Heart Failure With Reduced Ejection Fraction (HFrEF), Low T3 Syndrome
Conditions
Keywords
Heart Failure, HFrEF, Low T3 Syndrome
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.
Interventions
DRUGLiothyronine
Liothyronine (L-triiodothyronine or LT3) in the 5 mcg tablet dose formulation. Minimum LT3 dose was 2.5 mcg three times daily and the maximum LT3 dose was 12.5 mcg three times daily.
OTHERPlacebo
A placebo tablet matching in appearance to LT3 tablets. Minimum placebo tablet dose was 1/2 tablet three times daily and the maximum placebo dose was 2 1/2 tablets three times daily.
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
University of Pennsylvania
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Masking description
Participant, Investigators and Care Providers are blinded to LT3 vs. Placebo and T3 results. There will be 1 unblinded physician in the study.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Liothyronine (LT3), Then 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.
Liothyronine: Liothyronine (L-triiodothyronine or LT3) in the 5 mcg tablet dose formulation. Minimum LT3 dose was 2.5 mcg three times daily and the maximum LT3 dose was 12.5 mcg three times daily.
Placebo: A placebo tablet matching in appearance to LT3 tablets. Minimum placebo tablet dose was 1/2 tablet three times daily and the maximum placebo dose was 2 1/2 tablets three times daily. | 14 |
| Placebo, Then 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.
Liothyronine: Liothyronine (L-triiodothyronine or LT3) in the 5 mcg tablet dose formulation. Minimum LT3 dose was 2.5 mcg three times daily and the maximum LT3 dose was 12.5 mcg three times daily.
Placebo: A placebo tablet matching in appearance to LT3 tablets. Minimum placebo tablet dose was 1/2 tablet three times daily and the maximum placebo dose was 2 1/2 tablets three times daily. | 14 |
| Total | 28 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| First Period (8 Weeks) | Lost to Follow-up | 1 | 0 |
| First Period (8 Weeks) | Protocol Violation | 1 | 0 |
Baseline characteristics
| Characteristic | Liothyronine (LT3), Then Placebo | Placebo, Then Liothyronine | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 9 Participants | 6 Participants | 15 Participants |
| Age, Categorical Between 18 and 65 years | 5 Participants | 8 Participants | 13 Participants |
| Age, Continuous | 63.9 years STANDARD_DEVIATION 11 | 59.0 years STANDARD_DEVIATION 12.3 | 61.4 years STANDARD_DEVIATION 11.9 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 0 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 12 Participants | 14 Participants | 26 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 4 Participants | 6 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 12 Participants | 10 Participants | 22 Participants |
| Region of Enrollment United States | 14 participants | 14 participants | 28 participants |
| Sex: Female, Male Female | 2 Participants | 4 Participants | 6 Participants |
| Sex: Female, Male Male | 12 Participants | 10 Participants | 22 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 28 | 0 / 28 |
| other Total, other adverse events | 15 / 28 | 9 / 28 |
| serious Total, serious adverse events | 0 / 28 | 0 / 28 |
Outcome results
Primary
Cardiac Rhythm Monitoring by 14 Day Patch Rhythm Assessment
Number of participants with atrial fibrillation or ventricular tachycardia \>= 4 beats
Time frame: continuous during intervention (14 days)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Liothyronine (LT3) | Cardiac Rhythm Monitoring by 14 Day Patch Rhythm Assessment | 11 Number of participants with events |
| Placebo | Cardiac Rhythm Monitoring by 14 Day Patch Rhythm Assessment | 19 Number of participants with events |
Primary
T3 Level
Number of participants with T3 levels above upper limit of reference range
Time frame: 8 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Liothyronine (LT3) | T3 Level | 4 Participants |
| Placebo | T3 Level | 0 Participants |
Secondary
Activity Measured Via Actigraphy
Remotely sensed minutes/day of cumulative light, moderate, or vigorous activity in minutes/day after 8 weeks of LT3 or placebo
Time frame: 8 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Liothyronine (LT3) | Activity Measured Via Actigraphy | 241 minutes/day | Standard Deviation 83 |
| Placebo | Activity Measured Via Actigraphy | 265 minutes/day | Standard Deviation 82 |
Secondary
Change in Kansas City Cardiomyopathy Questionnaire (KCCQ) Quality of Life
Change in KCCQ from baseline to 8 weeks, 0-100 scale, higher is better
Time frame: 8 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Liothyronine (LT3) | Change in Kansas City Cardiomyopathy Questionnaire (KCCQ) Quality of Life | 0.6 units on a scale | Standard Deviation 6.8 |
| Placebo | Change in Kansas City Cardiomyopathy Questionnaire (KCCQ) Quality of Life | -0.6 units on a scale | Standard Deviation 10.3 |
Secondary
Change in NT-proBNP Levels
Change in B-type natriuretic peptide levels, Pg/mL, from baseline to 8 weeks
Time frame: 8 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Liothyronine (LT3) | Change in NT-proBNP Levels | 66.1 pg/mL | Standard Deviation 248.3 |
| Placebo | Change in NT-proBNP Levels | 98.7 pg/mL | Standard Deviation 450.9 |
Secondary
Change in Peak Maximal Rate of Oxygen Consumption During Exercise (VO2 Max)
Change in peak rate of oxygen consumption during exercise between baseline and 8 weeks
Time frame: 8 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Liothyronine (LT3) | Change in Peak Maximal Rate of Oxygen Consumption During Exercise (VO2 Max) | 11.18 ml/kg/min | Standard Deviation 4.24 |
| Placebo | Change in Peak Maximal Rate of Oxygen Consumption During Exercise (VO2 Max) | 10.78 ml/kg/min | Standard Deviation 4.31 |