Mono vs Dual Therapy for Pediatric Pulmonary Hypertension

(MoD Trial)

Recruiting at 14 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

100 Participants Needed

Trial Summary

What is the purpose of this trial?

The investigators' central hypothesis is that early combination therapy with two PAH-specific oral therapies that have been shown to be well tolerated in the pediatric population, sildenafil and bosentan, will result in better World Health Organization (WHO) functional class at 12 months after initiation of PAH treatment than therapy with sildenafil alone.

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.

What data supports the idea that Mono vs Dual Therapy for Pediatric Pulmonary Hypertension is an effective drug?

The available research shows that using a combination of drugs (dual therapy) like sildenafil and bosentan can be more effective than using just one drug (mono therapy) for treating pediatric pulmonary hypertension. For example, the Kids Mod PAH trial is investigating whether starting treatment with both sildenafil and bosentan leads to better outcomes in children compared to using sildenafil alone. This study aims to see improvements in how children feel and function over time. Another study found that combining sildenafil with another drug improved certain health measures in patients with a specific type of pulmonary hypertension. These findings suggest that dual therapy might offer more benefits than using a single drug. ^{1 2 3 4 5}

What safety data exists for mono and dual therapy in pediatric pulmonary hypertension?

Existing safety data for pediatric pulmonary hypertension treatments include studies on sildenafil and bosentan. Sildenafil has shown a similar acute safety profile in children as in adults, but concerns exist about its long-term use, with differing recommendations from regulatory agencies. The FDA advises against its use in children, while the EMA supports low doses. Combination therapies, such as sildenafil with ambrisentan, have been found safe and effective in adults, and real-world data suggest ambrisentan and tadalafil are tolerable in children. However, more pediatric-specific data is needed to fully understand long-term safety. ^{1 6 7 8 9}

Is the drug Sildenafil a promising treatment for pediatric pulmonary hypertension?

Yes, Sildenafil is a promising drug for treating pediatric pulmonary hypertension. It has been used successfully in children, showing benefits like improved heart function and exercise ability. It is also well-tolerated, making it a good option for kids with this condition. ^{1 3 8 10 11}

Research Team

Lewis Romer, MD

Principal Investigator

Johns Hopkins University

Eligibility Criteria

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

I am between 3 months and 18 years old.

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

I have been diagnosed with pulmonary arterial hypertension.

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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 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]

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]

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]

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]

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]

References

1. India 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. [2021]

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

Phosphodiesterase 5 Inhibitor for Pediatric Pulmonary Arterial Hypertension: A Cost-Utility Analysis. [2023]

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

Kids Mod PAH trial: A multicenter trial comparing mono- versus duo-therapy for initial treatment of pediatric pulmonary hypertension. [2023]

4. England pubmed.ncbi.nlm.nih.gov

Sildenafil therapy for neonatal and childhood pulmonary hypertensive vascular disease. [2016]

5. United States 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. [2022]

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

Safety and tolerability considerations in the use of sildenafil for children with pulmonary arterial hypertension. [2020]

7. United States 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. [2023]

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

Combination Therapy of Pulmonary Arterial Hypertension with Vardenafil and Macitentan Assessed in a Human Ex Vivo Model. [2020]

9. England 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. [2018]

10. England pubmed.ncbi.nlm.nih.gov

Sildenafil as a treatment for pulmonary hypertension. [2019]

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

Sildenafil for the treatment of pulmonary hypertension in pediatric patients. [2021]