Clinical trial NCT03554291: Repurposing a Histamine Antagonist to Benefit Patients With Pulmonary Hypertension
Official title: Repurposing a Histamine Antagonist to Benefit Patients With Pulmonary Hypertension
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Pulmonary Arterial Hypertension
Right Heart Failure
Keywords: famotidine
H2 blocker
H2 antagonist
Lead sponsor: University of Washington
Sponsor class: OTHER
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
First posted: 2018-06-13
Enrollment: 80
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Change in Six-minute Walk Distance
timeFrame: 0 to 24 weeks
Secondary outcomes:
measure: Chang in Log-transformed BNP
timeFrame: 0 to 24 weeks
measure: Proportion of Participants With New York Heart Association (NYHA) Functional Class of I or II at Week 24
timeFrame: 24 weeks
measure: Change in Right Ventricular Morphology by Echocardiogram (RV Dilation and TAPSE)
timeFrame: 0 to 24 weeks
measure: Change in Health Related Quality of Life (emPHasis-10 Questionnaire)
timeFrame: 0 to 24 weeks
measure: 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.
timeFrame: 0 to 24 weeks
Other outcomes:
measure: Invasive Hemodynamics (Sub-study): Stroke Volume Index
timeFrame: 0 to 24 weeks
measure: Cardiopulmonary Exercise Testing (Sub-study): Maximal Oxygen Uptake
timeFrame: 0 to 24 weeks
measure: Invasive Hemodynamics (Sub-study): Hemodynamics
timeFrame: 0 to 24 weeks
measure: Cardiopulmonary Exercise Testing (Sub-study): Exercise
timeFrame: 0 to 24 weeks
Locations:
city: Seattle
country: United States
facility: University of Washington Medical Center
state: Washington
Study officials:
affiliation: University of Washington
name: Peter J Leary, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Leary PJ, Barr RG, Bluemke DA, Bristow MR, Kronmal RA, Lima JA, Ralph DD, Ventetuolo CE, Kawut SM. H2 receptor antagonists and right ventricular morphology: the MESA right ventricle study. Ann Am Thorac Soc. 2014 Nov;11(9):1379-86. doi: 10.1513/AnnalsATS.201407-344OC.
citation: Leary PJ, Tedford RJ, Bluemke DA, Bristow MR, Heckbert SR, Kawut SM, Krieger EV, Lima JA, Masri CS, Ralph DD, Shea S, Weiss NS, Kronmal RA. Histamine H2 Receptor Antagonists, Left Ventricular Morphology, and Heart Failure Risk: The MESA Study. J Am Coll Cardiol. 2016 Apr 5;67(13):1544-1552. doi: 10.1016/j.jacc.2016.01.045.
citation: Leary PJ, Kronmal RA, Bluemke DA, Buttrick PM, Jones KL, Kao DP, Kawut SM, Krieger EV, Lima JA, Minobe W, Ralph DD, Tedford RJ, Weiss NS, Bristow MR. Histamine H2 Receptor Polymorphisms, Myocardial Transcripts, and Heart Failure (from the Multi-Ethnic Study of Atherosclerosis and Beta-Blocker Effect on Remodeling and Gene Expression Trial). Am J Cardiol. 2018 Jan 15;121(2):256-261. doi: 10.1016/j.amjcard.2017.10.016. Epub 2017 Oct 20.
citation: Leary PJ, Hess E, Baron AE, Branch KR, Choudhary G, Hough CL, Maron BA, Ralph DD, Ryan JJ, Tedford RJ, Weiss NS, Zamanian RT, Lahm T. H2 Receptor Antagonist Use and Mortality in Pulmonary Hypertension: Insight from the VA-CART Program. Am J Respir Crit Care Med. 2018 Jun 15;197(12):1638-1641. doi: 10.1164/rccm.201801-0048LE. No abstract available.