Developing Oral LT3 Therapy for Heart Failure - HFpEF (DOT3HF-HFpEF)

Developing Oral LT3 Therapy For Heart Failure With Preserved Ejection Fraction

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.

Study Overview

• Status: Completed
• Conditions: Heart Failure With Preserved Ejection Fraction; Low Triiodothyronine Syndrome
• Intervention / Treatment: Drug: liothyronine; Other: Placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 28
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Penn Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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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Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: 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.	Drug: 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.; Other Names: LT3; Other: 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.
Placebo Comparator: 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.	Drug: 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.; Other Names: LT3; Other: 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Atrial Fibrillation or Ventricular Tachycardia >=4 Beats	Number with atrial fibrillation or ventricular tachycardia >=4 beats	continuous during intervention (14 days)
T3 Level	Number 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)	Peak rate of oxygen consumption at 8 weeks	8 weeks
Measure of Quality of Life	Change in Kansas City Cardiomyopathy Questionnaire, KCCQ scale of 0 to 100, higher score is better outcome, from baseline to 8 weeks	8 weeks
Actigraphy	Remotely sensed minutes/day of cumulative light, moderate or vigorous activity after 8 weeks of LT3 or placebo	8 weeks
NT-proBNP Levels	Change in B-type natriuretic peptide, Pg/mL, from baseline to 8 weeks	8 weeks

Collaborators and Investigators

• Sponsor: University of Pennsylvania
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI)
• Investigators: Principal Investigator: Anne R Cappola, MD,ScM, University of Pennsylvania

Study record dates

Study Major Dates

• Study Start (Actual): March 8, 2020
• Primary Completion (Actual): October 31, 2023
• Study Completion (Actual): October 31, 2023

Study Registration Dates

• First Submitted: September 30, 2019
• First Submitted That Met QC Criteria: September 30, 2019
• First Posted (Actual): October 1, 2019

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: December 17, 2024
• Last Verified: December 1, 2024

More Information

Terms related to this study

• Keywords: Heart Failure, HFpEF, Low T3 Syndrome
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Heart Diseases; Heart Failure
• Other Study ID Numbers: 833681p; 1R61HL146390-01 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No