Remodulin as Add-on Therapy for the Treatment of Persistent Pulmonary Hypertension of the Newborn

Study Overview
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Brief Summary
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This pilot study aims to assess the safety and treatment effect of acute dosing with IV Remodulin in neonates with persistent pulmonary hypertension of the newborn (PPHN).

Detailed Description
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This study will enroll subjects with PPHN who do not show an adequate response to inhaled nitric oxide with the hypothesis that the addition of intravenous (IV) Remodulin will reduce the rate of clinical worsening as compared to standard of care. Additionally, this study aims to evaluate the treatment effect of Remodulin and better understand the dosing and pharmacokinetics in the neonatal population.

Official Title
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Intravenous Remodulin (Treprostinil) as Add-on Therapy for the Treatment of Persistent Pulmonary Hypertension of the Newborn: A Randomized, Placebo-Controlled, Safety and Efficacy Study

Conditions
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Persistent Pulmonary Hypertension of the Newborn

Intervention / Treatment
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* Drug: IV Remodulin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Parent(s) or guardian provides consent for the subject to participate, as per institutional policy At least 2 kg at Screening Gestational age ≥ 34 weeks and ≤ 14 days old at Screening Diagnosis of PPHN, which is either idiopathic in nature or associated with the following: meconium aspiration syndrome (MAS), pneumonia, respiratory distress syndrome (RDS), sepsis, birth hypoxia, perinatal encephalopathy or unilateral congenital diaphragmatic hernia (CDH) Currently requiring ventilator support Receiving iNO with two OIs of 15 or greater separated by at least 30 minutes after receiving iNO for at least 3 hours Echocardiographic evidence of pulmonary hypertension with elevated right ventricle pressure Dedicated venous access for the administration of study drug (central line or peripherally inserted central venous catheter) Exclusion Criteria: Previous or concurrent use of a phosphodiesterase-5 inhibitor (PDE5i), endothelin receptor antagonist (ERA), or prostanoid Significant congenital heart disease (CHD) as detected by ECHO (excluding presence of minor defects such as small secundum atrial septal defect (ASD), minor valvular abnormalities, or expected transitional findings such as a patent foramen ovale (PFO), or patent ductus arteriosus (PDA). Subjects with small muscular, restrictive ventricular septal defect (VSD) may be enrolled Clinically significant, untreated active pneumothorax at Screening Evidence of clinically significant bleeding Necrotizing entercolitis; ≥ Bells stage II at Screening Uncontrolled hypotension; mean systemic pressures ≤ 35 mmHg at Screening. Uncontrolled coagulopathy and / or untreated thrombocytopenia; defined as <50,000 platelets /µL at Screening History of severe (Grade 3 or 4) intracranial hemorrhage Currently receiving ECMO or has immediate plans to initiate ECMO Expected duration on mechanical ventilation of less than 48 hours Life expectancy is less than two months or has a lethal chromosomal anomaly Contraindication to ECMO Bilateral congenital diaphragmatic hernia Active seizures at Screening Currently participating in another clinical drug study (excluding observational registries)

Ages Eligible for Study
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Minimum Age: 1 Hour
Maximum Age: 14 Days

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: IV Remodulin<br>IV Remodulin will be initiated at 1 ng/kg/min. The dose will be increased in up to 2 ng/kg/min increments every 2 hrs until the OI is <10 (in the absence of dose-limiting side effects). | Drug: IV Remodulin<br>* Treprostinil is a chemically stable tricyclic analogue of prostacyclin.<br>* Other names: treprostinil;|
| Placebo Comparator: Placebo<br>Placebo will be initiated at 1 ng/kg/min. The dose will be increased in up to 2 ng/kg/min increments every 2 hrs until the OI is <10 (in the absence of dose-limiting side effects). | Drug: Placebo<br>* matching placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluate the rate of clinical worsening in neonates with PPHN | Efficacy will be assessed by a composite endpoint of clinical worsening as defined by the following: Initiation of additional pulmonary vasodilator therapy Initiation of extracorporeal mechanical oxygenation (ECMO) per institutional policies Death | Up to Day 14 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to discontinuation of inhaled nitric oxide (iNO) |  | Up to Day 56 | 
| Change in oxygenation index (OI) | OI= [MAP(mmHg) x FiO2(%) / PaO2(mmHg)] x 100 | Hour 12, hour 24, hour 72, Day 7 and Day 14/ or prior to study drug discontiuation | 
| Time on mechanical ventilation |  | Up to Day 56 | 
| Time to initiation of ECMO |  | Up to Day 56 | 
| Mean treprostinil plasma concentration per dose achieved | Two blood samples will be collected from each patient for treprostinil pharmacokinetic (PK) analysis. Plasma samples will be analyzed for treprostinil using a validated bioanalytical plasma assay. | 24 hours after initiation of Remodulin and immediately prior to wean | 
| Safety | Assessment of adverse events, change in vital signs, and change in labs. | up to Day 56 | 
| Change in partial pressure of oxygen in arterial blood (PaO2) / fraction of inspired oxygen (FiO2) [P/F ratio] |  | Hour 12, hour 24, and hour 72 | 
| Change in N-terminal pro-Brain Natriuretic Peptide (NT-proBNP) |  | Day 7, Day 14, prior to study drug wean, study drug discontinuation | 
| Change in pre and post-ductal oxygen saturation (SpO2) |  | Hour 6, hour 12, hour 24, and hour 72 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PPHN