Clinical Trials Register

Summary
EudraCT Number:	2014-004166-23
Sponsor's Protocol Code Number:	A1481157
Clinical Trial Type:	Outside EU/EEA
Date on which this record was first entered in the EudraCT database:	2015-05-11
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
H.4 THIRD COUNTRY IN WHICH THE TRIAL WAS FIRST AUTHORISED

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A. Protocol Information

A.2

EudraCT number

2014-004166-23

A.3

Full title of the trial

A 7-Day, Open-Label, Multicenter, Pharmacokinetic (PK) Study (Part 1) Followed by A 7-Day, Randomized, Multicenter, Double-Blind, Placebo-Controlled, Dose-Ranging, Parallel Group Study (Part 2) of Intravenous (IV) Sildenafil in the Treatment of Neonates With Persistent Pulmonary Hypertension of the Newborn (PPHN) or Hypoxic Respiratory Failure and at Risk for PPHN

A.3.1

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

Study Evaluating the Pharmacokinetics, Efficacy and Safety of Sildenafil in Neonates With Persistent Pulmonary Hypertension of the Newborn (PPHN) or Hypoxic Respiratory Failure and at Risk for PPHN

A.4.1

Sponsor's protocol code number

A1481157

A.7

Trial is part of a Paediatric Investigation Plan

Yes

A.8

EMA Decision number of Paediatric Investigation Plan

P/196/2014

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Pfizer, Inc.
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.
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 East 42nd Street
B.5.3.2	Town/ city	New York, NY
B.5.3.3	Post code	10017
B.5.3.4	Country	United States
B.5.4	Telephone number	18007181021
B.5.5	Fax number	13037391119
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 Limited UK
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	Yes
D.2.5.1	Orphan drug designation number	(EU/3/03/178)
D.3 Description of the IMP
D.3.1	Product name	Revatio
D.3.2	Product code	UK-92,480
D.3.4	Pharmaceutical form	Solution for injection
D.3.4.1	Specific paediatric formulation	Yes
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	SILDENAFIL CITRATE
D.3.9.1	CAS number	139755-83-2
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	1
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 (PPHN) or Hypoxic Respiratory Failure and at Risk for PPHN

E.1.1.1

Medical condition in easily understood language

A syndrome of persistent pulmonary hypertension in the newborn (high blood pressure in the lungs)

E.1.1.2

Therapeutic area

Diseases [C] - Respiratory Tract Diseases [C08]

MedDRA Classification

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

1. To evaluate the pharmacokinetics of intravenous (IV) sildenafil in near-term and term newborns with PPHN or with hypoxic respiratory failure and at risk for PPHN to determine doses for Part 2 of the study (Part1)
2. To determine the efficacy of IV sildenafil in near-term and term newborns with PPHN or with hypoxic respiratory failure and at risk for PPHN (Part 2 )

E.2.2

Secondary objectives of the trial

1. To assess the safety and tolerability of IV sildenafil as measured by clinical laboratory parameters, physical exam, vital signs (Blood Pressure [BP], Heart Rate [HR], Respiratory Rate [RR] and oxygen [O2] saturation), oxygenation index (OI), and the frequency and severity of adverse events (Parts 1 and 2)
2. To characterize the PK of sildenafil in newborns that have PPHN or hypoxic respiratory failure and at risk of developing PPHN. To describe the relationship between sildenafil concentration and the primary endpoint using a population pharmacokinetic-pharmacodynamic (PK-PD) model-based analysis (Part 2 only)
3. To evaluate the healthcare resource utilization associated with sildenafil therapy (Part 2 only) PART 2 was not conducted.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Signed informed consent from legally acceptable guardian
2. PPHN or hypoxic respiratory failure associated with Idiopathic PPHN, Meconium aspiration syndrome, Respiratory distress syndrome, Sepsis, Pneumonia
3. Less than or equal to 72 hours of age
4. Greater than or equal to 34 week gestational age
5. Oxygenation index greater than or equal to (≥)15 on 2 separate occasions calculated using blood gases taken at least 30 minutes apart prior to study drug infusion (Part1) or prior to randomization (Part 2)

E.4

Principal exclusion criteria

1. Prior use of inhaled nitrogen oxide (iNO) for Part 2 only (Prior use of iNO is allowed for Part 1 )
2. Prior or immediate need for CPR (cardiopulmonary resuscitation) or ECMO (extracorporeal membrane oxygen)
3. Profound hypoxemia
4. Low pulmonary vascular resistance (PVR) as evidenced by large left to right intracardiac or ductal shunting based on the screening echocardiogram
5. Hypotension (mean arterial pressure [MAP] <35 mm Hg) or shock any time during screening
6. Life threatening or lethal congenital anomaly
7. Congenital heart disease exclusive of interatrial communication or patent ductus arteriosus
8. Lung hypoplasia syndromes diagnosed on the basis of prolonged oligohydramnios or hydrops fetalis
9. Congenital diaphragmatic hernia
10. Active seizures (within 12 hours of study drug infusion [Part 1] or randomization Part 2])
11. Apgar score of <3 at 5 minutes after birth
12. Bleeding diathesis
13. Receipt of any other experimental drug or device
14. Receipt of any prohibited concurrent medication/therapy at any time prior to randomization: Potent cytochrome P450 3A4 inhibitors (example, erythromycin, ketoconazole, itraconazole, and protease inhibitors), Ritonavir or Nicorandil, Endothelin antagonists (example tracleer, bosentan), Nitrates or Nitric Oxide (NO) donors in any form, except the prior or concurrent use of iNO. (subject would be eligible if nitroprusside was used, only if it was discontinued at least 2 hours prior to study drug infusion),Vasodilators (example alpha blockers, magnesium sulfate, calcium channel blockers, other phosphodiesterase inhibitors, prostacyclins, etc), excluding milrinone, which was allowed during as concurrent therapy, Supplemental arginine administered for the purpose of improving NO-dependent vasodilation. (maintenance quantities in total parental nutrition were allowed), Open-label sildenafil other than study drug.
15. Impairment of renal function (serum creatinine greater than [>] 2.5 × upper limit of normal [ULN]), hepatic function (Alanine Transferase [ALT] or Aspartate Amino Transferase [AST] > 3 × ULN or conjugated bilirubin > 2 × ULN), or haematological abnormalities: Severe anaemia (haemoglobin < 9 gram per decilitre [g/dl]), thrombocytopenia (platelets < 50,000 cells per micro millilitre [cells/mcl], or leucopenia (white blood cells < 2,500 cells/mcl) at the screening examination.
16. Known hereditary degenerative retinal disorders such as retinitis pigmentosa.
17. Symptoms of drug or alcohol related withdrawal.
18. Investigator’s discretion on a subject.

E.5 End points

E.5.1

Primary end point(s)

Plasma Concentration of Sildenafil and UK-103320 Population Pharmacokinetics

E.5.1.1

Timepoint(s) of evaluation of this end point

5, 30 minutes post-infusion; every 24 hours from start of infusion; before end of infusion; at 1, 4, 8, 12, 24, 48, 72 hours post-infusion in Part 1

E.5.2

Secondary end point(s)

N/A Part 2 was not conducted.

E.5.2.1

Timepoint(s) of evaluation of this end point

N/A Part 2 was not conducted.

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

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

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)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

E.8.1.1

Randomised

Yes

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

sequential dose escalation

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

Will this trial be conducted at a single site globally?

E.8.4

Will this trial be conducted at multiple sites globally?

Yes

E.8.6 Trial involving sites outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

Specify the countries outside of the EEA in which trial sites are planned

United States

E.8.7

Trial has a data monitoring committee

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

LVLS

E.8.9 Initial estimate of the duration of the trial

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)

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

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

F.4 Planned number of subjects to be included

F.4.2

For a multinational trial

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)

IV sildenafil added to existing care.

G. Investigator Networks to be involved in the Trial

H.4 Third Country in which the Trial was first authorised
H.4.1	Third Country in which the trial was first authorised:	United States

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