Summary

Eligibility
for people ages 4 months to 18 years (full criteria)
Location
at San Francisco, California and other locations
Dates
study started
estimated completion
Principal Investigator
by Jeffrey Fineman, MD

Description

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.

Official Title

Kids MoD PAH Trial: Mono- vs. Duo-Therapy for Pediatric Pulmonary Arterial Hypertension

Details

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.

Keywords

Pediatric Pulmonary Hypertension Hypertension, Pulmonary Pulmonary Arterial Hypertension Hypertension Bosentan Sildenafil Citrate Mono-Therapy with Sildenafil Duo-Therapy with Sildenafil + Bosentan

Eligibility

You can join if…

Open to people ages 4 months to 18 years

  • 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.

You CAN'T join if...

, 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).

Locations

  • The Regents of the University of California, San Francisco accepting new patients
    San Francisco California 94158 United States
  • Seattle Children's Hospital accepting new patients
    Seattle Washington 98105 United States

Lead Scientist at UCSF

Details

Status
accepting new patients
Start Date
Completion Date
(estimated)
Sponsor
Johns Hopkins University
ID
NCT04039464
Phase
Phase 3 research study
Study Type
Interventional
Participants
Expecting 100 study participants
Last Updated