A Phase 1, Randomized, Double-Blinded, Placebo-Controlled Study to Evaluate Safety, Tolerability, Pharmacokinetics, And Preliminary Efficacy of Single and Multiple Ascending Doses of IB-001 in Healthy Participants and Participants With Chronic Hepatitis B
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- 入组人数
- 80
- 试验地点
- 3
- 主要终点
- Part A and Part B: Incidence and Severity of Treatment-Emergent Adverse Events (TEAEs).
研究概览
简要总结
This study will examine the safety and tolerability of single and multiple doses of IB-001, and will be conducted in two parts:
Part A: SAD study in approximately 50 Healthy Volunteers (HV). Part B: MAD study in approximately 30 adult participants living with Chronic Hepatitis B (CHB).
详细描述
This is a first-in-human, double-blind, randomized, placebo-controlled Phase 1 study of IB-001 administered subcutaneously to evaluate safety, tolerability, PK/PD, and preliminary antiviral activity.
The study is comprised of two parts:
Part A: Single-dose, multicohort, dose-finding study in approximately 50 adult Healthy Volunteers (HV) in up to five cohorts (n=10 per cohort; 8 active:2 placebo). Participants will receive a single sub-cutaneous dose of investigational product followed by a 28-day post treatment follow-up.
Part B: Multidose, multicohort study in Treatment-Naïve or Currently-Not-Treated Adults with Chronic Hepatitis B (CHB).
Approximately 30 adult participants (up to 3 cohorts; n=10 per cohort; 8 active:2 placebo). Once-weekly sub-cutaneous dosing over 4 weeks with 6-week post-treatment follow-up. Dose recommendations in both Part A and Part B will be made by the Safety Review Committee (SRC) based on review of emerging safety data.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Care Provider, Investigator)
盲法说明
Sponsor
入排标准
- 年龄范围
- 18 Years 至 70 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •PART A: Healthy Volunteers
- •Inclusion Criteria:
- •Able and willing to provide written informed consent.
- •Male or female aged 18 to 70 years.
- •Females must not be of childbearing potential OR those who are of childbearing potential must be non-pregnant and non-lactating and willing to use a highly effective method of contraception. Males whose partners are of childbearing potential must either be surgically sterile or willing to use a highly effective acceptable method of contraception.
- •Non-tattooed, clear injection site suitable for SC injection and monitoring in the opinion of the Investigator.
排除标准
- •Healthy Volunteer participants must not meet any of the following criteria at Screening or upon admission to the site (on Day -1).
- •Major surgery requiring general anesthesia within 12 weeks prior to Screening or is expected to have surgery requiring general anesthesia during the course of the study.
- •History of severe allergic or anaphylactic reactions, or sensitivity to the IP or its constituents.
- •Blood donation or blood loss of ≥ 1 unit (450 mL) of whole blood within 4 weeks before Screening or plasma donations within 7 days prior to dosing of investigational product (IP).
- •Any underlying medical condition (including but not limited to gastrointestinal, renal, hepatic, neurological, hematological, endocrinological, tumor, pulmonary, immune, mental, or cardiovascular and cerebrovascular diseases).
- •History of malignancy, except for non-melanoma skin cancer, excised more than 1 year prior to Screening or cervical intraepithelial neoplasia that has been successfully cured more than 5 years prior to Screening.
- •Current hepatitis A virus (HAV) infection, hepatitis B virus (HBV) infection, hepatitis C virus (HCV) infection.
- •Positive test for HIV-1 or HIV-2 antibodies.
- •Any other active infection requiring systemic antiviral or antimicrobial therapy that will not be completed within 2 weeks of first dosing.
- •Clinically significant abnormalities on Screening ECG or history of cardiac arrhythmias, risk factors for Torsade de Pointes (hypokalemia, hypomagnesemia, decompensated heart failure and acute myocardial infarction), and a QTcF > 450 ms (males) or QTcF > 470 ms (females) at Screening.
- •Physical examination findings at Screening that are considered clinically significant by the Investigator and likely to adversely impact study conduct and/or interpretation.
- •Clinically significant abnormal vital signs
- •Laboratory abnormalities considered clinically significant by the Investigator at Screening. From Cohort A3 onwards, participants with blood platelet counts < 150 × 109/L or absolute neutrophil counts < 1.5 × 109/L will be excluded.
- •Use of any prescribed or over-the-counter medications (including vitamins or herbal remedies) within 2 weeks of first dosing or within 5 times the elimination half-life of the medication prior to first dosing.
- •Any suspicion or history of drug and/or alcohol abuse within the last year.
- •Pregnant or planning to become pregnant during the course of the study, or currently breastfeeding.
- •Use of more than 5 cigarettes, or equivalent, a day in the 3 months prior to Screening. Is unwilling to abstain from nicotine-containing products for 48 hours prior to admission to the site and during the in-house stay at the clinical research unit.
- •Receipt of any investigational drug or product within 90 days of Study Day 1 or within 5 times the elimination half-life of the medication prior to first dosing with the IP, whichever is earlier. Receipt of an invasive medical device within 90 days before first dosing with the IP that in the opinion of the PI or designee may impact the ability of the participant to complete all protocol-required procedures. Participants must not have participated in interventional clinical studies more than 4 times per year.
- •Use of any prescribed or over-the-counter medications (including vitamins, supplements, or herbal remedies) within 2 weeks of first dosing with the IP or within 5 times the elimination half-life of the medication prior to first dosing with the IP (whichever is longer). Note: Simple analgesia (paracetamol < 2 g/day, nonsteroidal anti-inflammatory drug [NSAID] at therapeutic doses) may be permitted at the discretion of the PI, and may only be used as premedication prior to dosing of IP if recommended by the SRC.
- •Has received live vaccine(s) within 28 days of Screening or plans to receive live vaccines within 28 days of dosing with the IP on Study Day
- •Note: COVID-19 vaccines are not considered live vaccines.
- •Any suspicion or history of drug and/or alcohol abuse within the last year.
- •Positive toxicology Screening panel (urine test including qualitative identification of tetrahydrocannabinol, cocaine, amphetamines, benzodiazepines, opiates, methadone, methamphetamines, ecstasy, and phencyclidine).
- •Positive alcohol breath test at Screening and/or on Study Day -
- •History (within 90 days of Screening) of alcohol consumption exceeding 2 standard drinks per day on average (1 standard drink = 10 grams of alcohol). Alcohol consumption will be prohibited at least 48 hours before dosing with the IP on Study Day 1, and during the in-house stay at the clinical research unit.
- •Uses more than 5 cigarettes, or equivalent, per day in the 3 months prior to Screening, and/or is unwilling to abstain from nicotine-containing products for 48 hours prior to admission to the site and during the in-house stay at the clinical research unit.
- •Pregnant (positive serum pregnancy test at Screening or a positive urine pregnancy test predose on Study Day -1), planning to become pregnant during the course of the study, or currently breastfeeding.
- •Any other factor that makes it inappropriate for study participation per the Investigator's judgment.
- •PART B: Participants with Chronic Hepatitis B (CHB)
- •Inclusion Criteria:
- •Able and willing to provide written informed consent.
- •Male or female aged 18 to 70 years,
- •BMI between 18 and 35 kg/m
- •Females must not be of childbearing potential OR those who are of childbearing potential must be non-pregnant and non-lactating and willing to use a highly effective method of contraception. Males whose partners are of childbearing potential must either be surgically sterile or willing to use a highly effective acceptable method of contraception.
- •Diagnosed with CHB and are HBeAg-negative (on 2 occasions at least 6 months apart) and have HBsAg titers of ≥ 100 IU/mL at Screening.
- •Participants must be treatment naive (i.e., have never received treatment with HBV antiviral medicines [NUCs, IFN] or an investigational anti-HBV agent) or currently not treated (i.e., not been on treatment with approved [NUCs, IFN] or investigational anti-HBV medicines within 12 months prior to randomization).
- •Vital signs and physical examination are normal, or abnormal values are not clinically significant in the opinion of the Investigator.
- •Exclusion Criteria:
- •Evidence or history of liver disease of non-HBV etiology, including but not limited to HAV, HCV, HDV, or HEV (endemic regions only) infections; drug- or alcohol-related liver disease; autoimmune hepatitis; hemochromatosis; Wilson's disease; α-1 antitrypsin deficiency; primary biliary cirrhosis; primary sclerosing cholangitis; non-alcoholic steatohepatitis; or any other non-HBV liver disease considered clinically significant by the Investigator. Participants with metabolic dysfunction-associated steatotic liver disease without any signs of steatohepatitis or those with documented Gilbert's Syndrome, are eligible.
- •Diagnosed or suspected hepatocellular carcinoma (HCC).
- •Significant liver fibrosis or cirrhosis (FibroScan result > 8.5 kPa within 12 months of Screening; Prior liver biopsy with Metavir F3 fibrosis or F4 cirrhosis within 2 years of Screening; AST-to-Platelet Index (APRI) > 1 and FibroTest result > 0.5 within 12 months of Screening).
- •Positive for HIV-1 or HIV-2 at Screening.
- •Active infection requiring systemic antiviral or antimicrobial therapy that will not be completed within 2 weeks of first dosing of investigational product (IP).
- •Any of the following clinical laboratory values at Screening: ALT or AST ≥ 3 × ULN; blood platelet counts < 120 × 109/L; absolute neutrophil count < 1.3 × 109/L; hemoglobin < 10.0 g/dL; serum total bilirubin ≥ 1 × ULN (Note: for participants with documented Gilbert's Syndrome, total bilirubin ≥ 2 × ULN is acceptable); serum albumin < 35 g/L; eGFR of < 60 mL/min/1.73 m2; INR > 1.2 × ULN.
- •History of severe allergic or anaphylactic reactions, or sensitivity to the IP or constituents.
- •Blood donation or blood loss of ≥ 1 unit (450 mL) of whole blood within 4 weeks before Screening or plasma donations within 7 days prior to first dosing with the IP.
- •History or presence of immune-mediated disease (e.g., systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, autoimmune hepatitis, sarcoidosis, psoriasis of greater than mild severity, autoimmune uveitis), or cerebrovascular, chronic pulmonary or cardiac disease associated with functional limitation, retinopathy, uncontrolled thyroid disease (thyroid stimulating hormone [TSH] > 10 or < 0.4 mU/L), or uncontrolled seizure disorder, as determined by the Investigator. Participants who are positive for anti-thyroglobulin antibodies or anti-thyroid peroxidase antibodies will be excluded.
- •History or presence of significant (as judged by the Investigator) cardiovascular, respiratory, renal, gastrointestinal, endocrine, hematological disorders, or diagnosed central or peripheral neurological disease, capable of significantly altering the absorption, metabolism, or elimination of drugs, of constituting a safety-related risk when taking the study treatment, requiring premedication, or of interfering with the interpretation of the data.
- •Clinically significant 12-lead ECG abnormalities on Screening ECG or history of cardiac arrhythmias, risk factors for Torsade de Pointes (hypokalemia, hypomagnesemia, decompensated heart failure and acute myocardial infarction), and cardiac arrhythmias, risk factors for Torsade de Pointes (hypokalemia, hypomagnesemia, decompensated heart failure and acute myocardial infarction), and QTcF > 450 ms for males or QTcF > 470 ms for females at Screening.
- •Physical examination findings that are considered clinically significant by the Investigator and likely to adversely impact study conduct and/or interpretation.
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研究组 & 干预措施
Arm 2: Placebo
Participants receiving placebo, follow the same dosing schedule as the active arm (single dose in Part A; once-weekly for 4 weeks in Part B).
干预措施: Placebo (Other)
Arm 1: IB-001
Participants receive IB-001, administered subcutaneously according to the assigned cohort schedule. In Part A, participants receive a single dose. In Part B, participants receive once-weekly dosing for 4 weeks.
干预措施: IB-001 (Drug)
结局指标
主要结局
Part A and Part B: Incidence and Severity of Treatment-Emergent Adverse Events (TEAEs).
时间窗: Through Day 29 (Part A), through Day 64 (Part B).
Treatment-Emergent Adverse Events (TEAEs) are adverse events that first appear or worsen in severity during the course of the clinical study, regardless of whether they are related to the investigational product (IP) or not. TEAEs will be coded using MedDRA and summarized by SOC, PT, severity, and relationship to IP. Treatment-related AEs (possibly/probably/definitely related) will also be summarized separately. A by-participant AE listing will be provided
Part A and Part B: Number of Participants with Adverse Events (AEs) by Severity
时间窗: Through Day 29 (Part A), through Day 64 (Part B)
An AE is any unfavorable medical occurrence in a study participant administered an investigational product. The AE does not necessarily have a causal relationship with the treatment. All AEs will be graded for severity according to NCI-CTCAE classification. If an appropriate AE term is not found in NCI-CTCAE, the AE will be graded as follows: Grade 1 (mild); Grade 2 (Moderate); Grade 3 (Severe); Grade 4 (Severe) and Grade 5 (Death).
Part A and Part B: Number of Participants with Adverse Events (AEs) of Special Interest (AESIs)
时间窗: Through Day 29 (Part A), through Day 64 (Part B)
AEs of special interest include Cytokine Release Syndrome (CRS), Injection Site Reactions (ISRs) and Unexplained Liver Biochemistry Elevations. Reported AESIs will be graded according to NCI-CTCAE classification. If an appropriate AE term is not found in NCI-CTCAE, the AESI will be graded as follows: Grade 1 (mild); Grade 2 (Moderate); Grade 3 (Severe); Grade 4 (Severe) and Grade 5 (Death).
Part A and Part B: Number of Participants with Clinically Significant Changes in Laboratory Parameters
时间窗: Through Day 15 (Part A), through Day 64 (Part B)
Assessment Method - Number of participants with clinical laboratory abnormalities (serum chemistry, hematology, and coagulation) will be reported.
Part A and Part B: Number of Participants with Clinically Significant Changes in Vital Signs.
时间窗: Through Day 15 (Part A), through Day 64 (Part B)
Number of participants with vital signs abnormalities will be reported. Vital signs include body temperature, pulse rate, respiratory rate, and blood pressure.
Part A and Part B: Number of Patients with Clinically Significant Changes in Cardiac Parameters.
时间窗: Through Day 15 (Part A), through Day 64 (Part B)
Number of participants with electrocardiogram (ECG) abnormalities will be reported.
次要结局
- Part A and Part B: Number of Patients with Clinically Significant Anti-Drug Antibodies (ADAs).(Through Day 29 (Part A), through Day 64 (Part B))
- Part B: Changes from Baseline in HBsAg levels over time.(Through Day 64 (Part B))
- Part B: Change from Baseline in Anti-HBs Antibody Titers over time.(Through Day 64)
- Part B: Reduction from Baseline in HBV DNA levels over time.(Through Day 64)
- Part A and Part B: PK Parameter - Maximum Observed Serum Concentration (Cmax) of IB-001(Through Day 29 (Part A), through Day 64 (Part B))
- Part A and Part B: PK Parameter - Area under the Serum Concentration Time Curve (AUC) of IB-001.(Through Day 29 (Part A), through Day 64 (Part B))
- Part A and Part B: PK Parameter - Time to Observed Maximum Serum Concentration (Tmax) of IB-001.(Through Day 29 (Part A), through Day 64 (Part B))
- Part A and Part B: PK Parameter - Terminal Half Life (T1/2) of IB-001.(Through Day 29 (Part A), through Day 64 (Part B))