Clinical Trials Register

Summary
EudraCT Number:	2012-002619-24
Sponsor's Protocol Code Number:	A1481316
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2012-12-11
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Germany - BfArM

A.2

EudraCT number

2012-002619-24

A.3

Full title of the trial

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

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

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

A.4.1

Sponsor's protocol code number

A1481316

A.7

Trial is part of a Paediatric Investigation Plan

Yes

A.8

EMA Decision number of Paediatric Investigation Plan

P/158/2012

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Pfizer Inc., 235 East 42nd Street, New York, NY 10017
B.1.3.4	Country	United States
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Pfizer Inc., 235 East 42nd Street, New York, NY 10017
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Pfizer Inc
B.5.2	Functional name of contact point	Clinical Trials.gov Call Center
B.5.3	Address:
B.5.3.1	Street Address	235 E 42nd Street
B.5.3.2	Town/ city	New York
B.5.3.3	Post code	NY 10017
B.5.3.4	Country	United States
B.5.4	Telephone number	+1 800 7181021
B.5.5	Fax number	+1 303 7391119
B.5.6	E-mail	ClinicalTrials.gov_Inquiries@pfizer.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Revatio
D.2.1.1.2	Name of the Marketing Authorisation holder	Pfizer Ltd
D.2.1.2	Country which granted the Marketing Authorisation	European Union
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.4	Pharmaceutical form	Solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	NA
D.3.9.1	CAS number	171599-83-0
D.3.9.2	Current sponsor code	UK-92,480
D.3.9.3	Other descriptive name	SILDENAFIL CITRATE
D.3.9.4	EV Substance Code	SUB04386MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	0.8
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Solution for injection
D.8.4	Route of administration of the placebo	Intravenous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Persistent pulmonary hypertension of the newborn

E.1.1.1

Medical condition in easily understood language

Persistent pulmonary hypertension of the newborn

E.1.1.2

Therapeutic area

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

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10053592
E.1.2	Term	Newborn persistent pulmonary hypertension
E.1.2	System Organ Class	100000004850

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

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.

E.2.2

Secondary objectives of the trial

•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.

E.2.3

Trial contains a sub-study

E.3

Principal 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 (start of 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 subjects 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.

E.4

Principal 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 taken before randomization if possible or 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.

E.5 End points

E.5.1

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.

E.5.1.1

Timepoint(s) of evaluation of this end point

Day 14 or hospital discharge

E.5.2

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.

E.5.2.1

Timepoint(s) of evaluation of this end point

Day 14 or hospital discharge

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Austria

Belgium

Canada

Finland

France

Germany

Italy

Netherlands

Norway

Spain

Sweden

Switzerland

United Kingdom

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

As per Protocol

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

Yes

F.1.1

Number of subjects for this age range:

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

Yes

F.1.1.2.1

Number of subjects for this age range:

F.1.1.3

Newborns (0-27 days)

Yes

F.1.1.3.1

Number of subjects for this age range:

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

F.1.3

Elderly (>=65 years)

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

Yes

F.3.3.7.1

Details of other specific vulnerable populations

Minors

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

Post Trial Treatment is Standard Care.

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2013-01-07

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-02-26

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2020-09-28

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