A trial to evaluate the effectiveness and safety of intravenous Sildenafil in the treatment of neonates with persistent pulmonary hypertension of the newborn or hypoxic respiratory failure and risk for PPHN

• Register: EUCTR
• Last refreshed on: 26 October 2020
• Main ID: EUCTR2012-002619-24-BE
• Date of registration: 25/10/2012
• Prospective Registration: Yes
• Primary sponsor: Pfizer Inc., 235 East 42nd Street, New York, NY 10017
• Public title: A trial to evaluate the effectiveness and safety of intravenous Sildenafil in the treatment of neonates with persistent pulmonary hypertension of the newborn or hypoxic respiratory failure and risk for PPHN
• Scientific title: A MULTI-CENTRE, RANDOMIZED, PLACEBO-CONTROLLED, DOUBLE-BLIND, TWO-ARMED, PARALLEL GROUP STUDY TO EVALUATE EFFICACY AND SAFETY OF IV SILDENAFIL IN THE TREATMENT OF NEONATES WITH PERSISTENT PULMONARY HYPERTENSION OF THE NEWBORN (PPHN) OR HYPOXIC RESPIRATORY FAILURE AND AT RISK FOR PPHN, WITH A LONG TERM FOLLOW-UP INVESTIGATION OF DEVELOPMENTAL PROGRESS 12 AND 24 MONTHS AFTER COMPLETION OF STUDY TREATMENT
• Date of first enrolment: 04/03/2013
• Target sample size: 64
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2012-002619-24
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes; Randomised: yes; Open: no; Single blind: no; Double blind: yes; Parallel group: yes; Cross over: no; Other: no; If controlled, specify comparator, Other Medicinial Product: no; Placebo: yes; Other: no; Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Austria, Belgium, Canada, Denmark, Finland, France, Germany, Italy, Netherlands, Norway, Spain, Sweden, Switzerland, United Kingdom

Contacts

• Name: Clinical Trials.gov Call Center
• Affiliation: Pfizer Inc

• Name: Clinical Trials.gov Call Center
• Affiliation: Pfizer Inc

Key inclusion & exclusion criteria

Inclusion criteria:
Subject eligibility should be reviewed and documented by an appropriately qualified member of the investigator’s study team before subjects are included in the study.

Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the study:
1. PPHN or hypoxic respiratory failure (HRF) at risk for PPHN associated with:
• Idiopathic PPHN;
• Meconium aspiration syndrome;
• Sepsis; or
• Pneumonia.
2. =96 hours of age at randomization (study medication must begin
within 6 hours after randomization) and =34 weeks of gestation at screening.
3. OI >15 and <60, calculated using two blood gases taken at least 30 minutes apart prior to randomization.
4. Concurrent treatment with iNO at 10-20 ppm on =50% oxygen.
5. Screening echocardiogram, required before randomization if possible or within 24 hours of screening, to assess presence of pulmonary hypertension (defined as evidence of right to left shunting) and to eliminate subjects with large left to right intracardiac or ductal shunting.
6. Screening cranial ultrasound, required before randomization if possible or within 24 hours of screening, to eliminate patients with clinically significant intracranial bleeds per investigator judgment.
7. Evidence of a personally signed and dated informed consent document indicating that the subject’s legal representative has been informed of all pertinent aspects of the study; and
8. Subjects whose legal representative is willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
Are the trial subjects under 18? yes
Number of subjects for this age range: 64
F.1.2 Adults (18-64 years) no
F.1.2.1 Number of subjects for this age range
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range

Exclusion criteria:
Subjects presenting with any of the following will not be included in the study:
1. Prior or immediate need for ECMO or CPR(defined as "full resuscitation outside the delivery room" including chest compression
and medications such as adrenaline / epinephrine).
2. Expected duration of mechanical ventilation of less than 48 hours.
3. Life-threatening or lethal congenital anomaly.
4. Profound hypoxemia: PaO2 <30 mm Hg on any arterial blood gas drawn within 30 minutes of starting study drug infusion.
5. Severe hypotension or shock at baseline (mean arterial pressure (MAP) <30 mmHg) not responsive to medical management, or shock any time during screening.
6. Significant congenital heart disease or defect exclusive of inter-atrial communication or patent ductus arteriosus.
7. Large left to right intracardiac or ductal shunting (diagnosed from echocardiogram taken before randomization if possible or within 24 hours of screening).
8. Large clinically significant intracranial bleed (diagnosed from cranial ultrasound within 24 hours of screening).
9. Lung hypoplasia syndromes diagnosed on the basis of prolonged oligohydramnios or hydrops faetalis.
10. Congenital diaphragmatic hernia.
11. Clinically significant active seizures, as per clinical judgment of the investigator.
12. Apgar score of <3 at 5 minutes after birth.
13. Bleeding diathesis, as per clinical judgment of the investigator.
14. Receipt of any prohibited concurrent medication/therapy at any time prior to screening:
• Potent cytochrome P450 3A4 inhibitors (eg, erythromycin, ketoconazole, itraconazole, and protease inhibitors), erythromycin ophthalmic ointment is allowed;
• Ritonavir or nicorandil;
• Endothelin antagonists (eg, Tracleer (RTM)/bosentan, Letairis(RTM)/ambrisentan, etc);
• PDE5 inhibitors (eg, sildenafil, tadalafil, vardenafil), IV or per orogastric tube;
• Nitrates or nitric oxide donors, except iNO (A subject is eligible if nitroprusside was used only if it was discontinued at least 2 hours prior to study drug infusion; iNO may be used per protocol);
• Vasodilators (eg, alpha blockers, magnesium sulfate as infusion, calcium channel blockers, other PDE inhibitors, prostacyclins, etc) at study entry (Excludes milrinone, which is allowed during the study as concurrent therapy) at study entry; or
• Supplemental arginine administered for the purpose of improving NO-dependent vasodilation (Maintenance quantities in total parental nutrition (TPN) are allowed).
15. Known hereditary degenerative retinal disorders, such as retinitis pigmentosa.
16. Symptoms of drug- or alcohol-related withdrawal.
17. In the opinion of the investigator, a subject inappropriate for the study for any reason.
18. Other acute or severe medical conditions, or marked laboratory abnormalities that may increase the risk associated with study participation or investigational product administration, or may interfere with the interpretation of study results and, in the
judgment of the investigator, would make the subject inappropriate for entry into this study.
19. Participation in any other experimental studies involving other drug or non-interventional therapies before the current study begins and/or during study participation.
Subjects who are relatives of investigational site staff members or Pfizer employees directly involved in the conduct of the trial.


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Persistent pulmonary hypertension of the newborn
MedDRA version: 20.0 Level: LLT Classification code 10053592 Term: Newborn persistent pulmonary hypertension System Organ Class: 100000004850

Therapeutic area: Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]

Intervention(s)

Trade Name: Revatio
Pharmaceutical Form: Solution for injection
CAS Number: 171599-83-0
Current Sponsor code: UK-92,480
Other descriptive name: SILDENAFIL CITRATE
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 0.8-
Pharmaceutical form of the placebo: Solution for injection
Route of administration of the placebo: Intravenous use

Primary Outcome(s)

Primary end point(s): Assessed at Day 14 or hospital discharge, whichever occurs first:
• Time on iNO treatment after initiation of IV study drug for subjects without treatment failure;
• Treatment failure rate, defined as need for additional treatment targeting PPHN, need for ECMO, or death during the study.

Secondary Objective: •To monitor the developmental progress of patients with PPHN treated with IV sildenafil or placebo, at 12 and 24 months after the end of study treatment.
• Pharmacokinetics (PK): To further characterize the PK of sildenafil and its major metabolite UK-103,320 in neonates with PPHN or HRF and at risk of developing PPHN.

Main Objective: The primary objectives of this study are to evaluate the efficacy and safety of IV sildenafil when added to iNO for the treatment of neonates with PPHN or hypoxic respiratory failure and at risk for PPHN.

Timepoint(s) of evaluation of this end point: Day 14 or hospital discharge

Secondary Outcome(s)

Secondary end point(s): Assessed at Day 14 or hospital discharge, whichever occurs first:
• Time to final weaning of mechanical ventilation for PPHN;
• Time from initiation of study drug to treatment failure (additional drug treatment targeting PPHN, ECMO, or death); each component will also be evaluated separately;
• Proportion of subjects with individual components of treatment failure (needing additional treatment targeting PPHN, needing ECMO, or who die);
• Change in OI at 6, 12, and 24 hours from baseline;
• Change in differential saturation (pre- and post-ductal) at 6, 12, and 24 hours from baseline;
• Change in P/F ratio at 6, 12, and 24 hours from baseline;
• Sildenafil and its major metabolite UK-103,320 plasma concentrations and the corresponding PK parameters obtained from a population PK analysis; and
• Safety parameters: Incidence and severity of adverse events and abnormal laboratory parameters.

Timepoint(s) of evaluation of this end point: Day 14 or hospital discharge

Secondary ID(s)

A1481316

Source(s) of Monetary Support

Pfizer Inc., 235 East 42nd Street, New York, NY 10017

Ethics review

Status: Approved
Approval date: 04/03/2013
Contact:

Results

• Results available: Yes
• Date Posted: 17/07/2019
• URL: https://www.clinicaltrialsregister.eu/ctr-search/trial/2012-002619-24/results