Remodulin as Add-on Therapy for the Treatment of Persistent Pulmonary Hypertension of the Newborn
- Conditions
- Persistent Pulmonary Hypertension of the Newborn
- Interventions
- Drug: IV RemodulinDrug: Placebo
- Registration Number
- NCT02261883
- Lead Sponsor
- United Therapeutics
- Brief Summary
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).
- 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).
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 42
- 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)
- 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 & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description IV Remodulin 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. Placebo 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.
- Primary Outcome Measures
Name Time Method Number of Subjects Experiencing Clinical Worsening 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).
- Secondary Outcome Measures
Name Time Method Change in Pre- and Post-ductal Oxygen Saturation (SpO2) 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.
Change in Oxygenation Index (OI) 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.
Time to Initiation of ECMO 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.
Change in P/F Ratio 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.
Change in N-terminal Pro-Brain Natriuretic Peptide (NT-proBNP) 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.
Time to Clinical Worsening 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).
Time to Discontinuation of Inhaled Nitric Oxide (iNO) 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.
Trial Locations
- Locations (14)
Stanford Children's Hospital
🇺🇸Palo Alto, California, United States
Johns Hopkins Hospital
🇺🇸Baltimore, Maryland, United States
Arkansas Children's Hospital
🇺🇸Little Rock, Arkansas, United States
Children's Hospital of Los Angeles
🇺🇸Los Angeles, California, United States
Ann and Robert H. Lurie Children's Hospital of Chicago
🇺🇸Chicago, Illinois, United States
All Children's Hospital
🇺🇸Saint Petersburg, Florida, United States
University of Mississippi Medical Center - Baston Children's Hospital
🇺🇸Jackson, Mississippi, United States
Nationwide Childrens Hospital
🇺🇸Columbus, Ohio, United States
Columbia University Medical Center
🇺🇸New York, New York, United States
Cook Children's Medical Center
🇺🇸Fort Worth, Texas, United States
University of Virginia Health Systems (UVA)
🇺🇸Charlottesville, Virginia, United States
Children's Mercy Hospital
🇺🇸Kansas City, Missouri, United States
Seattle Children's Hospital
🇺🇸Seattle, Washington, United States
Children's Hospital of Wisconsin
🇺🇸Wauwatosa, Wisconsin, United States