Mono vs. Dual Therapy for Pediatric Pulmonary Arterial Hypertension

NCT04039464 | Completed Phase 3 DMC FDA Drug

• 5 other identifiers: IRB00300590UG3HL151458UH3HL1514581U24TR0016091U24TR004440
• Study Type: interventional
• Target: 28
• Locations: 1 country
• Sites: 10

Brief Summary

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.

Conditions

Pediatric Pulmonary Hypertension

Outcome Measures

Primary Outcomes (1)

• Change in WHO functional class (FC) of Mono vs. Dual Therapy

  There are four WHO functional classes: Class I: Pulmonary hypertension without resulting limitation of physical activity; Ordinary physical activity does not cause undue dyspnea or fatigue, or chest pain or near-syncope; Class II: Pulmonary hypertension resulting in a slight limitation of physical activity; Comfortable at rest; Ordinary physical activity causes undue dyspnea or fatigue, or chest pain or near-syncope; Class III: Pulmonary hypertension resulting in a marked limitation of physical activity; Comfortable at rest; Less than ordinary physical activity causes undue dyspnea or fatigue, or chest pain or near-syncope; Class IV: Pulmonary hypertension resulting in inability to carry out any physical activity without symptoms; Signs of right heart failure; Marked limitation of physical activity; Dyspnea and/or fatigue may be present at rest; Discomfort. This will be an assessment of a change from one class to another per participant in each arm.

  Baseline, 12 months

Secondary Outcomes (1)

• Time to clinical worsening (TTCW)

  24 months

Study Arms (2)

Monotherapy with Sildenafil Group

ACTIVE COMPARATOR

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

Drug: Mono-Therapy with Sildenafil

Duo Therapy with Sildenafil + Bosentan Group

ACTIVE COMPARATOR

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

Drug: Duo-Therapy with Sildenafil + Bosentan

Interventions

Mono-Therapy with Sildenafil DRUG

The subjects will be randomized to receive sildenafil alone and will undergo study procedures as outlined in section 1.3. There will not be a placebo group.

Also known as: Revatio monotherapy

Monotherapy with Sildenafil Group

Duo-Therapy with Sildenafil + Bosentan DRUG

The subjects will be randomized to receive combination up-front therapy sildenafil and bosentan and will undergo study procedures as outlined in section 1.3. There will not be a placebo group.

Also known as: Dual therapy with Revatio and Tracleer

Duo Therapy with Sildenafil + Bosentan Group

Eligibility Criteria

• Age: 3 Months - 18 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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) (note that agents used for vasoreactivity testing during cardiac catheterization, or for acute periprocedural stabilization will be discontinued prior to study enrollment these include inhaled nitric oxide and/or prostacyclin analogs) a. 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:
• i. 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.
• ii. There is no clinical or imaging evidence of left heart dysfunction; iii. 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; iv. 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 (PLEASE NOTE that only patients with Group 1.1, 1.2, 1.3, and 1.4.4 or Group 3 PAH will be included and this does not include those with much rarer presentations with connective tissue disease, HIV infection, portal hypertension, schistosomiasis, or persistent PAH of the newborn);
• Current WHO FC II or III.

You may not qualify if:

• Inability or failure to provide informed consent;
• The presence of syncope, overt RV failure, cyanotic "spells" or systemic hypotension within 4 weeks of enrollment;
• Evidence of diffuse or focal pulmonary venous disease, left-sided heart functional disease;
• Known hypersensitivity to metabolites, or formulation components such as vehicle, preservatives or fillers that are contained in the investigational drugs;
• Pregnancy or breastfeeding;
• Documented history in the medical record of noncompliance with other medical regimens within one year of screening;
• Recent (within 1 year) history of alcohol or illicit drug abuse;
• Participation in any clinical study involving another investigational drug or device within 4 weeks;
• Comorbidities
• a. Disorders treated with cyclosporine A or glyburide
• b. Disorders treated with CYP3A Inhibitors and Beta Blockers
• c. Congenital heart disease that was repaired within 6 months of enrollment;
• serum ALT or AST lab value that is \> 2xULN
• serum bilirubin lab value that is \> 1.5xULN
• creatinine clearance \< 30 mL/min;

Sponsors & Collaborators

• Johns Hopkins University: lead
• National Heart, Lung, and Blood Institute (NHLBI): collaborator
• National Center for Advancing Translational Sciences (NCATS): collaborator

Study Sites (10)

Children's Hospital Colorado

Aurora, Colorado, 80045, United States

Location

Johns Hopkins All Children's Hospital

St. Petersburg, Florida, 33701, United States

Location

Johns Hopkins Medical Institutions

Baltimore, Maryland, 21287, United States

Location

Boston Children's Hospital

Boston, Massachusetts, 02115, United States

Location

Columbia University Medical Center

New York, New York, 10032, United States

Location

New York Medical College

Valhalla, New York, 10595, United States

Location

Vanderbilt University Medical Center

Nashville, Tennessee, 37232, United States

Location

Baylor College of Medicine

Houston, Texas, 77030, United States

Location

Seattle Children's Hospital

Seattle, Washington, 98105, United States

Location

Medical College of Wisconsin

Milwaukee, Wisconsin, 53226, United States

Location

MeSH Terms

Interventions

Sildenafil Citrate; Bosentan

Intervention Hierarchy (Ancestors)

Sulfonamides; Amides; Organic Chemicals; Sulfones; Sulfur Compounds; Piperazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Benzenesulfonamides; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Pyrimidines

Study Officials

• Lewis Romer, MD

  Johns Hopkins University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 1, 2019
• First Posted: July 31, 2019
• Study Start: August 1, 2022
• Primary Completion: December 31, 2025
• Study Completion: December 31, 2025
• Last Updated: February 18, 2026

Record last verified: 2026-02

Data Sharing

• IPD Sharing: Will share
• Time Frame: 1 year after study completion
• Access Criteria: Written request

Locations

US (10)