Clinical Trials Register

Summary
EudraCT Number:	2010-018332-41
Sponsor's Protocol Code Number:	RibaC
National Competent Authority:	Denmark - DHMA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2010-04-07
Trial 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

Denmark - DHMA

A.2

EudraCT number

2010-018332-41

A.3

Full title of the trial

A Randomized, Open-label, Parallel Group, Multicenter Pilot Study Evaluating the Efficacy and Safety of Alternative Dosing of Ribavirin vs. Standard of Care Dosing in Combination with Peginterferon alpha-2a in Interferon Naïve Patients with Chronic Hepatitis C Genotype 1 Infection

A.3.2

Name or abbreviated title of the trial where available

RibaC

A.4.1

Sponsor's protocol code number

RibaC

A.7

Trial is part of a Paediatric Investigation Plan

Information not present in EudraCT

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Dept. of Infectious diseases / virology University of Gothenburg
B.1.3.4	Country	Sweden
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support
B.4.2	Country
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation
B.5.2	Functional name of contact point

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	Pegasys 180mcg/135mcg
D.2.1.1.2	Name of the Marketing Authorisation holder	Roche
D.2.1.2	Country which granted the Marketing Authorisation	Denmark
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.3.1	Product name	Pegasys
D.3.4	Pharmaceutical form	Injection*
D.3.4.1	Specific paediatric formulation	Information not present in EudraCT
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 2A
D.3.9.1	CAS number	198153-51-4
D.3.10	Strength
D.3.10.1	Concentration unit	µg microgram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	135
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	PEGINTERFERON ALFA 2A
D.3.9.1	CAS number	198153-51-4
D.3.10	Strength
D.3.10.1	Concentration unit	µg microgram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	180
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)	Information not present in EudraCT
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	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	Information not present in EudraCT
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	Information not present in EudraCT
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	Yes
D.3.11.13.1	Other medicinal product type	Immunostimulating
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	Copegus 200mg/400mg
D.2.1.1.2	Name of the Marketing Authorisation holder	Roche
D.2.1.2	Country which granted the Marketing Authorisation	Denmark
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.3.1	Product name	Copegus
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	Information not present in EudraCT
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.3.9.1	CAS number	36791-04-5
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.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	RIBAVIRIN
D.3.9.1	CAS number	36791-04-5
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	400
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)	Information not present in EudraCT
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	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	Information not present in EudraCT
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	Information not present in EudraCT
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	Yes
D.3.11.13.1	Other medicinal product type	Antiviral product

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 infection

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	12.1
E.1.2	Level	LLT
E.1.2	Classification code	10008912
E.1.2	Term	Chronic hepatitis C

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To evaluate the efficacy of (A) 2 weeks of high dose of ribavirin (“loading”, ≥26 mg/kg/day for 14 days followed by ≥13 mg/kg/day) vs. (B) 4 weeks of ribavirin dosing before initiation of PEG-interferon dosing (“priming”, ≥13 mg/kg/day) followed by concentration targeted (≥ 2.5 mg/L (10.25 μmol/L) 28 days after initiation of ribavirin therapy) dosing of ribavirin in combination with peginterferon alpha-2a in interferon naïve patients with chronic hepatitis C (CHC) virus genotype 1 infection as compared to (C) standard-of-care dosing of ribavirin (≥13 mg/kg/day without monitoring of ribavirin concentrations) in combination with peginterferon alpha-2a as evaluated by the early viral kinetic response and SVR measured by effect on the initial decline of HCV-RNA (during the first days after initiating peginterferon and ribavirin therapy) and second phase decline (day 7 to week 12 of therapy).

E.2.2

Secondary objectives of the trial

To prospectively evaluate:
•efficacy of 2 week loading or 4 week priming as evaluated by the proportion of patients achieving VRVR, RVR, cEVR, and pEVR
•predictive value of monitoring of viral load at day 0, 3, 7 and 28
•association between the trough concentrations of ribavirin and the therapeutic efficacy
•association between plasma IP-10 and the therapeutic efficacy.
•effect of IL-28B ploymorfism on the viral kinetic response.
•effect of baseline vitamin D concentrations on the viral kinetic response.
•effect of baseline IP-10 concentrations on the viral kinetic response.
•association between liver histology and the therapeutic efficacy.
•association between liver stiffness as evaluated by the FibroScan and the therapeutic efficacy.
•association between liver fibrosis as evaluated by the GUCI and APRI indexes as well as hyaluronic acid, and the therapeutic efficacy.
•association between BMI and age and the therapeutic efficacy.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Written informed consent
• Male and female patients >/=18 years of age
• Serologic evidence of chronic hepatitis C infection by an anti-HCV antibody test
• Serum HCV-RNA >/=15 IU/mL.
• HCV genotype 1 infection confirmed within the past 2 years preceding the initiation of test drug dosing.
• Compensated liver disease (Child-Pugh Grade A clinical classification)
• Patients with cirrhosis or transition to cirrhosis must have an abdominal ultrasound, CT scan, or MRI scan without evidence of hepatocellular carcinoma and a serum AFP ≤100 ng/mL within 2 months of randomization
• Negative urine or blood pregnancy test (for women of childbearing potential) documented within the 24-hour period prior to the first dose of study drug
• All fertile males and females receiving ribavirin must be using effective contraception during treatment and during 4 months for female patients / 7 months for male patients after end of treatment
• Subject must weigh between 45 and 105 kg at screening

E.4

Principal exclusion criteria

• Women with ongoing pregnancy or breast feeding
• IFN/ peg-interferon with or without ribavirin therapy at any previous time
• Therapy with any systemic anti-viral, anti-neoplastic or immunomodulatory treatment (including supraphysiologic doses of steroids and radiation) *6 months prior to the first dose of study drug
• Any investigational drug </=6 weeks prior to the first dose of study drug.
• HCV genotype 2, 3, 4, 5, 6, or 7 infection.
• Positive test at screening for anti-HAV IgM Ab, HBsAg, anti-HBc IgM Ab, anti-HIV Ab
• Evidence of a medical condition associated with chronic liver disease other than HCV (e.g., hemochromatosis, autoimmune hepatitis, metabolic liver disease, alcoholic liver disease, toxin exposures)
• History or other evidence of decompensated liver disease
• Neutrophil count <1500 cells/mm3 or platelet count <90,000 cells/mm3 at screening
• Serum creatinine level >2 mg/dl (>124 µmol/L) or creatinine clearance ≤50 ml/minute at screening
• Severe psychiatric disease, especially depression, as judged by the treating physician.
• History of a severe seizure disorder or current anticonvulsant use
• History of immunologically mediated disease, severe chronic pulmonary disease associated with functional limitation, severe cardiac disease, major organ transplantation or other evidence of severe illness, malignancy, or any other conditions which would make the patient, in the opinion of the investigator, unsuitable for the study
• Thyroid dysfunction not adequately controlled (TSH and T4 levels out of normal range)
• Evidence of severe retinopathy (e.g. CMV retinitis, macula degeneration) or clinically relevant ophthalmological disorder due to diabetes mellitus or hypertension
• Evidence of drug abuse (including excessive alcohol consumption) in accordance with local therapeutic traditions.
• Inability or unwillingness to provide informed consent or abide by the requirements of the study
• Male partners of women who are pregnant
• Hemoglobin <12 g/dL in women or <13 g/dL in men at screening.
• Any patient with an increased baseline risk for anemia (e.g. thalassemia major, spherocytosis, history of GI bleeding, etc) or for whom anemia would be medically problematic coagulopathy.
• Patients with documented or presumed coronary artery disease or cerebrovascular disease should not be enrolled if, in the judgment of the investigator, an acute decrease in hemoglobin by up to 4 g/dL (as may be seen with ribavirin therapy) would not be well-tolerated

E.5 End points

E.5.1

Primary end point(s)

The early virological response as measures by the decline in HCV-RNA during the first 12 weeks (in particular the first and second phase decline) of peginterferon alpha-2a and ribavirin therapy in the three study arms.

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

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)

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

Yes

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

standard dose regime

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

E.8.6.2

Trial being conducted completely outside of the EEA

Information not present in EudraCT

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

last patients last visit

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	No
F.1.1.1	In Utero	No
F.1.1.2	Preterm newborn infants (up to gestational age < 37 weeks)	No
F.1.1.3	Newborns (0-27 days)	No
F.1.1.4	Infants and toddlers (28 days-23 months)	No
F.1.1.5	Children (2-11years)	No
F.1.1.6	Adolescents (12-17 years)	No
F.1.2	Adults (18-64 years)	Yes
F.1.3	Elderly (>=65 years)	Yes
F.2 Gender
F.2.1	Female	Yes
F.2.2	Male	Yes
F.3 Group of trial subjects
F.3.1	Healthy volunteers	No
F.3.2	Patients	Yes
F.3.3	Specific vulnerable populations	Yes
F.3.3.1	Women of childbearing potential not using contraception For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2010-04-07.	Yes
F.3.3.2	Women of child-bearing potential using contraception	Yes
F.3.3.3	Pregnant women	No
F.3.3.4	Nursing women	No
F.3.3.5	Emergency situation	No
F.3.3.6	Subjects incapable of giving consent personally	No
F.3.3.7	Others	No
F.4 Planned number of subjects to be included
F.4.1	In the member state	25
F.4.2	For a multinational trial
F.4.2.1	In the EEA	105
F.4.2.2	In the whole clinical trial	105

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

2010-05-10

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2010-04-12

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2012-07-31

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