For Providers

Importance of the Study

Pediatric pulmonary arterial hypertension (PAH) is a severe and often progressive disease. Despite the availability of targeted drugs for PAH in adults, data regarding the use of these agents remains extremely limited for children. There is also a lack of multicenter randomized clinical trials in this area. This results in off-label use of PAH medications and uncertainties of optimal clinical endpoints for such studies in children.

The Kids MoD PAH study aims to address this disparity in clinical evidence by conducting a Phase III randomized, open-label trial. This trial will compare the safety and efficacy of first line combo therapy (sildenafil + bosentan) to first line monotherapy (sildenafil alone) in 100 newly diagnosed, treatment naive pediatric participants enrolled at 12 North American PPHNet Consortium Centers.

Objective

The primary objective of this study is to compare two treatment strategies:
First-line combination therapy (sildenafil and bosentan), versus
First-line monotherapy (sildenafil) in pediatric subjects with PAH.

Duration of Study Participation

24 months

Study Design

Phase III, Randomized, Open-Label, Pragmatic, Superiority Trial Study

Duration

5 years

Population

100 newly diagnosed, treatment naïve pediatric participants ages 3 mos-18 years with WSPH Group 1 or 3 pulmonary arterial hypertension (PAH) and WHO FC II or III symptoms

Study Intervention

Sildenafil monotherapy vs. sildenafil + bosentan dual therapy

Primary Endpoint

WHO FC at twelve months after initiation of study drug therapy

Secondary Endpoint

Time to clinical worsening; WHO FC at twenty four months, PK and safety of study drug(s), ECHO metrics of right ventricular pressure and function, 6MWD for subjects 8+ years of age, serum NT-proBNP levels

Exploratory Endpoints

Actigraphy metrics, QoL, biomarkers

Which participants are eligible?

Inclusion Criteria

• Children who have not been treated with long-term targeted PAH drug therapy, which include calcium channel blockers (CCB); prostanoids, endothelin receptor antagonists (ERA) or PDE-5 inhibitors (PDE5i)
• Children who have been receiving subtherapeutic dosing of sildenafil (and no other standing therapy) for less than 2 weeks at the time of their referral for evaluation at a PH Center, may be included after a washout period of two days. Subtherapeutic is defined as dosage less than those shown in Section 6.1.2 sildenafil dosing chart. If, prior to the initial diagnostic cardiac catheterization, the independent clinical practitioner is planning to stop low dose sildenafil that is judged to not have therapeutic impact on hemodynamics by echocardiography, one may include this candidate for enrollment. These children will be followed closely during the washout period for clinical findings of cardiorespiratory changes, and with echocardiography and NT-proBNP measurements. Abnormal findings on these screening tests will prompt consideration of acute initiation of inhaled nitric oxide therapy. Therapy for pulmonary hypertension as determined by randomization for the study, may be started immediately after the two day washout period.
• Diagnosis of PAH by cardiology diagnostics
  • Diagnosis by cardiac catheterization with in the previous six months: PAH is defined as the presence of mean pulmonary artery pressure > 25mmHg, pulmonary capillary wedge pressure (or left atrial or left ventricular end diastolic pressure) ≤ 15 mmHg, and pulmonary vascular resistance index (PVRI) > 3 Woods Units
  • For infants less than one year of age for whom cardiac catheterization is not considered as part of the clinical team’s recommended approach, enrollment will be possible without catheterization if the following four criteria are met:
    • Two separate echocardiograms clearly demonstrate pulmonary hypertension by at least three of the following metrics:
      • Elevated MPA pressure (early diastolic PR peak gradient >20 mmHg)
      • Right ventricular hypertrophy (qualitative as mild to severe)
      • Right atrial enlargement (scales for age will be provided)
      • Elevated right ventricular systolic pressure (>35mmHg) on at least two at least two reliable spectral Doppler envelopes during the echocardiogram and in the setting of normal for age documented systolic blood pressure at least two reliable spectral Doppler envelopes during the echocardiogram.
      • Flattening or (R to L) bowing of the interventricular septum (qualitative or by elevated eccentricity index)
      • Diminished RV function (RV fractional area change <35%) and/or TAPSE below published normal range for age and weight.
    • There is no clinical or imaging evidence of left heart dysfunction;
    • Pulmonary venous stenosis and atresia are ruled out by CT angiography or MRI unless all four pulmonary veins are unequivocally normal on the two separate echocardiograms;
    • There is no evidence of hemodynamically significant left-to-right shunting across an unrestricted systemic to pulmonary shunt (this is unlikely to be a concern for PFO, small ASD, or restrictive PDA or VSD).
• Age ≥3 months to < 18 years (until just before the 18th birthday);
• WSPH groups 1 or 3 NOT due to unrepaired congenital heart disease (other than a patent foramen ovale), OR single ventricle, OR Eisenmenger’s syndrome
• Current WHO FC II or III.

Kids MoD PAH Participant Journey

Interested in learning more?

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JHM IRB Protocol

#IRB00300590

Principle Investigator

Lewis H Romer, MD

Led by investigators from

• Johns Hopkins Medicine

• Duke University School of Medicine

• New York Medical College

• Colorado University School of Medicine

• PPHNet

Funded by

National Heart, Lung, and
Blood Institute (NHLBI)