Valsartan for Pulmonary Hypertension

(REVAMP-PH Trial)

Overseen By Nancy Liston, MS

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of Washington

Must not be taking: ACE inhibitors, ARBs, ARNIs

Disqualifiers: Pregnancy, Non-group 1 hypertension, others

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 5 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 4

Duration: 24 weeks

60 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial requires that you stop taking ACE-inhibitors, ARBs, or ARNIs at least 30 days before joining. If you're on these medications, you'll need to stop them before participating.

What data supports the effectiveness of the drug Valsartan for treating pulmonary hypertension?

Research in rodents shows that Valsartan can help reduce pulmonary hypertension by lowering blood pressure in the lungs and preventing harmful changes in blood vessels. This suggests it might be a useful treatment for pulmonary hypertension in humans. ^{1 2 3 4 5}

How does the drug Valsartan differ from other treatments for pulmonary hypertension?

Valsartan is unique because it is an angiotensin II receptor blocker, which means it prevents a specific chemical in the body from causing blood vessels to tighten, helping to lower blood pressure. Unlike some other treatments for pulmonary hypertension, Valsartan is primarily used for high blood pressure and heart failure, and its role in pulmonary hypertension is still being explored. ^{6 7 8 9 10}

What is the purpose of this trial?

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.

Research Team

Peter Leary, MD, PhD

Principal Investigator

University of Washington

Eligibility Criteria

Adults aged 18-80 with WHO Group 1 Pulmonary Arterial Hypertension, able to walk at least 50 meters, and have specific heart catheterization results. Excluded are those with very low blood pressure or kidney function issues, expected short survival due to other diseases, certain lung conditions, recent investigational drug use, left heart disease, pregnancy/lactation, non-group 1 pulmonary hypertension or allergy to similar medications.

Inclusion Criteria

My heart tests show high lung blood pressure and I'm on specific treatment for it.

I can walk at least 50 meters, with or without help.

You had a heart test within the past five years that showed high pressure in the arteries of your lungs, low pressure in the veins of your lungs, and resistance in the blood vessels.

Exclusion Criteria

You are not expected to live for more than 1 year due to another serious illness.

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

My heart's left side is weak, with an ejection fraction below 40%.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive valsartan or placebo for 24 weeks. Visits occur at weeks 0, 2, 12, and 24, with echocardiograms at weeks 0 and 24. Some visits may be completed remotely.

24 weeks

4 visits (in-person/remote)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Valsartan

Trial Overview The trial is testing the safety and effectiveness of Valsartan (40 mg), an angiotensin receptor blocker for treating pulmonary arterial hypertension over a course of 24 weeks. Participants will be randomly assigned to receive either Valsartan or a placebo in this Phase 2 study.

Participant Groups

Group I: Valsartan Experimental Treatment 1 Intervention

Valsartan 40mg capsule taken twice daily for 24 weeks.

Group II: Placebo Placebo Group 1 Intervention

Placebo capsule taken twice daily for 24 weeks.

Valsartan is already approved in European Union, United States, Canada, Japan, China for the following indications:

Approved in European Union as Diovan for:

• Hypertension
• Heart failure
• Left ventricular dysfunction

Approved in United States as Diovan for:

• Hypertension
• Heart failure

Approved in Canada as Diovan for:

• Hypertension
• Heart failure

Approved in Japan as Valsartan for:

• Hypertension
• Heart failure

Approved in China as Valsartan for:

• Hypertension

Who Is Running the Clinical Trial?

University of Washington

Lead Sponsor

Trials

1,858

Recruited

2,023,000+

National Heart, Lung, and Blood Institute (NHLBI)

Collaborator

Trials

3,987

Recruited

47,860,000+

Findings from Research

The combination of sacubitril/valsartan (LCZ 696) and bosentan significantly reduces pulmonary pressures and improves right ventricular function in rat models of severe pulmonary hypertension, demonstrating superior efficacy compared to either drug alone.

This dual therapy not only protects against vascular remodeling but also increases levels of beneficial markers like atrial natriuretic peptide (ANP) and cyclic guanosine monophosphate (cGMP), suggesting a mechanism that enhances cardiovascular health in the context of pulmonary arterial hypertension.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Additive protective effects of sacubitril/valsartan and bosentan on vascular remodelling in experimental pulmonary hypertension. Chaumais, MC., Djessas, MRA., Thuillet, R., et al.[2022]

In a study of 500 patients with pulmonary arterial hypertension, initial combination therapy with ambrisentan and tadalafil significantly reduced the risk of clinical failure events by 50% compared to monotherapy, indicating its efficacy as a first-line treatment.

The combination therapy also led to greater improvements in key health markers, such as a 67.2% reduction in N-terminal pro-brain natriuretic peptide levels and a median increase of 48.98 meters in 6-minute walk distance, although it was associated with more frequent side effects like peripheral edema and headaches.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Initial Use of Ambrisentan plus Tadalafil in Pulmonary Arterial Hypertension. Galiè, N., Barberà, JA., Frost, AE., et al.[2022]

In a study of Japanese patients with pulmonary arterial hypertension (PAH), macitentan showed significantly higher treatment persistence compared to ambrisentan and bosentan after its approval in 2015, with median persistence of 18 months for macitentan versus 6 and 8 months for ambrisentan and bosentan, respectively.

The analysis included real-world data from 2008 to 2020, involving 153 patients on bosentan, 51 on ambrisentan before macitentan's approval, and 331 on macitentan after approval, indicating that macitentan may be a more effective long-term treatment option for PAH.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative Treatment Persistence and Adherence to Endothelin Receptor Antagonists Among Patients with Pulmonary Arterial Hypertension in Japan: A Real-World Administrative Claims Database Study. Omura, J., Makanji, Y., Tanabe, N., et al.[2023]

Valsartan, an AT1 receptor blocker, significantly reduced the development of pulmonary hypertension (PH) in both rats and mice, as shown by lower right ventricular pressure and less lung vascular remodeling.

The study revealed that valsartan works by inhibiting smooth muscle cell proliferation and reducing the expression of factors involved in extracellular matrix remodeling, suggesting it could be an effective treatment for PH.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Valsartan attenuates pulmonary hypertension via suppression of mitogen activated protein kinase signaling and matrix metalloproteinase expression in rodents. Lu, Y., Guo, H., Sun, Y., et al.[2018]

In a study of 28 Chinese patients with pulmonary hypertension, ambrisentan significantly improved exercise capacity, as measured by the six-minute walk distance, increasing from 372 m to 443 m after 12 weeks (P = 0.000).

The treatment also led to improvements in the World Health Organization functional class and a reduction in NT-proBNP levels, indicating better heart function, while showing no significant changes in liver function, suggesting it is well-tolerated.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Efficacy and safety of ambrisentan therapy in Chinese patients with pulmonary hypertension]. Chen, FD., Zhou, DX., Di, RM., et al.[2016]

Valsartan is an effective angiotensin receptor blocker that helps treat hypertension and is comparable in efficacy to ACE inhibitors for patients with myocardial infarction and heart failure.

In patients with congestive heart failure who cannot tolerate ACE inhibitors, valsartan not only reduces mortality but also decreases hospitalizations related to heart failure when used alongside ACE inhibitors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Valsartan: the past, present and future. Køber, L., Torp-Pedersen, C.[2009]

At a dose of 80 mg/day, valsartan effectively lowers blood pressure with a side effect profile similar to ACE inhibitors, but with a lower incidence of cough.

Valsartan does not show a clear advantage over losartan and has not been proven to prevent complications related to high blood pressure, making its use less validated compared to other antihypertensive medications like diuretics and beta-blockers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Valsartan. Just a second-line antihypertensive drug. [2018]

In the VALIANT trial, valsartan was found to be as effective as captopril in reducing mortality and cardiovascular issues in patients with heart failure or left ventricular systolic dysfunction after a heart attack, indicating its efficacy in high-risk populations.

Valsartan was generally well tolerated, and combining it with captopril did not provide extra benefits and was less tolerated, suggesting that valsartan could be a preferable option for post-myocardial infarction treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Valsartan: a review of its use in patients with heart failure and/or left ventricular systolic dysfunction after myocardial infarction. Croom, KF., Keating, GM.[2018]

Bosentan is the first oral dual endothelin receptor antagonist approved for treating pulmonary arterial hypertension, significantly improving exercise capacity and symptoms in patients.

Large-scale studies have confirmed bosentan's long-term safety and tolerability, making it a crucial treatment option for pulmonary arterial hypertension and potentially other endothelin-related diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bosentan: a dual endothelin receptor antagonist. Rubin, LJ., Roux, S.[2019]

Valsartan effectively reduces blood pressure in children and adolescents with hypertension, showing significant dose-dependent reductions in both systolic and diastolic blood pressure after just 2 weeks of treatment in a study involving participants aged 6-16 years.

In a comparison trial, valsartan was found to be as effective as enalapril in lowering blood pressure over 12 weeks, with similar rates of patients achieving target blood pressure levels, and it was well tolerated over a treatment period of up to 52 weeks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Valsartan: in children and adolescents with hypertension. Croxtall, JD.[2021]

References

1. England pubmed.ncbi.nlm.nih.gov

Additive protective effects of sacubitril/valsartan and bosentan on vascular remodelling in experimental pulmonary hypertension. [2022]

2. United States pubmed.ncbi.nlm.nih.gov

Initial Use of Ambrisentan plus Tadalafil in Pulmonary Arterial Hypertension. [2022]

3. United States pubmed.ncbi.nlm.nih.gov

Comparative Treatment Persistence and Adherence to Endothelin Receptor Antagonists Among Patients with Pulmonary Arterial Hypertension in Japan: A Real-World Administrative Claims Database Study. [2023]

4. Greece pubmed.ncbi.nlm.nih.gov

Valsartan attenuates pulmonary hypertension via suppression of mitogen activated protein kinase signaling and matrix metalloproteinase expression in rodents. [2018]

5. China pubmed.ncbi.nlm.nih.gov

[Efficacy and safety of ambrisentan therapy in Chinese patients with pulmonary hypertension]. [2016]

6. England pubmed.ncbi.nlm.nih.gov

Valsartan: the past, present and future. [2009]

7. Canada pubmed.ncbi.nlm.nih.gov

Valsartan. Just a second-line antihypertensive drug. [2018]

8. New Zealand pubmed.ncbi.nlm.nih.gov

Valsartan: a review of its use in patients with heart failure and/or left ventricular systolic dysfunction after myocardial infarction. [2018]

9. England pubmed.ncbi.nlm.nih.gov

Bosentan: a dual endothelin receptor antagonist. [2019]

10. Switzerland pubmed.ncbi.nlm.nih.gov

Valsartan: in children and adolescents with hypertension. [2021]