LT4/LT3 Combination Therapy Versus LT4 Monotherapy in Patients With Autoimmune Hypothyroidism. (T3-4-Hypo)

June 9, 2023 updated by: M. Medici

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

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.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

After obtaining informed consent we will enroll patients with autoimmune hypothyroidism and persistent tiredness despite normalized TSH levels on LT4 monotherapy. A general physical examination will be performed, and in- and exclusion criteria will be checked. This also includes an ECG to prevent including patients with a functional or structural abnormal heart. The study will start with a run-in period, during which all patients switch to blinded generic LT4, which is produced and distributed by the trial pharmacy. This is because there are seven LT4 preparations available in the Netherlands with different pharmacokinetic properties, which would otherwise introduce substantial bias. Previous research has shown that 36% of patients need dose adjustments when switching to other LT4 preparations. Therefore, serum TSH levels are measured every 8 weeks, and medication dosages adjusted if needed, in order to obtain normal serum TSH levels, defined as TSH levels within the assay-specific reference range. For trial feasibility, patients will be excluded from this study and referred back to their referring physician when a normal TSH cannot be reached with a maximum of two dose adjustments. Once a normal TSH has been measured, the final run-in TSH measurement will be performed 8 weeks later. This is because we want to ensure that we only enroll patients with a stable (i.e. normal) TSH on a stable dose of generic LT4, as recent dose adjustments could otherwise impact the tiredness questionnaire scores at the start of the RCT. This TSH measurement will be combined with a repeat ECG and the patient will be asked whether tiredness with a large negative impact on daily life is still present. Patients will enter Stage 2 (RCT) when they have a normal TSH, no ECG abnormalities, and indicate they have persistent tiredness. Patients not fulfilling these criteria will be excluded from this study and referred back to their referring physician. The expected duration of the run-in period will be 4-8 months, depending on the number of dose adjustments.

Stage 2 includes a 1-year double-blind randomized placebo-controlled trial comparing LT4/LT3 with LT4/placebo treatment. At baseline, patients are randomized to either LT4/LT3 or LT4/placebo treatment. Serum TSH levels are measured at every visit, and medication dosages adjusted if needed, with the goal to normalize serum TSH levels, defined as TSH levels within the assay-specific reference range. Patients are excluded and referred back to their referring physician in case a normal TSH cannot be reached with the available study medication dosages (62,5 - 237,5 µg LT4 monotherapy dose). Visits will take place at baseline, and weeks 8, 16, 26, 39 and 52. The density of visits is higher at the beginning as this is the period when dose adjustments are particularly expected. At every visit, patients are asked to complete questionnaires on thyroid related complaints and quality of life (ThyPRO), general quality of life (EuroQoL-5D-5L and EuroQoL-5D-VAS), medical consumption (iMCQ) and productivity losses (iPCQ). At baseline and 52 weeks, additional blood will also be drawn to determine genetic variants, (thyroid hormone) metabolites and collect material for biobanking, as these data will be key to identify subgroups who are likely to respond to LT4/LT3 combination therapy. Although we do not expect any detrimental effects of these low physiological LT3 dosages, and previous studies neither reported any detrimental effects, we will explore the effects of LT4/LT3 combination therapy on the most important thyroid hormone target organs (bone, cardiovascular, metabolic and brain). This will improve communication between medical professionals and patients, providing them with comprehensive information on the balance between the potential benefits and harms of combination therapy vs monotherapy and will enable shared-decision making that better addresses individual needs of patients. For bone, serum bone markers will be determined at baseline and 52 weeks, and DXA scans will be performed at baseline and 52 weeks in a subgroup of 200 individuals. For cardiovascular and metabolic endpoints, blood pressure, pulse rate, weight, and waist circumference are measured at every visit. Fat percentages will be assessed on the beforementioned DXA scans. A repeat ECG will be performed at 52 weeks. To objectively explore effects on neurocognitive function, next to the subjective ThyPRO questionnaire scores, neurocognitive tests will be performed in a subgroup of 200 patients at baseline and 52 weeks.

Study Type

Interventional

Enrollment (Estimated)

600

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • Netherlands
      • Amsterdam, Netherlands
      • Arnhem, Netherlands
      • Dirksland, Netherlands
      • Dordrecht, Netherlands
      • Goes, Netherlands
      • Groningen, Netherlands
        • Recruiting
        • University Medical Center Groningen
        • Contact:
      • Leiden, Netherlands
        • Not yet recruiting
        • Leiden University Medical Center
        • Contact:
      • Maastricht, Netherlands
        • Not yet recruiting
        • Maastricht University Medical Center
        • Contact:
      • Nijmegen, Netherlands
      • Rotterdam, Netherlands
        • Recruiting
        • Erasmus Medical Center
        • Contact:
      • Rotterdam, Netherlands
      • Schiedam, Netherlands
      • Sittard, Netherlands
      • Utrecht, Netherlands
      • Veldhoven, Netherlands
        • Not yet recruiting
        • Máxima Medical Center
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

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)

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Triple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: LT4/LT3 combination therapy
The intervention group is treated with once daily a LT4 tablet and twice daily a LT3 tablet with a LT4:LT3 ratio 16:1.
Drug: LT3 (liothyronine)
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.
Other Names:
  • Intervention group LT4/LT3 combination therapy
Placebo Comparator: LT4/placebo therapy
The control group is treated with once daily a LT4 tablet and twice daily a placebo tablet.
Drug: Placebo
Addition of placebo (LT4 monotherapy) in patients with persistent tiredness on LT4 monotherapy.
Other Names:
  • Control group LT4/placebo therapy

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Mean change from baseline to 52 weeks in the ThyPRO tiredness subscale scores.
Time Frame: 52 weeks

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
Time Frame: 52 weeks
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 Outcome Measures

Outcome Measure
Measure Description
Time Frame
Mean change from baseline to 52 weeks in the ThyPRO-39 composite scale* scores.
Time Frame: 52 weeks

The Composite scale is based on 22 items from the Tiredness, Cognition, Anxiety, Depressivity, Emotional Susceptibility, Impaired Social life, Impaired Daily Life and Overall QoL subscales of the Thyroid specific Patient Reported Outcome (ThyPRO) questionnaire, with each subscale ranging from 0-100 (higher scores indicate a worse outcome).

The ThyPRO questionnaire will be performed at every RCT visit.
52 weeks
Change from baseline to 52 weeks in the ThyPRO tiredness subscale scores ≥ minimal important difference (=14.3).
Time Frame: 52 weeks

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
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).
Time Frame: 52 weeks

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
Mean change from baseline to 52 weeks in the ThyPRO tiredness subscale scores in participants with a normal-range TSH level at 52 weeks.
Time Frame: 52 weeks

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
Determinants of the effects of LT4/LT3 combination therapy on tiredness.
Time Frame: 52 weeks

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
The (determinants of the) effects of LT4/LT3 combination therapy compared to LT4 therapy alone on other thyroid related complaints and quality of life.
Time Frame: 52 weeks

Thyroid specific Patient Reported Outcome (ThyPRO) questionnaire, with the subscales ranging from 0-100 (higher scores indicate a worse outcome).

ThyPRO Questionnaires will be performed at every RCT visit.
52 weeks
Number of adverse events in the LT4/LT3 combination therapy compared to the LT4 monotherapy groups.
Time Frame: 52 weeks

AEs are defined as any undesirable experience occurring to a subject during the study, whether or not considered related to the investigational product / trial procedure. All following AEs according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be recorded, for which we also refer to the SmPCs for LT4 and LT3:

  • Hyperthyroidism (endocrine disorders subgroup)
  • Hypothyroidism (endocrine disorders subgroup)
  • All cardiac disorders subgroups
  • Erythroderma, rash and urticaria (skin and subcutaneous disorders subgroups)

All other AEs will be recorded from CTCAE v 5.0 grade 3 onwards (= severe or medically significant but not immediately life-threatening).
52 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

M. Medici

Collaborators

ZonMw: The Netherlands Organisation for Health Research and Development
ACE Pharmaceuticals BV

Investigators

  • Principal Investigator: Marco Medici, MD PhD, Erasmus Medical Center

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

October 7, 2022

Primary Completion (Estimated)

May 1, 2026

Study Completion (Estimated)

May 1, 2026

Study Registration Dates

First Submitted

November 1, 2021

First Submitted That Met QC Criteria

January 4, 2023

First Posted (Actual)

January 12, 2023

Study Record Updates

Last Update Posted (Actual)

June 12, 2023

Last Update Submitted That Met QC Criteria

June 9, 2023

Last Verified

June 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • NL74281.078.21

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

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.

IPD Sharing Time Frame

six months after database lock

IPD Sharing Access Criteria

Upon request to the Principal investigator, with a sufficiently substantiated study proposal.

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL
  • SAP
  • ICF
  • CSR

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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