
Longer than P75 for phase_3
19 active sites
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
Click on a node to explore related trials.
Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
November 1, 2021
CompletedStudy Start
First participant enrolled
October 7, 2022
CompletedFirst Posted
Study publicly available on registry
January 12, 2023
CompletedPrimary Completion
Last participant's last visit for primary outcome
January 1, 2028
ExpectedStudy Completion
Last participant's last visit for all outcomes
January 1, 2028
February 26, 2025
August 1, 2024
5.2 years
November 1, 2021
February 25, 2025
Conditions
Keywords
Outcome Measures
Primary Outcomes (2)
Mean change from baseline to 52 weeks in the ThyPRO tiredness subscale scores.
Thyroid specific Patient Reported Outcome (ThyPRO) questionnaire, with the tiredness subscale ranging from 0-100 (higher scores indicate a worse outcome). ThyPRO Questionnaires will be performed at every RCT visit.
52 weeks
Effect sizes in genetic subgroups
In case it is confirmed that LT4/LT3 combination therapy reduces tiredness compared to LT4 treatment alone, we will simultaneously investigate whether effect sizes are higher in patients with genetic variation in the type 2 deiodinase (DIO2-rs225014) and effect sizes are higher in patients with genetic variation in the monocarboxylate transporter 10 (MCT10-rs17606253), ensuring control of the study-wise type 1 error (of 5% two-sided) across these three main questions.
52 weeks
Secondary Outcomes (7)
Mean change from baseline to 52 weeks in the ThyPRO-39 composite scale* scores.
52 weeks
Change from baseline to 52 weeks in the ThyPRO tiredness subscale scores ≥ minimal important difference (=14.3).
52 weeks
Mean change from baseline to 52 weeks in the ThyPRO tiredness subscale scores in participants with a baseline score > 57 (= population mean, unpublished results; personal communication with Dr T Watt, developer of the ThyPRO questionnaire).
52 weeks
Mean change from baseline to 52 weeks in the ThyPRO tiredness subscale scores in participants with a normal-range TSH level at 52 weeks.
52 weeks
Determinants of the effects of LT4/LT3 combination therapy on tiredness.
52 weeks
- +2 more secondary outcomes
Study Arms (2)
LT4/LT3 combination therapy
ACTIVE COMPARATORThe intervention group is treated with once daily a LT4 tablet and twice daily a LT3 tablet with a LT4:LT3 ratio 16:1.
LT4/placebo therapy
PLACEBO COMPARATORThe control group is treated with once daily a LT4 tablet and twice daily a placebo tablet.
Interventions
Addition of liothyronine (LT4/LT3 combination therapy) in patients with persistent tiredness on LT4 monotherapy. To investigate whether addition of LT3 is effective in relieving tiredness.
Addition of placebo (LT4 monotherapy) in patients with persistent tiredness on LT4 monotherapy.
Eligibility Criteria
You may qualify if:
- 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.
You may not qualify if:
- 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)
- 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)
Contact the study team to confirm eligibility.
Sponsors & Collaborators
- M. Medicilead
- ZonMw: The Netherlands Organisation for Health Research and Developmentcollaborator
- ACE Pharmaceuticals BVcollaborator
Study Sites (19)
Flevoziekenhuis
Almere Stad, Netherlands
Amsterdam UMC - Location AMC
Amsterdam, Netherlands
Gelre ziekenhuizen
Apeldoorn, Netherlands
Rijnstate
Arnhem, Netherlands
Amphia ziekenhuis
Breda, Netherlands
Van Weel-Bethesda Hospital
Dirksland, Netherlands
Albert Schweitzer Hospital
Dordrecht, Netherlands
Treant
Emmen, Netherlands
Admiraal de Ruyter Hospital
Goes, Netherlands
University Medical Center Groningen
Groningen, Netherlands
Saxenburgh MC
Hardenberg, Netherlands
Radboudumc
Nijmegen, Netherlands
Erasmus Medical Center
Rotterdam, Netherlands
Maasstad Hospital
Rotterdam, Netherlands
Franciscus Gasthuis & Vlietland
Schiedam, Netherlands
Zuyderland
Sittard, Netherlands
University Medical Center Utrecht
Utrecht, Netherlands
Maxima Medical Center
Veldhoven, Netherlands
Vie Curie MC
Venlo, Netherlands
Related Publications (1)
Phan GQ, Yavuz S, Stamatouli AM, Madan R, Chen S, Grover AC, Nilubol N, Bedoya P, Trankle C, Markley R, Abbate A, Celi FS. A feasibility double-blind trial of levothyroxine vs. levothyroxine-liothyronine in postsurgical hypothyroidism. Front Endocrinol (Lausanne). 2025 Mar 10;16:1522753. doi: 10.3389/fendo.2025.1522753. eCollection 2025.
PMID: 40130156DERIVED
Related Links
MeSH Terms
Conditions
Interventions
Intervention Hierarchy (Ancestors)
Study Officials
- PRINCIPAL INVESTIGATOR
Marco Medici, MD PhD
Erasmus Medical Center
Central Study Contacts
Study Design
- Study Type
- interventional
- Phase
- phase 3
- Allocation
- RANDOMIZED
- Masking
- TRIPLE
- Who Masked
- PARTICIPANT, CARE PROVIDER, INVESTIGATOR
- Masking Details
- double blind
- Purpose
- TREATMENT
- Intervention Model
- PARALLEL
- Sponsor Type
- OTHER
- Responsible Party
- SPONSOR INVESTIGATOR
- PI Title
- Dr. M. Medici
Study Record Dates
First Submitted
November 1, 2021
First Posted
January 12, 2023
Study Start
October 7, 2022
Primary Completion (Estimated)
January 1, 2028
Study Completion (Estimated)
January 1, 2028
Last Updated
February 26, 2025
Record last verified: 2024-08
Data Sharing
- IPD Sharing
- Will share
- Shared Documents
- STUDY PROTOCOL, SAP, ICF, CSR
- Time Frame
- six months after database lock
- Access Criteria
- Upon request to the Principal investigator, with a sufficiently substantiated study proposal.
A subset of the final data will be made available after an embargo period upon request. Most likely aggregated and filtered in order to maintain anonimity of individual patient data. The choice of online repository still has to be made.