Back to resultsRemodulin as Add-on Therapy for the Treatment of Persistent Pulmonary Hypertension of the Newborn
Primary Purpose
Persistent Pulmonary Hypertension of the Newborn
Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
IV Remodulin
Placebo
Sponsored by
About this trial
This is an interventional treatment trial for Persistent Pulmonary Hypertension of the Newborn focused on measuring PPHN
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)
Sites / Locations
- Arkansas Children's Hospital
- Children's Hospital of Los Angeles
- Stanford Children's Hospital
- All Children's Hospital
- Ann and Robert H. Lurie Children's Hospital of Chicago
- Johns Hopkins Hospital
- University of Mississippi Medical Center - Baston Children's Hospital
- Children's Mercy Hospital
- Columbia University Medical Center
- Nationwide Childrens Hospital
- Cook Children's Medical Center
- University of Virginia Health Systems(UVA)
- Seattle Children's Hospital
- Children's Hospital of Wisconsin
Arms of the Study
Arm 1
Arm 2
Arm Type
Active Comparator
Placebo Comparator
Arm Label
IV Remodulin
Placebo
Arm Description
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).
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).
Outcomes
Primary Outcome Measures
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
Secondary Outcome Measures
Time to discontinuation of inhaled nitric oxide (iNO)
Change in oxygenation index (OI)
OI= [MAP(mmHg) x FiO2(%) / PaO2(mmHg)] x 100
Time on mechanical ventilation
Time to initiation of ECMO
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.
Safety
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]
Change in N-terminal pro-Brain Natriuretic Peptide (NT-proBNP)
Change in pre and post-ductal oxygen saturation (SpO2)
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT02261883
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
Study Type
Interventional
2. Study Status
Record Verification Date
July 2023
Overall Recruitment Status
Completed
Study Start Date
May 2015 (undefined)
Primary Completion Date
September 27, 2022 (Actual)
Study Completion Date
September 27, 2022 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
United Therapeutics
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Persistent Pulmonary Hypertension of the Newborn
Keywords
PPHN
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
70 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
IV Remodulin
Arm Type
Active Comparator
Arm Description
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).
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
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 Type
Drug
Intervention Name(s)
IV Remodulin
Other Intervention Name(s)
treprostinil
Intervention Description
Treprostinil is a chemically stable tricyclic analogue of prostacyclin.
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
matching placebo
Primary Outcome Measure Information:
Title
Evaluate the rate of clinical worsening in neonates with PPHN
Description
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
Time Frame
Up to Day 14
Secondary Outcome Measure Information:
Title
Time to discontinuation of inhaled nitric oxide (iNO)
Time Frame
Up to Day 56
Title
Change in oxygenation index (OI)
Description
OI= [MAP(mmHg) x FiO2(%) / PaO2(mmHg)] x 100
Time Frame
Hour 12, hour 24, hour 72, Day 7 and Day 14/ or prior to study drug discontiuation
Title
Time on mechanical ventilation
Time Frame
Up to Day 56
Title
Time to initiation of ECMO
Time Frame
Up to Day 56
Title
Mean treprostinil plasma concentration per dose achieved
Description
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.
Time Frame
24 hours after initiation of Remodulin and immediately prior to wean
Title
Safety
Description
Assessment of adverse events, change in vital signs, and change in labs.
Time Frame
up to Day 56
Title
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
Title
Change in N-terminal pro-Brain Natriuretic Peptide (NT-proBNP)
Time Frame
Day 7, Day 14, prior to study drug wean, study drug discontinuation
Title
Change in pre and post-ductal oxygen saturation (SpO2)
Time Frame
Hour 6, hour 12, hour 24, and hour 72
10. Eligibility
Sex
All
Minimum Age & Unit of Time
1 Hour
Maximum Age & Unit of Time
14 Days
Accepts Healthy Volunteers
No
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)
Facility Information:
Facility Name
Arkansas Children's Hospital
City
Little Rock
State/Province
Arkansas
ZIP/Postal Code
72202
Country
United States
Facility Name
Children's Hospital of Los Angeles
City
Los Angeles
State/Province
California
ZIP/Postal Code
90027
Country
United States
Facility Name
Stanford Children's Hospital
City
Palo Alto
State/Province
California
ZIP/Postal Code
94304
Country
United States
Facility Name
All Children's Hospital
City
Saint Petersburg
State/Province
Florida
ZIP/Postal Code
33701
Country
United States
Facility Name
Ann and Robert H. Lurie Children's Hospital of Chicago
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60611
Country
United States
Facility Name
Johns Hopkins Hospital
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21287
Country
United States
Facility Name
University of Mississippi Medical Center - Baston Children's Hospital
City
Jackson
State/Province
Mississippi
ZIP/Postal Code
39216
Country
United States
Facility Name
Children's Mercy Hospital
City
Kansas City
State/Province
Missouri
ZIP/Postal Code
64108
Country
United States
Facility Name
Columbia University Medical Center
City
New York
State/Province
New York
ZIP/Postal Code
10032-3784
Country
United States
Facility Name
Nationwide Childrens Hospital
City
Columbus
State/Province
Ohio
ZIP/Postal Code
43205
Country
United States
Facility Name
Cook Children's Medical Center
City
Fort Worth
State/Province
Texas
ZIP/Postal Code
76104
Country
United States
Facility Name
University of Virginia Health Systems(UVA)
City
Charlottesville
State/Province
Virginia
ZIP/Postal Code
22908
Country
United States
Facility Name
Seattle Children's Hospital
City
Seattle
State/Province
Washington
ZIP/Postal Code
98105
Country
United States
Facility Name
Children's Hospital of Wisconsin
City
Wauwatosa
State/Province
Wisconsin
ZIP/Postal Code
53226
Country
United States
12. IPD Sharing Statement
Citations:
PubMed Identifier
19057613
Citation
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.
Results Reference
background
PubMed Identifier
9036320
Citation
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.
Results Reference
background
PubMed Identifier
10675427
Citation
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.
Results Reference
background
PubMed Identifier
11897647
Citation
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.
Results Reference
background
PubMed Identifier
17400684
Citation
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.
Results Reference
background
PubMed Identifier
20022264
Citation
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.
Results Reference
background
PubMed Identifier
21035821
Citation
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.
Results Reference
background
PubMed Identifier
17317374
Citation
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.
Results Reference
background
PubMed Identifier
1603138
Citation
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.
Results Reference
background
PubMed Identifier
15243302
Citation
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.
Results Reference
background
PubMed Identifier
14681345
Citation
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.
Results Reference
background
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Remodulin as Add-on Therapy for the Treatment of Persistent Pulmonary Hypertension of the Newborn
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