Clinical Trials Register

Summary
EudraCT Number:	2011-004129-28
Sponsor's Protocol Code Number:	NP27946
National Competent Authority:	Slovakia - SIDC (Slovak)
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2011-12-06
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

Slovakia - SIDC (Slovak)

A.2

EudraCT number

2011-004129-28

A.3

Full title of the trial

Study To Evaluate Safety, Tolerability, Pharmacokinetics and Antiviral Activity of Ritonavir-Boosted DANOPREVIR in Combination With Peginterferon Alfa-2a Plus Ribavirin in Treatment-naive Patients and with addition of RO5024048 in Previous Null Responder Patients With Chronic Hepatitis C Genotype 1 or 4 and Compensated Cirrhosis.

Klinické skúšanie na zhodnotenie bezpečnosti, znášanlivosti, farmakokinetiky a antivirálnej
aktivity DANOPREVIRU zosilneného Ritonavirom v kombinácii s Peginterferónom Alfa-2a
a Ribavirinom u neliečených pacientov s chronickou hepatitídou typu C genotypu 1 alebo 4
a kompenzovanou cirhózou a s pridaním produktu RO5024048 u pacientov, ktorí nereagovali
na predchádzajúcu liečbu s chronickou hepatitídou typu C genotypu 1 alebo 4
a kompenzovanou cirhózou.

A.3.1

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

A study to find out the how your body reacts, absorbs, metabolizes and eliminates a combination of drugs and their ability to reduce the activity of a virus that causes permanent inflammation of the liver (Hepatitis C virus).

A.4.1

Sponsor's protocol code number

NP27946

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	F. Hoffmann-La Roche
B.1.3.4	Country	Switzerland
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	F. Hoffmann-La Roche AG
B.4.2	Country	Switzerland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	F. Hoffmann-La Roche Ltd.
B.5.2	Functional name of contact point	Trial Information Support Line-TISL
B.5.3	Address:
B.5.3.1	Street Address	Grenzacherstrasse 124
B.5.3.2	Town/ city	Basel
B.5.3.3	Post code	4070
B.5.3.4	Country	Switzerland
B.5.4	Telephone number	+4161 688 1111
B.5.5	Fax number	+4161 691 9391
B.5.6	E-mail	global.rochegenentechtrials@roche.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	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Danoprevir
D.3.2	Product code	RO5190591/F24
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	Danoprevir
D.3.9.2	Current sponsor code	RO5190591
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	100
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	Comparator
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	Norvir
D.2.1.1.2	Name of the Marketing Authorisation holder	Abbott Laboratories 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.3.2	Product code	Ro0326047
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	RITONAVIR
D.3.9.1	CAS number	155213-67-5
D.3.9.2	Current sponsor code	RO0326047
D.3.9.4	EV Substance Code	SUB10342MIG
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	100
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: 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	No
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	RO5024048
D.3.2	Product code	RO5024048/F14
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.3.9.2	Current sponsor code	RO5024048
D.3.9.3	Other descriptive name	HCV Polymerase Inhibitor Prodrug
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	500
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

Viral infection called Hepatitis C which causes damage to the liver

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	14.0
E.1.2	Level	LLT
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

safety, tolerability, pharmacokinetics (PK) and antiviral activity of RO5190591/ritonavir (danoprevir/r) in combination with peginterferon and ribavirin in treatment-naïve genotype 1 or 4 chronic hepatitis C patients with compensated cirrhosis and danoprevir/r +RO5024048 in combination with peginterferon and ribavirin in null responder genotype 1 or 4 chronic hepatitis C patients with compensated cirrhosis

E.2.2

Secondary objectives of the trial

characterize the emergence of danoprevir (DNV) and/or RO5024048 resistance.
evaluate Rapid Virological Response (RVR), complete Early Virological Response (cEVR), and Sustained Virological Response (SVR) in each cohort

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Gender : Male and Female
• History of CHC GT 1 or GT 4, documented with HCV genotype and serum HCV RNA of > 1 x 105 IU/mL at Screening.
• HCV-treatment-naive Cohort 1 (ie, have never received treatment for their condition including but not limited to IFN-based therapy, RBV, or other anti-viral agents with established or perceived activity against HCV).
• HCV prior P/R null responders for Cohort 2. Documentation of previous treatment failure after starting treatment with approved doses of PEG-IFN plus RBV. Patients must have been adherent to previous therapy and have taken a minimum of approximately 80% of the previous course of therapy for a least the first 12 weeks as estimated by the investigator in consultation with the patients and must have failed treatment as a consequence of null virologic response (<2 log 10 reduction in HCV RNA at week 12).
• Liver biopsy confirming cirrhosis: Knodell score = 4, Metavir score = 4, Batts & Ludwig score = 4, or Ishak modified HAI score ≥ 5
• Compensated cirrhosis (Child-Pugh A)
• Patients must have an abdominal ultrasound, computerized tomography (CT) scan, or magnetic resonance imaging (MRI) scan without evidence of hepatocellular carcinoma (within 6 months prior to Screening), and a serum alfa-fetoprotein (AFP) <100ng/mL (< 100 μg/L at Screening).

E.4

Principal exclusion criteria

• History or presence of decompensated liver disease (history of ascites, hepatic encephalopathy, hepatocellular carcinoma, or bleeding esophageal varices).
• For Cohort 2: Patients who discontinued previous P/R therapy due to reasons other than null response (eg, intolerability, lost to follow up, noncompliance).
• Presence or history of non-hepatitis C chronic liver disease, including but not limited to, autoimmune hepatitis, alfa-1-antitrypsin deficiency, C282Y homozygous hemochromatosis, Wilson’s disease, drug- or toxin-induced liver disease, alcohol-related liver disease, primary biliary cirrhosis, sclerosing cholangitis, and porphyria cutanea tarda causing liver pathology or requiring phlebotomy.
• Positive Hepatitis B surface antigen (HBsAg) or human immunodeficiency virus (HIV) antibody at Screening.
• Use of blood transfusion growth factors (including, but not limited to, granulocyte colony stimulating factor or erythropoietin) or any other therapeutic agents to elevate hematology parameters to facilitate patient entry into the study within 3 months before Screening
• History of severe psychiatric disease
• Laboratory parameters: ALT > 10x ULN; Bi ≥1.5x ULN; serum amylase or lipase > 1.5 x ULN; Hgb < 12- g/L (males), < 120 g/L (females): HA1c ≥8.5;CrCl < 70 mL/min, microproteinuria and Uprotein/Cr ratio ≥ 0.3 (33.89 mg/mmoL; ANC ≤ 1500 /μL; platelets ≤ 90,000/μL

E.5 End points

E.5.1

Primary end point(s)

safety, tolerability, pharmacokinetics (PK) and antiviral activity

E.5.1.1

Timepoint(s) of evaluation of this end point

Study visits to assess safety, tolerability, PK and antiviral activity (PD) are scheduled at the following time points:
Screening (day-56 to day-36), rescreening (day -35 to day -2if necessary), Day -1, Day 1, 2, 3, 6, 8, 12, 13, 14, 15, then every 2 weeks during treatment (wk 4, 6, 8, 10, 1 2, 14, 16, 18, 20, 22, 24)At three off-treatment follow-up visits: at 4, 12 and 24 weeks following end of treatment

E.5.2

Secondary end point(s)

-Development of resistant mutations to danoprevir (DNV) and/or RO5024048 treatment
-Rapid Virological Response (RVR), complete Early Virological Response (cEVR), and Sustained Virological Response (SVR) in each cohort

E.5.2.1

Timepoint(s) of evaluation of this end point

RVR at study week 4, cEVR at study week 24, SVR at 24 weeks post 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

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

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

Yes

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

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

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.8.4.1

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

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

Australia

Canada

France

New Zealand

Poland

Slovakia

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

End of trial – safety and antiviral activity of DNV/r, Pegasys, Copegus +/- RO5024048 at the follow up visit 24 weeks after the end of study medication, including assessment of viral mutation occurance.

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

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)

F.1.1.6

Adolescents (12-17 years)

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)

Yes

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

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.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

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)

Participation in the study does not guarantee a cure from HCV; however, two of the planned study medications (P/R) are approved for the treatment of HCV. Patients will be asked to continue in an observational trial if they meet the following criteria. [A] Persistence of resistant mutations: 1.5 year follow-up for patients with evidence of genotypic resistance to DNV/r and/or RO5024048 and [B] Long-term follow-up: 3 year follow-up for patients achieving SVR.

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

2011-12-23

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-01-24

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2013-08-28

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