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

Sponsor

United Therapeutics (Industry)

Overall Status

Recruiting

CT.gov ID

NCT02261883

Collaborator

(none)

Enrollment

Locations

Arms

Duration (Months)

Patients Per Site

Patients Per Site Per Month

Study Details

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).

Condition or Disease	Intervention/Treatment	Phase
Persistent Pulmonary Hypertension of the Newborn	Drug: IV Remodulin Drug: Placebo	Phase 2

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 Design

Study Type:

Interventional

Anticipated Enrollment :

70 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

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 Start Date :

May 1, 2015

Anticipated Primary Completion Date :

Dec 1, 2022

Anticipated Study Completion Date :

Dec 1, 2022

Arms and Interventions

Arm	Intervention/Treatment
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).	Drug: IV Remodulin Treprostinil is a chemically stable tricyclic analogue of prostacyclin. Other Names: treprostinil
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).	Drug: Placebo matching placebo

Arm

Intervention/Treatment

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).

Drug: IV Remodulin

Treprostinil is a chemically stable tricyclic analogue of prostacyclin.

Other Names:

treprostinil

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).

Drug: Placebo

matching placebo

Outcome Measures

Primary Outcome Measures

Evaluate the rate of clinical worsening in neonates with PPHN [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

Secondary Outcome Measures

Time to discontinuation of inhaled nitric oxide (iNO) [Up to Day 56]
Change in oxygenation index (OI) [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 [Up to Day 56]
Time to initiation of ECMO [Up to Day 56]
Mean treprostinil plasma concentration per dose achieved [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 [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] [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]

Eligibility Criteria

Criteria

Ages Eligible for Study:

1 Hour to 14 Days

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	St. Joseph's Hospital and Medical Center	Phoenix	Arizona	United States	85013
2	Arkansas Children's Hospital	Little Rock	Arkansas	United States	72202
3	Children's Hospital of Los Angeles	Los Angeles	California	United States	90027
4	Children's Hospital of Orange County	Orange	California	United States	92868
5	Stanford Children's Hospital	Palo Alto	California	United States	94304
6	Rady Children's Hospital San Diego	San Diego	California	United States	92123
7	Children's National Medical Center	Washington	District of Columbia	United States	20010
8	Nicklaus Children's Hospital	Miami	Florida	United States	33155-3009
9	All Children's Hospital	Saint Petersburg	Florida	United States	33701
10	Ann and Robert H. Lurie Children's Hospital of Chicago	Chicago	Illinois	United States	60611
11	Kosair Children's Hospital	Louisville	Kentucky	United States	40202
12	Johns Hopkins Hospital	Baltimore	Maryland	United States	21287
13	Boston Children's	Boston	Massachusetts	United States	02115
14	C.S. Mott Children's Hospital	Ann Arbor	Michigan	United States	48109
15	University of Mississippi Medical Center - Baston Children's Hospital	Jackson	Mississippi	United States	39216
16	Children's Mercy Hospital	Kansas City	Missouri	United States	64108
17	Columbia University Medical Center	New York	New York	United States	10032-3784
18	Nationwide Childrens Hospital	Columbus	Ohio	United States	43205
19	Cook Children's Medical Center	Fort Worth	Texas	United States	76104
20	Texas Children's Hospital	Houston	Texas	United States	77030
21	University of Virginia Health Systems(UVA)	Charlottesville	Virginia	United States	22908
22	Seattle Children's Hospital	Seattle	Washington	United States	98105
23	Children's Hospital of Wisconsin	Wauwatosa	Wisconsin	United States	53226