Clinical Trials Register

Summary
EudraCT Number:	2021-005362-18
Sponsor's Protocol Code Number:	HBIGforcure
National Competent Authority:	Germany - PEI
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2021-11-29
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

Germany - PEI

A.2

EudraCT number

2021-005362-18

A.3

Full title of the trial

Hepatitis B immunoglobulins to induce HBsAg clearance in patients with chronic hepatitis B

A.3.1

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

Hepatitis B immunoglobulins to induce HBsAg clearance in patients with chronic hepatitis B

A.4.1

Sponsor's protocol code number

HBIGforcure

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	Biotest AG
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	Medical School Hannover
B.5.2	Functional name of contact point	Department of Gastroenterology
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	+491761 532 4645
B.5.5	Fax number	+495115328142
B.5.6	E-mail	studien.mhh.gas@mh-hannover.de

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	Hepatect CP
D.2.1.1.2	Name of the Marketing Authorisation holder	Biotest Pharma GmbH
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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	Infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	not applicable
D.3.9.3	Other descriptive name	HUMAN HEPATITIS B IMMUNOGLOBULIN
D.3.9.4	EV Substance Code	SUB12037MIG
D.3.10	Strength
D.3.10.1	Concentration unit	IU/ml international unit(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	50
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)	Yes
D.3.11.7	Plasma derived medicinal product	Yes
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	Zutectra®
D.2.1.1.2	Name of the Marketing Authorisation holder	Biotest Pharma GmbH
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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	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	not applicable
D.3.9.3	Other descriptive name	HUMAN HEPATITIS B IMMUNOGLOBULIN
D.3.9.4	EV Substance Code	SUB12037MIG
D.3.10	Strength
D.3.10.1	Concentration unit	IU/ml international unit(s)/millilitre
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	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)	Yes
D.3.11.7	Plasma derived medicinal product	Yes
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

HBeAg negative patients with chronic HBV infection will be allocated into two different cohorts, cohort A and cohort B.

E.1.1.1

Medical condition in easily understood language

HBeAg negative patients with chronic HBV infection

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	21.0
E.1.2	Level	PT
E.1.2	Classification code	10052297
E.1.2	Term	Hepatitis B e antigen negative
E.1.2	System Organ Class	10022891 - Investigations

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 objective of this study is as follows:
- To evaluate the efficacy of 12-weeks treatment with hepatitis B immunoglobulins in two different cohorts of patients with chronic hepatitis B defined by the proportion of subjects being HBsAg negative at treatment week 12

E.2.2

Secondary objectives of the trial

The secondary objectives of this study are as follows:
- To analyze the decline of HBsAg during treatment
- To evaluate the post-treatment HBsAg kinetics/response
- To determine HBV-DNA levels during and after treatment with hepatitis B immunoglobulins
- To evaluate the biochemical disease activity (normalization of serum ALT levels)
- To determine the quality of life (SF-36)

Assessment of safety:
Adverse events (AEs) will be collected throughout the study (upon first administration of the IMPs up to 24 weeks after discontinuation of therapy, FU24).

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. Confirmation of chronic HBV infection documented by:
positive HBsAg at least 12 months before screening
4. Cohort A: NA treatment for at least 12 months before screening. HBV-DNA should be
below the lower limit of detection at screening. HBsAg positive and <100 IU/ml.
HBeAg negative.
5. Cohort B: Untreated with NAs for at least 12 months before screening. HBV-DNA <
2000 IU/ml. HBsAg positive and < 100 IU/ml. HBeAg-negative.
6. Subject has not been treated with any investigational drug or device within 42 days
before the screening visit or within 5 half-lives for investigational drugs, whichever is
longer.
7. Transient Elastography (FibroScan) < 7.5 kPa at screening.
8. ALT levels < 1.5 times of upper the limit of normal at screening for both cohorts
9. Body mass idex (BMI) > 18kg/m²
10. 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). Complete abstinence from intercourse. Periodic abstinence (e.g.,
calendar, ovulation, symptothermal, postovulation 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 the end of FU:
•intrauterine device (IUD) with a failure rate of < 1% per year
•bilateral tubal sterilization
•vasectomy in male partner
•hormone-containing contraceptive:
o combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation:
- oral
- intravaginal
- transdermal
o progestogen-only hormonal contraception associated with inhibition of ovulation:
- oral
- injectable
- implantable
11. Subject must be able to comply with the dosing instructions for study drug administration and be 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 hepatitis B) 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 hepatitis B) are
also excluded.
2. Co-infection with hepatitis C virus (defined as HCV RNA positive. HCV RNA
negative/anti-HCV-positive patients can be included) or co-infection with HIV.
3. Clinical hepatic decompensation (i.e. clinical ascites, encephalopathy or variceal
hemorrhage).
4. 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.
5. Significant drug allergy (such as anaphylaxis or hepatotoxicity).
6. Pregnant or nursing female or male with pregnant female partner
7. 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
investigator must approve medication, the diagnosis and prescription. Uncontrolled
users of intravenous drugs will not be permitted to enroll in the study.
8. live-attenuated virus vaccinations such as: measles, mumps, rubella and varicella 4
weeks before and up to three months after administration of hepatitis B
immunoglobulins. If not required by an emergency situation, passive or active
immunizations or administration of plasma preparations or of other
immunoglobulins is not allowed during the study.
9. A recent SARS-COV2 infection in the last 4 weeks prior to screening

E.5 End points

E.5.1

Primary end point(s)

Primary efficacy endpoint:
- HBsAg negativity at week 12 of antiviral therapy

E.5.1.1

Timepoint(s) of evaluation of this end point

week 12

E.5.2

Secondary end point(s)

Secondary endpoint(s):
1) HBsAg decline at weeks 1, 2, 4, 8 and 12 of treatment
2) post-treatment HBsAg negativity up to FU week 24
3)HBV DNA levels during and after hepatitis B immunoglobulin treatment will be reported
for each cohort
4) biochemical response (proportion of subjects who reached ALT normalization (ALT ≤
ULN) at week 12 of treatment)
5) quality of life during treatment and follow-up (SF-36)

6)Assessment of safety: Adverse events (AEs) will be collected throughout the study (upon first
administration of the IMPs up to 24 weeks after discontinuation of therapy, FU24) and will
be reported with absolute and relative frequencies along with the corresponding 95%
confidence intervals.

E.5.2.1

Timepoint(s) of evaluation of this end point

1) weeks 1, 2, 4, 8 and 12 of treatment
2) up to FU week 24
3)during and after hepatitis B immunoglobulin treatment
4) week 12
5)during treatment and follow-up
6)upon first administration of the IMPs up to 24 weeks after discontinuation of therapy, FU24

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

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)

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

Yes

E.8.4

The trial involves multiple sites in the 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

last visit of the last patient (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)

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)

None

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

2022-04-13

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2022-03-25

P. End of Trial
P.	End of Trial Status	Ongoing

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