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)
Heart failure with reduced ejection fraction and low serum T3 levels
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.
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
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