Repurposing Valsartan May Protect Against Pulmonary Hypertension (REVAMP-PH)

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.

Study Overview

• Status: Recruiting
• Conditions: Pulmonary Arterial Hypertension; Right Ventricular Dysfunction; Right Heart Failure; Pulmonary Vascular Disorder
• Intervention / Treatment: Drug: Valsartan 40 mg; Drug: Placebo

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.

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.

• Study Type: Interventional
• Enrollment (Estimated): 60
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Laurie Hogl, RRT; Phone Number: 206.543.8334; Email: lalnaser@uw.edu
• Study Contact Backup: Name: Nancy Liston, MS; Phone Number: 206.543.8334; Email: nmliston@uw.edu

Study Locations

• United States
  • Washington
    • Seattle, Washington, United States, 98195
      • Recruiting
      • University of Washington Medical Center
      • Contact: Laurie Hogl; Phone Number: 206-543-8334; Email: lalnaser@uw.edu
      • Principal Investigator: Peter J Leary, MD, PhD
      • Sub-Investigator: Yonatan Buber, MD
      • Sub-Investigator: Sam G Rayner, MD
      • Sub-Investigator: Lia M Barros, DNP

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Male or female, age 18 to 80
2. WHO Group 1 Pulmonary Arterial Hypertension
3. NYHA Functional Class II, III, or IV at screening (Appendix 2 for Functional Class Decision Aid)
4. 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
5. 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
6. Able to walk with/without a walking aid for a distance of at least 50 meters

Exclusion Criteria:

1. Pregnant or lactating
2. Non-group 1 pulmonary hypertension or veno-occlusive disease
3. 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 %
4. Has received or will receive an investigational drug, device, or study within 30 days or during the course of study
5. ACE-inhibitor, ARB or ARNI use within 30 days of randomization.
6. Left sided myocardial disease as evidenced by left ventricular ejection fraction < 40%
7. 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
8. Anticipated survival less than 1 year due to concomitant disease
9. Allergy or angioedema with ACE-inhibitor use
10. Potassium >5mEq/L or sCr >2mg/dL at screening
11. SBP <90mmHg at screening

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Valsartan; Valsartan 40mg capsule taken twice daily for 24 weeks.	Drug: Valsartan 40 mg; Valsartan 40mg twice daily for 24 weeks.; Other Names: Diovan
Placebo Comparator: Placebo; Placebo capsule taken twice daily for 24 weeks.	Drug: Placebo; Placebo twice daily for 24 weeks.

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in invasive hemodynamics (sub-study): Stroke Volume Index	To determine whether valsartan increases stroke volume index at 24 weeks	0 to 24 weeks
Change in invasive hemodynamics (sub-study): Wedge pressure	Exploratory: To explore whether valsartan is associated with differences in wedge pressure at 24 weeks	0 to 24 weeks
Change in invasive hemodynamics (sub-study): Right Atrial pressure	Exploratory: To explore whether valsartan is associated with differences in right atrial pressure at 24 weeks	0 to 24 weeks
Change in invasive hemodynamics (sub-study): Pulmonary Vascular Resistance	Exploratory: To explore whether valsartan is associated with differences in pulmonary vascular resistance at 24 weeks	0 to 24 weeks
Change in Cardiopulmonary Exercise Testing (sub-study): Maximal oxygen uptake	To determine whether valsartan increases maximal oxygen uptake in individuals with pulmonary arterial hypertension at 24 weeks	0 to 24 weeks
Change in Cardiopulmonary Exercise Testing (sub-study): Ve/VCO2 slope	Exploratory: To explore whether valsartan decreases the Ve/VCO2 slope in individuals with pulmonary arterial hypertension over 24 weeks	0 to 24 weeks
Change in Cardiopulmonary Exercise Testing (sub-study): Total wattage	Exploratory: To explore whether valsartan increases total achieved wattage in individuals with pulmonary arterial hypertension over 24 weeks	0 to 24 weeks

Collaborators and Investigators

• Sponsor: University of Washington
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI)
• Investigators: Principal Investigator: Peter Leary, MD, PhD, University of Washington

Publications and helpful links

General Publications

• Lahm T, Hess E, Baron AE, Maddox TM, Plomondon ME, Choudhary G, Maron BA, Zamanian RT, Leary PJ. Renin-Angiotensin-Aldosterone System Inhibitor Use and Mortality in Pulmonary Hypertension: Insights From the Veterans Affairs Clinical Assessment Reporting and Tracking Database. Chest. 2021 Apr;159(4):1586-1597. doi: 10.1016/j.chest.2020.09.258. Epub 2020 Oct 5.

Study record dates

Study Major Dates

• Study Start (Actual): February 28, 2024
• Primary Completion (Estimated): July 1, 2027
• Study Completion (Estimated): July 1, 2027

Study Registration Dates

• First Submitted: September 7, 2023
• First Submitted That Met QC Criteria: September 13, 2023
• First Posted (Actual): September 25, 2023

Study Record Updates

• Last Update Posted (Actual): March 15, 2024
• Last Update Submitted That Met QC Criteria: March 13, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Respiratory Tract Diseases; Lung Diseases; Hypertension; Vascular Diseases; Pulmonary Arterial Hypertension; Hypertension, Pulmonary; Ventricular Dysfunction; Ventricular Dysfunction, Right; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; Valsartan
• Other Study ID Numbers: STUDY00018685; R61HL167848 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No