Riociguat + Treprostinil for Pulmonary Arterial Hypertension

Overseen By Valerie Boss, MS

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: University of Arizona

Must be taking: Treprostinil

Must not be taking: Pulmonary vasoactive, Nitrates, CYP3A4 inhibitors

Disqualifiers: Heart failure, Lung disease, Liver impairment, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

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

Compensation: Varies

Number of Visits: Unknown

Duration: 12 weeks

20 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether a combination of two drugs, Treprostinil and Riociguat, is more effective than Treprostinil alone for individuals with advanced pulmonary arterial hypertension (PAH). PAH causes high blood pressure in the arteries connecting the heart to the lungs, making breathing and daily activities difficult. Suitable candidates for this trial have been diagnosed with PAH (specifically WHO Category I) and require Treprostinil injections as part of their treatment. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants an opportunity to contribute to the potential availability of a new treatment option.

Will I have to stop taking my current medications?

The trial requires that you have not taken any pulmonary vasoactive medication in the last 12 weeks and that you are not on certain medications like strong CYP3A4 inhibitors or nitrates. It's best to discuss your current medications with the trial team to see if any need to be stopped.

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

Research has shown that both Riociguat and Treprostinil have been studied for their safety in treating pulmonary arterial hypertension (PAH). A previous study found Riociguat to be well-tolerated by patients, with improvements observed in several areas related to PAH. Serious side effects, such as fainting, were rare, occurring in about 1% of those taking Riociguat, compared to 4% who took a placebo.

Treprostinil, another drug used for PAH, has been part of many studies and is generally considered safe, though it may have side effects. Researchers are testing the combination of Riociguat and Treprostinil to determine if it is more effective than Treprostinil alone.

This trial is in the later stages of testing, indicating that these drugs have already undergone earlier safety tests. While results so far are promising, new side effects can sometimes appear as more people use the treatment. It is important to discuss any concerns with a doctor. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Riociguat and Treprostinil for treating Pulmonary Arterial Hypertension (PAH) because it targets the condition in a unique way. Most PAH treatments, like endothelin receptor antagonists or phosphodiesterase-5 inhibitors, work by dilating blood vessels to reduce pressure. However, the combination of Riociguat and Treprostinil offers a dual approach: Riociguat enhances the nitric oxide pathway to improve blood flow, while Treprostinil, a prostacyclin analog, directly dilates blood vessels and inhibits platelet aggregation. This synergistic action could potentially offer improved outcomes for patients by addressing the disease from multiple angles.

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

Research has shown that using Riociguat and Treprostinil together might improve treatment for pulmonary arterial hypertension (PAH). In this trial, participants will receive both medications. Riociguat can enhance exercise capacity and overall function in PAH patients by activating an enzyme that widens blood vessels, thereby lowering lung pressure. Treprostinil, commonly used for PAH, relaxes blood vessels and boosts blood flow. Studies suggest that combining these medications might be more effective than using Treprostinil alone. Early results are promising, particularly in improving symptoms and overall heart and lung function. ^{1 2 3 5 6}

Who Is on the Research Team?

Franz Rischard, DO

Principal Investigator

University of Arizona

Are You a Good Fit for This Trial?

This trial is for individuals with advanced pulmonary arterial hypertension (PAH), specifically WHO Category I, showing certain heart pressure levels during tests. Participants must require Treprostinil as determined by a pulmonary hypertension specialist.

Inclusion Criteria

Resting mPAP ≥ 25 mmHg with a wedge pressure of ≤ 15mmHg during right heart catheterization.

My doctor says I need injections for my lung condition.

I have been diagnosed with a specific type of high blood pressure in the lungs.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a combination of Treprostinil and Riociguat or Treprostinil alone to evaluate effects on right ventriculo-vascular coupling and morphology

12 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Riociguat Pill
• Treprostinil Injectable Product

Trial Overview The study aims to compare the effects of using both Treprostinil (an injectable drug) and Riociguat (a pill) versus just Treprostinil alone on heart function and shape in patients with advanced PAH.

How Is the Trial Designed?

Group I: Experimental Experimental Treatment 2 Interventions

Treprostinil and Riociguat

Who Is Running the Clinical Trial?

University of Arizona

Lead Sponsor

Trials

545

Recruited

161,000+

Published Research Related to This Trial

In a study of 32 adult patients with congenital heart disease-associated pulmonary arterial hypertension (CHD-PAH), subcutaneous treprostinil treatment for 12 months resulted in a significant increase in exercise capacity, as measured by a 114-meter improvement in the 6-minute walk distance (6-MWD) (P<0.001).

The treatment was generally safe, with the most common side effects being infusion-site erythema and pain; however, one patient discontinued due to intolerable pain, and no major complications were reported.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Subcutaneous treprostinil in congenital heart disease-related pulmonary arterial hypertension. Skoro-Sajer, N., Gerges, C., Balint, OH., et al.[2019]

In a 16-week study involving 350 patients with pulmonary arterial hypertension (PAH), oral sustained-release treprostinil showed a non-significant improvement in the 6-minute walk distance (6MWD) compared to placebo, with a median difference of 11 meters (P = .07).

Patients on higher doses of oral treprostinil (1.25 to 16 mg) experienced greater improvements in 6MWD and dyspnea scores, indicating that effective dosing may enhance treatment outcomes for PAH.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral treprostinil for the treatment of pulmonary arterial hypertension in patients on background endothelin receptor antagonist and/or phosphodiesterase type 5 inhibitor therapy (the FREEDOM-C study): a randomized controlled trial. Tapson, VF., Torres, F., Kermeen, F., et al.[2022]

The EXPERT study monitored the long-term safety of riociguat in 956 patients with chronic thromboembolic pulmonary hypertension (CTEPH) over a period of 1 to 4 years, confirming that its safety profile aligns with previous clinical trial data.

Common adverse events included peripheral edema (11.7%) and dizziness (7.5%), while serious adverse events like right ventricular failure (7.4%) were also noted, but overall rates of severe complications like hemoptysis and hypotension remained low.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Riociguat treatment in patients with chronic thromboembolic pulmonary hypertension: Final safety data from the EXPERT registry. Ghofrani, HA., Gomez Sanchez, MA., Humbert, M., et al.[2021]

Riociguat is the first approved medication in the class of soluble guanylate cyclase stimulators, effectively treating both chronic thromboembolic hypertension (CTEPH) and pulmonary arterial hypertension (PAH) by restoring nitric oxide's therapeutic effects.

In clinical trials, riociguat demonstrated significant improvements in exercise capacity (measured by 6-minute walk distance) for both PAH and CTEPH patients, with tolerable side effects, although careful monitoring of blood pressure is necessary due to the risk of hypotension.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Riociguat: a novel new drug for treatment of pulmonary hypertension. Makowski, CT., Rissmiller, RW., Bullington, WM.[2017]

Long-term treatment with subcutaneous treprostinil significantly improved pulmonary artery pressure and functional parameters in patients with moderate-to-severe pulmonary arterial hypertension (PAH), with a follow-up duration averaging about 984 days.

The addition of oral bosentan to treprostinil therapy was safe and led to further significant improvements in pulmonary arterial pressure and exercise capacity, indicating that combination therapy can enhance treatment outcomes for PAH.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treprostinil-based therapy in the treatment of moderate-to-severe pulmonary arterial hypertension: long-term efficacy and combination with bosentan. Benza, RL., Rayburn, BK., Tallaj, JA., et al.[2018]

In a study of 8 young children with refractory pulmonary arterial hypertension, subcutaneous treprostinil therapy led to significant early improvements in functional class and hemodynamics, with 7 out of 8 patients showing positive responses.

The treatment was generally well-tolerated, with manageable site pain in all but one child, suggesting that treprostinil could be a valuable rescue therapy for this condition, although more research is needed with larger patient groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Add-on therapy with subcutaneous treprostinil for refractory pediatric pulmonary hypertension. Levy, M., Celermajer, DS., Bourges-Petit, E., et al.[2017]

The combination of oral sildenafil and inhaled treprostinil was found to be safe and well tolerated in patients with pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH), showing no relevant side effects during the study.

This combination therapy resulted in significant improvements in pulmonary vascular resistance and mean pulmonary arterial pressure, indicating a strong potential for effective long-term treatment of these conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acute effects of the combination of sildenafil and inhaled treprostinil on haemodynamics and gas exchange in pulmonary hypertension. Voswinckel, R., Reichenberger, F., Enke, B., et al.[2022]

Treprostinil can be safely administered via a miniaturized pump at low infusion rates (0.1-0.2 mL/hr) for 12 weeks in patients with pulmonary arterial hypertension (PAH), with no catheter occlusions reported during the study.

While the treatment showed improvements in walking distance and dyspnea scores, there were some adverse events like headache and nausea, and pump complications were noted in 5 out of 12 patients, indicating the need for further research on safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Delivery of intravenous treprostinil at low infusion rates using a miniaturized infusion pump in patients with pulmonary arterial hypertension. Tapson, VF., McLaughlin, VV., Gomberg-Maitland, M., et al.[2019]

In a 16-week study involving 39 patients with severe pulmonary arterial hypertension, a rapid up-titration dosing regimen of subcutaneous treprostinil was well tolerated, with only 8% of patients discontinuing due to infusion site pain, which was reported by 97% of participants.

The treatment led to significant improvements in clinical parameters, including increased walking distance and better heart function, indicating that proactive pain management can enhance the effectiveness of treprostinil therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety, Tolerability and Clinical Effects of a Rapid Dose Titration of Subcutaneous Treprostinil Therapy in Pulmonary Arterial Hypertension: A Prospective Multi-Centre Trial. Grünig, E., Benjamin, N., Lange, TJ., et al.[2022]

A 77-year-old female patient with inoperable chronic thromboembolic pulmonary hypertension (CTEPH) showed significant recovery after being treated with a combination of riociguat and inhaled treprostinil, following previous treatments that were ineffective.

Riociguat, which stimulates cyclic GMP production in pulmonary artery smooth muscle, may have a unique interaction with treprostinil that enhances treatment outcomes, suggesting that this combination therapy warrants further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination therapy with riociquat and inhaled treprostinil in inoperable and progressive chronic thromboembolic pulmonary hypertension. Swisher, JW., Elliott, D.[2020]

Citations

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Riociguat (Adempas): a Novel Agent For the Treatment of ... Riociguat is a first-in-class oral medication that adds to the treatment options for PAH. It is also the only agent approved for CTEPH, albeit in select ...

2. hhs.texas.gov hhs.texas.gov/sites/default/files/documents/jan-2024-durb-agenda-item5x.pdf

Pulmonary Arterial Hypertension (PAH) Agents, Oral and ... Studies establishing inhaled treprostinil (Tyvaso) effectiveness for PAH predominately included patients with NYHA Functional Class III symptoms and etiologies ...

3. sciencedirect.com sciencedirect.com/science/article/pii/S0954611123000847

The role of riociguat in combination therapies for ... In this review, we highlight the clinical evidence for riociguat and discuss its potential role in upfront combination therapy for the treatment of PAH.

4. nejm.org nejm.org/doi/full/10.1056/NEJMoa1209655

Riociguat for the Treatment of Pulmonary Arterial ... Riociguat, a soluble guanylate cyclase stimulator, has been shown in a phase 2 trial to be beneficial in the treatment of pulmonary arterial hypertension.

5. publications.ersnet.org publications.ersnet.org/content/erj/45/5/1303

Riociguat for the treatment of pulmonary arterial hypertension Long-term riociguat was well tolerated in patients with pulmonary arterial hypertension, and led to sustained improvements in exercise capacity and functional ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8172220/

Efficacy and safety of novel-targeted drugs in the treatment ... To assess the efficacy and safety of PAH therapies, five efficacy outcomes [6-minute walking distance (6MWD), mean pulmonary arterial pressure (mPAP), WHO ...