Clinical Trials Register

Summary
EudraCT Number:	2005-000963-25
Sponsor's Protocol Code Number:	A1481156
National Competent Authority:	Sweden - MPA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2005-04-06
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

Sweden - MPA

A.2

EudraCT number

2005-000963-25

A.3

Full title of the trial

A Multicenter, Long-Term Extension Study to Assess Safety of Oral Sildenafil in the Treatment of Subjects Who Have Completed Study A1481131

A.3.1

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

Oral Revatio in Pediatric PAH- Long term follow on study to A1481131

A.3.2

Name or abbreviated title of the trial where available

N/A

A.4.1

Sponsor's protocol code number

A1481156

A.7

Trial is part of a Paediatric Investigation Plan

Yes

A.8

EMA Decision number of Paediatric Investigation Plan

P/114/2011

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Pfizer Limited, Ramsgate Road, Sandwich, Kent, UK
B.1.3.4	Country	United Kingdom
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 Limited, Ramsgate Road, Sandwich. Kent UK
B.4.2	Country	United Kingdom
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 cneter
B.5.3	Address:
B.5.3.1	Street Address	235 E42 nd 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	+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	No
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.3.4	Pharmaceutical form	Film-coated 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	sildenafil (as citrate)
D.3.9.1	CAS number	N/A
D.3.9.3	Other descriptive name	UK-92,480
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	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
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	Yes
D.2.5.1	Orphan drug designation number	EU/3/03/178
D.3 Description of the IMP
D.3.4	Pharmaceutical form	Film-coated 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	sildenafil (as citrate)
D.3.9.1	CAS number	N/A
D.3.9.3	Other descriptive name	UK-92,480
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

E.1.1.2

Therapeutic area

Body processes [G] - Circulatory and Respiratory Physiological Phenomena [G09]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.1
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 assess the safety and tolerability of oral sildenafil in the chronic treatment of pediatric subjects with PAH.

E.2.2

Secondary objectives of the trial

The secondary objectives are;
- To describe long-term (≥1 year) efficacy of oral sildenafil in these subjects
- To assess survival status of subjects who have discontinued study drug

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

· Pediatric subjects, who enrolled in and completed Study A1481131;
· Females of childbearing potential who are sexually active must be practicing a suitable method of birth control so that in the opinion of the investigator, they will not become pregnant during the study; and
· The investigator must obtain written informed consent and assent where applicable before the subject is considered for enrollment in Study A1481156. The inclusion of a subject more than once in the same clinical trial is not permissible.
All inclusion criteria must be adhered to.

E.4

Principal exclusion criteria

• Pediatric subjects, who did not complete Study A1481131.
• Subjects with known hereditary degenerative retinal disorders (such as retinitis
pigmentosa) or history of non-arteritic anterior ischemic optic neuropathy (NAION).

The exclusion criteria must be adhered to.

E.5 End points

E.5.1

Primary end point(s)

Safety Parameters:
· Standard safety data;
· Ocular safety measures: Change from A1481156 baseline in ocular safety tests;
· Need for downtitration in dose due to intolerability;
· Need for discontinuation due to intolerability; and
· Growth and development.

Other Outcome Parameters:
To assess 1-year efficacy data, the following endpoints will be described;
Percent change from A1481131 baseline to Week 36 of the extension Study A1481156 in the following exercise endpoints in subjects who are developmentally able to perform the CPX test:
· Peak VO2 normalized to body weight using an exercise tolerance test (bicycle ergometry);
· Respiratory Exchange Ratio (RER);
· Time to maximum VO2;
· Total ventilation (VE);
Change from A1481131 baseline to Week 36 of the extension Study A1481156 in:
· CHQ-PF28 as assessed by the physical and psychosocial scales;
· WHO PH functional class;
· End tidal O2 and CO2;
· Anaerobic threshold (AT);
· Percent predicted peak VO2 in subjects who are developmentally able to perform the CPX test;
· Subject (Parent)/Physician global assessment;
· Background therapy.

To assess sustainability of effect after A1481131, the following endpoints will be described;
From A1481156 baseline to assessment times specified in study schedule:
· Percent change in peak VO2 normalized to body weight using an exercise tolerance test (bicycle ergometry) in subjects developmentally able to perform the exercise;
· Change in CHQ PF28 scales;
· Change in WHO PH functional class.

E.5.1.1

Timepoint(s) of evaluation of this end point

Weeks 12,24,36, 48 every 12 weeks

E.5.2

Secondary end point(s)

Long-term Efficacy:'Other Outcome Parameters: To assess 1-year efficacy data, the following endpoints will be described; Percent change from A1481131 baseline to Week 36 of the extension Study A1481156 in the following exercise endpoints in subjects who are developmentally able to perform the CPX test: •Peak VO2 normalized to body weight using an exercise tolerance test (bicycle ergometry); •Respiratory Exchange Ratio (RER); •Time to maximum VO2; •Total ventilation (VE); Change from A1481131 baseline to Week 36 of the extension Study A1481156 in: •CHQ-PF28 as assessed by the physical and psychosocial scales; •WHO PH functional class; •End tidal O2 and CO2; •Anaerobic threshold (AT); •Percent predicted peak VO2 in subjects who are developmentally able to perform the CPX test; •Subject (Parent)/Physician global assessment; •Background therapy. To assess sustainability of effect after A1481131, the following endpoints will be described; From A1481156 baseline to assessment times specified in study schedule: •Percent change in peak VO2 normalized to body weight using an exercise tolerance test (bicycle ergometry) in subjects developmentally able to perform the exercise

E.5.2.1

Timepoint(s) of evaluation of this end point

Weeks 12,24,36, 48 every 12 weeks

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

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

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

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

Low, medium and high sildenafil dose groups

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the 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

Brazil

Chile

Colombia

Costa Rica

Guatemala

Hungary

India

Italy

Malaysia

Mexico

Poland

Russian Federation

Sweden

Taiwan

Thailand

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

All subjects may continue in the study until sildenafil is approved for marketing for treatment of PAH, a predetermined endpoint is reached (eg, death or transplant) or the study is discontinued. Subjects will be unblinded to their study medication after the last subject has completed the A1481131 study and the database has been locked.

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:

217

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:

123

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)

Yes

F.1.2.1

Number of subjects for this age range:

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

Yes

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

Study subjects in the preceding study A1481131 were of the age 1-17 years old. A person with parental responsibility and or a legal representative must give consent and may withdraw the young person at any time.

F.3.3.7

Others

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

200

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)

The Sponsor will ensuring that the subjects have a continued supply of sildenafil, where the investigator believes it is necessary and appropriate for the individual subject to continue treatment. This supply may be commercially available sildenafil, within a follow-on protocol, named patient programme or a donation programme, in keeping with local availability and regulations

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

2005-05-30

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2005-04-25

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2012-12-24

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