Clinical Trials Register

Summary
EudraCT Number:	2016-003978-41
Sponsor's Protocol Code Number:	A1481298
Clinical Trial Type:	Outside EU/EEA
Date on which this record was first entered in the EudraCT database:	2016-10-13
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

2016-003978-41

A.3

Full title of the trial

A Phase 3, Multi-center, Open label Study To Investigate Safety, Efficacy, And Tolerability Of Sildenafil Citrate In Pediatric Patients With Pulmonary Arterial Hypertension

A.3.1

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

Safety And Efficacy Of Sildenafil In Children With Pulmonary Arterial Hypertension

A.4.1

Sponsor's protocol code number

A1481298

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT01642407

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Pfizer, Inc.
B.1.3.4	Country	Japan
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 E 42nd Street
B.5.3.2	Town/ city	New York
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.govCallCenter@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 10 mg/ml powder for oral suspension
D.2.1.1.2	Name of the Marketing Authorisation holder	Pfizer Limited
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
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 POS
D.3.2	Product code	G04BE03
D.3.4	Pharmaceutical form	Powder for oral suspension
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	171
D.3.9.1	CAS number	599-83-0
D.3.9.2	Current sponsor code	A148
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	10
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.IMP: 2
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 20 mg film coated tablets
D.2.1.1.2	Name of the Marketing Authorisation holder	Pfizer Limited
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
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 Tablets
D.3.2	Product code	G04BE03
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	171
D.3.9.1	CAS number	599-83-0
D.3.9.2	Current sponsor code	A148
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 milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	20
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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Pulmonary arterial hypertension

E.1.1.1

Medical condition in easily understood language

Pulmonary arterial hypertension (PAH)

E.1.1.2

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	19.0
E.1.2	Level	PT
E.1.2	Classification code	10064911
E.1.2	Term	Pulmonary arterial hypertension
E.1.2	System Organ Class	10038738 - Respiratory, thoracic and mediastinal disorders

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

The primary objective is to investigate changes of patient status with sildenafil treatment [> 20 kg: 20 mg TID (60 mg/day), ≤ 20 kg: 10 mg TID (30 mg/day)] for individual Japanese pediatric patients with PAH based on Right heart catheter (RHC) test, WHO functional class, BNP and pro-BNP at Week 16.

E.2.2

Secondary objectives of the trial

 To investigate safety of sildenafil in Japanese pediatric patients with PAH during 16 weeks.
 To investigate pharmacokinetics of sildenafil and UK-103,320 at steady state in Japanese pediatric patients with PAH.
 To investigate long-term safety and efficacy of sildenafil in Japanese pediatric patients with PAH who completed Part 1 and are willing to continue sildenafil treatment (Part 2).

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

 Subjects weighing ≥8 kg.
 Subjects who have symptomatic pulmonary arterial hypertension due to one of the following conditions:
 Idiopathic pulmonary arterial hypertension; or Heritable pulmonary arterial hypertension; or Pulmonary arterial hypertension associated with congenital systemic-to-pulmonary shunts. If the defect(s) is repaired, the subject's condition should be stabilized hemodynamically; or Pulmonary arterial hypertension associated with d-transposition of the great arteries repaired within the first 30 days of life; or Pulmonary arterial hypertension in subjects who have undergone surgical repair of other congenital heart lesions and the condition should be stabilized hemodynamically and do not have clinically significant residual left-sided heart disease.
 Subjects with a mean pulmonary artery pressure ≥25 mmHg at rest, PCWP ≤15 mmHg, and PVRI ≥3 Wood units x m2. If PCWP is not available, then mean LA pressure ≤15 mmHg or LVEDP ≤15 mmHg in the absence of left atrial obstruction.

E.4

Principal exclusion criteria

 Subjects with Left-sided heart disease.
 Subjects with Down syndrome.
 Subjects with Obstructive Sleep Apnea, regardless of treatment status.
 Subjects with Pericardial constriction.
 Subjects with significant (2+ for regurgitation) valvular disease other than tricuspid or pulmonary regurgitation.
 Acutely decompensated heart failure within previous 30 days from screening.
 Subjects who have had an atrial septostomy within previous 6 months of screening.
 Subjects with hemodynamic instability or hypo- or hypertension at screening.
 Subjects with a history of stroke, myocardial infarction or life threatening arrhythmia within 6 months of screening.
 Subjects with moderate to severe restrictive pulmonary disease (Total Lung Capacity or Forced Vital Capacity ≤60% of normal) or history of severe lung disease.
 Subjects with bronchopulmonary dysplasia and other chronic lung diseases.
 Subjects with history of pulmonary embolism.
 Subjects with known hereditary degenerative retinal disorders (such as retinitis pigmentosa) or history of non-arteritic anterior ischemic optic neuropathy.
 Subjects who are known to be HIV positive.
 Subjects with impairment of renal function (serum creatinine >2.5 × ULN) or hepatic function (ALT and/or AST >3 × ULN; and/or bilirubin ≥2 mg/dL). Hematological abnormalities (e.g., severe anemia, Hgb <10 g/dL, leukopenia, WBC <2500/µL).
 Subjects with severe hepatic dysfunction (Child-Pugh classification C).
 Change in class of medication for CHF or PAH within the 10 days prior to qualifying right heart catheterization.
 Subjects who are currently prescribed and/or taking nitrates or nitric oxide donors in any form.
 Subjects taking chronic arginine supplementation.
 Subjects who have received parenteral inotropic medication or parenteral vasodilators within 30 days of Day 1.
 Subjects who are receiving alpha-blockers, nicorandil, amiodarone or potent cytochrome P450 3A4 inhibitors.
 Subjects receiving chronic treatment with off-label sildenafil within 30 days of Day 1 are excluded. Subjects receiving an endothelin antagonist，PED5 inhibitor or, prostacyclin/prostacyclin analogue within 30 days of randomization are excluded except for beraprost.
 Pregnant females; breastfeeding females; males and females of childbearing potential not using highly effective contraception or not agreeing to continue highly effective contraception for at least 28 days after last dose of investigational product.
 Current or past illicit drug use or alcoholism excepting if abstinence can be documented for ≥1 year.
 Participation in another clinical trial of an investigational drug or device (including placebo) within 30 days of screening for entry into the present study.
 Other severe acute or chronic medical or psychiatric condition or laboratory abnormality 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.

E.5 End points

E.5.1

Primary end point(s)

 Change from Baseline in Pulmonary vascular resistance index (PVRI) [Timepoints: Baseline, Week 16]
 Change from Baseline in Mean pulmonary artery pressure (mPAP) [Timeponts: Baseline, Week 16]
 Change from Baseline in World Health Organization (WHO) Functional Class in Participants with PAH [Timepoints: Baseline, Week 4, 8, 16]
 Change from baseline in B-type Natriuretic Peptide (BNP) at Week 16 [Timepoints: Baseline, Week 16]
 Change from baseline in N-terminal pro-BNP (NT pro-BNP) at Week 16 [Timepoints: Baseline, Week 16]

E.5.1.1

Timepoint(s) of evaluation of this end point

E.5.2

Secondary end point(s)

 Number of Participants With Adverse Events (AEs) by Seriousness and Relationship to Treatment [Timepoints: Baseline up to Week 16]
 Change from Baseline in Diastolic Blood Pressure [Timepoints: Baseline, Week 4, 8, 16]
 Change from Baseline in Systolic Blood Pressure [Timepoints: Baseline, Week 4, 8, 16]
 Number of Participants With Laboratory Test Values of Potential Clinical Importance [Timepoints: Baseline up to Week 16]
 Change from baseline in 12-lead electrocardiogram (ECG) [Timepoints: Baseline, Week 16]
 Change from baseline in Ocular safety [Timepoints: Baseline, Week 16]
 Change from baseline in Hemodynamic parameters [Timepoints: Baseline, Week 16]
 Change from baseline in Echocardiogram parameters [Timepoints: Baseline, Week 16]
 Maximum Observed Plasma Concentration (Cmax) [Timepoints: Pre-dose, 1, 2, 4 and 8 hrs post-dose]
 Area Under the Curve from Time Zero to end of dosing interval (AUCtau) [Timepoints: Pre-dose, 1, 2, 4 and 8 hrs post-dose]
 Number of Participants With Adverse Events (AEs) by Seriousness and Relationship to Treatment [Timepoints: From Baseline to End of study]
 Change from Baseline in Diastolic Blood Pressure at each visit [Time Frame: From Baseline to End of study]
 Change from Baseline in Systolic Blood Pressure at each visit [Timepoints: From Baseline to End of study]
 Number of Participants With Laboratory Test Values of Potential Clinical Importance [Timepoints: From Baseline to End of study]
 Change from baseline in 12-lead ECG [Timepoints: Baseline, Week 52, End of treatment]
 Change from baseline in Ocular safety [Timepoints: Baseline, Week 52, End of treatment]
 Change from Baseline in WHO Functional Class in Participants with PAH at each visit [Timepoints: From Baseline to End of treatment]
 Change from baseline in BNP [Time Frame: Baseline, Week 52, End of treatment]
 Change from baseline in N-terminal pro-B-type natriuretic peptide (NT pro-BNP) [Timepoints: Baseline, Week 52, End of treatment]

E.5.2.1

Timepoint(s) of evaluation of this end point

 Baseline up to Week 16]
 Baseline, Week 4, 8, 16]
 Baseline, Week 4, 8, 16]
 Baseline up to Week 16]
 Baseline, Week 16]
 Baseline, Week 16]
 Baseline, Week 16]
 Baseline, Week 16]
 Pre-dose, 1, 2, 4 and 8 hrs post-dose]
 Pre-dose, 1, 2, 4 and 8 hrs post-dose]
 From Baseline to End of study]
 From Baseline to End of study]
 From Baseline to End of study]
 From Baseline to End of study]
 Baseline, Week 52, End of treatment]
 Baseline, Week 52, End of treatment]
 From Baseline to End of treatment]
 Baseline, Week 52, End of treatment]
 Baseline, Week 52, End of treatment]

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

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

E.8.1.1

Randomised

E.8.1.2

Open

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

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.8.3

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

Yes

E.8.6.3

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

Japan

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

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)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

Yes

F.1.1.4.1

Number of subjects for this age range:

F.1.1.5

Children (2-11years)

Yes

F.1.1.5.1

Number of subjects for this age range:

F.1.1.6

Adolescents (12-17 years)

Yes

F.1.1.6.1

Number of subjects for this age range:

F.1.2

Adults (18-64 years)

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

F.1.3.1

Number of subjects for this age range:

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

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

children under 18

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)

NONE

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:	Japan

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