Mono vs. Dual Therapy for Pediatric Pulmonary Arterial Hypertension (MoD)
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|ClinicalTrials.gov Identifier: NCT04039464|
Recruitment Status : Not yet recruiting
First Posted : July 31, 2019
Last Update Posted : August 30, 2021
|Condition or disease||Intervention/treatment||Phase|
|Pediatric Pulmonary Hypertension||Drug: Mono-Therapy with Sildenafil Drug: Duo-Therapy with Sildenafil + Bosentan||Phase 3|
A Phase III, randomized, open label, pragmatic trial to compare the safety and efficacy of first-line combination therapy (sildenafil and bosentan) to first-line monotherapy (sildenafil alone) in pediatric subjects with WHO Functional Classes II or III and precapillary pulmonary hypertension of Group 1 (PAH caused by idiopathic, heritable, drugs or toxins, congenital heart disease, or connective tissue disease) or Group 3 (PAH caused by lung disease or hypoxemia) according to the WHO (Nice) classification system. Precapillary pulmonary hypertension will be defined by standard criteria as mean pulmonary artery pressure over 25 mmHg and/or pulmonary vascular resistance index (PVRI) > 3, as well as pulmonary capillary wedge pressure (or left ventricular end diastolic pressure) ≤ 15 mmHg as determined by cardiac catheterization.
Study subjects will be followed with current standard of care assessments and diagnostics, including longitudinal clinical evaluations, determinations of functional class (FC), serial NT-pro-Brain Natriuretic Peptide (NT-proBNP) levels, and echocardiography. Data from these studies will be analyzed in central core facilities that will be used by all participating study sites.
Clinical endpoints are the focus of this study. However, additional data collection is planned for exploratory aims to examine the potential role for future application of novel metrics of outcomes in children with PAH (e.g., pediatric QOL and actigraphy), as described below. The investigators also plan to collect blood, swab and urine samples to determine whether inherent genomic variations or novel proteomic biomarkers will associate with clinical responsiveness to interventions within the cohort. Bio-specimens will be obtained to further test the hypothesis that therapeutic responders will have a different genomic or proteomic profile as compared to subjects who do not respond well to therapy.
Bio-specimens will include the following:
- Blood for DNA, peripheral blood mononuclear cells, plasma, and serum; and
- Paired Box Gene (PAXgene) tubes for RNA and miRNA studies; and
- Urine for biomarker analysis.
Because sildenafil and bosentan have different mechanisms of action targeting different intracellular pathways, combination therapy is a rational treatment strategy for pediatric patients with PAH. Past work in adult PAH suggests that combination therapy with longer duration agents with the same mechanisms of action may cause greater and more sustained improvement in clinical course in comparison with monotherapy. Whether children with PAH respond and tolerate combination therapy better than monotherapy has not been studied. In addition, despite a growing experience with sequential therapy, additional medications are added only after clinical deterioration or failure to sustain responsiveness.
Pharmacokinetics will be assessed during this study in order to determine whether drug levels or compliance with therapy affect outcomes in this cohort. In addition, pharmacokinetics data and related clinical responses from mono- and dual therapy participants will be compared. Interactions between these agents are well known, whereby bosentan decreases sildenafil levels. As a result, sildenafil levels during mono- and combination therapy will be further defined by the planned pharmacokinetics in the current protocol. In addition to strengthening this current study design, such data will form a basis for optimizing the use of these agents and potential strategies for dose adjustments in the broader scope of clinical care in the future.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||100 participants|
|Intervention Model:||Parallel Assignment|
|Masking:||Double (Investigator, Outcomes Assessor)|
|Official Title:||Kids MoD PAH Trial: Mono- vs. Duo-Therapy for Pediatric Pulmonary Arterial Hypertension|
|Estimated Study Start Date :||October 1, 2021|
|Estimated Primary Completion Date :||September 30, 2026|
|Estimated Study Completion Date :||September 30, 2026|
Active Comparator: Monotherapy with Sildenafil Group
mono-therapy: first-line monotherapy (sildenafil alone) - in pediatric subjects with PAH.
Drug: Mono-Therapy with Sildenafil
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.
Other Name: Revatio monotherapy
Active Comparator: Duo Therapy with Sildenafil + Bosentan Group
duo-therapy: compare two treatment strategies - first-line combination therapy (sildenafil and bosentan)
Drug: Duo-Therapy with Sildenafil + Bosentan
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.
Other Name: Dual therapy with Revatio and Tracleer
- Change in WHO functional class (FC) of Mono vs. Dual Therapy [ Time Frame: Baseline, 12 months ]
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.
- Time to clinical worsening (TTCW) [ Time Frame: 24 months ]TTCW has become increasingly used in multicenter randomized clinical trials of adult pulmonary hypertension (PH) and will be used in this trial to capture time (in days) from study enrollment to clinical worsening. Disease progression will be defined as deterioration in WHO FC and the need for additional therapy for subjects less than 8 years of age. Subjects that are over 8 years old will follow adult criteria for this event - both deterioration in WHO FC and more than a 15% decrease in 6 minute walk distance (MWD) from baseline. TTCW is defined as a composite including disease progression, hospitalization for worsening PH, addition of other prostanoid drug therapies, Potts shunt, lung transplantation or atrial septostomy, and all-cause death.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04039464
|Contact: Lewis Romer, MD||(410) email@example.com|
|United States, Maryland|
|Johns Hopkins University|
|Baltimore, Maryland, United States, 21287|
|Contact: Lewis Romer, MD 410-955-6412 firstname.lastname@example.org|
|Principal Investigator:||Lewis Romer, MD||Johns Hopkins University|