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.

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.

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

One participant withdrew from the study after randomization but before receipt of study drug and without knowledge of their assigned arm. They were not included in analyses in accordance with the plan to proceed with modified intent to treat.

Adverse events were collected over 24 weeks.

Events were collected during all study visits and on a continuous basis as reported by participants or their proxies.