Developing Oral LT3 Therapy for Heart Failure - HFrEF

Study Overview
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Brief Summary
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Investigation of the safety, feasibility, and preliminary efficacy of thyroid hormone therapy with Liothyronine (LT3) in individuals with heart failure with reduced ejection fraction (HFrEF) and low triiothyronine (T3) syndrome by conducting a randomized, double-blind, placebo-controlled cross-over study with a two week washout period between treatments.

Detailed Description
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The overall goal is to determine the safety, feasibility, and preliminary efficacy of administering oral LT3 therapy in the study population of participants with heart failure with reduced ejection fraction (HFrEF). Each treatment period will be approximately 8 weeks in duration, with weekly titration of study drug for 4 weeks, followed by a maintenance dose for 4 weeks, then 2-week washout before crossing over to the other arm (placebo or drug). LT3 will be titrated to T3 levels.

Official Title
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Developing Oral LT3 Therapy For Heart Failure With Reduced Ejection Fraction

Conditions
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Heart Failure With Reduced Ejection Fraction, Low Triiodothyronine Syndrome

Intervention / Treatment
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* Drug: liothyronine or placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men and women aged ≥18 years NYHA Class I, II or III heart failure EF≤40 percent within the past year An implantable cardioverter-defibrillator (ICD) Stable doses of neurohormonal blockade for 30 days TSH and free T4 level within the laboratory reference range and total T3 level <94 ng/dL Exclusion Criteria: Hypertrophic or restrictive cardiomyopathy Uncorrected severe primary valvular disease Arrhythmia that results in irregular heart rate Inability to perform VO2max exercise testing Severe lung disease, including treatment with oral steroids within past 6 months for exacerbation of obstructive lung disease or use of daytime supplemental oxygen Serum creatinine > 3.0 mg/dL History of cirrhosis LVAD use Heart failure hospitalization within past month Acute coronary syndrome, coronary intervention or ablation therapy within past 2 months or cardiac surgery, percutaneous repair of a valve or septal defect repair within the past 6 months Taking thyroid extract, LT4, LT3, amiodarone, or medication that affects the absorption or metabolism of thyroid hormone; gastrointestinal conditions that affect the absorption of thyroid hormone If female, current or planned pregnancy within the timeframe of study participation Any medical condition that in the opinion of the investigator, will interfere with the safe completion of the study.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Liothyronine (LT3)<br>Liothyronine (L-triiodothyronine or LT3) in the 5 mcg tablet dose formulation. Minimum LT3 dose will be 2.5 mcg three times daily and the maximum LT3 dose will be 12.5 mcg three times daily. | Drug: liothyronine or placebo<br>* Each treatment period of liothyronine or placebo will be approximately 8 weeks in duration, with weekly titration of study drug for four weeks, followed by a maintenance dose for 4 weeks, then 2-week washout before crossing over to receive the alternate therapy - placebo or LT3.<br>|
| Placebo Comparator: Placebo<br>A placebo tablet matching in appearance to LT3 tablets dosed equivalently. Minimum placebo tablet dose will be 1/2 tablet (2.5 mcg equivalent) three times daily and the maximum placebo dose will be 2 1/2 tablets (12.5 mcg equivalent) three times daily. | Drug: liothyronine or placebo<br>* Each treatment period of liothyronine or placebo will be approximately 8 weeks in duration, with weekly titration of study drug for four weeks, followed by a maintenance dose for 4 weeks, then 2-week washout before crossing over to receive the alternate therapy - placebo or LT3.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cardiac Rhythm Monitoring by 14 day Patch Rhythm Assessment | Percent increase (atrial fibrillation, ventricular tachycardia, supraventricular and ventricular) ectopy | continuous during intervention (14 days) | 
| T3 Level | Percentage of participant T3 levels above upper limit of reference range | 8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Peak Maximal Rate of Oxygen Consumption During Exercise (VO2 Max) | Change peak rate of oxygen consumption | 8 weeks | 
| Measure of Quality of Life | Change in Kansas City Cardiomyopathy Questionnaire, KCCQ | 8 weeks | 
| Actigraphy | Change in remotely sensed difference in counts per minute (CPM) | 8 weeks | 
| NT-proBNP levels | Change in B-type natriuretic peptide, Pg/mL | 8 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Heart Failure, HFrEF, Low T3 Syndrome