Clinical Trials Register

Summary
EudraCT Number:	2004-000558-22
Sponsor's Protocol Code Number:	P02538
Clinical Trial Type:	Outside EU/EEA
Date on which this record was first entered in the EudraCT database:	2018-09-14
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

2004-000558-22

A.3

Full title of the trial

Assessment of the Safety, Efficacy, Tolerability and Pharmacokinetics of PEG-Intron® Plus REBETOL® in Pediatric Patients With Chronic Hepatitis C

PIP decision numbe: P/64/2008

A.3.1

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

Assessment of the Safety, Efficacy, Tolerability and Pharmacokinetics of PEG-Intron® Plus REBETOL® in Pediatric Patients With Chronic Hepatitis C

A.4.1

Sponsor's protocol code number

P02538

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT00761735

A.5.4

Other Identifiers

Name:	P02538 Part I	Number:	NCT00104052
Name:	Merck Sharp & Dohme Corp.	Number:	MK-4031-075

A.7

Trial is part of a Paediatric Investigation Plan

Yes

A.8

EMA Decision number of Paediatric Investigation Plan

P/92/2008

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Merck Sharp & Dohme Corp., a Subsidiary of Merck & Co., 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	Merck Sharp & Dohme Corp., a Subsidiary of Merck & Co., 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	Merck Sharp & Dohme Corp., a Subsidiary of Merck & Co., Inc.
B.5.2	Functional name of contact point	Barbara Haber
B.5.3	Address:
B.5.3.1	Street Address	2015 Galloping Hill Road
B.5.3.2	Town/ city	Kenilworth, NJ
B.5.3.3	Post code	07033
B.5.3.4	Country	United States
B.5.4	Telephone number	+12673053729

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	Rebetol
D.2.1.1.2	Name of the Marketing Authorisation holder	Merck Sharp & Dohme Limited
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	Capsule, hard
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	RIBAVIRIN
D.3.9.3	Other descriptive name	RIBAVIRIN
D.3.9.4	EV Substance Code	SUB10297MIG
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	200
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	PegIntron
D.2.1.1.2	Name of the Marketing Authorisation holder	Merck Sharp & Dohme Limited
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	Powder and solvent for solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	PEGINTERFERON ALFA-2B
D.3.9.3	Other descriptive name	PEGINTERFERON ALFA-2B
D.3.9.4	EV Substance Code	SUB12549MIG
D.3.10	Strength
D.3.10.1	Concentration unit	µg microgram(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	50 to 150
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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: 3
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	Rebetol
D.2.1.1.2	Name of the Marketing Authorisation holder	Merck Sharp & Dohme Limited
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	Oral solution
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	RIBAVIRIN
D.3.9.3	Other descriptive name	RIBAVIRIN
D.3.9.4	EV Substance Code	SUB10297MIG
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	40
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

Chronic hepatitis C

E.1.1.1

Medical condition in easily understood language

Chronic hepatitis C

E.1.1.2

Therapeutic area

Diseases [C] - Virus Diseases [C02]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.1
E.1.2	Level	PT
E.1.2	Classification code	10008912
E.1.2	Term	Chronic hepatitis C
E.1.2	System Organ Class	10021881 - Infections and infestations

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Part I:
To assess the safety, efficacy and tolerability of the combination of
PEG-Intron 60 μg/m2 once weekly (QW) plus REBETOL 15 mg/kg/day in pediatric subjects with chronic hepatitis C.

Part II:
- Confirm the durability of the virologic response in pediatric subjects with chronic hepatitis C who were sustained responders at 24 weeks post-treatment in the Protocol No. P02538 study.
- Characterize the long-term safety, including growth and sexual
maturation, in pediatric subjects who were treated with peginterferon alfa-2b plus ribavirin in the Protocol No. P02538 study.

E.2.2

Secondary objectives of the trial

Part I:
To measure the multiple-dose pharmacokinetics of PEG-Intron and
REBETOL in pediatric subjects with chronic hepatitis C.

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

Intensive pharmacokinetic (Part I)

Tanner Staging Assessment for Long-term Follow-up Study (Part II)

E.3

Principal inclusion criteria

Part I
1.Children age 3-17 years old
2.Individuals weighing ≤ 90 kg
3.Previously untreated children with chronic hepatitis C (HCV RNA qPCR plasma positive)
4.Individuals with any HCV (hepatitis C virus) genotype
5.Hematology laboratory results of:
a.Hemoglobin (HGB) ≥ 11 g/dL for females or ≥ 12g/dL for males,
b.White Blood Cell Count (WBC) ≥ 3,000/mm^3,
c.Neutrophils ≥ 1,500/mm^3,
d.Platelets ≥ 100,000/mm^3
6.Chemistry laboratory results of:
a.Normal Thyroid Stimulating Hormone (TSH), albumin, creatinine, and Bilirubin,
b.Antinuclear antibody (ANA) ≤ 1:160,
c.Fasting Glucose 70-140 mg/dL.
7.Compensated liver disease
8.Historic or pre-treatment liver biopsy slides available
9.No significant co-existing psychiatric disease
10.Those with diabetes, hypertension, or birth prior to 32 weeks gestational age must have normal eye exams and retinal photographs (these will be done as part of the study before hepatitis C treatment is given)
11.Patients and partners of patients willing to use adequate contraception during the course of the study
12.Abstain from alcohol and any other illicit drugs

Part II
1.Informed consent must be obtained from the participant or the participant's parent or legal guardian prior to any long-term follow-up study-related procedures. According to local laws and/or IRB/IEC requirements, participants may also need to provide written assent.
2.The participant must have received at least one dose of peginterferon alfa-2b and ribavirin in the Protocol No. P02538 study.
3.The participant must have completed the 24-week post-treatment follow-up in the P02538 Part 1 study. All participants whether sustained responders, relapsers, or nonresponders are eligible to participate.

E.4

Principal exclusion criteria

Part I
1.Serum ALT >10 times the upper limit of normal within the 6 months prior to study
2.Previous hepatitis C treatment
3.Children with liver disease not caused by hepatitis C
4.Most recent liver biopsy is normal
5.Individuals infected with the hepatitis B virus and/or human immunodeficiency virus (HIV)
6.Known blood disorders such as hemoglobinopathy, coagulopathy, or G6PD deficiency
7.Known immunodeficiency disorders requiring immunoglobulin therapy
8.Body organ transplant
9.Any known or suspected cancer within the past 5 years
10.Children with chronic pulmonary disease
11.Individuals who have a medical condition that would likely require systemic steroids
12.Those with a history of central nervous system (CNS) trauma or seizure disorders
13.Individuals with pre-existing psychiatric disorders including but not limited to moderate to severe depression
14.Current or previous use of lithium or antipsychotic drugs
15.Patients with clinically significant electrocardiogram (ECG) abnormalities and/or significant cardiovascular dysfunction (e.g., angina, congestive heart failure, recent myocardial infarction, uncontrolled hypertension, significant arrhythmia, cardiac sequelae from Kawasaki disease, cardiomyopathy, and/or history of congenital heart disease)
16.Insulin-dependent diabetes mellitus or poorly controlled non-insulin dependent diabetes mellitus
17.Immunologically mediated disease (e.g., inflammatory bowel disease [Crohn's disease, ulcerative colitis], rheumatoid arthritis, idiopathic thrombocytopenic purpura, systemic lupus erythematosus, autoimmune hemolytic anemia, scleroderma, severe psoriasis, or symptomatic thyroid disorder)
18.History of substance abuse, including alcohol (e.g., binge drinking, blackouts), intravenous drugs and inhaled drugs
19.Subjects who have a history of pregnancy or who are pregnant and/or breast feeding. Subjects who intend to become pregnant during the study period. Subjects with partners who intend to become pregnant during the study period
20.Subjects with clinically significant retinal abnormalities such as known retinopathy of prematurity or other retinopathies

Part II
1.Concurrent participation in any other clinical study.
2.Retreatment with any antiviral or immunomodulatory drug for chronic hepatitis C after completion of, or discontinuation from, the treatment phase of the P02538 Part 1 study.
3.Any condition that in the opinion of the Investigator would make the participant unsuitable for enrollment.

E.5 End points

E.5.1

Primary end point(s)

Part I
Number of Participants With a Sustained Virologic Response (SVR) at 24 Weeks Post-treatment
Part II
1.Number of Participants Who Relapsed At End of LTFU Year 5
2.Mean Height Percentiles of Participants Over LTFU
3.Mean Weight Percentiles of Participants Over LTFU
4.Mean Body Mass Index (BMI) Percentiles of Participants Over LTFU
5.Mean Age at Attained Tanner Stages (Sexual Maturity) at End of LTFU (Last Observation) By Gender

E.5.1.1

Timepoint(s) of evaluation of this end point

Part I
Up to 48-week treatment duration. Follow-up of 24 weeks.

Part II
1.Part 2 LTFU Year 5
2., 3. and 4. Part 1 Pre-treatment Baseline, Part 2 LTFU Year 1, Part 2 LTFU Year 2, Part 2 LTFU Year 3, Part 2 LTFU Year 4, Part 2 LTFU Year 5, Last Available LTFU Visit (up to 5 years)
5. Last assessment of the Part 2 LTFU (up to 5 years)

E.5.2

Secondary end point(s)

Not applicable

E.5.2.1

Timepoint(s) of evaluation of this end point

Not applicable

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

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

Yes

E.6.13.1

Other scope of the trial description

Tolerability

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

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

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

Argentina

Chile

Puerto Rico

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..
The study was divided in 2 parts: Part I (Treatment and Follow-up Period 1) and Part II (5-year long term follow-up ) .

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

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:

107

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)

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.1.3

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

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

107

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:	United States

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