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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
Sponsor:
Information provided by (Responsible Party):
Johns Hopkins University

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.

Condition or disease Intervention/treatment Phase
Pediatric Pulmonary Hypertension Drug: Mono-Therapy with Sildenafil Drug: Duo-Therapy with Sildenafil + Bosentan Phase 3

Detailed Description:

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:

  1. Blood for DNA, peripheral blood mononuclear cells, plasma, and serum; and
  2. Paired Box Gene (PAXgene) tubes for RNA and miRNA studies; and
  3. 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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 100 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Investigator, Outcomes Assessor)
Primary Purpose: Treatment
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


Arm Intervention/treatment
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




Primary Outcome Measures :
  1. 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.



Secondary Outcome Measures :
  1. 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.



Information from the National Library of Medicine

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Ages Eligible for Study:   4 Months to 18 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Diagnoses of precapillary pulmonary hypertension (PAH) by cardiac catheterization within the previous 4 weeks prior to screening as defined by: mean pulmonary artery pressure > 25 mmHg and/or pulmonary vascular resistance index (PVRI) > 3 Wood units*m2; and pulmonary capillary wedge pressure (or left ventricular end diastolic pressure) < or = 15 mmHg (to rule out significant contributions of left heart disease that may complicate the course and response to therapy);
  • Age > or = 4 months to < 18 years;
  • Subjects should also meet the following 2 criteria:
  • World Symposium on Pulmonary Hypertension Groups 1 or 3;
  • Current WHO Functional Classes II or III.

Exclusion Criteria, An individual who meets any of the following criteria will be excluded from participation in this study:

  • Inability to obtain informed consent;
  • WHO Functional Class IV, or the presence of overt right heart failure (RV) failure with syncope, cyanotic spells or systemic hypotension;
  • Evidence of diffuse or focal pulmonary venous disease, left-sided heart functional disease;
  • Unrepaired congenital heart disease other than a patent foramen ovale, single ventricles, or Eisenmenger's syndrome;
  • Pre-existing standing PAH therapy (calcium channel blockade, phosphodiesterase type 5 inhibitor, endothelin receptor antagonists, or chronic prostanoid). This does not need to include agents used for vasoreactivity testing, or for acute or periprocedural stabilization. All prior PAH therapy must be discontinued for a minimum of seven days prior to enrollment into this study. Safety concerns regarding the prospect of a hiatus in therapy for a wash out period prior to enrollment in this study will be brought to the attention of the DSMB for adjudication;
  • History of discontinuation of endothelin receptor antagonists (ERA) or phosphodiesterase-5 inhibitors (PDE5i) treatment due intolerance or safety issues;
  • Known hypersensitivity to investigational products, metabolites, or formulation excipients;
  • Pregnancy or breastfeeding;
  • Documented history in the medical record of noncompliance with previous medical regimens within one year of screening;
  • Recent (within 1 year) history of alcohol or illicit drug abuse;
  • Participation in a clinical study involving another investigational drug or device within 4 weeks;
  • Comorbidities:
  • disorders treated with cyclosporine A or glyburide
  • disorders treated with cytochrome (CYP3A) Inhibitors and Beta Blockers
  • congenital heart disease repaired within 6 months of enrollment;+
  • Laboratory values of exclusion:
  • serum Alanine Aminotransferase (ALT) or Aspartate Transaminase (AST) lab value that is > bilirubin (2xULN) at the Screening Visit
  • serum bilirubin lab value that is > bilirubin (1.5xULN) at the screening visit
  • creatinine clearance < 30 mL/min;
  • Inability to comply with all study procedures and availability for duration of study;
  • age < 4 months or > 18 years (please note that study subjects that are > or = 16 years of age at the time of enrollment will achieve legal majority age by the study's end and a transition to adult status with an adult consent form will be planned for those subjects);
  • Inability to take enteral medication;
  • Inability to agree to lifestyle considerations throughout the study; For subjects with reproductive potential, those who are unwilling or unable to use an acceptable method of contraception during this protocol and for four weeks thereafter;
  • For female participants with reproductive potential, inability to use a highly effective form of contraception for the one month prior to initiation of study drug (note that eligibility may be restored after one month of the use of appropriate contraception).

Information from the National Library of Medicine

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


Contacts
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Contact: Lewis Romer, MD (410) 955-6412 lromer@jhmi.edu

Locations
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United States, Maryland
Johns Hopkins University
Baltimore, Maryland, United States, 21287
Contact: Lewis Romer, MD    410-955-6412    lromer@jhmi.edu   
Sponsors and Collaborators
Johns Hopkins University
Investigators
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Principal Investigator: Lewis Romer, MD Johns Hopkins University
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Responsible Party: Johns Hopkins University
ClinicalTrials.gov Identifier: NCT04039464    
Other Study ID Numbers: IRB00293670
First Posted: July 31, 2019    Key Record Dates
Last Update Posted: August 30, 2021
Last Verified: August 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description:

This study will be conducted in accordance with the following publication and data sharing policies and regulations:

National Institutes of Health (NIH) Public Access Policy, which ensures that the public has access to the published results of NIH funded research. It requires scientists to submit final peer-reviewed journal manuscripts that arise from NIH funds to the digital archive PubMed Central upon acceptance for publication.

This study will comply with the NIH Data Sharing Policy and Policy on the Dissemination of NIH-Funded Clinical Trial Information and the Clinical Trials Registration and Results Information Submission rule. As such, this trial will be registered at ClinicalTrials.gov, and results information from this trial will be submitted to ClinicalTrials.gov. In addition, every attempt will be made to publish results in peer-reviewed journals.

Time Frame: 1 year after study completion
Access Criteria: Written request

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Additional relevant MeSH terms:
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Hypertension, Pulmonary
Hypertension
Vascular Diseases
Cardiovascular Diseases
Lung Diseases
Respiratory Tract Diseases
Bosentan
Sildenafil Citrate
Vasodilator Agents
Phosphodiesterase 5 Inhibitors
Phosphodiesterase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Urological Agents
Antihypertensive Agents
Endothelin Receptor Antagonists