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

• ClinicalTrials.gov Identifier: NCT06053580
• Recruitment Status: Recruiting
• First Posted: September 25, 2023
• Last Update Posted: March 15, 2024
• Sponsor: University of Washington
• Collaborator: National Heart, Lung, and Blood Institute (NHLBI)
• Information provided by (Responsible Party): Peter Leary, University of Washington

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Pulmonary Arterial Hypertension; Right Heart Failure; Right Ventricular Dysfunction; Pulmonary Vascular Disorder	Drug: Valsartan 40 mg; Drug: Placebo	Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 60 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Repurposing Valsartan May Protect Against Pulmonary Hypertension
• Actual Study Start Date: February 28, 2024
• Estimated Primary Completion Date: July 1, 2027
• Estimated Study Completion Date: July 1, 2027

Arms and Interventions

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 Name: Diovan
Placebo Comparator: Placebo; Placebo capsule taken twice daily for 24 weeks.	Drug: Placebo; Placebo twice daily for 24 weeks.

Outcome Measures

Primary Outcome Measures :

1. Six-minute walk distance [ Time Frame: 0 to 24 weeks ]
   To determine whether valsartan increases six-minute walk distance at 24 weeks in men and women with pulmonary arterial hypertension.

Secondary Outcome Measures :

1. Change in BNP [ Time Frame: 0 to 24 weeks ]
   To determine whether valsartan reduces BNP at 24 weeks
2. Change in New York Heart Association (NYHA) functional class [ Time Frame: 0 to 24 weeks ]
   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)
3. Change in right ventricular morphology by echocardiogram (right ventricular dilation) [ Time Frame: 0 to 24 weeks ]
   To determine whether valsartan improves right ventricular morphology at 24 weeks including improved right ventricular dilation
4. Change in right ventricular morphology by echocardiogram (tricuspid annular plane systolic excursion(TAPSE)) [ Time Frame: 0 to 24 weeks ]
   To determine whether valsartan improves right ventricular morphology at 24 weeks including improved TAPSE
5. Change in health related quality of life (emPHasis-10 questionnaire) [ Time Frame: 0 to 24 weeks ]
   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)
6. Frequency of escalation for PAH focused care (increased diuretics, escalating doses of pulmonary vasodilators, and/or adding additional pulmonary vasodilators) [ Time Frame: 0 to 24 weeks ]
   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)

Other Outcome Measures:

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

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 80 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Contacts

Contact: Laurie Hogl, RRT; 206.543.8334; lalnaser@uw.edu

Contact: Nancy Liston, MS; 206.543.8334; nmliston@uw.edu

Locations

United States, Washington

University of Washington Medical Center; Recruiting

Seattle, Washington, United States, 98195

Contact: Laurie Hogl 206-543-8334 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

Sponsors and Collaborators

University of Washington

National Heart, Lung, and Blood Institute (NHLBI)

Investigators

• Principal Investigator: Peter Leary, MD, PhD; University of Washington

More Information

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.

• Responsible Party: Peter Leary, Associate Professor, School of Medicine, University of Washington
• ClinicalTrials.gov Identifier: NCT06053580
• Other Study ID Numbers: STUDY00018685; R61HL167848 ( U.S. NIH Grant/Contract )
• First Posted: September 25, 2023
• Last Update Posted: March 15, 2024
• Last Verified: March 2024

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• 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

Additional relevant MeSH terms:

Hypertension, Pulmonary; Pulmonary Arterial Hypertension; Hypertension; Ventricular Dysfunction; Ventricular Dysfunction, Right; Vascular Diseases; Cardiovascular Diseases; Heart Diseases; Lung Diseases; Respiratory Tract Diseases; Valsartan; Antihypertensive Agents; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; Molecular Mechanisms of Pharmacological Action