Mono vs Dual Therapy for Pediatric Pulmonary Hypertension

(MoD Trial)

Not currently recruiting at 16 trial locations

Overseen By Lewis Romer, MD

Age: < 65

Sex: Any

Trial Phase: Phase 3

Sponsor: Johns Hopkins University

Must not be taking: Cyclosporine, Glyburide, CYP3A inhibitors, others

Disqualifiers: Syncope, RV failure, Pregnancy, 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

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 12 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if using two medications, sildenafil (also known as Viagra, Revatio, Aronix, Liberize, Nipatra, or Grandipam) and bosentan (also known as Tracleer), together is more effective than using only sildenafil for treating pulmonary hypertension (high blood pressure in the lungs) in children. Researchers believe that combining these treatments early might improve children's functioning with this condition over a year. Children diagnosed with pulmonary hypertension who have not yet received long-term targeted drugs may be suitable candidates for this trial. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to a potentially groundbreaking treatment for pulmonary hypertension in children.

Do I need to stop my current medications to join the trial?

The trial requires that participants have not been treated with long-term targeted PAH drug therapy. If you are on a low dose of sildenafil for less than two weeks, you may need to stop it for a two-day washout period before joining. The protocol does not specify other medications, but certain drugs like cyclosporine A, glyburide, CYP3A inhibitors, and beta blockers are exclusions.

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

Research has shown that sildenafil is generally safe for children with pulmonary arterial hypertension (PAH). One study found that sildenafil can reduce the risk of death in these patients. However, higher doses might cause safety issues, so it is crucial to adhere to the prescribed amount.

When combined with bosentan, studies indicate that this treatment is also safe for children. This combination has improved patients' conditions without major problems. Always follow the prescribed dose and consult healthcare providers with any concerns.

Both treatments have been used in children with PAH and have demonstrated promising safety when used correctly. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard treatments for pediatric pulmonary hypertension, which often involve a single medication, this trial explores both monotherapy with sildenafil and a combination therapy with sildenafil and bosentan. Researchers are excited about sildenafil because it works by relaxing blood vessels in the lungs, making it easier for the heart to pump blood, and is already widely used in adults. The combination with bosentan, a drug that blocks certain substances that tighten blood vessels, could potentially offer a more powerful approach by addressing the condition through two different mechanisms. This dual-action approach might improve symptoms more effectively than current single-drug treatments.

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

Studies have shown that sildenafil, which participants in this trial may receive as monotherapy, can greatly improve exercise ability and oxygen levels in children with pulmonary hypertension. Children usually tolerate it well, with some common side effects like headaches and skin flushing. This trial will also explore a dual therapy approach, where participants receive both sildenafil and bosentan. Research suggests that adding bosentan to sildenafil could enhance these benefits. Bosentan, when combined with other treatments, has proven effective for long-term management of the condition. Using both medications together may lead to better results than using sildenafil alone. ^{6 7 8 9 10}

Who Is on the Research Team?

Lewis Romer, MD

Principal Investigator

Johns Hopkins University

Are You a Good Fit for This Trial?

This trial is for children aged 3 months to under 18 years with a diagnosis of pediatric pulmonary arterial hypertension, who haven't used long-term PAH drugs. They should be in WHO functional class II or III and able to take oral medications. Kids with certain heart diseases, drug abuse history, noncompliance issues, or on conflicting medications can't join.

Inclusion Criteria

My child has not been on long-term PAH medication.

I have been diagnosed with pulmonary arterial hypertension.

My pulmonary hypertension is not caused by specific heart conditions.

Exclusion Criteria

I am not taking cyclosporine A, glyburide, CYP3A inhibitors, or beta blockers, and I did not have congenital heart disease surgery in the last 6 months.

My child, over 1 year old, has a specific type of high blood pressure in the lungs and responds well to certain tests.

Inability to comply with study procedures and availability for duration of study

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either monotherapy with sildenafil or combination therapy with sildenafil and bosentan

12 months

Regular visits for clinical evaluations and diagnostics

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 months

Periodic follow-up visits

Pharmacokinetics Assessment

Pharmacokinetics will be assessed to determine drug levels and compliance with therapy

Concurrent with treatment phase

What Are the Treatments Tested in This Trial?

Interventions

• Bosentan
• Sildenafil

Trial Overview The study tests if using two drugs (Sildenafil + Bosentan) together works better than just one (Sildenafil alone) for improving health status in kids with pulmonary hypertension after one year of treatment. It's checking the effectiveness of early combination therapy versus monotherapy.

How Is the Trial Designed?

Group I: Monotherapy with Sildenafil Group Active Control 1 Intervention

mono-therapy: first-line monotherapy (sildenafil alone) - in pediatric subjects with PAH.

Group II: Duo Therapy with Sildenafil + Bosentan Group Active Control 1 Intervention

duo-therapy: compare two treatment strategies - first-line combination therapy (sildenafil and bosentan)

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

Approved in United States as Viagra for:

• Erectile dysfunction
• Pulmonary arterial hypertension

Approved in European Union as Viagra for:

• Erectile dysfunction
• Pulmonary arterial hypertension

Approved in United States as Revatio for:

• Pulmonary arterial hypertension

Approved in Canada as Sildenafil for:

• Erectile dysfunction
• Pulmonary arterial hypertension

Approved in Japan as Sildenafil for:

• Erectile dysfunction
• Pulmonary arterial hypertension

Who Is Running the Clinical Trial?

Johns Hopkins University

Lead Sponsor

Trials

2,366

Recruited

15,160,000+

National Heart, Lung, and Blood Institute (NHLBI)

Collaborator

Trials

3,987

Recruited

47,860,000+

National Center for Advancing Translational Sciences (NCATS)

Collaborator

Trials

394

Recruited

404,000+

Published Research Related to This Trial

The Kids Mod PAH Trial is a multicenter Phase III study designed to evaluate whether upfront combination therapy with sildenafil and bosentan is more effective than sildenafil alone in improving pulmonary hypertension outcomes in children, addressing a significant gap in pediatric care.

The primary endpoint of the trial is the World Health Organization (WHO) functional class after 12 months, with additional secondary endpoints including clinical worsening, echocardiographic assessments, and quality of life measures, aiming to establish a strong foundation for future pediatric clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Kids Mod PAH trial: A multicenter trial comparing mono- versus duo-therapy for initial treatment of pediatric pulmonary hypertension. Collaco, JM., Abman, SH., Austin, ED., et al.[2023]

In a study of 25 children under 5 years old with pulmonary hypertension, sildenafil significantly improved hemodynamics, reducing the right ventricular to systemic systolic blood pressure ratio from 1.0 to 0.5, indicating better heart function.

Sildenafil effectively prevented rebound pulmonary hypertension after stopping inhaled nitric oxide, with a notable decrease in right ventricular pressure to systemic systolic pressure ratio from 1.0 to 0.4, and showed no adverse effects on kidney or liver function.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sildenafil therapy for neonatal and childhood pulmonary hypertensive vascular disease. Humpl, T., Reyes, JT., Erickson, S., et al.[2016]

In a study involving 10 children with pulmonary hypertension due to congenital cardiac defects, sildenafil significantly reduced pulmonary artery pressure at all tested doses (0.5 to 2.0 mg/kg) without affecting systemic arterial or central venous pressures.

The findings suggest that a lower dose of 0.5 mg/kg every 4 hours is as effective as the higher 2.0 mg/kg dose, indicating potential for dose optimization; however, further research is needed to confirm the safety and efficacy of these dosing regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of escalating doses of sildenafil on hemodynamics and gas exchange in children with pulmonary hypertension and congenital cardiac defects. Raja, SG., Danton, MD., MacArthur, KJ., et al.[2022]

Sildenafil has been studied in 193 children with pulmonary hypertension across 16 studies and 28 case reports, showing it can help reduce the need for inhaled nitric oxide after cardiac surgery.

Safety data indicate that sildenafil is generally well tolerated in children with idiopathic pulmonary arterial hypertension and pulmonary arterial hypertension linked to congenital heart disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sildenafil for the treatment of pulmonary hypertension in pediatric patients. Huddleston, AJ., Knoderer, CA., Morris, JL., et al.[2021]

In a study of 43 children with pulmonary hypertension, combination therapy with ambrisentan and tadalafil showed significant improvements in exercise capacity and hemodynamics, particularly in those who were treatment-naïve or on monotherapy, with a notable increase in 6-minute walk distance and reductions in pulmonary artery pressure and vascular resistance.

The treatment was well-tolerated, with only three patients discontinuing due to side effects, and no deaths or lung transplants reported, indicating a favorable safety profile for this combination therapy in pediatric patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and tolerability of combination therapy with ambrisentan and tadalafil for the treatment of pulmonary arterial hypertension in children: Real-world experience. Issapour, A., Frank, B., Crook, S., et al.[2023]

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]

Sildenafil has a similar acute safety profile in children as seen in adults for treating pulmonary arterial hypertension (PAH), but concerns about its long-term safety in children persist.

Regulatory agencies are divided on sildenafil's use in children: the FDA advises against it, while the European Medicines Agency allows low-dose use, highlighting the need for careful consideration of pediatric data in treatment decisions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and tolerability considerations in the use of sildenafil for children with pulmonary arterial hypertension. Dodgen, AL., Hill, KD.[2020]

Sildenafil, commonly known for treating erectile dysfunction, has been successfully used in three children with severe, chronic pulmonary hypertension, suggesting potential efficacy in pediatric cases.

Chronic pulmonary hypertension in children is rare and challenging to manage, highlighting the importance of exploring new treatment options like sildenafil for improving outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sildenafil as a treatment for pulmonary hypertension. Carroll, WD., Dhillon, R.[2019]

In a study of 45 patients with pulmonary arterial hypertension (PAH) already on bosentan treatment, a single dose of sildenafil significantly reduced mean pulmonary vascular resistance (PVR) by 15%, similar to the effects of inhaled nitric oxide.

The findings indicate that combining sildenafil with bosentan may provide additional hemodynamic benefits without unexpected safety issues, supporting further long-term studies on this combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acute hemodynamic effects of single-dose sildenafil when added to established bosentan therapy in patients with pulmonary arterial hypertension: results of the COMPASS-1 study. Gruenig, E., Michelakis, E., Vachiéry, JL., et al.[2018]

A cost-utility analysis comparing tadalafil and sildenafil for treating pediatric pulmonary arterial hypertension in Colombia found that tadalafil is significantly more expensive, with an incremental cost of US $15,270 compared to sildenafil.

Despite tadalafil providing an additional 1.00 quality-adjusted life-year (QALY), it is not considered cost-effective at a willingness-to-pay threshold of US $5,180 per QALY, indicating that sildenafil remains the more economically viable option for treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phosphodiesterase 5 Inhibitor for Pediatric Pulmonary Arterial Hypertension: A Cost-Utility Analysis. Buendía, JA., Lindarte, EF., Guerrero Patiño, D.[2023]

In a randomized trial involving 27 patients with pulmonary arterial hypertension (PAH), combination therapy using sildenafil and ambrisentan showed significant improvements in functional class and mean pulmonary artery pressure after 12 weeks.

The combination therapy was found to be safe and effective, suggesting that using both medications together may provide better management for PAH compared to using sildenafil alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A randomized, double-blind, placebo-controlled study to evaluate sildenafil, ambrisentan combination therapy in pulmonary hypertension, particularly of Eisenmenger syndrome. Mohammed, S., Vijayvergiya, R., Malhotra, S., et al.[2021]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4943407/

Sildenafil in pediatric pulmonary arterial hypertension - PMC Sildenafil significantly improved ventilatory efficiency during peak and submaximal exercise. Headache: 33%; flushing: 19%; dizziness: 7%; nausea/vomiting: 7%; ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/15823634/

Safety and efficacy of Sildenafil therapy in children with ... Medium term Sildenafil therapy improves oxyhaemoglobin saturations and exercise tolerance in children with pulmonary hypertension without any side effects.

3. ahajournals.org ahajournals.org/doi/10.1161/circulationaha.110.016667

A Randomized, Double-Blind, Placebo-Controlled, Dose ... Conclusions—. Sixteen-week sildenafil monotherapy is well tolerated in pediatric pulmonary arterial hypertension. Percent change in PV̇o2 for the ...

4. sciencedirect.com sciencedirect.com/science/article/abs/pii/S1058981319301109

Effectiveness and short-term survival associated with ... Oral therapy with sildenafil added to conventional treatments has improved patient outcomes in terms of exercise capacity and hemodynamics.

5. pfizer.com pfizer.com/news/press-release/press-release-detail/pfizer_announces_results_from_phase_3_trial_of_revatio_sildenafil_citrate_in_newborns_with_persistent_pulmonary_hypertension

Pfizer Announces Results from Phase 3 Trial of Revatio® ... Treatment with IV sildenafil when added to iNO did not result in a statistically significant reduction in treatment failure rate or time on iNO ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4687613/

Safety and tolerability considerations in the use of sildenafil ... Here, we review the available pediatric data regarding dosing, acute, and long-term safety and efficacy of sildenafil for the treatment of PAH ...

7. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/33077013/

Safety and effect of sildenafil on treating paediatric ... Sildenafil therapy reduces the mortality of PAH patients, but its effects on the haemodynamic outcomes and other clinical outcomes are still unclear.

8. fda.gov fda.gov/media/173041/download

Reassured by adult safety study, FDA approves sildenafil ... The randomized trial demonstrated that patients receiving Revatio had slightly higher mean increases from baseline in peak volume of oxygen ...

9. ahajournals.org ahajournals.org/doi/10.1161/CIRCULATIONAHA.123.068107

Randomized, Multicenter Study to Assess the Effects of ... The STARTS-1 trial (Sildenafil in Treatment-I Children, Aged 1 to 17 Years, With Pulmonary Arterial Hypertension) showed an improvement in peak ...

10. acc.org acc.org/Latest-in-Cardiology/Journal-Scans/2024/06/27/15/11/randomized-multicenter-study

Effects of Different Doses of Sildenafil for Pulmonary ... Safety concerns arose particularly after pediatric data suggested an association of higher mortality with higher doses of sildenafil. To ...