Developing Oral LT3 Therapy for Heart Failure - HFrEF

Phase 1

Completed

• Conditions: Heart Failure With Reduced Ejection Fraction (HFrEF); Low T3 Syndrome
• Interventions: Drug: Liothyronine; Other: Placebo

• Registration Number: NCT04112316
• Lead Sponsor: University of Pennsylvania

Brief Summary

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 triiodothyronine (T3) syndrome by conducting a randomized, double-blind, placebo-controlled cross-over study with a two-week washout period between treatments.

Detailed Description

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). The study will consist of two treatment periods - 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.

Study Timeline

• Study First Submitted: 2019-09-30
• Study First Submitted QC: 2019-09-30
• Study First Posted: 2019-10-02
• Study Start: 2020-02-11
• Primary Completion: 2023-10-31
• Study Completion: 2023-10-31
• Disposition First Submitted: 2024-07-24
• Results First Submitted: 2024-08-27
• Status Verified: 2024-12
• Results First Submitted QC: 2024-12-16
• Last Update Submitted: 2024-12-16
• Results First Posted: 2024-12-24
• Disposition First Posted: 2024-12-24
• Last Update Posted: 2024-12-24

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 28

Inclusion Criteria

1. Men and women aged ≥18 years
2. NYHA Class I, II or III heart failure
3. EF≤40 percent within the past year
4. An implantable cardioverter-defibrillator (ICD)
5. Stable doses of neurohormonal blockade for 30 days
6. TSH and free T4 level within the laboratory reference range and total T3 level <94 ng/dL

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Exclusion Criteria

1. Hypertrophic or restrictive cardiomyopathy
2. Uncorrected severe primary valvular disease
3. Arrhythmia that results in irregular heart rate
4. Inability to perform VO2max exercise testing
5. Severe lung disease, including treatment with oral steroids within past 6 months for exacerbation of obstructive lung disease or use of daytime supplemental oxygen
6. Serum creatinine > 3.0 mg/dL
7. History of cirrhosis
8. LVAD use
9. Heart failure hospitalization within past month
10. 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
11. 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
12. If female, current or planned pregnancy within the timeframe of study participation
13. Any medical condition that in the opinion of the investigator, will interfere with the safe completion of the study.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Liothyronine (LT3), then placebo	Liothyronine	Participants received liothyronine first, 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 placebo for 8 weeks.
Liothyronine (LT3), then placebo	Placebo	Participants received liothyronine first, 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 placebo for 8 weeks.
Placebo, then liothyronine	Liothyronine	Participants received placebo first, with weekly sham titration for four weeks, followed by a maintenance dose for 4 weeks, then 2-week washout before crossing over to receive LT3 for 8 weeks.
Placebo, then liothyronine	Placebo	Participants received placebo first, with weekly sham titration for four weeks, followed by a maintenance dose for 4 weeks, then 2-week washout before crossing over to receive LT3 for 8 weeks.

Primary Outcome Measures

Name	Time	Method
Cardiac Rhythm Monitoring by 14 Day Patch Rhythm Assessment	continuous during intervention (14 days)	Number of participants with atrial fibrillation or ventricular tachycardia \>= 4 beats
T3 Level	8 weeks	Number of participants with T3 levels above upper limit of reference range

Secondary Outcome Measures

Name	Time	Method
Change in Peak Maximal Rate of Oxygen Consumption During Exercise (VO2 Max)	8 weeks	Change in peak rate of oxygen consumption during exercise between baseline and 8 weeks
Change in Kansas City Cardiomyopathy Questionnaire (KCCQ) Quality of Life	8 weeks	Change in KCCQ from baseline to 8 weeks, 0-100 scale, higher is better
Activity Measured Via Actigraphy	8 weeks	Remotely sensed minutes/day of cumulative light, moderate, or vigorous activity in minutes/day after 8 weeks of LT3 or placebo
Change in NT-proBNP Levels	8 weeks	Change in B-type natriuretic peptide levels, Pg/mL, from baseline to 8 weeks

Trial Locations

Locations (1)

PennMedicine; 🇺🇸 Philadelphia, Pennsylvania, United States