Effect of triiodothyronine (T3) in heart failure with reduced ejection (HFrEF)

ISRCTN	ISRCTN11121053
DOI	https://doi.org/10.1186/ISRCTN11121053
Integrated Research Application System (IRAS)	1013521
Sponsor's protocol code number	016529 10889
Sponsor	Newcastle upon Tyne Hospitals NHS Foundation Trust
Funder	National Institute for Health and Care Research

Submission date: 19/03/2026
Registration date: 21/05/2026
Last edited: 21/05/2026

Recruitment status: Not yet recruiting
Overall study status: Ongoing
Condition category: Circulatory System

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Record updated in last year

Plain English summary of protocol

Background and study aims
Heart failure (HF) affects around one million people in the UK. The thyroid gland produces hormones, including Triiodothyronine (T3) which helps the heart to pump normally. Some people with HF have low levels of T3. Three small studies have shown that it is safe to give HF patients T3 supplements, and that T3 supplements may help the heart to pump better after 6 weeks.
Aim: To compare the effect of T3 supplements with a placebo (dummy capsule) on exercise capacity, health-related quality of life (HRQoL) and heart function over 24- weeks in people with HF.
Research question: What is the effect of T3 supplements on exercise capacity in people with HF and low T3 levels?

Who can participate?
Participant population: 258 patients with moderate to severe HF with reduced ejection fraction and low blood T3 levels will be identified from 14 NHS hospitals.

What does the study involve?
Treatment schedule: 10 mcg oral liothyronine sodium (a synthetic T3 supplement) or matched dummy capsule (placebo) taken twice daily for 24 weeks. Randomisation/enrolment procedures: Participants who provide their consent will have a blood test to measure their T3 levels. Participants with low T3 will be randomly allocated to receive either 10 mcg of oral liothyronine sodium or placebo in addition to their usual HF treatment. Participants will have an equal (50/50) chance of receiving either the oral liothyronine sodium or placebo. Methods: This trial is ‘blinded’ (the research team and participant group will not know which group they are in until the end of the trial). Exercise capacity (the distance walked in metres during a 6-minute walk test), HRQoL and HF questionnaires, and heart function (echocardiograms) will be measured at Baseline and after 24-weeks of treatment. We will compare the change in exercise capacity from Baseline to 24 weeks between the two groups. If T3 is found to improve exercise capacity in people with HF and low T3 we will plan a bigger trial to find out if T3 is effective for other HF patients.

What are the possible benefits and risks of participating?
Everyone who joins will be asked to give up some of their time at the start of the trial (Baseline visit). If participants are eligible to take one of the trial treatments (T3 or placebo) they will need to give some more of their time at 10 weeks and 24 weeks (6 months) after they start the trial treatment. The major burden on participants is the time taken to complete EQ-5D-5L and the Minnesota HF questionnaires, and complete the six minute walking test at Baseline and 6 months. Participants will also have to remember to take their trial medication twice daily for 6 months. Blood samples will be taken by health care professionals who are trained to take blood (phlebotomists or clinicians) at the Screening visit, Baseline visit (if required) and 6 months visits (if participant provides consent for this). This will be similar to a regular blood test at a GP surgery or hospital. Some people feel mild discomfort when giving a blood sample. Sometimes there is mild bruising afterwards.
The amount of blood that we will take should not cause anaemia and we will keep a record of this in order to minimise this risk. Participants should tell their local research team if they have given blood (any amount) for any reason anywhere else in the past month. We will minimise the risks associated with the IMP by routine review by a trial steering committee, which will look at complication rates while the trial is running and can call a halt to the trial if unexpected complications arise.

Where is the study run from?
Centre for Trials Research, Cardiff University (UK)

When is the study starting and how long is it expected to run for?
May 2026 to April 2028

Who is funding the study?
National Institute for Health and Care Research (NIHR) (UK).

Who is the main contact?
salman.razvi@newcastle.ac.uk
YoungG4@cardiff.ac.uk

Contact information

Dr Grace Young
Public

Centre for Trials Research, 7th Floor, Neuadd Meirionnydd, Heath Park
Cardiff
CF14 4YS
United Kingdom

Email	YoungG4@cardiff.ac.uk

Dr Salman Razvi
Scientific, Principal investigator

Translational and Clinical Research Institute, Centre for Life, Central Parkway
Newcastle upon Tyne
NE1 3BZ
United Kingdom

Phone	+44 191 2418838
Email	salman.razvi@newcastle.ac.uk

Study information

Primary study design	Interventional
Allocation	Randomized controlled trial
Masking	Blinded (masking used)
Control	Placebo
Assignment	Single
Purpose	Treatment, Safety
Scientific title	A randomised, double-blind, placebo-controlled trial to evaluate the efficacy of orally administered Triiodothyronine (T3) for 24 weeks in patients with heart failure with reduced ejection (HFrEF)
Study acronym	The T3-HF Trial
Study objectives	Our primary objective is to compare exercise tolerance, defined as the change in distance walked (metres) during a 6-minute walk test from baseline to 24 weeks, in participants randomised to oral liothyronine sodium with participants receiving a placebo. Secondary objectives include assessing the effect of oral liothyronine use on: • Thyroid function • Serum markers of HF and inflammation • Functional classification for HF • Health-related QoL • LV function • Cardiac function • HR and new onset AF • Major adverse cardiovascular events (MACE) • Length of stay for any HF hospitalisation • Non-cardiovascular mortality • Mechanism(s) affecting exercise tolerance i.e. cardiac function
Ethics approval(s)	Submitted 18/03/2026, Wales REC 1 (Castlebridge 4, 15-19 Cowbridge Road East, Cardiff, CF11 9AB, United Kingdom; no telephone number provided; Wales.REC1@wales.nhs.uk), ref: 26/WA/0098
Health condition(s) or problem(s) studied	Heart failure with reduced ejection fraction and low serum T3 levels
Intervention	Intervention: 10 mcg oral liothyronine sodium capsule taken orally twice daily for 24 weeks. Control: Matched placebo capsule, taken orally twice daily for 24 weeks. All randomised participants will be followed-up at 10 weeks to assess compliance and 24-weeks to assess primary outcome measure (distance walked in metres during 6-minute walking test) and secondary outcomes measures, including Thyroid function assessed by TSH, FT4 and FT3 tests; Serum markers of heart failure (assessed by plasma levels of NT pro-BNP) and inflammation (assessed by high sensitivity CRP), Functional classification for HF (assessed by NYHA class); HRQoL assessed using EQ-5D-5L, and Minnesota Living with Heart Failure; LV function measured by LVEF assessed by 2D echocardiography; Cardiac function measured by GLS and GCS, assessed by 2D echocardiography; Heart rate and new-onset atrial fibrillation (assessed by ECG); MACE (defined as: cardiovascular mortality; AMI; hospitalisation for HF; stroke; hospitalisation for unstable angina or coronary revascularisation procedure); Length of stay for any HF hospitalisation assessed by clinical notes review; Non-cardiovascular mortality; and Mechanism(s) affecting exercise tolerance i.e. cardiac function. Eligible participants will be randomised 1:1 using a minimisation algorithm with a random element to either active treatment (10 mcg oral liothyronine sodium) or control (placebo). Allocations will be balanced by site, sex, age category (≤65 years/>65 years), and ischaemic cause of HFrEF (yes/no). The online randomisation program will be developed by the Cardiff CTR and will be embedded within the trial database with controlled access.
Intervention type	Drug
Phase	Phase III
Drug / device / biological / vaccine name(s)	Liothyronine sodium
Primary outcome measure(s)	The distance covered by the participant in 6 minutes measured using the 6 minute walking test at baseline and the end of the intervention at 24 weeks
Key secondary outcome measure(s)	Thyroid function measured using TSH, FT4 and FT3 tests at Screening and 24 weeks Serum markers of heart failure measured using plasma levels of NT pro-BNP and inflammation by high-sensitivity CRP at baseline and 24 weeks Functional classification for HF measured using the NYHA class at screening and 24 weeks Health-related QoL measured using EQ-5D-5L, and Minnesota Living with Heart Failure, at baseline and 24 weeks LV function measured using LVEF by 2D echocardiography at screening (most recent LVEF from previous 24 months used) and 24 weeks Cardiac function measured using GLS and GCS by 2D echocardiography at baseline (most recent GLS and GCS from previous 24 months) and 24 weeks Heart rate and new-onset atrial fibrillation measured using ECG at baseline and 24 weeks MACE, defined as: cardiovascular mortality; AMI; hospitalisation for HF; stroke; hospitalisation for unstable angina or coronary revascularisation procedure, measured using a clinical notes review at 24 weeks Length of stay for any HF hospitalisation measured using a clinical notes review at 24 weeks Non-cardiovascular mortality measured using a clinical notes review at 24 weeks Mechanism(s) affecting exercise tolerance i.e. cardiac function measured using 2D echocardiography at 24 weeks
Completion date	30/04/2028

Eligibility

Participant type(s)
Age group	Mixed
Lower age limit	18 Years
Upper age limit	120 Years
Sex	All
Target sample size at registration	258
Key inclusion criteria	1. Adults aged 18 years or older who are able to provide informed consent 2. Those with moderate to severe HFrEF (defined as LVEF ≤40% on the most recent echocardiogram) 3. Participants with chronic and stable HF (diagnosed ≥3 months before recruitment and no inpatient admission to hospital for HF exacerbations <1 month before recruitment) 4. Those with serum free T3 levels ≤4.0 pmol/L 5. Those on maximally tolerated guideline-directed medical therapies for HFrEF
Key exclusion criteria	1. Taking medications affecting thyroid function (including levothyroxine, antithyroid drugs, amiodarone, lithium and sodium valproate) 2. Participating in another interventional trial if it is deemed to interfere with the assessment of the primary outcome by the local investigator 3. Unable to attempt the 6MWT (as it would be unethical to include a person in an intervention trial where they would not be contributing to the primary outcome) 4. Currently pregnant or are planning to become pregnant in the next 24 weeks 5. Newly diagnosed with overt hypothyroidism (serum TSH higher than the upper limit of the reference range and a low serum free T4 level) or hyperthyroidism (low TSH with normal or elevated FT4 levels) 6. Any current comorbidity expected to reduce life expectancy to ≤6 months
Date of first enrolment	25/05/2026
Date of final enrolment	30/04/2027

Locations

Countries of recruitment

United Kingdom
England

Study participating centres

The Newcastle upon Tyne Hospitals NHS Foundation Trust

Freeman Hospital
Freeman Road
High Heaton
Newcastle upon Tyne
NE7 7DN
England

Gateshead Health NHS Foundation Trust

Queen Elizabeth Hospital
Sheriff Hill
Gateshead
NE9 6SX
England

North Tees and Hartlepool NHS Foundation Trust

University Hospital of Hartlepool
Holdforth Road
Hartlepool
TS24 9AH
England

Liverpool Heart & Chest Hospital

Broadgreen Hospital
Thomas Drive
Liverpool
L14 3PE
England

Hull University Teaching Hospitals NHS Trust

Hull Royal Infirmary
Anlaby Road
Hull
HU3 2JZ
England

Leeds Teaching Hospitals NHS Trust

St. James's University Hospital
Beckett Street
Leeds
LS9 7TF
England

Northumbria Healthcare NHS Foundation Trust (headquarters)

Rake Lane
North Shields
NE29 8NH
England

South Tees Hospitals NHS Foundation Trust

James Cook University Hospital
Marton Road
Middlesbrough
TS4 3BW
England

Results and Publications

Individual participant data (IPD) Intention to share	Yes
IPD sharing plan	The datasets generated during and/or analysed during the current study are/will be available upon request from the Centre for Trials Research, Cardiff University.

Editorial Notes

19/03/2026: Trial's existence confirmed by NHS HRA.