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

Trial Summary

What is the purpose of this trial?

The purpose of this study is to determine if there is a greater effect to patients with advanced pulmonary arterial hypertension (PAH) by using a combination of two drugs, Treprostinil and Riociquat versus Treprostinil alone

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.

What data supports the effectiveness of the drug combination of Riociguat and Treprostinil for treating pulmonary arterial hypertension?

Research shows that Treprostinil, when used alone or with other drugs, helps improve symptoms in people with pulmonary arterial hypertension. It has been effective in various forms, like subcutaneous (under the skin) and oral, for improving heart and lung function in these patients. ^{1 2 3 4 5}

Is the combination of Riociguat and Treprostinil safe for humans?

Riociguat and Treprostinil have been studied separately and in combination for conditions like pulmonary hypertension. Riociguat is generally well-tolerated, but can cause low blood pressure, and Treprostinil can cause pain at the injection site. The combination has shown positive outcomes in some cases, but more research is needed to fully understand its safety. ^{2 4 6 7 8}

How is the drug Riociguat + Treprostinil unique for treating pulmonary arterial hypertension?

The combination of Riociguat and Treprostinil is unique because Riociguat directly stimulates the production of cyclic GMP, which helps relax blood vessels in the lungs, while Treprostinil is a long-acting prostacyclin analog that improves blood flow. This combination may offer enhanced treatment outcomes for patients with pulmonary arterial hypertension compared to using each drug alone. ^{5 7 8 9 10}

Research Team

Franz Rischard, DO

Principal Investigator

University of Arizona

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

References

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

Subcutaneous treprostinil in congenital heart disease-related pulmonary arterial hypertension. [2019]

2. England pubmed.ncbi.nlm.nih.gov

Acute effects of the combination of sildenafil and inhaled treprostinil on haemodynamics and gas exchange in pulmonary hypertension. [2022]

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

Add-on therapy with subcutaneous treprostinil for refractory pediatric pulmonary hypertension. [2017]

4. Switzerland 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. [2022]

5. United States 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. [2022]

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

Riociguat: a novel new drug for treatment of pulmonary hypertension. [2017]

7. England pubmed.ncbi.nlm.nih.gov

Combination therapy with riociquat and inhaled treprostinil in inoperable and progressive chronic thromboembolic pulmonary hypertension. [2020]

8. England pubmed.ncbi.nlm.nih.gov

Riociguat treatment in patients with chronic thromboembolic pulmonary hypertension: Final safety data from the EXPERT registry. [2021]

9. United States 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. [2018]

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

Delivery of intravenous treprostinil at low infusion rates using a miniaturized infusion pump in patients with pulmonary arterial hypertension. [2019]