Developing Oral LT3 Therapy for Heart Failure - HFpEF

Heart Failure With Preserved Ejection Fraction Clinical Trial

— DOT3HF-HFpEF  

Official title:

Developing Oral LT3 Therapy For Heart Failure With Preserved Ejection Fraction

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04111536
• Other study ID #: 833681p
• Secondary ID: 1R61HL146390-01
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: March 8, 2020
• Est. completion date: October 31, 2023

Study information

• Verified date: January 2024
• Source: University of Pennsylvania
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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). 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 28
• Est. completion date: October 31, 2023
• Est. primary completion date: October 31, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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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Related Conditions & MeSH terms

• Heart Failure
• Heart Failure With Preserved Ejection Fraction
• Low Triiodothyronine Syndrome

Intervention

Drug:
• liothyronine or placebo
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.

Locations

Country	Name	City	State
United States	Penn Medicine	Philadelphia	Pennsylvania

Sponsors (2)

Lead Sponsor	Collaborator
University of Pennsylvania	National Heart, Lung, and Blood Institute (NHLBI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Cardiac Rhythm Monitoring by 14 day Patch Rhythm Assessment	Percent increase (atrial fibrillation, ventricular tachycardia, supraventricular and ventricular) ectopy	continuous during intervention (14 days)
Primary	T3 Level	Percentage of participant T3 levels above upper limit of reference range	8 weeks
Secondary	Peak Maximal Rate of Oxygen Consumption During Exercise (VO2 Max)	Change peak rate of oxygen consumption	8 weeks
Secondary	Measure of Quality of Life	Change Kansas City Cardiomyopathy Questionnaire, KCCQ	8 weeks
Secondary	Actigraphy	Change in remotely sensed difference in counts per minute (CPM)	8 weeks
Secondary	NT-proBNP Levels	Change in B-type natriuretic peptide, Pg/mL	8 weeks