A Phase 2, Open-label, Randomized, Two-part, Multiple Dose Study Evaluating the Safety, Pharmacokinetics, and Antiviral Efficacy of SB 9200 in Subjects Infected With Chronic Hepatitis B Virus
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 80
- 试验地点
- 3
- 主要终点
- Part A: Proportion of subjects reporting an adverse event (AE) and HBV DNA decline
研究概览
简要总结
This is a Phase 2, open-label,randomized, multiple dose, varied administration regimen study with 2 parts (Parts A and B) in Subjects Infected with Chronic Hepatitis B Virus
详细描述
This is a Phase 2, open-label, randomized, multiple dose, varied administration regimen study with 2 parts (Parts A and B).
Part A will utilize an ascending dose cohort design with sequential cohorts. Each cohort will be evaluated by the DSMB for safety. Additional cohorts may be added by the DSMB to determine doses of SB 9200 that exhibit significant antiviral response and safety.
Approximately 80 subjects will be assigned sequentially to 1 of the following dosing cohorts (20 subjects per cohort) and randomized in a 4:1 ratio (active:placebo) within each cohort. Randomization will be stratified so that no more than 2 HBeAg positive subjects will be assigned to receive placebo.
- SB 9200 25 mg or matching placebo administered qd
- SB 9200 50 mg or matching placebo administered qd
- SB 9200 100 mg or matching placebo administered qd
- SB 9200 200 mg or matching placebo administered qd
After informed consent is obtained, subjects will enter a Screening period, which will last up to 28 days. Once all eligibility criteria are confirmed and the subject is randomized, subjects will receive the IP or placebo as a 2-week supply of capsules/tablets. All randomized subjects will receive the IP or matching placebo for a total of 12 weeks. All subjects will then receive tenofovir 300 mg qd for an additional 12 weeks of treatment.
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)
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
- 否
入选标准
- •Documented evidence of chronic HBV infection (eg, HBsAg positive for at least 6 months or HBV DNA positive for at least 6 months). In the absence of documented evidence of HBsAg or HBV DNA, the subject must be HBsAg positive, and anti-HBc (IgM) negative at Screening.
- •Not on any antiviral medications for at least 6 months. If a subject is HBeAg negative, they will be eligible if they have not received antiviral medications for at least 3 months. Antiviral medications include lamivudine, telbivudine, adefovir, tenofovir, entecavir, IFN therapies of any type, and all other medications with potential antiviral activity.
- •HBV DNA > 2000 IU/mL for HBeAg-negative subjects and > 20000 IU/mL for HBeAg-positive subjects at Screening
- •ALT > ULN, but < 5 x the ULN and ≤ 200 U/L
- •Ultrasound, computed tomography (CT) scan, or magnetic resonance imaging (MRI) within 3 months of randomization date with no evidence of hepatocellular carcinoma
- •Must be willing and able to comply with all study requirements
- •Negative urine or serum pregnancy test (for women of childbearing potential [WOCBP]) documented within the 24-hour period prior to the first dose of test drug. If the urine pregnancy test is positive, a follow-up serum test is required for confirmation. Additionally, all fertile males with partners of childbearing age and females must be using reliable contraception during the study and for 3 months after treatment completion. All fertile males must also refrain from sperm donation while on IP and for 3 months after completion of IP.
- •Must have the ability to understand and sign a written ICF; consent must be obtained prior to initiation of study procedures
- •Inclusion Criteria for Extension Period:
- •Subjects who meet all of the following inclusion criteria may be eligible to be enrolled into the Extension Period:
- •Signed informed consent form
- •Subject was randomized in Part A or Part B
排除标准
- •Subjects who meet any of the following exclusion criteria are not to be enrolled in this study:
- •Any prior liver biopsy evidence of metavir F3 or F4 disease
- •Any history of decompensation of liver disease including history of ascites, encephalopathy, or varices
- •Evidence of cirrhosis as defined by Fibroscan at the Screening Visit of ≥ 8 kilopascals (kPa) or both a Fibrotest ≥ 0.65 and AST:platelet ratio index (APRI) ≥ 1.0 (subjects will not be excluded if only 1 of the Fibrotest or APRI result is higher than allowed) or have had evidence of Metavir F3-F4 on liver biopsy at any time.
- •Laboratory parameters not within defined thresholds: white blood cells (WBC) < 4000 cells/µL, (SI unit < 4.0 × 109/L), hemoglobin (HgB) < 12 g/dL (SI unit < 120 g/L) for females, < 13 g/dL (SI unit < 130 g/L) for males, platelets < 130,000 per µL, (SI unit < 130 × 109/L), albumin < 3.5 g/dL,(SI unit < 35 g/L), international normalized ratio (INR) > 1.5, total bilirubin > 1.2 mg/dL, (SI unit > 20.52 µmol/L), or alpha-fetoprotein (AFP) > 50 ng/mL (SI unit > 180.25 nmol/L). Subjects with an elevated indirect bilirubin and known Gilbert's disease can be included if direct bilirubin is within normal limits. Subjects with an AFP > 50 ng/mL but ˂ 500 ng/mL can be included if computed tomography (CT) scan or magnetic resonance imaging (MRI) performed within 3 months shows no evidence of hepatocellular carcinoma
- •Creatinine > 1.2 mg/dL, (SI unit > 106.08 µmol/L), creatinine clearance < 50 mL/min, (SI unit < 0.83 L/s/m2)
- •Co-infection with hepatitis C virus (HCV), human immunodeficiency virus (HIV), or hepatitis D virus
- •Evidence or history of hepatocellular carcinoma
- •Malignancy within 5 years prior to Screening, with the exception of specific cancers that are cured by surgical resection (basal cell skin cancer, etc). Subjects under evaluation for possible malignancy are not eligible.
- •Significant cardiovascular, pulmonary, or neurological disease
- •Received solid organ or bone marrow transplant
- •Received within 3 months of Screening or expected to receive prolonged therapy with immunomodulators (eg, corticosteroids) or biologics (eg, monoclonal antibody, IFN)
- •Subjects currently taking medication(s) that are transported through organic anion transporting polypeptide 1 (OATP1) including, but not limited to, atazanavir, rifampin, cyclosporine, eltrombopag, gemfibrozil, lopinavir/ritonavir, and saquinavir
- •Use of another investigational agent within 3 months of Screening
- •Current alcohol or substance abuse judged by the Investigator to potentially interfere with compliance
- •Females who are pregnant or may wish to become pregnant during the study
- •If the Investigator believes the prospective subject will not be able to comply with the requirements of the protocol and complete the study
- •Any medical condition, in the opinion of the Investigator, that could interfere with evaluation of the study objectives or safety of the subjects
- •Exclusion Criteria for Extension Period Subjects who meet any of the following exclusion criteria are not to be enrolled into the Extension Period:
- •Any condition, comorbidity, or laboratory abnormality that, based on the package insert of tenofovir or in the opinion of the Investigator, excludes the subject
- •Subjects who were withdrawn from Part A or Part B due to an AE or serious adverse event (SAE) related to the use of tenofovir
- •Participation in any other interventional study
- •Subject fully terminated from Part A or Part B
研究组 & 干预措施
Part A Cohort 1: 25mg SB 9200
Part A Cohort 1: 25mg SB 9200. After 12 weeks of SB 9200 this medication will be stopped. From weeks 12 - 24 patients will be given 12 weeks of Tenofovir (current standard of care)
干预措施: SB 9200 (Drug)
Part A Cohort 1: 25mg Placebo
Part A Cohort 1: 25mg Placebo. After 12 weeks of Placebo this medication will be stopped. From weeks 12 - 24 patients will be given 12 weeks of Tenofovir (current standard of care)
干预措施: Placebo (Drug)
Part A Cohort 2: 50mg SB 9200
Part A Cohort 2: 50mg SB 9200. After 12 weeks of SB 9200 this medication will be stopped. From weeks 12 - 24 patients will be given 12 weeks of Tenofovir (current standard of care)
干预措施: SB 9200 (Drug)
Part A Cohort 2: 50mg Placebo
Part A Cohort 2: 50mg Placebo. After 12 weeks of Placebo this medication will be stopped. From weeks 12 - 24 patients will be given 12 weeks of Tenofovir (current standard of care)
干预措施: Placebo (Drug)
Part A Cohort 3: 100mg SB 9200
Part A Cohort 3: 100mg SB 9200. After 12 weeks of SB 9200 this medication will be stopped. From weeks 12 - 24 patients will be given 12 weeks of Tenofovir (current standard of care)
干预措施: SB 9200 (Drug)
Part A Cohort 3: 100mg Placebo
Part A Cohort 3: 100mg Placebo. After 12 weeks of Placebo this medication will be stopped. From weeks 12 - 24 patients will be given 12 weeks of Tenofovir (current standard of care)
干预措施: Placebo (Drug)
Part A Cohort 4: 200mg SB 9200
Part A Cohort 4: 200mg SB 9200. After 12 weeks of SB 9200 this medication will be stopped. From weeks 12 - 24 patients will be given 12 weeks of Tenofovir (current standard of care)
干预措施: SB 9200 (Drug)
Part A Cohort 4: 200mg Placebo
Part A Cohort 4: 200mg Placebo. After 12 weeks of Placebo this medication will be stopped. From weeks 12 - 24 patients will be given 12 weeks of Tenofovir (current standard of care)
干预措施: Placebo (Drug)
Part B: SB 9200 with tenofovir
Part B: SB 9200 selected dose from Part A administered in combination with tenofovir 300 mg qd. After 12 weeks of SB 9200 this medication will be stopped. From weeks 12 - 24 patients will be given 12 weeks of Tenofovir (current standard of care)
干预措施: SB 9200 (Drug)
Part B: Tenofovir 300 mg
Part B: Tenofovir 300 mg qd monotherapy. After 12 weeks of SB 9200 this medication will be stopped. From weeks 12 - 24 patients will be given 12 weeks of Tenofovir (current standard of care)
干预措施: Tenofovir (Drug)
结局指标
主要结局
Part A: Proportion of subjects reporting an adverse event (AE) and HBV DNA decline
时间窗: 12 weeks
The primary endpoint for safety and efficacy in Part A is the proportion of subjects reporting an adverse event (AE) or experiencing a clinically significant AE or laboratory abnormality from baseline (Randomisation) to end of SB 9200 treatment (12 weeks) and change from baseline to Week 12 in Log10 HBV DNA.
Part B: Proportion of subjects reporting an adverse event (AE) and hepatitis B surface antigen decline
时间窗: 12 weeks
The primary endpoints for safety and efficacy in Part B is the proportion of subjects reporting an adverse event (AE) or experiencing a clinically significant AE or laboratory abnormality from baseline (Randomisation) to end of SB 9200 treatment (12 weeks) and the proportion of subjects with hepatitis B surface antigen decline (12 weeks)
次要结局
- Change in HBeAg in log10 IU/mL from Baseline to Weeks 2, 4, 8, 12, 14, and 24 (Part A)(Weeks 2, 4, 8, 12, 14, and 24 weeks)
- Proportion of subjects with HBeAg or HBsAg loss and seroconversion at Weeks 2, 4, 8, 12, 14, and 24 (Part A)(2, 4, 8, 12, 14, and 24 weeks)
- Proportion of subjects with HBeAg or HBsAg loss and seroconversion at Weeks 2, 4, 6, 12, 14, and 24 (Part B)(2, 4, 6, 12, 14, and 24 weeks)
- Maximum observed plasma SB 9200 plasma concentration (Cmax) and determination of pharmacokineticPK parameters for SB 9200 and, Rp -SB 9000, and Sp SB 9000 (Parts A and B)(0 - 24 hours)
- Change in serum HBV DNA, HBsAg, and HBV RNA at 2, 4, 6, 12, 14, and 24 weeks (Part B)(2, 4, 6, 12, 14, and 24 weeks)
- Change in serum HBV DNA, HBsAg, and HBV RNA at 2, 4, 8, 12, 14, and 24 weeks (Part A)(2, 4, 8, 12, 14, and 24 weeks)
- Change in HBeAg in log10 IU/mL from Baseline to Weeks 2, 4, 6, 12, 14, and 24 (Part B)(2, 4, 6, 12, 14, and 24 weeks)
- Proportion of subjects with HBsAg ≥ 1 log10 reduction from Baseline to Week 12 (Part B)(12 weeks)