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Trial registered on ANZCTR


Registration number
ACTRN12619000271101
Ethics application status
Approved
Date submitted
17/01/2019
Date registered
22/02/2019
Date last updated
14/02/2023
Date data sharing statement initially provided
22/02/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
RO7191863 in patients with chronic hepatitis B
Scientific title
An Observer-blind, Randomized Study with an Open-label Part to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Subcutaneous Administration of RO7191863 with Multiple Doses and Different Regimens in Virologically Suppressed Patients with Chronic Hepatitis B Infection
Secondary ID [1] 296884 0
Protocol No.: NP40479
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Chronic Hepatitis B Infection 310817 0
Condition category
Condition code
Infection 309493 309493 0 0
Other infectious diseases
Oral and Gastrointestinal 309937 309937 0 0
Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The study will be conducted in one (or potentially two) parts, Part A and Part B. The study drug of interest, RO7191863, will be administered via subcutaneous injection at an appropriate body site, e.g. abdomen or upper thigh at a dose of up to 3 mg/kg body weight (BW). The administration site will be rotated so that the nature of any injection site reactions may be better understood.

Part A consists of 5 cohorts:
MAD1: 0.4 mg/kg RO7191863 x 3 doses over 7 weeks
MAD2: 1.2 mg/kg RO7191863 x 3 doses over 7 weeks
MAD3: 1.2 mg/kg RO7191863 x 3 doses over 5 weeks
MAD4: 1.2 mg/kg RO7191863 or placebo x 5 doses over 9 weeks
MAD5: Maximum of 3.0 mg/kg RO7191863 or placebo x 5 doses over 9 weeks
MAD5a (Potential cohort): RO7191863 x 5 doses over 9 weeks

The increase of doses (from 0.4 to 1.2 mg/kg, and from 1.2 to 3.0 mg/kg body weight, respectively) will be informed by the safety data of the completed cohorts.

This study consists of an optional sub-study, Fine Needle Aspirate (FNA) of the liver that may be offered to participants entering cohort MAD5 at one or more selected sites with established expertise. FNAs of the liver will be assessed to explore one or more intra-hepatic PD measures and potentially PK measures to explore the effects of RO7191863 in the target organ.

A further cohort (MAD5a, following the same dosing schedule as in MAD5) may be opened if required to allow for the inclusion of additional participants into the FNA sub-study.

Depending on the numbers enrolled in Part A of, e.g., female participants or HBeAg-positive participants, conduct of the corresponding optional Part B cohorts might be justified for the collection of additional safety data in these patient groups.

Part B (potential):
Two open-label MAD cohorts (MAD6, MAD7): anticipated dose level (3.0 mg/kg) once a week, ranging from 5 up to 12 doses.

Participants must discontinue study treatment if there is non-compliance with study requirements as judged by the Investigator and in consultation with the Sponsor.
Intervention code [1] 313159 0
Treatment: Drugs
Comparator / control treatment
Placebo - saline
Control group
Placebo

Outcomes
Primary outcome [1] 318542 0
To assess the safety and tolerability of RO7191863 after multiple ascending subcutaneous doses in CHB patients:
- Incidence, severity, and causal relationship of adverse events
- Changes in vital signs, physical and electrocardiogram findings, and clinical laboratory results
- Incidence of injection site reactions
Timepoint [1] 318542 0
Adverse events and ISRs will be assessed at screening and baseline visit, and at scheduled timepoints during the study as follows:
Part A MAD1 and MAD2:
- Treatment period: Day 1, 2, 8, 15, 22, 23, 29, 36, 43, 44 of study
- Early Termination Visit
- Follow Up period: Day 50, 71, 99, 127 of study

Part A MAD3:
- Treatment period: Day 1, 2, 8, 15, 16, 22, 29, 30 of study
- Early Termination Visit
- Follow Up period: Day 36, 57, 85, 113 of study

Part A MAD4 and MAD5:
- Treatment period: Day 1, 2, 8, 15, 16, 22, 29, 30, 36, 43, 44, 50, 57, 58 of study
- Early Termination Visit
- Follow Up period: Day 64, 85, 113, 141 of study

Part B MAD 6:
- Treatment period: Day 1, 2, 8, 15, 22, 29, 30 of study
- Early Termination Visit
- Follow Up period: Day 36, 57, 85, 113 of study

Part B MAD7:
- Treatment period: Day 1, 2, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78, 79 of study
- Early Termination Visit
- Follow Up period: Day 85, 106, 134, 162 of study

Vital signs and ECG will be assessed at screening visit and at scheduled timepoints during the study as follows:

Part A MAD1 and MAD2:
- Treatment period: Day 1, 8, 15, 22, 29, 36, 43 of study
- Early Termination Visit
- Follow Up period: Day 50, 71, 99, 127 of study

Part A MAD3:
- Treatment period: Day 1, 8, 15, 22, 29 of study
- Early Termination Visit
- Follow Up period: Day 36, 57, 85, 113 of study

Part A MAD4 and MAD5
- Treatment period: Day 1, 8, 15, 22, 29, 36, 43, 50, 57 of study
- Early Termination Visit
- Follow Up period: Day 64, 85, 113, 141 of study

Part B MAD 6:
- Treatment period: Day 1, 8, 15, 22, 29 of study
- Early Termination Visit
- Follow Up period: Day 36, 57, 85, 113 of study

Part B MAD7
- Treatment period: Day 1, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78, of study
- Early Termination Visit
- Follow Up period: Day 85, 106, 134, 162 of study
Secondary outcome [1] 365319 0
Pharmacokinetics: To assess plasma PK of RO7191863 after multiple ascending SC doses in CHB patients. The following PK parameters will be calculated:
- Time to maximum concentration (Tmax).
- Maximum plasma concentration observed (Cmax).
- Area under the curve (AUC) for various time intervals post dose.
Timepoint [1] 365319 0
Blood samples will be taken at scheduled timepoints during the study as follows:
Part A MAD1 and MAD2:
- Treatment period: Day 1, 2, 8, 15, 22, 23, 29, 36, 43, 44 of study
- Early Termination Visit
- Follow Up period: Day 50, 71, 99, 127 of study

Part A MAD3:
- Treatment period: Day 1, 2, 8, 15, 16, 22, 29, 30 of study
- Early Termination Visit
- Follow Up period: Day 36, 57, 85, 113 of study

Part A MAD4 and MAD5:
- Treatment period: Day 1, 2, 8, 15, 16, 22, 29, 30, 36, 43, 44, 50, 57, 58 of study
- Early Termination Visit
- Follow Up period: Day 64, 85, 113,141 of study

Part B MAD 6:
- Treatment period: Day 1, 2, 8, 15, 22, 29, 30 of study
- Early Termination Visit
- Follow Up period: Day 36, 57, 85, 113 of study

Part B MAD7:
- Treatment period: Day 1, 2, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78, 79 of study
- Early Termination Visit
- Follow Up period: Day 85, 106, 134, 162 of study
Secondary outcome [2] 365999 0
Pharmacodynamics: To assess the antiviral activity of RO7191863 after multiple ascending SC doses in CHB patients.
Timepoint [2] 365999 0
Blood samples will be taken at scheduled timepoints during the study as follows:
Part A MAD1 and MAD2:
- Treatment period: Day 1, 22, 43 of study
- Early Termination Visit
- Follow Up period: Day 50, 71, 99, 127 of study

Part A MAD3:
- Treatment period: Day 1, 8, 15, 22, 29 of study
- Early Termination Visit
- Follow Up Period: Day 36, 57, 85, 113 of study

Part A MAD4 and MAD5:
- Treatment period: Day 1, 8, 15, 22, 29, 36, 43, 50, 57 of study
- Early Termination Visit
- Follow Up Period: Day 64, 85, 113, 141 of study

Part B MAD 6:
- Treatment period: Day 1, 8, 15, 22, 29 of study
- Early Termination Visit
- Follow Up period: Day 36, 57, 85, 113 of study

Part B MAD7:
- Treatment period: Day 1, 15, 29, 36, 50, 64, 78 of study
- Early Termination Visit
- Follow Up period: Day 85, 106, 134, 162 of study
Secondary outcome [3] 366992 0
Pharmacokinetics: To assess urine PK of RO7191863 after multiple ascending SC doses in CHB patients. Additional PK parameters may be calculated (e.g., apparent clearance [CL/F], terminal half-life [t1/2], K [elimination rate constant]). Additional urine parameters may be calculated, e.g., cumulative amount of drug excreted in urine over defined time periods (Ae).
Timepoint [3] 366992 0
Urine samples will be taken at scheduled timepoints as follows:
Part A MAD1 and MAD2:
- Treatment period: Day 1, 22, 43 of study

Part A MAD3:
- Treatment period: Day 1, 15, 29 of study

Part A MAD4 and MAD5:
- Treatment period: Day 1, 15, 29, 43, 57 of study

Part B MAD 6:
- Treatment period: Day 1, 29 of study

Part B MAD7:
- Treatment period: Day 1, 78 of study

Eligibility
Key inclusion criteria
Participants are eligible to be included in the study only if all of the following criteria apply:

Informed Consent
1. Able and willing to provide written informed consent and to comply with the study protocol according to ICH and local regulations.

Age
2. Participant must be between 18 to 65 years (inclusive) at the time of signing the informed consent.

Weight
3. Body weight of < 150 kg, and body mass index (BMI) within the range of 18 to 32 kg/m2 (inclusive).

Sex
4. Male and female participants agree to protocol defined methods of contraception.

Type of Participants and Disease Characteristics
5. Positive serum HBsAg status for > 6 months.

6. Serum HBsAg level >= 250 IU/mL.

7. On stable entecavir or tenofovir (alone or in combination) treatment, and having received the same NUC in the 3 months prior to Randomization.

8. HBV DNA below the lower limit of quantification (LLQ) for > or equals to 6 months prior to Screening by local testing, and confirmed at Screening.

9. No current diagnosis of significant liver fibrosis or cirrhosis (F3 or above). No history of cirrhosis. A past F3 staging that has regressed to < F3 on NUC therapy is acceptable for inclusion.

10. Transient elastography showing a level of liver stiffness not indicative of significant liver fibrosis.

11. Screening laboratory values within normal ranges, or judged to be not clinically significant by the Investigator.

12. Negative test results for anti-nuclear antibodies, anti-mitochondrial antibodies, anti-smooth muscle antibodies, anti-thyroperoxidase and anti-platelet antibodies.
Minimum age
18 Years
Maximum age
65 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. History or presence of significant cardiovascular, respiratory, hepatic, renal, gastrointestinal, endocrine, haematological disorders, or diagnosed central or peripheral neurological disease, capable of altering the absorption, metabolism, or elimination of drugs, of constituting a risk when taking the study treatment, or of interfering with the interpretation of the data.

2. Personal or familial history or symptomatology indicative of a risk of immune-mediated disease. Personal history of thyroid disease.

3. History or presence of bridging fibrosis or cirrhosis or decompensated liver disease.

4. History or presence of a medical condition associated with liver disease other than HBV infection. Other known hepatic or biliary abnormalities.

5. History of or suspicion of hepatocellular carcinoma.

6. History of lymphoma, leukaemia, or malignancy within the past five years.

7. History of having received or currently receiving any systemic anti-neoplastic or immune-modulatory treatment.

8. History of organ transplantation.

9. Estimated glomerular filtration rate (eGFR) < 70 mL/min/1.73m^2.

10. Expected to need any other systemic antiviral therapy at any time during participation in the study.

11. Positive hepatitis D virus (HDV) or hepatitis C virus (HCV) antibody test result.

12. Positive for HIV infection at Screening.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Who is / are masked / blinded?



Intervention assignment
Other design features
Cohorts MAD1 to 3 and MAD5a will be a open-label part of the study and subjects will receive RO7191863. There will not be a placebo involved for these cohorts.
Phase
Phase 1
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
25/02/2019
Actual
25/03/2019
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
49
Accrual to date
41
Final
Recruitment outside Australia
Country [1] 21154 0
Hong Kong
State/province [1] 21154 0
Country [2] 21172 0
Thailand
State/province [2] 21172 0
Country [3] 21173 0
New Zealand
State/province [3] 21173 0
Country [4] 21174 0
Korea, Republic Of
State/province [4] 21174 0
Country [5] 21175 0
Bulgaria
State/province [5] 21175 0
Country [6] 21176 0
United Kingdom
State/province [6] 21176 0
Country [7] 21177 0
France
State/province [7] 21177 0
Country [8] 25261 0
Canada
State/province [8] 25261 0

Funding & Sponsors
Funding source category [1] 301454 0
Commercial sector/Industry
Name [1] 301454 0
F. Hoffmann-La Roche
Country [1] 301454 0
Switzerland
Primary sponsor type
Commercial sector/Industry
Name
F. Hoffmann-La Roche
Address
Grenzacherstrasse 124,
4070 Basel
Country
Switzerland
Secondary sponsor category [1] 301145 0
Commercial sector/Industry
Name [1] 301145 0
Covance New Zealand Limited
Address [1] 301145 0
86 Highbrook Drive,
Highbrook, Auckland 2013
Country [1] 301145 0
New Zealand

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 302189 0
Central Health and Disability Ethics Committee
Ethics committee address [1] 302189 0
Ministry of Health
Ethics Department
PO Box 5013
Wellington 6011
Ethics committee country [1] 302189 0
New Zealand
Date submitted for ethics approval [1] 302189 0
23/11/2018
Approval date [1] 302189 0
07/02/2019
Ethics approval number [1] 302189 0
18/CEN/244

Summary
Brief summary
RO7191863 is being developed for the curative treatment of chronic hepatitis B virus (HBV) infection. This is the first study with RO7191863 in humans, designed to assess the safety, tolerability and pharmacokinetics of different doses in participants diagnosed with chronic hepatitis B (CHB).
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 89418 0
Prof Edward Gane
Address 89418 0
Auckland Clinical Studies
3 Ferncroft Street
Auckland 1010
New Zealand
Country 89418 0
New Zealand
Phone 89418 0
+64 2 1548371
Fax 89418 0
Email 89418 0
[email protected]
Contact person for public queries
Name 89419 0
Ms Roche Trial Information Hotline
Address 89419 0
F. Hoffmann-La Roche AG.
Grenzacherstrasse 124
CH-4070 Basel
Switzerland
Country 89419 0
Switzerland
Phone 89419 0
+41 61 6878333
Fax 89419 0
Email 89419 0
[email protected]
Contact person for scientific queries
Name 89420 0
Ms Roche Trial Information Hotline
Address 89420 0
F. Hoffmann-La Roche AG.
Grenzacherstrasse 124
CH-4070 Basel
Switzerland
Country 89420 0
Switzerland
Phone 89420 0
+41 61 6878333
Fax 89420 0
Email 89420 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Not planned at the current, any requests will be followed according to the Roche Global Policy on Sharing of Clinical Study Information.


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseAssessing the developing pharmacotherapeutic landscape in hepatitis B treatment: a spotlight on drugs in phase II clinical trials.2022https://dx.doi.org/10.1080/14728214.2022.2074977
N.B. These documents automatically identified may not have been verified by the study sponsor.