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) - TheT3-HF Trial

Research question: What is the effect of triiodothyronine (T3) supplementation on exercise tolerance in patients with heart failure with reduced ejection fraction (HFrEF) and low serum T3?

Background: Heart failure (HF) affects ~1 million people in the UK and costs the NHS ~£2 billion annually. The most common form of HF presents with reduced ejection fraction (HFrEF) for which there is no known cure. HF reduces exercise tolerance, impairs quality of life, and increases the risk of hospital admissions and mortality.

Thyroid hormones are critical for normal cardiac functioning by regulating myocardial metabolic functioning. Low serum levels of the thyroid hormone triiodothyronine (T3), is observed in 10-25% of patients with HFrEF and is associated with reduced myocardial T3 concentrations and severity of HFrEF. Patients with HFrEF and low T3 have reduced exercise tolerance and higher mortality than patients with similar cardiac function and normal T3 levels.

Therefore, HFrEF patients with low T3 levels are at an increased risk of morbidity and mortality. Furthermore, if intervention with T3 is shown to be beneficial, this high-risk subgroup of HFrEF patients could benefit from T3 supplementation. A meta-analysis of 3 randomised controlled trials of T3 in a small number of patients with HF has demonstrated that treatment is safe and may improve cardiac function.

An appropriately powered trial is needed to evaluate the efficacy and safety of T3 in a larger group of patients.

Aim: To determine the effect of T3 supplementation on exercise tolerance in people with chronic HFrEF and low serum T3 levels.

Objectives: 1. To compare exercise tolerance (6-minute walking test (6MWT) distance) in patients with HFrEF and low T3 levels following 24 weeks of T3 supplementation or placebo

2. To evaluate the mechanism(s) of T3 supplementation on exercise tolerance through an embedded mediation analysis of change in cardiac function

3. Assess the safety of T3 supplementation and its effects on quality of life, left ventricular function and hospital admissions 4. Assess the willingness of participants to participate in the trial (internal pilot).

Methods: A multicentre double-blind randomised controlled trial of T3 (10 mcg twice daily) or placebo for 24 weeks in 256 patients with moderate to severe HFrEF (LVEF<40%) and low serum T3 levels (<4.0 pmol/L). An internal pilot assessing recruitment practices will be completed by interviewing participants who consented (n=10) and declined (n=10). The primary outcome will be a change in exercise tolerance assessed by a change in 6MWT distance at 24 weeks.

Secondary outcomes include cardiac systolic and diastolic function (2-D echocardiography), N-terminal pro-brain natriuretic peptide (NT pro-BNP), quality of life, hospitalisation rates and major cardiac events. The relationship between T3 treatment, cardiac function and exercise tolerance will be assessed using mediation analysis.

Timelines for delivery: Month 1 - 9 = setup and relevant approvals; Month 10 - 36 = participant recruitment; Month 37 - 42 = Data analysis and project report preparation.

Anticipated impact and dissemination: The results of this trial will be published in open-access journals, presented at cardiovascular and endocrine conferences, and shared with patient organisations. Tens of thousands of HFrEF patients with low T3 levels could benefit if T3 supplementation is demonstrated to be safe and efficacious in improving exercise tolerance.