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

Developing Oral LT3 Therapy For Heart Failure With Reduced Ejection Fraction

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.

Study Overview

• Status: Completed
• Conditions: Heart Failure With Reduced Ejection Fraction; Low Triiodothyronine Syndrome
• Intervention / Treatment: Drug: liothyronine or 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 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.

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

Contacts and Locations

• Study Contact: Name: Anne C Holland, BA; Phone Number: 215-573-0902; Email: anne.holland@pennmedicine.upenn.edu

Study Locations

• United States
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • PennMedicine

Participation Criteria

Eligibility Criteria

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

Description

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

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.

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); 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; 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.
Placebo Comparator: Placebo; 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; 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.

What is the study measuring?

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
Actigraphy	Change in remotely sensed difference in counts per minute (CPM)	8 weeks
Measure of Quality of Life	Change in Kansas City Cardiomyopathy Questionnaire, KCCQ	8 weeks
NT-proBNP levels	Change in B-type natriuretic peptide, Pg/mL	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): February 11, 2020
• Primary Completion (Actual): August 31, 2023
• Study Completion (Actual): August 31, 2023

Study Registration Dates

• First Submitted: September 30, 2019
• First Submitted That Met QC Criteria: September 30, 2019
• First Posted (Actual): October 2, 2019

Study Record Updates

• Last Update Posted (Actual): September 26, 2023
• Last Update Submitted That Met QC Criteria: September 22, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: Heart Failure, HFrEF, Low T3 Syndrome
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Heart Failure
• Other Study ID Numbers: 833681r; 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
• product manufactured in and exported from the U.S.: No