A Study to Evaluate the Safety, Tolerability and Pharmacokinetics and Pharmacodynamics of RO7062931in Healthy Volunteers and Subjects With Chronic Hepatitis B

NCT03038113 | Completed Phase 1 Results

• 1 other identifier: BP39405
• Study Type: interventional
• Target: 119
• Locations: 7 countries
• Sites: 19

Brief Summary

This randomized study will be conducted in two parts to evaluate the safety, tolerability, pharmacodynamics, and pharmacokinetics of subcutaneous administration of RO7062931. Part 1 will include only healthy participants and Part 2 will include only participants with chronic hepatitis B (CHB). Part 1 is an adaptive, single-ascending dose study with an adaptive dose-escalating schedule to determine the best dose to be evaluated in participants with CHB. Part 2 is an adaptive, parallel multiple-dose study comprised of three sub-parts which will be used to further refine the dose and dosing regimen, and to evaluate the safety and efficacy of RO7062931 when administered with standard-of-care (SoC) therapy.

Conditions

Chronic Hepatitis B

Outcome Measures

Primary Outcomes (10)

• Percentage of Participants With Adverse Events (AEs) and AEs of Special Interest

  An adverse event is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events. AEs of Special Interest were defined as: i.) elevated ALT/AST in combination with elevated bilirubin/clinical jaundice, ii.) suspected transmission of infectious agent by the study drug, iii.) severe injection site reactions, iv.) ALT elevation ≥10x ULN, v.) creatinine elevation ≥1.5x ULN or ≥50% from baseline.

  Up to day 113

• Percentage of Participants With Laboratory Abnormalities Based on Hematology, Blood Chemistry, Coagulation, and Urinalysis Test Results - Part 1

  Marked reference range has been predefined for each laboratory parameter. The marked reference range is broader than the standard reference range. Values falling outside the marked reference range that also represent a defined change from baseline will be considered marked laboratory abnormalities (i.e., potentially clinically relevant). If a baseline value is not available for a study subject, the midpoint of the standard reference range will be used as the study participant baseline value for the purposes of determining marked laboratory abnormalities.

  Screening, Days -1, 2, 8, 15, 29, 85

• Percentage of Participants With Laboratory Abnormalities Based on Hematology, Blood Chemistry, Coagulation, and Urinalysis Test Results - Part 2

  Marked reference range has been predefined for each laboratory parameter. The marked reference range is broader than the standard reference range. Values falling outside the marked reference range that also represent a defined change from baseline will be considered marked laboratory abnormalities (i.e., potentially clinically relevant). If a baseline value is not available for a study subject, the midpoint of the standard reference range will be used as the study participant baseline value for the purposes of determining marked laboratory abnormalities.

  Screening, Days -1, 2, 8, 15, 29, at discontinuation, Days 36, 43, 57, 85, 113

• Percentage of Participants With Electrocardiogram (ECG) Abnormalities Based on ECG Interpretation - Part 1

  Participants were monitored for clinically-significant RO7062931-related ECG changes, defined as QTcF \> 500 msec, or \> 60 msec longer than the pre-dose baseline, within the first 48 hours post-dose.

  Day 1 (1,4,8,12h), Days 2 and 8, Follow Up Days 15, 29, 85

• Percentage of Participants With Electrocardiogram (ECG) Abnormalities Based on ECG Interpretation - Part 2

  Participants were monitored for clinically-significant RO7062931-related ECG changes, defined as QTcF \> 500 msec, or \> 60 msec longer than the pre-dose baseline, within the first 48 hours post-dose.

  Day 1 (1,4,8h), Days 2,8,15,22 (1h and 8h), Day 23, Day 29 (1,4,8h), Day 30, Follow Up Days 36, 43, 50, 57, 78, 85, 106, 113

• Percentage of Participants With T-Wave Abnormalities Based on T-Wave Assessment - Part 1

  Table entries provide the percentage of participants with abnormalities during treatment assessment. Abnormalities reported in participants with missing baseline values are included. Baseline is the Participant's last observation prior to initiation of study drug.

  Day 1 (1,4,8,12h), Days 2 and 8, Follow Up Days 15, 29, 85

• Percentage of Participants With U-Wave Abnormalities Based on U-Wave Assessment - Part 1

  Table entries provide the percentage of participants with abnormalities during treatment assessment. Abnormalities reported in participants with missing baseline values are included. Baseline is the Participant's last observation prior to initiation of study drug.

  Day 1 (1,4,8,12h), Days 2 and 8, Follow Up Days 15, 29, 85

• Percentage of Participants With T-Wave Abnormalities Based on T-Wave Assessment - Part 2

  Table entries provide the percentage of participants with abnormalities during treatment assessment. Abnormalities reported in participants with missing baseline values are included. Baseline is the Participant's last observation prior to initiation of study drug.

  Day 1 (1,4,8h), Days 2,8,15,22 (1h and 8h), Day 23, Day 29 (1,4,8h), Day 30, Follow Up Days 36, 43, 50, 57, 78, 85, 106, 113

• Percentage of Participants With U-Wave Based on U-Wave Assessment - Part 2

  Table entries provide the percentage of participants with abnormalities during treatment assessment. Abnormalities reported in participants with missing baseline values are included. Baseline is the Participant's last observation prior to initiation of study drug.

  Day 1 (1,4,8h), Days 2,8,15,22 (1h and 8h), Day 23, Day 29 (1,4,8h), Day 30, Follow Up Days 36, 43, 50, 57, 78, 85, 106, 113

• Percentage of Participants With QTcF Values Between 450 Msec - 480 Msec - Part 2

  Table entries provide the percentage of participants with abnormalities during treatment assessment. Abnormalities reported in participants with missing baseline values are included. Baseline is the Participant's last observation prior to initiation of study drug.

  Day 1 (1,4,8h), Days 2,8,15,22 (1h and 8h), Day 23, Day 29 (1,4,8h), Day 30, Follow Up Days 36, 43, 50, 57, 78, 85, 106, 113

Secondary Outcomes (19)

• Maximum Plasma Concentration (Cmax) After Single Ascending Doses - Part 1

  Days 1-8

• Cmax After Multiple Ascending Doses - Part 2

  Days 1-113

• Time to Reach Maximum Plasma Concentration (Tmax) After Single-Ascending Doses - Part 1

  Days 1-8

• Tmax After Multiple Ascending Doses - Part 2

  Days 1-113

• Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUC0-inf) After Single-Ascending Doses - Part 1

  Days 1-8

Study Arms (2)

Part 1: Single-Ascending Dose (SAD)

EXPERIMENTAL

Healthy volunteers will be enrolled in up to 8 cohorts with doses starting from 0.1 mg/kg and escalating sequentially after review of safety and pharmacokinetic (PK) data.

Drug: RO7062931; Drug: Placebo

Part 2: Multiple Ascending Dose

EXPERIMENTAL

Participants with Chronic Hepatitis B will enrolled in Part 2. In Part 2a, participants will receive two monthly injections of either 3 doses equivalent to a multiple of the saturation dose or placebo in a 1:1:1:1 ratio. In Part 2b, a dose selected from Part 2a will be administered to participants randomized into 4 cohorts where they will be dosed weekly (QW) or bi-weekly (Q2W). Each of the cohorts in Part 2b will include participants receiving active drug or placebo in a 3:1 ratio. In Part 2c, NUC-suppressed CHB participants will receive either RO7062931+NUC for up to 24 weeks, or RO7062931+NUC+an immune modulator for up to 48 weeks, at a dose determined from Part 2a and 2b. Part 2c may also enroll treatment-naive immune-active CHB participants.

Drug: RO7062931; Drug: Placebo; Drug: Immune Modulator

Interventions

RO7062931 DRUG

Administered subcutaneously in Parts 1 and 2. Part 1 will be administered in single-ascending doses after 0.1 mg/kg starting dose. Subsequent doses of 0.3, 1, 2 and 4 mg/kg may be administered based upon tolerability. In Part 2a, participants will receive two monthly doses of either 0.4, 0.8, 1.2 times the saturation dose or placebo. In Part 2b, a dose selected from Part 2a will be administered to participants randomized into 4 cohorts QW or Q2W. In Part 2c, participants will receive RO7062831 QW on top of another therapy for up to 24 or 48 weeks.

Part 1: Single-Ascending Dose (SAD); Part 2: Multiple Ascending Dose

Placebo DRUG

Part 1 cohorts: active drug vs placebo 4:1. Part 2a 4 parallel cohorts of 3 active drug doses and placebo in 1:1:1:1. Part 2b active drug vs placebo in 3:1 in 2 parallel cohorts.

Part 1: Single-Ascending Dose (SAD); Part 2: Multiple Ascending Dose

Immune Modulator DRUG

Participants in Part 2c will receive an immune modulator subcutaneously QW for up to 48 weeks.

Part 2: Multiple Ascending Dose

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• FOR HEALTHY VOLUNTEERS ONLY - PART 1 -
• A Body Mass Index (BMI) between 18 to 30 kg/m2 inclusive and a body weight of at least 50 kg.
• Women should be of non-childbearing potential. A woman is considered to be of childbearing potential if she is post-menarcheal but has not reached a post-menopausal state and has not undergone surgical sterilization (removal of ovaries and/or uterus).
• Men must agree to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures during treatment and up to 105 days after the last dose, and agree to refrain from donating sperm.
• Non-smoker (nor tobacco containing products) for at least 90 days prior to dosing on Day 1 and agree to remain as non-smoker during the study.
• FOR CHB PARTICIPANTS ONLY - PARTS 2a and 2b:
• A BMI between 18 to 32 kg/m2 inclusive.
• Chronic hepatitis B (HBV) infection.
• Positive test for HBsAg for more than 6 months prior to randomization and HBsAg titer ≥ 10\^3 IU/mL at screening.
• On entecavir, tenofovir, adefovir or telbivudine treatment for at least 6 months prior to randomization and will remain on stable treatment during the study.
• HBV deoxyribonucleic acid (DNA) ≤ 90 IU/mL for at least the preceding 6 months.
• Screening laboratory values (hematology, chemistry, urinalysis) obtained up to 56 days prior to first study treatment within normal ranges.
• Liver biopsy, fibroscan® or equivalent test obtained within the past 6 months demonstrating liver disease consistent with chronic HBV infection without evidence of bridging fibrosis or cirrhosis
• Women should be of non-childbearing potential. A woman is considered to be of childbearing potential if she is post-menarcheal but has not reached a post-menopausal state and has not undergone surgical sterilization (removal of ovaries and/or uterus).
• Men must agree to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures during treatment and up to 105 days after the last dose, and agree to refrain from donating sperm.

You may not qualify if:

• FOR HEALTHY VOLUNTEERS ONLY - PART 1:
• History of drug or alcohol abuse or dependence in previous 6 months.
• Positive urine drug and alcohol screen or positive cotinine test at screening or Day -1.
• Positive result on hepatitis B (HBV), hepatitis C (HCV), or human immunodeficiency virus (HIV) 1 and 2.
• Confirmed blood pressure or resting pulse rate outside of accepted ranges.
• Participation in an investigational drug or device study within 90 days prior to screening.
• Donation of blood over 500 mL within three months prior to screening.
• Any major illness within the one month, or any febrile illness within two weeks preceding the screening visit.
• Alcohol consumption of more than 2 standard drinks per day on average.
• FOR CHB PARTICIPANTS ONLY - PARTS 2a and 2b:
• History or other evidence of bleeding from esophageal varices.
• Decompensated liver disease.
• History of or suspicion of hepatocellular carcinoma or alpha fetoprotein (AFP) ≥ 13 ng/mL at Screening
• History or other evidence of a medical condition associated with chronic liver disease other than HBV infection.
• Documented history or other evidence of metabolic liver disease within one year of randomization or documented history of infection with hepatitis D virus.

Sponsors & Collaborators

• Hoffmann-La Roche: lead

Study Sites (19)

Royal Melbourne Hospital

Parkville, Victoria, 3050, Australia

Location

Linear Clinical Research Limited

Nedlands, Western Australia, 6009, Australia

Location

Queen Mary Hospital

Hong Kong, Hong Kong

Location

Prince of Wales Hospital

Shatin, New Territories, Hong Kong

Location

Auckland Clinical Studies

Auckland, 1142, New Zealand

Location

Middlemore Hospital

Auckland, 1640, New Zealand

Location

National University Hospital; Dept of Gastroenterology & Hepatology

Singapore, 119228, Singapore

Location

Singapore General Hospital; Gastroenterology & Hepatology

Singapore, 169608, Singapore

Location

Chuncheon Sacred Heart Hospital

Gangwon-Do, 200-704, South Korea

Location

Gangnam Severance Hospital

Seoul, 06273, South Korea

Location

ChungAng University Hospital

Seoul, 06973, South Korea

Location

University of Ulsan College of Medicine, Asan Medical Center, Digestive Disease Center

Seoul, 138736, South Korea

Location

SMG-SNU Boramae Medical Center

Seoul, 156-707, South Korea

Location

Kaohsiung Medical University Chung-Ho Memorial Hospital

Kaohsiung City, 807, Taiwan

Location

Chang Gung Medical Foundation - Kaohsiung Branch

Kaohsiung City, Taiwan

Location

Taipei Veterans General Hospital

Taipei, 112, Taiwan

Location

Chang Gung Medical Foundation Linkou Branch

Taoyuan, 333, Taiwan

Location

Siriraj Hospital; Dept. of Medicine

Bangkok, 10700, Thailand

Location

Maharaj Nakorn Chiang Mai Hospital

Chiang Mai, 50200, Thailand

Location

Related Publications (1)

• Gane E, Yuen MF, Kim DJ, Chan HL, Surujbally B, Pavlovic V, Das S, Triyatni M, Kazma R, Grippo JF, Buatois S, Lemenuel-Diot A, Krippendorff BF, Mueller H, Zhang Y, Kim HJ, Leerapun A, Lim TH, Lim YS, Tanwandee T, Kim W, Cheng W, Hu TH, Wat C. Clinical Study of Single-Stranded Oligonucleotide RO7062931 in Healthy Volunteers and Patients With Chronic Hepatitis B. Hepatology. 2021 Oct;74(4):1795-1808. doi: 10.1002/hep.31920. Epub 2021 Aug 25.

  PMID: 34037271 DERIVED

MeSH Terms

Conditions

Hepatitis B, Chronic

Interventions

RO7062931; March8 protein, mouse

Condition Hierarchy (Ancestors)

Hepatitis B; Blood-Borne Infections; Communicable Diseases; Infections; Hepadnaviridae Infections; DNA Virus Infections; Virus Diseases; Hepatitis, Viral, Human; Hepatitis, Chronic; Hepatitis; Liver Diseases; Digestive System Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Results Point of Contact

• Title: Medical Communications
• Organization: Hoffmann-La Roche

genentech@druginfo.com

800-821-8590

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 30, 2017
• First Posted: January 31, 2017
• Study Start: February 6, 2017
• Primary Completion: October 18, 2019
• Study Completion: October 18, 2019
• Last Updated: December 24, 2020
• Results First Posted: December 24, 2020

Record last verified: 2020-11

Data Sharing

• IPD Sharing: Will not share

Locations

SG (2); HK (2); AU (2); KR (5); TH (2); NZ (2); TW (4)