Clinical Trials Register

Summary
EudraCT Number:	2013-001081-42
Sponsor's Protocol Code Number:	HepNet-aHCV-IV
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2014-07-29
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

Germany - BfArM

A.2

EudraCT number

2013-001081-42

A.3

Full title of the trial

Interferon-free Treatment of Acute Genotype 1 Hepatitis C Virus Infection with Ledipasvir/Sofosbuvir Fixed-Dose Combination - The HepNet Acute HCV IV Study

A.3.1

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

Interferon-free Treatment of Acute Genotype 1 Hepatitis C Virus Infection with Ledipasvir/Sofosbuvir

A.4.1

Sponsor's protocol code number

HepNet-aHCV-IV

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	Hannover Medical School
B.1.3.4	Country	Germany
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	Gilead Sciences Europe Ltd
B.4.2	Country	European Union
B.4.1	Name of organisation providing support	German Center for Infection Research (DZIF), partner site Hannover-Braunschweig
B.4.2	Country	Germany
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Hannover Medical School
B.5.2	Functional name of contact point	Prof. Dr. med. Michael Manns
B.5.3	Address:
B.5.3.1	Street Address	Carl-Neuberg-Str. 1
B.5.3.2	Town/ city	Hannover
B.5.3.3	Post code	30625
B.5.3.4	Country	Germany
B.5.4	Telephone number	+49 511 5323305

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	Ledipasvir/sofosbuvir fixed-dose combination
D.3.2	Product code	LDV/SOF FDC
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	SOF
D.3.9.1	CAS number	1190307-88-0
D.3.9.2	Current sponsor code	GS-7977
D.3.9.3	Other descriptive name	SOFOSBUVIR
D.3.9.4	EV Substance Code	SUB121170
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.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	LDV
D.3.9.1	CAS number	1256388-51-8
D.3.9.2	Current sponsor code	GS-5885
D.3.9.3	Other descriptive name	LEDIPASVIR
D.3.9.4	EV Substance Code	SUB120165
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	90
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

Adults with acute genotype 1 hepatitis C virus (HCV) infection

E.1.1.1

Medical condition in easily understood language

Adults with acute infection of the liver, caused by the hepatitis C virus (HCV)

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	18.1
E.1.2	Level	LLT
E.1.2	Classification code	10072848
E.1.2	Term	Hepatitis C virus genotype 1 positive
E.1.2	System Organ Class	100000004848

E.1.2 Medical condition or disease under investigation

E.1.2	Version	18.1
E.1.2	Level	PT
E.1.2	Classification code	10065051
E.1.2	Term	Acute hepatitis C
E.1.2	System Organ Class	10021881 - Infections and infestations

E.1.2 Medical condition or disease under investigation

E.1.2	Version	18.1
E.1.2	Level	LLT
E.1.2	Classification code	10019752
E.1.2	Term	Hepatitis C virus (HCV)
E.1.2	System Organ Class	100000004848

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

The primary objectives of this study are as follows:
• To evaluate the efficacy of treatment with ledipasvir (LDV)/sofosbuvir (SOF) FDC for 6 weeks in patients with acute genotype 1 HCV infection as measured by the proportion of subjects with sustained viral response (HCV RNA < LLOQ TND) 12 weeks after discontinuation of therapy (SVR12)
• To evaluate the safety and tolerability of LDV/SOF FDC -containing regimens administered for up to 6 weeks in patients with acute genotype 1 HCV infection

E.2.2

Secondary objectives of the trial

The secondary objectives of this study are as follows:
• To determine the durability of response 24 weeks after discontinuation of therapy (SVR24) measured by the proportion of subjects with sustained viral response (HCV RNA < LLOQ TND) 24 weeks after discontinuation of therapy (SVR 24)
• To evaluate the kinetics of circulating HCV RNA during treatment and after treatment discontinuation measured as mean viral load during treatment (Baseline, week 2, 4, 6) and after treatment discontinuation (Follow up week 4, 12, 24)
• To evaluate the emergence of viral resistance to LDV/SOF FDC during treatment and after treatment discontinuation
The exploratory objectives of this study are as follows:
• To assess any relationship between HCV-specific T cell responses and treatment efficacy
• To assess any relationship between NK cell phenotype and function and treatment efficacy
• To assess any relationship between circulating serum chemokines and treatment efficacy and safety

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Subjects must meet all of the following inclusion criteria to be eligible for participation in this study.
1. Willing and able to provide written informed consent
2. Male or female, age ≥18 years
3. HCV RNA ≥ 103 IU/mL at Screening
4. Confirmation of acute genotype 1 HCV infection documented by either: documented seroconversion to HCV antibody positivity within the 4 months preceding screening or known or suspected exposure to HCV within the 4 months preceding screening with 10 times elevated serum ALT level at screening or 4 weeks preceding screening without evidence of confounding liver disorders
5. If the patient visits a physician due to symptoms of acute HCV, no greater than a 12 week interval may have elapsed between the time of the visit and screening
6. Non-cirrhotic. Absence of cirrhosis will be determined based on clinical parameter or ultrasound.
7. Body mass index (BMI) ≥ 18 kg/m2
8. Screening ECG without clinically significant abnormalities
9. Subjects must have the following laboratory parameters at screening:
a) Hemoglobin ≥ 10 g/dL
b) Platelets ≥ 90,000/μL
c) INR ≤1.5 x ULN unless subject has known hemophilia or is stable on an anticoagulant regimen affecting INR
d) Albumin ≥3 g/dL
e) HbA1c ≤10%
f) Creatinine clearance (CLcr) ≥60 mL/min, as calculated by the Cockcroft-Gault equation (Cockcroft and Gault 1976)
10. Subject has not been treated with any investigational drug or device within 42 days of the Screening visit
11. A negative serum pregnancy test is required for female subjects (unless surgically sterile or women ≥ 54 years of age with cessation for 24 ≥ months of previously occurring menses, see Appendix 2 for definitions).
Complete abstinence from intercourse. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) is not permitted.
or
Consistent and correct use of 1 of the following methods of birth control listed below, in addition to a male partner who correctly uses a condom, from the date of Screening until 30 days after last dose of study drug:
• intrauterine device (IUD) with a failure rate of < 1% per year
• female barrier method: cervical cap or diaphragm with spermicidal agent
• tubal sterilization
• vasectomy in male partner
• hormone-containing contraceptive:
• implants of levonorgestrel
• injectable progesterone
• oral contraceptives (either combined or progesterone only)
• contraceptive vaginal ring
• transdermal contraceptive patch
12. Male subjects must agree to refrain from sperm donation from the day of screening and for at least 90 days after the last dose of study drug.
13. Subject must be of generally good health as determined by the Investigator.
14. Subject must be able to comply with the dosing instructions for study drug administration and able to complete the study schedule of assessments.

E.4

Principal exclusion criteria

Subjects who meet any of the following exclusion criteria are not to be enrolled in this study.
1. Clinically-significant illness (other than HCV) or any other major medical disorder that, in the opinion of the investigator, may interfere with subject treatment, assessment or compliance with the protocol; subjects currently under evaluation for a potentially clinically-significant illness (other than HCV) are also excluded.
2. Gastrointestinal disorder or post operative condition that could interfere with the absorption of the study drug (for example, gastric bypass or severe ulcerative colitis).
3. Difficulty with blood collection and/or poor venous access for the purposes of phlebotomy.
4. Clinical hepatic decompensation (i.e., clinical ascites, encephalopathy or variceal hemorrhage).
5. Solid organ transplantation.
6. Significant pulmonary disease or significant cardiac disease.
7. Psychiatric hospitalization, suicide attempt, and/or a period of disability as a result of their psychiatric illness within the last 2 years. Subjects with psychiatric illness that is well-controlled on a stable treatment regimen for at least 12 months prior to screening or has not required medication in the last 12 months may be included.
8. Malignancy within 5 years prior to screening, with the exception of specific cancers that are entirely cured by surgical resection (basal cell skin cancer, etc). Subjects under evaluation for possible malignancy are not eligible.
9. Significant drug allergy (such as anaphylaxis or hepatotoxicity).
10. Any prior treatment for HCV infection including prior exposure to any inhibitor of the NS5B and NS5A.
11. Pregnant or nursing female or male with pregnant female partner.
12. Chronic liver disease of a non-HCV etiology (e.g., hemochromatosis, autoimmune hepatitis, alcoholic liver disease, Wilson’s disease, α1 antitrypsin deficiency, cholangitis).
13. Infection with hepatitis B virus (HBV; defined as HBsAg-positive) or human immunodeficiency virus (HIV).
14. Chronic use of systemically administered immunosuppressive agents (e.g., prednisone equivalent > 10 mg/day)
15. Clinically-relevant drug or alcohol abuse within 12 months of screening including any uncontrolled drug use within 6 months of screening. A positive drug screen will exclude subjects unless it can be explained by a prescribed medication; the diagnosis and prescription must be approved by the investigator. Uncontrolled users of intravenous drugs will not be permitted to enroll in the study.
16. Donation or loss of more than 400 mL blood within 2 months prior to Baseline/Day 1.
17. Use of any prohibited concomitant medications as described in Section 5.4 within 21 days of the Baseline/Day 1 visit. Use of Amiodaron as concomitant medication is prohibited as described in Section 5.4 within 60 days of Baseline/Day 1 visit.
18. Known hypersensitivity to LDV, SOF or formulation excipients.

E.5 End points

E.5.1

Primary end point(s)

• To evaluate the efficacy of treatment with ledipasvir (LDV)/sofosbuvir (SOF) FDC for 6 weeks in patients with acute genotype 1 HCV infection as measured by the proportion of subjects with sustained viral response (HCV RNA < LLOQ TND) 12 weeks after discontinuation of therapy (SVR12)
• To evaluate the safety and tolerability of LDV/SOF FDC-containing regimens administered for up to 6 weeks in patients with acute genotype 1 HCV infection

E.5.1.1

Timepoint(s) of evaluation of this end point

1) 12 weeks after discontinuation of therapy
2) All safety data collected on or after the date that investigational medicinal product was first dispensed up to the date of last dose of investigational medicinal product {+ 30 days}

E.5.2

Secondary end point(s)

• To determine the durability of response 24 weeks after discontinuation of therapy (SVR24)
• To evaluate the kinetics of circulating HCV RNA during treatment and after treatment discontinuation
• To evaluate the emergence of viral resistance to LDV/SOF FDC during treatment and after treatment discontinuation
The exploratory objectives of this study are as follows:
• To assess any relationship between HCV-specific T cell responses and treatment efficacy
• To assess any relationship between NK cell phenotype and function and treatment efficacy
• To assess any relationship between circulating serum chemokines and treatment efficacy

E.5.2.1

Timepoint(s) of evaluation of this end point

1) 24 weeks after discontinuation
2) measurements every Visit
3) measurements every Visit
4) measurements every Visit
5) measurements every Visit
6) measurements every Visit

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

Yes

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)

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

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

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

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

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.8.9.1

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

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.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)

After the end of study patients will come to follow up appointments according to the judgement of the attending physician. In case of non-response the patient will be treated according to the treatment recommendation and current guidelines respectively.

G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1
G.4.1	Name of Organisation	Hannover Medical School Dep. of Gastroenterology, Hepatology and Endocrinology,HepNet Study House of the German Liver F
G.4.3.4	Network Country	Germany

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2014-08-22

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-10-21

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2016-06-13

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