Clinical trial NCT03038113: A Study to Evaluate the Safety, Tolerability and Pharmacokinetics and Pharmacodynamics of RO7062931in Healthy Volunteers and Subjects With Chronic Hepatitis B
Official title: A Randomized, Sponsor-Open, Placebo-Controlled Study to Evaluate Safety, Tolerability and Pharmacokinetics and Pharmacodynamics of Subcutaneous Administration of RO7062931 With Single Ascending Doses in Healthy Volunteers and Multiple Doses and Modified Regimens in Virologically Suppressed Patients With Chronic Hepatitis B Virus Infection
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Chronic Hepatitis B
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2017-01-31
Enrollment: 119
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

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.


Eligibility criteria: Inclusion Criteria:

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.

FOR CHB PARTICIPANTS ONLY - PART 2c

* BMI between 18 to 32 kg/m2 inclusive
* CHB infection (HBsAg-positive for at least 6 months)
* For NUC-suppressed CHB participants: Must have been treated with a single NUC for at least 12 months, and have been on the same NUC therapy for at least 3 months prior to screening; HBV DNA \<lower limit of quantification (LLOQ) at screening and in the 6 months prior to screening (at least one measurement must be \>30 days prior to screening); alanine aminotransferase (ALT) \</=2x upper limit of normal (ULN) for \>6 months prior to screening and confirmed at screening; total bilirubin within normal range at screening, except for patients with Gilbert's syndrome
* For treatment-naive and immune-active participants: HBV DNA at screening \>/=2x10\^4 IU/mL for HBeAg positive participants, or \>/=2x10\^3 IU/mL for HBeAg negative participants; elevated serum ALT\>2 ULN to \</=5, 2 values within 6 months, at least one of which is at screening and that are at least 14 days apart; total bilirubin within normal range except for participants with Gilbert's syndrome
* Screening laboratory values (hematology, chemistry, urinalysis) obtained up to 28 days prior to first study treatment within normal ranges
* Liver biopsy, fibroscan, or equivalent test obtained within the last 6 months demonstrating liver disease consistent with chronic HBV infection without evidence of bridging fibrosis or cirrhosis
* Women should be of non-childbearing potential
* Men must agree to remain abstinent or use contraception, and agree to refrain from donating sperm

Exclusion Criteria:

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.
* Positive test for hepatitis A (IgM anti-HAV), hepatitis C, or HIV.
* Organ transplantation.
* Significant acute infection or any other clinically significant illness within 2 weeks of randomization.
* Abnormal renal function.
* Participation in an investigational drug or device study within 30 days prior to randomization.
* Donation or loss of blood over 500 mL within 3 months prior to starting study medication.
* Administration of any blood product within 3 months of randomization.
* History or evidence of alcohol abuse (consumption of more than 2 standard drinks per day on average).

FOR CHB PARTICIPANTS ONLY - PART 2c

* History or other evidence of bleeding from esophageal varices
* Evidence of liver cirrhosis or decompensated liver disease
* One or more of the following laboratory abnormalities at screening: Total serum bilirubin \> ULN (except for participants with Gilbert's disease); international normalized ratio (INR) \> 1.1 ULN; serum albumin \< 3.5 g/dL; AFP \>13 ng/mL; positive results for anti-mitochondrial antibodies (AMA \> 1:80), anti-nuclear antibody (ANA \> 1:80), anti-smooth muscle antibody (ASMA \> 1:40), anti-thyroperoxidase antibodies (a-TPO), anti-thyroglobulin, or anti-platelet antibodies; thyroid stimulating hormone (TSH) outside of normal range; platelet count \<100,000 cells/mm\^3; hemoglobin \<12 g/dL (females) or \<13 g/dL (males); white blood cell count \<2500 cells/mm\^3; and neutrophil count \<1500 cells/mm\^3
* History or other evidence of a medical condition associated with chronic liver disease other than HBV infection
* History of thyroid disease poorly controlled on prescribed medications or clinically relevant abnormal thyroid function tests
* Documented history or other evidence of metabolic liver disease within one year of randomization
* Positive test for hepatitis A, hepatitis C, or HIV
* History of organ transplantation
* Participation in an investigational drug or device study within 30 days prior to screening or previous treatment with an investigational agent for HBV within 6 months prior to screening
* Significant acute infection or any other clinically significant illness within 2 weeks of randomization
* Abnormal renal function, including serum creatinine \> ULN or calculated creatinine clearance \< 70 mL/min
* Donation or loss of blood over 500 mL within 3 months prior to randomization
* Administration of any blood product within 3 months prior to randomization
* History of alcohol abuse and/or drug abuse

Primary outcomes:
measure: Percentage of Participants With Adverse Events (AEs) and AEs of Special Interest
timeFrame: Up to day 113
measure: Percentage of Participants With Laboratory Abnormalities Based on Hematology, Blood Chemistry, Coagulation, and Urinalysis Test Results - Part 1
timeFrame: Screening, Days -1, 2, 8, 15, 29, 85
measure: Percentage of Participants With Laboratory Abnormalities Based on Hematology, Blood Chemistry, Coagulation, and Urinalysis Test Results - Part 2
timeFrame: Screening, Days -1, 2, 8, 15, 29, at discontinuation, Days 36, 43, 57, 85, 113
measure: Percentage of Participants With Electrocardiogram (ECG) Abnormalities Based on ECG Interpretation - Part 1
timeFrame: Day 1 (1,4,8,12h), Days 2 and 8, Follow Up Days 15, 29, 85
measure: Percentage of Participants With Electrocardiogram (ECG) Abnormalities Based on ECG Interpretation - Part 2
timeFrame: 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
measure: Percentage of Participants With T-Wave Abnormalities Based on T-Wave Assessment - Part 1
timeFrame: Day 1 (1,4,8,12h), Days 2 and 8, Follow Up Days 15, 29, 85
measure: Percentage of Participants With U-Wave Abnormalities Based on U-Wave Assessment - Part 1
timeFrame: Day 1 (1,4,8,12h), Days 2 and 8, Follow Up Days 15, 29, 85
measure: Percentage of Participants With T-Wave Abnormalities Based on T-Wave Assessment - Part 2
timeFrame: 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
measure: Percentage of Participants With U-Wave Based on U-Wave Assessment - Part 2
timeFrame: 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
measure: Percentage of Participants With QTcF Values Between 450 Msec - 480 Msec - Part 2
timeFrame: 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:
measure: Maximum Plasma Concentration (Cmax) After Single Ascending Doses - Part 1
timeFrame: Days 1-8
measure: Cmax After Multiple Ascending Doses - Part 2
timeFrame: Days 1-113
measure: Time to Reach Maximum Plasma Concentration (Tmax) After Single-Ascending Doses - Part 1
timeFrame: Days 1-8
measure: Tmax After Multiple Ascending Doses - Part 2
timeFrame: Days 1-113
measure: Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUC0-inf) After Single-Ascending Doses - Part 1
timeFrame: Days 1-8
measure: AUC0-inf After Multiple Ascending Doses - Part 2
timeFrame: Days 1,22,29
measure: Area Under the Plasma Concentration-Time Curve From Time Zero Until the Last Quantifiable Time-Point (AUC0-last) After Single Ascending Doses - Part 1
timeFrame: Days 1-8
measure: AUC0-last After Multiple Ascending Doses - Part 2
timeFrame: Days 1,22,29
measure: Terminal Elimination Half-Life (t1/2) After Single Ascending Doses - Part 1
timeFrame: Days 1-8
measure: Terminal Elimination Half-Life (t1/2) After Multiple Ascending Doses - Part 2
timeFrame: Days 1-113
measure: Total Clearance (CL) After Single Ascending Doses - Part 1
timeFrame: Days 1-8
measure: Total Clearance (CL) After Multiple Ascending Doses - Part 2
timeFrame: Days 1-113
measure: Volume of Distribution (Vss) After Single Ascending Doses - Part 1
timeFrame: Days 1-8
measure: Volume of Distribution (Vss) After Multiple Ascending Doses - Part 2
timeFrame: Days 1-113
measure: Cumulative Amount Excreted Unchanged in Urine (Ae) After Single Ascending Doses - Part 1
timeFrame: Hours 0-4, 0-8, 0-12, and 0-24
measure: Cumulative Amount Excreted Unchanged in Urine (Ae) After Multiple Ascending Doses - Part 2
timeFrame: Days 1-113
measure: Change From Baseline of Quantitative HBsAg (qHBsAg) (log10) After Multiple Ascending Doses - Part 2
timeFrame: Days 1-113
measure: Summary of Maximum qHBsAg Decrease on Days 1-113 - Part 2
timeFrame: Day 1 - Day 113
measure: Summary of Time to Maximum qHBsAg Decrease on Day 1-113 - Part 2
timeFrame: Day 1 - Day 113
Other outcomes:
Locations:
city: Parkville
country: Australia
facility: Royal Melbourne Hospital
state: Victoria
city: Nedlands
country: Australia
facility: Linear Clinical Research Limited
state: Western Australia
city: Hong Kong
country: Hong Kong
facility: Queen Mary Hospital
city: Shatin, New Territories
country: Hong Kong
facility: Prince of Wales Hospital
city: Gangwon-Do
country: Korea, Republic of
facility: Chuncheon Sacred Heart Hospital
city: Seoul
country: Korea, Republic of
facility: Gangnam Severance Hospital
city: Seoul
country: Korea, Republic of
facility: ChungAng University Hospital
city: Seoul
country: Korea, Republic of
facility: University of Ulsan College of Medicine, Asan Medical Center, Digestive Disease Center
city: Seoul
country: Korea, Republic of
facility: SMG-SNU Boramae Medical Center
city: Auckland
country: New Zealand
facility: Auckland Clinical Studies
city: Auckland
country: New Zealand
facility: Middlemore Hospital
city: Singapore
country: Singapore
facility: National University Hospital; Dept of Gastroenterology & Hepatology
city: Singapore
country: Singapore
facility: Singapore General Hospital; Gastroenterology & Hepatology
city: Kaohsiung City
country: Taiwan
facility: Kaohsiung Medical University Chung-Ho Memorial Hospital
city: Kaohsiung
country: Taiwan
facility: Chang Gung Medical Foundation - Kaohsiung Branch
city: Taipei City
country: Taiwan
facility: Taipei Veterans General Hospital
city: Taoyuan City
country: Taiwan
facility: Chang Gung Medical Foundation Linkou Branch
city: Bangkok
country: Thailand
facility: Siriraj Hospital; Dept. of Medicine
city: Chiang Mai
country: Thailand
facility: Maharaj Nakorn Chiang Mai Hospital
Study officials:
References:
citation: 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.