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

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

Status

Terminated

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02261883

Enrollment

Registered

2014-10-10

Start date

2015-07-29

Completion date

2023-05-17

Last updated

2024-03-05

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Persistent Pulmonary Hypertension of the Newborn

Keywords

PPHN

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).

Interventions

DRUGIV Remodulin

Treprostinil is a chemically stable tricyclic analogue of prostacyclin.

DRUGPlacebo

Sodium citrate, sodium chloride, sodium hydroxide pellets, metacresol, and citric acid (anhydrous).

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Age

1 Hours to 14 Days

Healthy volunteers

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

Design outcomes

Primary

Measure	Time frame	Description
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

Measure	Time frame	Description
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 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 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.
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.
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.
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).

Countries

United States

Participant flow

Participants by arm

Arm	Count
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. IV Remodulin: Treprostinil is a chemically stable tricyclic analogue of prostacyclin.	20
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. Placebo: Sodium citrate USP/EP/JP, sodium chloride USP/EP/JP, sodium hydroxide pellets, metacresol, and citric acid (anhydrous).	21
Total	41

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Death	3	2
Overall Study	Physician Decision	1	0
Overall Study	Protocol Violation	1	0
Overall Study	Required ECMO Prior to Study Drug Administration	1	0
Overall Study	Withdrawal by Subject	0	1

Baseline characteristics

Characteristic	IV Remodulin	Placebo	Total
Age, Continuous	2.0 days	3.0 days	3.0 days
Birth Weight	3.08 kg	3.06 kg	3.06 kg
Ethnicity (NIH/OMB) Hispanic or Latino	3 Participants	2 Participants	5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	17 Participants	19 Participants	36 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants
Fraction of Inspired Oxygen (FiO2)	100.0 percentage of oxygen	100.0 percentage of oxygen	100.0 percentage of oxygen
Gestational Age	39.00 weeks	39.00 weeks	39.00 weeks
Inhaled Nitric Oxide (iNO)	20.00 ppm	20.00 ppm	20.00 ppm
N-terminal pro-B-type natriuretic peptide (NT-proBNP)	11194.0 pg/mL	16646.0 pg/mL	13628.0 pg/mL
Oxygenation Index	25.5 units on a scale	22.0 units on a scale	23.0 units on a scale
PaO2/FiO2 (P/F Ratio)	0.57 ratio	0.69 ratio	0.60 ratio
Partial Pressure of Oxygen (PaO2)	51.0 mmHg	57.0 mmHg	56.0 mmHg
PPHN Diagnosis Associated with Birth Hypoxia	1 Participants	1 Participants	2 Participants
PPHN Diagnosis Associated with Meconium Aspiration Syndrome	9 Participants	10 Participants	19 Participants
PPHN Diagnosis Associated with Respiratory Distress Syndrome	5 Participants	3 Participants	8 Participants
PPHN Diagnosis Associated with Sepsis	0 Participants	1 Participants	1 Participants
PPHN Diagnosis Associated with Unilateral Congenital Diaphragmatic Hernia	5 Participants	5 Participants	10 Participants
PPHN Diagnosis Idiopathic PPHN	0 Participants	1 Participants	1 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	1 Participants	0 Participants	1 Participants
Race (NIH/OMB) Black or African American	5 Participants	10 Participants	15 Participants
Race (NIH/OMB) More than one race	1 Participants	0 Participants	1 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	1 Participants	0 Participants	1 Participants
Race (NIH/OMB) White	12 Participants	11 Participants	23 Participants
Sex: Female, Male Female	10 Participants	10 Participants	20 Participants
Sex: Female, Male Male	10 Participants	11 Participants	21 Participants
Time Since Diagnosis	2.0 days	2.0 days	2.0 days

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	4 / 20	2 / 21
other Total, other adverse events	19 / 20	17 / 21
serious Total, serious adverse events	8 / 20	3 / 21

Outcome results

Primary

Number of Subjects Experiencing Clinical Worsening

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 frame: From Baseline to Day 14