Repurposing Valsartan May Protect Against Pulmonary Hypertension

Study Overview
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Brief Summary
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This is a Phase 2, single-center, randomized placebo controlled trial of valsartan (an angiotensin receptor blocker) in adults with pulmonary arterial hypertension. The study will evaluate the safety and clinical efficacy of a 24-week course of valsartan.

Detailed Description
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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. Valsartan is a well-tolerated and inexpensive medication that is currently used to treat hypertension and left heart failure. Preliminary results suggest that valsartan 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 valsartan can impact right heart function. Participants in the study will take valsartan or placebo for 24 weeks. They will have three study visits at 0, 2, 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. The visits at weeks 2 and 12 may be completed remotely for most participants. 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.

Official Title
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Repurposing Valsartan May Protect Against Pulmonary Hypertension

Conditions
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Pulmonary Arterial Hypertension, Right Heart Failure, Right Ventricular Dysfunction, Pulmonary Vascular Disorder

Intervention / Treatment
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* Drug: Valsartan 40 mg
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female, age 18 to 80 WHO Group 1 Pulmonary Arterial Hypertension NYHA Functional Class II, III, or IV at screening (Appendix 2 for Functional Class Decision Aid) Right heart catheterization within five years demonstrating a mean pulmonary arterial pressure of ≥25 mmHg, occlusion pressure of ≤15 mmHg, and resistance ≥ 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 or vital capacity of ≥ 60 % Has received or will receive an investigational drug, device, or study within 30 days or during the course of study ACE-inhibitor, ARB or ARNI use within 30 days of randomization. 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 Allergy or angioedema with ACE-inhibitor use Potassium >5mEq/L or sCr >2mg/dL at screening SBP <90mmHg at screening

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Valsartan<br>Valsartan 40mg capsule taken twice daily for 24 weeks. | Drug: Valsartan 40 mg<br>* Valsartan 40mg twice daily for 24 weeks.<br>* Other names: Diovan;|
| Placebo Comparator: Placebo<br>Placebo capsule taken twice daily for 24 weeks. | Drug: Placebo<br>* Placebo twice daily for 24 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Six-minute walk distance | To determine whether valsartan increases six-minute walk distance at 24 weeks in men and women with pulmonary arterial hypertension. | 0 to 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in BNP | To determine whether valsartan reduces BNP at 24 weeks | 0 to 24 weeks | 
| Change in New York Heart Association (NYHA) functional class | To determine whether valsartan improves New York Heart Association (NYHA) functional class at 24 weeks (NYHA Functional Class is a score from 1 to 4 where higher scores connote worse health-related impairment) | 0 to 24 weeks | 
| Change in right ventricular morphology by echocardiogram (right ventricular dilation) | To determine whether valsartan improves right ventricular morphology at 24 weeks including improved right ventricular dilation | 0 to 24 weeks | 
| Change in right ventricular morphology by echocardiogram (tricuspid annular plane systolic excursion(TAPSE)) | To determine whether valsartan improves right ventricular morphology at 24 weeks including improved TAPSE | 0 to 24 weeks | 
| Change in health related quality of life (emPHasis-10 questionnaire) | To determine whether valsartan 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) | 0 to 24 weeks | 
| Frequency of escalation for PAH focused care (increased diuretics, escalating doses of pulmonary vasodilators, and/or adding additional pulmonary vasodilators) | To determine whether valsartan decreases the need to escalate PAH focused care (increased diuretics, escalating doses of pulmonary vasodilators, and/or adding an additional pulmonary vasodilator) | 0 to 24 weeks |