AZD3427 for Heart Failure with Pulmonary Hypertension

(Re-PHIRE Trial)

No longer recruiting at 79 trial locations

Overseen By AstraZeneca Clinical Study Information Center

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: AstraZeneca

Must be taking: Diuretics

Disqualifiers: Lung disease, Long QT, Arrhythmia, others

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

Compensation: Varies

Number of Visits: 16

Duration: 24 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment called AZD3427, an experimental drug, to determine if it can alleviate symptoms in people with heart failure and pulmonary hypertension by reducing pressure in lung blood vessels. Participants will receive one of three doses of AZD3427 or a placebo every two weeks for 24 weeks. Suitable candidates have heart failure and pulmonary hypertension related to heart issues and are already on stable heart failure medication. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group of participants.

Do I have to stop taking my current medications for this trial?

The trial does not specify if you need to stop taking your current medications. However, participants must be on stable heart failure standard of care medication, including diuretics, to be eligible.

Will I have to stop taking my current medications?

The trial requires participants to be on stable heart failure standard of care medication, including diuretics, so you will not have to stop taking these medications.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that AZD3427 has been tested in people with heart failure. Results suggest it is safe, as patients tolerated it well without major safety issues. One study found that the body processed the drug effectively.

This trial is in Phase 2, indicating early testing, but initial safety results are promising. Prospective participants might find this information reassuring regarding the safety of AZD3427. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for heart failure with pulmonary hypertension?

Unlike the standard treatments for heart failure with pulmonary hypertension, which often include diuretics, beta-blockers, and vasodilators, AZD3427 is unique because it introduces a novel approach by possibly targeting specific pathways involved in the disease process. Researchers are excited about AZD3427 because it could offer a new mechanism of action that might improve how the heart and lungs work together, potentially leading to better outcomes for patients. Moreover, the treatment is administered in a straightforward and consistent manner—every two weeks—which could improve adherence and convenience compared to some existing options.

What evidence suggests that this trial's treatments could be effective for heart failure with pulmonary hypertension?

Research has shown that AZD3427 could be a promising treatment for heart failure with high blood pressure in the lungs. It imitates the hormone relaxin, which widens blood vessels and may reduce scarring. Early studies in patients found AZD3427 safe and well-tolerated. This trial will evaluate different doses of AZD3427, with participants receiving either Dose A, Dose B, or Dose C, while some will receive a placebo. The treatment aims to lower the pressure in the blood vessels between the heart and lungs. Although more research is needed, early results suggest that AZD3427 might help reduce this pressure and improve heart function. ^{1 2 3 4 5}

Are You a Good Fit for This Trial?

Adults over 18 with heart failure and pulmonary hypertension group 2, weighing at least 50 kg, on stable heart medications can join. They must have certain echocardiographic signs of PH and elevated artery pressure from a right heart catheterization. Excluded are those allergic to AZD3427 or similar drugs, who've had it before, with other types of PH, significant health issues, planned major heart procedures or severe lung disease.

Inclusion Criteria

I am willing and able to sign the consent form.

My heart ultrasound shows I might have pulmonary hypertension.

I am on a stable heart failure medication regimen, including water pills.

Exclusion Criteria

History of hypersensitivity to SC injections or devices

I have been hospitalized for heart failure.

I have previously taken AZD3427.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-5 weeks

2 visits (in-person)

Treatment

Participants receive a subcutaneous injection of AZD3427 or placebo every 2 weeks for 24 weeks

24 weeks

13 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

1 visit (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• AZD3427

Trial Overview The trial is testing AZD3427's effectiveness in reducing lung blood vessel resistance after six months compared to a placebo in patients with both heart failure and pulmonary hypertension group 2. Participants will be randomly assigned to receive either the drug or a placebo.

How Is the Trial Designed?

Group I: AZD3427 Dose C Experimental Treatment 1 Intervention

The participants will receive single dose of AZD3427 Dose C every 2 weeks for 24 weeks from Day 1 to Day 155.

Group II: AZD3427 Dose B Experimental Treatment 1 Intervention

The participants will receive single dose of AZD3427 Dose B every 2 weeks for 24 weeks from Day 1 to Day 155.

Group III: AZD3427 Dose A Experimental Treatment 1 Intervention

The participants will receive single dose of AZD3427 Dose A every 2 weeks for 24 weeks from Day 1 to Day 155.

Group IV: Placebo Placebo Group 1 Intervention

The participants will receive single dose of placebo every 2 weeks for 24 weeks from Day 1 to Day 155.

Who Is Running the Clinical Trial?

AstraZeneca

Lead Sponsor

Trials

4,491

Recruited

290,540,000+

Sir Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Dr. Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Medical Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Parexel

Industry Sponsor

Trials

322

Recruited

137,000+

Peyton Howell

Parexel

Chief Executive Officer

Master of Healthcare Administration from The Ohio State University, Bachelor of Arts in Health Communications from the University of Illinois

Dr. Austin Smith

Parexel

Chief Medical Officer since 2023

MD from the Royal College of Surgeons in Ireland

Published Research Related to This Trial

ZSY-27, a new phosphodiesterase inhibitor, effectively reduced mean pulmonary arterial pressure in dogs with pulmonary hypertension, indicating its potential as a treatment for this condition.

The drug did not affect mean arterial pressure, suggesting it specifically targets pulmonary hypertension without causing systemic blood pressure changes, which is a positive safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Selective pulmonary vasodilatory effect of ZSY-27 in dogs with pulmonary hypertension due to pulmonary embolism. Tajimi, K., Tanaka, H., Kasai, T., et al.[2019]

The combination of macitentan and vardenafil significantly enhances vasodilation in human pulmonary arteries compared to using either drug alone, suggesting a potential for improved treatment of pulmonary arterial hypertension (PAH).

Macitentan at lower concentrations effectively reduces vasoconstriction induced by endothelin-1, indicating its efficacy as a vasodilator, while the longer-acting metabolite ACT-132577 does not show additional benefits when combined with vardenafil.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination Therapy of Pulmonary Arterial Hypertension with Vardenafil and Macitentan Assessed in a Human Ex Vivo Model. Hoenicka, M., Golovchenko, S., Englert, L., et al.[2020]

The review focuses on the management strategies for severe pulmonary hypertension that occurs alongside right ventricular failure, which is critical for improving patient outcomes.

The relevance of these management strategies is particularly highlighted for adults suffering from acute respiratory distress syndrome (ARDS), suggesting a potential overlap in treatment approaches for these serious conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The pulmonary physician in critical care. 13: the pulmonary circulation and right ventricular failure in the ITU. McNeil, K., Dunning, J., Morrell, NW.[2020]

Inhaled nitrite was found to be safe for patients with pulmonary hypertension (PH), showing significant improvements in pulmonary pressures, especially in those with PH associated with heart failure with preserved ejection fraction (PH-HFpEF).

The treatment led to increased pulmonary artery compliance and reduced filling pressures in the heart, indicating potential efficacy for PH-HFpEF and Group 3 PH patients, although it did not significantly affect pulmonary vascular resistance in Group 1 patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acute hemodynamic effects of inhaled sodium nitrite in pulmonary hypertension associated with heart failure with preserved ejection fraction. Simon, MA., Vanderpool, RR., Nouraie, M., et al.[2023]

In a study of 113 Korean patients with pulmonary arterial hypertension (PAH) treated with selexipag over 24 weeks, adverse events (AEs) were more common during the dose-titration phase than during the maintenance phase, indicating careful monitoring is crucial during initial treatment.

The most frequent AEs included diarrhea, headache, nausea/vomiting, and myalgia, but importantly, the incidence and severity of these AEs did not increase with higher doses of selexipag, suggesting that higher doses can be safely managed without a corresponding rise in adverse effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-world practice patterns and characteristics of adverse events with selexipag in Korean patients with pulmonary arterial hypertension. Chang, SA., Lee, SH., Choi, JH., et al.[2022]

Oral phosphodiesterase inhibitors are promising treatments for pulmonary hypertension in heart failure, showing benefits in symptoms, blood flow, heart structure, and exercise capacity.

Future studies are needed to determine if these medications can also reduce the risk of serious health issues and death in patients with heart failure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pulmonary vasodilation in acute and chronic heart failure: empiricism and evidence. Guglin, M.[2021]

In a study of 133 Chinese patients with pulmonary arterial hypertension (PAH), ambrisentan significantly improved exercise capacity, with an increase in the 6-Minute Walk Distance (6-MWD) by an average of 53.6 meters after 12 weeks, indicating its efficacy in enhancing physical performance.

The safety profile of ambrisentan was consistent with global studies, with drug-related adverse events occurring in 34.3% of subjects, primarily peripheral edema and flushing, while four patients experienced serious adverse events, including two deaths.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of efficacy, safety and tolerability of Ambrisentan in Chinese adults with pulmonary arterial hypertension: a prospective open label cohort study. Huo, Y., Jing, ZC., Zeng, XF., et al.[2018]

In a study involving 64 patients with pulmonary arterial hypertension (PAH), ambrisentan significantly improved exercise capacity, as measured by a 36.1 meter increase in the 6-minute walk distance after 12 weeks, with consistent benefits across all tested doses (1, 2.5, 5, and 10 mg).

The treatment also led to improvements in symptoms and hemodynamics, including reduced pulmonary arterial pressure and increased cardiac index, while showing a low incidence of mild adverse events, indicating a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ambrisentan therapy for pulmonary arterial hypertension. Galié, N., Badesch, D., Oudiz, R., et al.[2023]

In a pilot study of 19 patients with severe pulmonary arterial hypertension (PAH), those treated with a triple combination therapy of intravenous epoprostenol, bosentan, and sildenafil showed significant improvements in walking distance and heart function after 4 months, with 17 patients improving to a better functional class.

The study reported a remarkable 100% survival rate at 1, 2, and 3 years for patients on this therapy, compared to an expected survival rate of 75%, 60%, and 49% based on standard predictions, suggesting that this combination therapy may offer substantial long-term benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Upfront triple combination therapy in pulmonary arterial hypertension: a pilot study. Sitbon, O., Jaïs, X., Savale, L., et al.[2018]

In a study comparing 118 patients with severe pulmonary hypertension (PH) due to lung disease to 74 patients with idiopathic pulmonary arterial hypertension (IPAH), those with lung disease were older and had worse overall health, leading to poorer survival rates, particularly among those with interstitial lung disease (ILD).

While treatment with pulmonary vasodilators did not improve walking distance or functional class in patients with severe PH and lung disease, it did result in a significant decrease in NT-proBNP levels, suggesting some benefit, though further research is needed to determine if these therapies can slow disease progression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Severe pulmonary hypertension in lung disease: phenotypes and response to treatment. Brewis, MJ., Church, AC., Johnson, MK., et al.[2015]

In a study of 44 patients with pulmonary hypertension and heart failure, intravenous levosimendan did not significantly reduce exercise-PCWP after 6 weeks, but it did lower PCWP across all exercise stages, indicating some hemodynamic benefits.

Levosimendan treatment led to a significant improvement in the 6-minute walk distance (6MWD) by 29.3 meters compared to placebo, suggesting it may enhance exercise capacity in these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Levosimendan Improves Hemodynamics and Exercise Tolerance in PH-HFpEF: Results of the Randomized Placebo-Controlled HELP Trial. Burkhoff, D., Borlaug, BA., Shah, SJ., et al.[2022]

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]

In a 1-year study of patients with pulmonary arterial hypertension (PAH), sitaxsentan at 100 mg showed a high overall survival rate of 96% and a lower risk of clinical worsening events (34%) compared to bosentan, which had an 88% survival rate and a 40% risk of worsening.

Sitaxsentan also demonstrated a lower incidence of elevated liver enzymes (6% risk for AST/ALT > 3 x ULN) and discontinuation due to adverse events (15%) compared to bosentan, which had a 14% risk for elevated liver enzymes and a 30% risk of discontinuation due to adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sitaxsentan for the treatment of pulmonary arterial hypertension: a 1-year, prospective, open-label observation of outcome and survival. Benza, RL., Barst, RJ., Galie, N., et al.[2021]

In a study of 15 children with pulmonary arterial hypertension (PAH), add-on selexipag was found to be safe and well-tolerated, with no deaths during treatment and improvements in key health metrics for about 50% of the patients.

Selexipag therapy led to significant improvements in right ventricular function and pulmonary pressures, indicating its potential efficacy in managing PAH in pediatric patients, especially in those who are less severely affected.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Selexipag for the treatment of children with pulmonary arterial hypertension: First multicenter experience in drug safety and efficacy. Hansmann, G., Meinel, K., Bukova, M., et al.[2021]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05737940

A Study of AZD3427 in Participants With Heart Failure and ... This study is intended to assess the ability of AZD3427 to reduce pulmonary vascular resistance (PVR) after 24 weeks of treatment in participants with heart ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39829393/

Relaxin mimetic in pulmonary hypertension associated ... AZD3427 is a functionally selective, long-acting mimetic of relaxin, a hormone that has the potential to induce vasodilation and prevent fibrosis.

3. clinicaltrials.cedars-sinai.edu clinicaltrials.cedars-sinai.edu/view/D8330C00003

AZD3427 in Heart Failure and Pulmonary Hypertension Due ... The purpose of this study is to evaluate the effectiveness, safety, and tolerability of an experimental drug called AZD3427, given in addition to.

4. thecvc.ca thecvc.ca/re-phire-study-explores-azd3427-for-pulmonary-hypertension-in-heart-failure/

Re-PHIRE Study Explores AZD3427 for Pulmonary ... A phase 1b study in heart failure patients demonstrated that AZD3427 has a favorable safety profile and good pharmacokinetics (how the body ...

5. astrazenecaclinicaltrials.com astrazenecaclinicaltrials.com/study/D8330C00003

A Study of AZD3427 in Participants with Heart Failure and ... This study is intended to assess the ability of AZD3427 to reduce pulmonary vascular resistance (PVR) after 24 weeks of treatment in participants with heart ...