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

• ClinicalTrials.gov Identifier: NCT02261883
• Recruitment Status: Completed
• First Posted: October 10, 2014
• Last Update Posted: May 25, 2023
• Sponsor: United Therapeutics
• Information provided by (Responsible Party): United Therapeutics

Tracking Information

• First Submitted Date: October 30, 2013
• First Posted Date: October 10, 2014
• Last Update Posted Date: May 25, 2023
• Study Start Date: May 2015
• Actual Primary Completion Date: September 27, 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: October 6, 2014)

Evaluate the rate of clinical worsening in neonates with PPHN [ Time Frame: Up to Day 14 ]

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

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: October 6, 2014)

• Time to discontinuation of inhaled nitric oxide (iNO) [ Time Frame: Up to Day 56 ]
• Change in oxygenation index (OI) [ Time Frame: Hour 12, hour 24, hour 72, Day 7 and Day 14/ or prior to study drug discontiuation ]
  OI= [MAP(mmHg) x FiO2(%) / PaO2(mmHg)] x 100
• Time on mechanical ventilation [ Time Frame: Up to Day 56 ]
• Time to initiation of ECMO [ Time Frame: Up to Day 56 ]
• Mean treprostinil plasma concentration per dose achieved [ Time Frame: 24 hours after initiation of Remodulin and immediately prior to wean ]
  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.
• Safety [ Time Frame: up to Day 56 ]
  Assessment of adverse events, change in vital signs, and change in labs.
• Change in partial pressure of oxygen in arterial blood (PaO2) / fraction of inspired oxygen (FiO2) [P/F ratio] [ Time Frame: Hour 12, hour 24, and hour 72 ]
• Change in N-terminal pro-Brain Natriuretic Peptide (NT-proBNP) [ Time Frame: Day 7, Day 14, prior to study drug wean, study drug discontinuation ]
• Change in pre and post-ductal oxygen saturation (SpO2) [ Time Frame: Hour 6, hour 12, hour 24, and hour 72 ]

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Remodulin as Add-on Therapy for the Treatment of Persistent Pulmonary Hypertension of the Newborn
• Official Title: 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
• Brief Summary: 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: 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.
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Persistent Pulmonary Hypertension of the Newborn

Intervention

• Drug: IV Remodulin
  Treprostinil is a chemically stable tricyclic analogue of prostacyclin.
  Other Name: treprostinil
• Drug: Placebo
  matching placebo

Study Arms

• Active Comparator: IV Remodulin
  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).
  Intervention: Drug: IV Remodulin
• Placebo Comparator: Placebo
  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).
  Intervention: Drug: Placebo

Publications *

• Steinhorn RH. Nitric oxide and beyond: new insights and therapies for pulmonary hypertension. J Perinatol. 2008 Dec;28 Suppl 3(Suppl 3):S67-71. doi: 10.1038/jp.2008.158.
• Neonatal Inhaled Nitric Oxide Study Group. Inhaled nitric oxide in full-term and nearly full-term infants with hypoxic respiratory failure. N Engl J Med. 1997 Feb 27;336(9):597-604. doi: 10.1056/NEJM199702273360901. Erratum In: N Engl J Med 1997 Aug 7;337(6):434.
• Clark RH, Kueser TJ, Walker MW, Southgate WM, Huckaby JL, Perez JA, Roy BJ, Keszler M, Kinsella JP. Low-dose nitric oxide therapy for persistent pulmonary hypertension of the newborn. Clinical Inhaled Nitric Oxide Research Group. N Engl J Med. 2000 Feb 17;342(7):469-74. doi: 10.1056/NEJM200002173420704.
• Simonneau G, Barst RJ, Galie N, Naeije R, Rich S, Bourge RC, Keogh A, Oudiz R, Frost A, Blackburn SD, Crow JW, Rubin LJ; Treprostinil Study Group. Continuous subcutaneous infusion of treprostinil, a prostacyclin analogue, in patients with pulmonary arterial hypertension: a double-blind, randomized, placebo-controlled trial. Am J Respir Crit Care Med. 2002 Mar 15;165(6):800-4. doi: 10.1164/ajrccm.165.6.2106079.
• Rubenfire M, McLaughlin VV, Allen RP, Elliott G, Park MH, Wade M, Schilz R. Transition from IV epoprostenol to subcutaneous treprostinil in pulmonary arterial hypertension: a controlled trial. Chest. 2007 Sep;132(3):757-63. doi: 10.1378/chest.06-2118. Epub 2007 Mar 30. Erratum In: Chest. 2007 Nov;132(5):1721.
• Hiremath J, Thanikachalam S, Parikh K, Shanmugasundaram S, Bangera S, Shapiro L, Pott GB, Vnencak-Jones CL, Arneson C, Wade M, White RJ; TRUST Study Group. Exercise improvement and plasma biomarker changes with intravenous treprostinil therapy for pulmonary arterial hypertension: a placebo-controlled trial. J Heart Lung Transplant. 2010 Feb;29(2):137-49. doi: 10.1016/j.healun.2009.09.005.
• Levy M, Celermajer DS, Bourges-Petit E, Del Cerro MJ, Bajolle F, Bonnet D. Add-on therapy with subcutaneous treprostinil for refractory pediatric pulmonary hypertension. J Pediatr. 2011 Apr;158(4):584-8. doi: 10.1016/j.jpeds.2010.09.025. Epub 2010 Oct 30.
• Ivy DD, Claussen L, Doran A. Transition of stable pediatric patients with pulmonary arterial hypertension from intravenous epoprostenol to intravenous treprostinil. Am J Cardiol. 2007 Mar 1;99(5):696-8. doi: 10.1016/j.amjcard.2006.09.119. Epub 2007 Jan 10.
• Christman BW, McPherson CD, Newman JH, King GA, Bernard GR, Groves BM, Loyd JE. An imbalance between the excretion of thromboxane and prostacyclin metabolites in pulmonary hypertension. N Engl J Med. 1992 Jul 9;327(2):70-5. doi: 10.1056/NEJM199207093270202.
• Laliberte K, Arneson C, Jeffs R, Hunt T, Wade M. Pharmacokinetics and steady-state bioequivalence of treprostinil sodium (Remodulin) administered by the intravenous and subcutaneous route to normal volunteers. J Cardiovasc Pharmacol. 2004 Aug;44(2):209-14. doi: 10.1097/00005344-200408000-00010.
• Wade M, Baker FJ, Roscigno R, DellaMaestra W, Hunt TL, Lai AA. Absolute bioavailability and pharmacokinetics of treprostinil sodium administered by acute subcutaneous infusion. J Clin Pharmacol. 2004 Jan;44(1):83-8. doi: 10.1177/0091270003261343.

Recruitment Information

• Recruitment Status: Completed
• Estimated Enrollment (submitted: October 6, 2014): 70
• Original Estimated Enrollment: Same as current
• Actual Study Completion Date: September 27, 2022
• Actual Primary Completion Date: September 27, 2022 (Final data collection date for primary outcome measure)

Eligibility Criteria

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)

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 1 Hour to 14 Days (Child)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT02261883
• Other Study ID Numbers: RIV-PN-201
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: United Therapeutics
• Original Responsible Party: Same as current
• Current Study Sponsor: United Therapeutics
• Original Study Sponsor: Same as current
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: United Therapeutics
• Verification Date: May 2023