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

February 6, 2024 updated by: United Therapeutics

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

This study assessed the safety and treatment effect of intravenous (IV) Remodulin as an add-on therapy in neonates with persistent pulmonary hypertension of the newborn (PPHN).

Study Overview

Status

Terminated

Conditions

Intervention / Treatment

Detailed Description

This study was designed to investigate if the addition of Remodulin reduced the rate of clinical worsening (defined as the need for additional treatment targeting PPHN, need for extracorporeal mechanical oxygenation [ECMO], or death) in neonatal subjects with PPHN who did not show an adequate response to inhaled nitric oxide (iNO). This study was part of a pediatric investigation plan agreed upon by the EMA (EMEA 000207-PIP01-08-M08).

Study Type

Interventional

Enrollment (Actual)

42

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Arkansas
      • Little Rock, Arkansas, United States, 72202
        • Arkansas Children's Hospital
    • California
      • Los Angeles, California, United States, 90027
        • Children's Hospital of Los Angeles
      • Palo Alto, California, United States, 94304
        • Stanford Children's Hospital
    • Florida
      • Saint Petersburg, Florida, United States, 33701
        • All Children's Hospital
    • Illinois
      • Chicago, Illinois, United States, 60611
        • Ann and Robert H. Lurie Children's Hospital of Chicago
    • Maryland
      • Baltimore, Maryland, United States, 21287
        • Johns Hopkins Hospital
    • Mississippi
      • Jackson, Mississippi, United States, 39216
        • University of Mississippi Medical Center - Baston Children's Hospital
    • Missouri
      • Kansas City, Missouri, United States, 64108
        • Children's Mercy Hospital
    • New York
      • New York, New York, United States, 10032-3784
        • Columbia University Medical Center
    • Ohio
      • Columbus, Ohio, United States, 43205
        • Nationwide Childrens Hospital
    • Texas
      • Fort Worth, Texas, United States, 76104
        • Cook Children's Medical Center
    • Virginia
      • Charlottesville, Virginia, United States, 22908
        • University of Virginia Health Systems (UVA)
    • Washington
      • Seattle, Washington, United States, 98105
        • Seattle Children's Hospital
    • Wisconsin
      • Wauwatosa, Wisconsin, United States, 53226
        • Children's Hospital of Wisconsin

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

1 hour to 2 weeks (Child)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Parent(s) or legal guardian provided consent for the subject to participate
  • Weight at least 2 kg at Screening
  • Gestational age of ≥34 weeks and ≤14 days old at Screening
  • Diagnosis of PPHN, which was either idiopathic in nature or associated with the following: meconium aspiration syndrome, pneumonia, respiratory distress syndrome, sepsis, birth hypoxia, perinatal encephalopathy, or unilateral congenital diaphragmatic hernia
  • Currently requiring ventilator support
  • Two consecutive oxygenation index (OI) of 15 or greater separated by at least 30 minutes, after receiving iNO for at least 3 hours
  • Echocardiographic (ECHO) 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, endothelin receptor antagonist, or prostanoid
  • Significant congenital heart disease as detected by ECHO, minor valvular abnormalities, or expected transitional findings such as a patent foramen ovale, or patent ductus arteriosus.
  • Clinically significant, untreated active pneumothorax at Screening
  • Evidence of clinically significant bleeding at Screening
  • Necrotizing enterocolitis (≥Bells stage II at Screening)
  • Uncontrolled hypotension (mean systemic pressures ≤35 mmHg at Screening)
  • Uncontrolled coagulopathy and / or untreated thrombocytopenia (<50,000 platelets/µL at Screening)
  • History of severe (Grade 3 or 4) intracranial hemorrhage at Screening
  • Currently receiving extracorporeal mechanical oxygenation (ECMO) or had immediate plans to initiate ECMO
  • Expected duration on mechanical ventilation of <48 hours
  • Life expectancy was less than 2 months or had a lethal chromosomal anomaly
  • Contraindication to ECMO
  • Bilateral congenital diaphragmatic hernia
  • Active seizures at Screening
  • Currently participating in another clinical drug study

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: IV Remodulin
The starting dose was 1 ng/kg/min (not to exceed to 2 ng/kg/min) and was titrated by up to 2 ng/kg/min every 2 hours, as tolerated and clinically indicated by the Investigator. Doses were titrated and maximized throughout the study until the desired clinical effect was observed or to each individual subject's maximally tolerated dose. There was no maximum dose.
Drug: IV Remodulin
Treprostinil is a chemically stable tricyclic analogue of prostacyclin.
Other Names:
  • Treprostinil
Placebo Comparator: Placebo
The starting dose was 1 ng/kg/min (not to exceed to 2 ng/kg/min) and was titrated by up to 2 ng/kg/min every 2 hours, as tolerated and clinically indicated by the Investigator. Doses were titrated and maximized throughout the study until the desired clinical effect was observed or to each individual subject's maximally tolerated dose. There was no maximum dose.
Drug: Placebo
Sodium citrate, sodium chloride, sodium hydroxide pellets, metacresol, and citric acid (anhydrous).

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of Subjects Experiencing Clinical Worsening
Time Frame: From Baseline to Day 14
Clinical worsening was a composite endpoint defined by the occurrence of 1 of the following: death, initiation of ECMO per institutional policies, or need for additional treatment (initiation of additional targeted pulmonary vasodilator therapy).
From Baseline to Day 14

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in Oxygenation Index (OI)
Time Frame: From Baseline to Hours 12, 24, and 72; Days 7 and 14; and/or prior to study drug discontinuation/weaning
OI is an assessment of how much oxygen from the lungs enters the blood when a subject inhales, calculated as: mean airway pressure (MAP) multiplied by fraction of inspired oxygen (FiO2) divided by partial pressure of oxygen in the arterial blood (PaO2), then multiplying by 100. An OI of 15 or less indicates mild hypoxia, 16 to 25 indicates moderate hypoxia, 26 to 40 indicates severe hypoxia, and more than 40 indicates very severe hypoxia.
From Baseline to Hours 12, 24, and 72; Days 7 and 14; and/or prior to study drug discontinuation/weaning
Change in P/F Ratio
Time Frame: From Baseline to Hours 12, 24, and 72
PaO2/FiO2 ratio, also referred to as P/F Ratio, is a calculation used to assess the severity of hypoxemia, which is a condition characterized by low levels of oxygen in the blood. A low P/F ratio suggests that the patient's oxygen levels are compromised relative to the amount of oxygen being provided.
From Baseline to Hours 12, 24, and 72
Change in Pre- and Post-ductal Oxygen Saturation (SpO2)
Time Frame: From Baseline to Hours 6, 12, 24, and 72
SpO2 is an assessment of how much oxygen is in the blood, measured by a pulse oximeter. Pre-ductal SpO2 is measured in the right hand or foot and is a reflection of the amount of oxygen flowing to the brain. Post-ductal SpO2 is measured in the left hand or foot, after the blood has mixed with less oxygenated blood from the rest of the body.
From Baseline to Hours 6, 12, 24, and 72
Change in N-terminal Pro-Brain Natriuretic Peptide (NT-proBNP)
Time Frame: From Baseline to Days 1, 2, 3, 7, and 14 (or prior to hospital discharge)
NT-proBNP is a hormone produced by the heart. Increased NT-proBNP concentration is associated with changes in right heart morphology and function. The main purpose of NT-proBNP testing is to see if the blood levels of this protein are within the expected range for a healthy individual.
From Baseline to Days 1, 2, 3, 7, and 14 (or prior to hospital discharge)
Time to Clinical Worsening
Time Frame: From Baseline to Day 56
Clinical worsening was assessed continuously during the study. Clinical worsening was a composite endpoint defined by the occurrence of 1 of the following: death, initiation of ECMO per institutional policies, or need for additional treatment (initiation of additional targeted pulmonary vasodilator therapy).
From Baseline to Day 56
Time to Initiation of ECMO
Time Frame: From Baseline to Day 56
Start of ECMO was assessed continuously during the study. ECMO is a life-support therapy that oxygenates blood by passing it through an artificial lung. The start time of ECMO, if needed, was recorded for each subject.
From Baseline to Day 56
Time to Discontinuation of Inhaled Nitric Oxide (iNO)
Time Frame: From Baseline to Day 56
Discontinuation of iNO was assessed continuously during the study. iNO works by relaxing the blood vessels in the lungs, which makes it easier for oxygen to be delivered to the body. The stop time of iNO was recorded for each subject.
From Baseline to Day 56

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

United Therapeutics

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

July 29, 2015

Primary Completion (Actual)

September 27, 2022

Study Completion (Actual)

May 17, 2023

Study Registration Dates

First Submitted

October 30, 2013

First Submitted That Met QC Criteria

October 6, 2014

First Posted (Estimated)

October 10, 2014

Study Record Updates

Last Update Posted (Actual)

March 5, 2024

Last Update Submitted That Met QC Criteria

February 6, 2024

Last Verified

February 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • RIV-PN-201

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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