Developing Oral LT3 Therapy for Heart Failure - HFpEF

NCT ID: NCT04111536

Last Updated: 2025-01-08

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 28 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-03-08
• Study Completion Date: 2023-10-31

Brief Summary

Investigation of the safety, feasibility, and preliminary efficacy of thyroid hormone therapy with Liothyronine (LT3) in individuals with heart failure with preserved ejection fraction (HFpEF) 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 preserved ejection fraction (HFpEF). 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.

Conditions

Heart Failure With Preserved Ejection Fraction; Low Triiodothyronine Syndrome

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

Liothyronine (LT3), then placebo

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.

Group Type: ACTIVE_COMPARATOR

liothyronine

Intervention Type: DRUG

Each treatment period of liothyronine was 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.

Placebo

Intervention Type: OTHER

Each treatment period of placebo was 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 - LT3.

Placebo, then Liothyronine

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.

Group Type: PLACEBO_COMPARATOR

liothyronine

Intervention Type: DRUG

Each treatment period of liothyronine was 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.

Placebo

Intervention Type: OTHER

Each treatment period of placebo was 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 - LT3.

Interventions

liothyronine

Each treatment period of liothyronine was 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.

Intervention Type: DRUG

Placebo

Each treatment period of placebo was 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 - LT3.

Intervention Type: OTHER

Other Intervention Names

LT3

Eligibility Criteria

Inclusion Criteria

Men and women aged ≥18 years; NYHA Class I, II or III heart failure or dyspnea on exertion without a clinically identifiable alternative cause; left ventricular ejection fraction greater than or equal to 40 percent; if taking antihypertensive medications, beta-blockers, SGLT2inhibitors, sacubitril/valsartan, or aldosterone antagonists, doses must be stable for at least 30 days. Elevated filling pressures as evidenced by at least 1 of the following:

1. Mitral E/e' ratio > 14 (either lateral or septal)

2. Mitral E/e' ratio > 8 (either lateral or septal), with low e' velocity (septal e'<7 cm/sec or lateral e'< 10 cm/sec), in addition to one of the following:

1. Enlarged left atrium (LA volume index >34 ml/m2)

2. Chronic loop diuretic use for control of symptoms

3. Elevated natriuretic peptides (BNP levels >100 ng/L or NT-proBNP levels >300 ng/L)

4. Tricuspid regurgitation velocity >2.8 m/s

3. Elevated invasively-determined filling pressures previously (resting LVEDP >16 mmHg or mean pulmonary capillary wedge pressure [PCWP] >12 mmHg; or PCWP/LVEDP ≥25 mmHg with exercise)

4. Acute heart failure decompensation with radiographic evidence of pulmonary venous congestion or alveolar edema, requiring IV diuretics within the past year

5. Probability of HFpEF>90%according to the HFpEF score,without a more likely apparent cause for symptoms as per Investigator assessment. TSH and free T4 level within the protocol specified reference range and total T3 level less than or equal to 0.94 ng/dL; if taking oral estrogen, dose must remain stable for duration of study participation.

Exclusion Criteria

Hypertrophic or restrictive cardiomyopathy or uncorrected severe primary valvular disease; inability to perform VO2max exercise testing; severe lung disease; treatment with oral steroids within past 6 months for an exacerbation of obstructive lung disease, or the use of daytime oxygen; serum creatinine > 3.0 mg/dL; history of cirrhosis; acute coronary syndrome or coronary artery intervention or ablation therapy within past 2 months; cardiac surgery or percutaneous valve or septal defect repair within the past 6 months; heart failure hospitalization within past month; 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; current or planned pregnancy within the timeframe of study participation; any medical condition that, in the opinion of the investigator, will interfere with safe completion of the study.

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• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Heart, Lung, and Blood Institute (NHLBI)

NIH

Sponsor Role: collaborator

University of Pennsylvania

OTHER

Sponsor Role: lead

Responsible Party

Anne Cappola, MD

Professor of Medicine

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Anne R Cappola, MD,ScM

Role: PRINCIPAL_INVESTIGATOR

University of Pennsylvania

Locations

Penn Medicine

Philadelphia, Pennsylvania, United States

Countries

United States

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

1R61HL146390-01

Identifier Type: NIH

Identifier Source: secondary_id

View Link

833681p

Identifier Type: -

Identifier Source: org_study_id