Pulmonary Arterial Hypertension, Right Heart Failure
Conditions
Keywords
famotidine, H2 blocker, H2 antagonist
Brief summary
This is a Phase 2, single-center, randomized placebo controlled trial of famotidine (an H2 receptor antagonist) in adults with pulmonary arterial hypertension. The study will evaluate the safety and clinical efficacy of a 24-week course of famotidine.
Detailed description
Pulmonary arterial hypertension (PAH) is one of many conditions that put stress and strain on the right side of the heart. This stress and strain can cause right heart failure. Although there are medications to treat PAH, there are currently no medications that act directly on the heart to improve right heart function. This is different than left heart failure where one of the cornerstones of treatment is medication targeted at the heart to improve left heart function. Famotidine is a well-tolerated, over-the-counter, and inexpensive medication. Preliminary results suggest that famotidine may help the right heart to adapt and strengthen when stressed instead of fail; however, these results are suggestive and not definitive. A randomized controlled trial is required to evaluate the possibility that famotidine can impact right heart function. Participants in the study will take famotidine or placebo for 24 weeks. They will have three study visits at 0, 12, and 24 weeks. These visits will add 20-30 minutes to the standard clinic visits at those time points and there will be an echocardiogram at weeks 0 and 24. There will also be one phone visit at 4 weeks to check-in. Some participants may elect to participate in exercise testing and/or right heart catheterization at weeks 0 and 24; however, this is not required to participate in the trial.
Interventions
OTHERPlacebo
Placebo capsule taken daily for 24 weeks.
DRUGFamotidine 20 MG
Famotidine 20 mg capsule taken daily for 24 weeks.
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
University of Washington
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Male or female, age 18 to 80 * WHO Group 1 Pulmonary Arterial Hypertension * NYHA Functional Class II, III, or IV at screening * Stable dose of pulmonary vasodilators for 30 days prior to randomization * Right heart catheterization within five years demonstrating a mean pulmonary arterial pressure of ≥ 25 mmHg, occlusion pressure of ≤ 15 mmHg, and pulmonary vascular resistance of ≥ 3 wood units * Participants with a right heart catheterization within five years demonstrating a mean pulmonary arterial pressure of ≥ 25 mmHg and occlusion pressure of 15 - 20 mmHg will be considered for inclusion if the pulmonary vascular resistance ≥ 9 wood units and they are being treated with pulmonary arterial hypertension specific therapy * Able to walk with/without a walking aid for a distance of at least 50 meters
Exclusion criteria
* Pregnant or lactating * Non-group 1 pulmonary hypertension or veno-occlusive disease * History of interstitial lung disease, unless subject has collagen vascular disease and has pulmonary function testing conducted within 12 months demonstrating a total lung capacity of ≥ 60 % * Has received or will receive an investigational drug, device, or study within 30 days or during the course of study * Left sided myocardial disease as evidenced by left ventricular ejection fraction \< 40% * Any other clinically significant illness or abnormal laboratory values (measured during the Screening period) that, in the opinion of the Investigator, might put the subject at risk of harm during the study or might adversely affect the interpretation of the study data * Anticipated survival less than 1 year due to concomitant disease * Regularly taking an H2 receptor antagonist within 30 days of enrollment * Creatinine clearance \< 30 mL/min * History of bariatric surgery * Current treatment for HIV
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Six-minute Walk Distance | 0 to 24 weeks | To determine whether famotidine increases six-minute walk distance at 24 weeks in men and women with pulmonary arterial hypertension |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Participants With New York Heart Association (NYHA) Functional Class of I or II at Week 24 | 24 weeks | NYHA functional class is graded from 1 to 4 (1: no symptoms of heart failure; 2: symptoms of heart failure with moderate exertion; 3: symptoms of heart failure with mild exertion; 4: symptoms of heart failure at rest). As such, NYHA functional class 1 is considered better than NYHA functional class 4. |
| Chang in Log-transformed BNP | 0 to 24 weeks | To determine whether famotidine reduces log-transformed BNP at 24 weeks |
| Change in Right Ventricular Morphology by Echocardiogram (RV Dilation and TAPSE) | 0 to 24 weeks | To determine whether famotidine improves right ventricular morphology at 24 weeks including improved right ventricular dilation and TAPSE |
| Change in Health Related Quality of Life (emPHasis-10 Questionnaire) | 0 to 24 weeks | To determine whether famotidine improves health related quality of life as estimated by the emPHasis-10 score (Each item on the emPHasis-10 questionnaire is scored on a semantic differential six-point scale (0-5), with contrasting adjectives at each end; EmPHasis-10 scores range from 0 to 50 with higher scores indicating worse quality of life). |
| Percent of Participants by Arm Who Added PAH Focused Care (Increased Diuretics, Escalating Doses of Pulmonary Vasodilators, and/or Adding Additional Pulmonary Vasodilators) Over 24 Weeks. | 0 to 24 weeks | To determine whether famotidine decreases the need to escalate PAH focused care (increased diuretics, escalating doses of pulmonary vasodilators, and/or adding an additional pulmonary vasodilator). The confidence interval includes a negative percent (e.g. a participant who de-escalated care). |
Other
| Measure | Time frame | Description |
|---|---|---|
| Invasive Hemodynamics (Sub-study): Hemodynamics | 0 to 24 weeks | Exploratory: To explore whether famotidine improves hemodynamics (wedge, RA, PVR) at 24 weeks |
| Cardiopulmonary Exercise Testing (Sub-study): Exercise | 0 to 24 weeks | Exploratory: To explore whether famotidine improves exercise (Ve/VCO2 ratio, total achieved wattage). |
| Cardiopulmonary Exercise Testing (Sub-study): Maximal Oxygen Uptake | 0 to 24 weeks | To determine whether famotidine increases maximal oxygen uptake in individuals with pulmonary arterial hypertension at 24 weeks |
| Invasive Hemodynamics (Sub-study): Stroke Volume Index | 0 to 24 weeks | To determine whether famotidine increases stroke volume index at 24 weeks |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Famotidine 20mg of oral famotidine (pill) daily
Other names: Pepcid
Famotidine 20 MG: Famotidine 20 mg capsule taken daily for 24 weeks. | 40 |
| Placebo Daily oral placebo (pill)
Placebo: Placebo capsule taken daily for 24 weeks. | 39 |
| Total | 79 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | COVID Travel Restriction- Partial Data Collected | 3 | 0 |
| Overall Study | Death | 2 | 1 |
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Famotidine | Total | Placebo |
|---|---|---|---|
| Age, Continuous | 49.9 years STANDARD_DEVIATION 13.7 | 50.6 years STANDARD_DEVIATION 13.2 | 51.4 years STANDARD_DEVIATION 12.7 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 6 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 37 Participants | 73 Participants | 36 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 2 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 3 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 2 Participants | 2 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 | 37 Participants | 72 Participants | 35 Participants |
| Sex: Female, Male Female | 32 Participants | 63 Participants | 31 Participants |
| Sex: Female, Male Male | 8 Participants | 16 Participants | 8 Participants |
| Six-minute walk distance | 414 meters STANDARD_DEVIATION 91 | 411 meters STANDARD_DEVIATION 99 | 407 meters STANDARD_DEVIATION 107 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 2 / 40 | 1 / 39 |
| other Total, other adverse events | 20 / 40 | 14 / 39 |
| serious Total, serious adverse events | 9 / 40 | 4 / 39 |
Outcome results
Primary
Change in Six-minute Walk Distance
To determine whether famotidine increases six-minute walk distance at 24 weeks in men and women with pulmonary arterial hypertension
Time frame: 0 to 24 weeks
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Famotidine | Change in Six-minute Walk Distance | -17.0 meters |
| Placebo | Change in Six-minute Walk Distance | 4.7 meters |
Secondary
Change in Health Related Quality of Life (emPHasis-10 Questionnaire)
To determine whether famotidine improves health related quality of life as estimated by the emPHasis-10 score (Each item on the emPHasis-10 questionnaire is scored on a semantic differential six-point scale (0-5), with contrasting adjectives at each end; EmPHasis-10 scores range from 0 to 50 with higher scores indicating worse quality of life).
Time frame: 0 to 24 weeks
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Famotidine | Change in Health Related Quality of Life (emPHasis-10 Questionnaire) | -1.7 score on a scale |
| Placebo | Change in Health Related Quality of Life (emPHasis-10 Questionnaire) | -1.3 score on a scale |
Secondary
Change in Right Ventricular Morphology by Echocardiogram (RV Dilation and TAPSE)
To determine whether famotidine improves right ventricular morphology at 24 weeks including improved right ventricular dilation and TAPSE
Time frame: 0 to 24 weeks
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Famotidine | Change in Right Ventricular Morphology by Echocardiogram (RV Dilation and TAPSE) | RV dilation | -1.5 RV basal diameter (cm)/TAPSE (mm) |
| Famotidine | Change in Right Ventricular Morphology by Echocardiogram (RV Dilation and TAPSE) | TAPSE | 0.1 RV basal diameter (cm)/TAPSE (mm) |
| Placebo | Change in Right Ventricular Morphology by Echocardiogram (RV Dilation and TAPSE) | RV dilation | 0.9 RV basal diameter (cm)/TAPSE (mm) |
| Placebo | Change in Right Ventricular Morphology by Echocardiogram (RV Dilation and TAPSE) | TAPSE | 0.7 RV basal diameter (cm)/TAPSE (mm) |
Secondary
Chang in Log-transformed BNP
To determine whether famotidine reduces log-transformed BNP at 24 weeks
Time frame: 0 to 24 weeks
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Famotidine | Chang in Log-transformed BNP | -0.05 Log of pg/mL |
| Placebo | Chang in Log-transformed BNP | 0.08 Log of pg/mL |
Secondary
Percent of Participants by Arm Who Added PAH Focused Care (Increased Diuretics, Escalating Doses of Pulmonary Vasodilators, and/or Adding Additional Pulmonary Vasodilators) Over 24 Weeks.
To determine whether famotidine decreases the need to escalate PAH focused care (increased diuretics, escalating doses of pulmonary vasodilators, and/or adding an additional pulmonary vasodilator). The confidence interval includes a negative percent (e.g. a participant who de-escalated care).
Time frame: 0 to 24 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Famotidine | Percent of Participants by Arm Who Added PAH Focused Care (Increased Diuretics, Escalating Doses of Pulmonary Vasodilators, and/or Adding Additional Pulmonary Vasodilators) Over 24 Weeks. | 8.1 model-based percentage of participants |
| Placebo | Percent of Participants by Arm Who Added PAH Focused Care (Increased Diuretics, Escalating Doses of Pulmonary Vasodilators, and/or Adding Additional Pulmonary Vasodilators) Over 24 Weeks. | 5.3 model-based percentage of participants |
Secondary
Proportion of Participants With New York Heart Association (NYHA) Functional Class of I or II at Week 24
NYHA functional class is graded from 1 to 4 (1: no symptoms of heart failure; 2: symptoms of heart failure with moderate exertion; 3: symptoms of heart failure with mild exertion; 4: symptoms of heart failure at rest). As such, NYHA functional class 1 is considered better than NYHA functional class 4.
Time frame: 24 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Famotidine | Proportion of Participants With New York Heart Association (NYHA) Functional Class of I or II at Week 24 | 0.71 Proportion participants NYHA class I/II |
| Placebo | Proportion of Participants With New York Heart Association (NYHA) Functional Class of I or II at Week 24 | 0.53 Proportion participants NYHA class I/II |
Other Pre-specified
Cardiopulmonary Exercise Testing (Sub-study): Exercise
Exploratory: To explore whether famotidine improves exercise (Ve/VCO2 ratio, total achieved wattage).
Time frame: 0 to 24 weeks
Other Pre-specified
Cardiopulmonary Exercise Testing (Sub-study): Maximal Oxygen Uptake
To determine whether famotidine increases maximal oxygen uptake in individuals with pulmonary arterial hypertension at 24 weeks
Time frame: 0 to 24 weeks
Other Pre-specified
Invasive Hemodynamics (Sub-study): Hemodynamics
Exploratory: To explore whether famotidine improves hemodynamics (wedge, RA, PVR) at 24 weeks
Time frame: 0 to 24 weeks
Other Pre-specified
Invasive Hemodynamics (Sub-study): Stroke Volume Index
To determine whether famotidine increases stroke volume index at 24 weeks
Time frame: 0 to 24 weeks