A Phase 3, Matrix Design, Partially Double-Blind, Randomized Study of the Efficacy and Safety of 50 mg Lonafarnib/100 mg Ritonavir BID With and Without 180 mcg PEG IFN-alfa-2a for 48 Weeks Compared With PEG IFN-alfa-2a Monotherapy and Placebo Treatment in Patients Chronically Infected With Hepatitis Delta Virus Being Maintained on Anti-HBV Nucleos(t)Ide Therapy (D-LIVR)
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 发起方
- 入组人数
- 407
- 试验地点
- 116
- 主要终点
- To compare the composite virologic and biochemical response rate at EOT in patients who receive LNF 50 mg/RTV 100 mg BID with PEG IFN-alfa-2a 180 mcg QW vs patients who receive placebo.
研究概览
简要总结
Two LNF-containing regimens will be evaluated in the D-LIVR Phase 3 study: (1) LNF/RTV/PEG IFN-alfa-2a and (2) LNF/RTV. Each of these arms will have efficacy endpoints that measure clinical benefit with regard to viral suppression and alanine aminotransferase (ALT) normalization. For each LNF-containing regimen, a composite endpoint of EOT (48 weeks) virologic response and ALT normalization will be used. Virologic response will be defined as a 2 log10 IU/mL reduction from baseline.
详细描述
This partially double-blind, randomized study will employ a matrix (factorial) design to evaluate the efficacy and safety of LNF 50 mg/RTV 100 mg twice per day (BID) with and without PEG IFN-alfa-2a 180 mcg once-weekly (QW) for 48 weeks compared to no treatment (placebo LNF and placebo RTV) in patients chronically infected with hepatitis delta virus (HDV) and receiving anti-HBV (hepatitis B virus) nucleos(t)ide maintenance therapy.
Approximately 400 patients will be randomized with an allocation ratio of 7:5:2:2 All patients will receive/maintain background anti-HBV nucleos(t)ide therapy with entecavir or tenofovir for at least 12 weeks prior to initiating study therapy.
All patients who complete 48 weeks of treatment will have a liver biopsy for histology assessment at EOT and will be followed for an additional 24 weeks off study 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
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Chronic HDV infection for at least 6 months in duration, documented by a positive HDV antibody test and HDV RNA ≥ 500 IU/mL.
- •Note: All genotypes of HDV permitted.
- •Demonstrable suppression of HBV DNA following at least 12 weeks of anti-HBV nucleos(t)ide treatment with entecavir or tenofovir prior to initiating therapy.
- •Serum ALT > 1.3 x upper limit of the normal range (ULN) and < 10 x ULN.
- •Baseline liver biopsy demonstrating evidence of chronic hepatitis.
- •ECGs demonstrating no acute ischemia or clinically significant abnormality.
- •Normal dilated retinal examination.
排除标准
- •General Exclusions
- •Previous use of LNF within 12 months.
- •Current or previous history of decompensated liver disease.
- •Co-infected with human immunodeficiency virus or hepatitis C virus (HCV) by detectable HIV RNA and HCV RNA, respectively.
- •Evidence of significant portal hypertension.
- •Current evidence or history of ascites requiring diuretics or paracentesis, or hepatic encephalopathy.
- •History of hepatocellular carcinoma.
- •Patients with any of the following:
- •Current eating disorder
- •Evidence of alcohol substance use disorder.
- •Drug abuse within the previous 6 months before screening.
- •Prior history or current evidence of any of the following:
- •Immunologically mediated disease,
- •Retinal disorder or clinically relevant ophthalmic disorder,
- •Any malignancy within 5 years before screening,
- •Cardiomyopathy or significant ischemic cardiac or cerebrovascular disease,
- •Chronic pulmonary disease,
- •Pancreatitis or colitis,
- •Severe or uncontrolled psychiatric disorder.
- •Other significant medical condition that may require intervention during the study.
- •Any condition that may impact proper absorption.
- •Therapy with an immunomodulatory agent, IFN-α (eg, IFN alfa-2a or IFN-alfa-2b, or pegylated IFN-alfa-2a or alfa 2b), cytotoxic agent, or chronic systemic corticosteroids within 12 months of screening.
- •Use of heparin or warfarin.
- •Systemic antibiotics, antifungals, or antivirals for treatment of active infection other than HBV.
- •Receipt of systemic immunosuppressive therapy.
- •History or evidence for any intolerance or hypersensitivity to LNF, RTV, PEG IFN-alfa-2a, tenofovir or entecavir.
研究组 & 干预措施
Group 4
placebo Lonafarnib + placebo Ritonavir
干预措施: Placebo Ritonavir (Drug)
Group 1
Lonafarnib 50 mg BID + Ritonavir 100 mg BID
干预措施: Ritonavir (Drug)
Group 1
Lonafarnib 50 mg BID + Ritonavir 100 mg BID
干预措施: Lonafarnib (Drug)
Group 2
Lonafarnib 50 mg BID + Ritonavir 100 mg BID + PEG IFN alfa-2a 180 mcg QW
干预措施: Lonafarnib (Drug)
Group 2
Lonafarnib 50 mg BID + Ritonavir 100 mg BID + PEG IFN alfa-2a 180 mcg QW
干预措施: Ritonavir (Drug)
Group 2
Lonafarnib 50 mg BID + Ritonavir 100 mg BID + PEG IFN alfa-2a 180 mcg QW
干预措施: PEG IFN-alfa-2a (Drug)
Group 3
placebo Lonafarnib + placebo Ritonavir + PEG IFN-alfa-2a 180 mcg QW
干预措施: PEG IFN-alfa-2a (Drug)
Group 3
placebo Lonafarnib + placebo Ritonavir + PEG IFN-alfa-2a 180 mcg QW
干预措施: Placebo Lonafarnib (Drug)
Group 3
placebo Lonafarnib + placebo Ritonavir + PEG IFN-alfa-2a 180 mcg QW
干预措施: Placebo Ritonavir (Drug)
Group 4
placebo Lonafarnib + placebo Ritonavir
干预措施: Placebo Lonafarnib (Drug)
结局指标
主要结局
To compare the composite virologic and biochemical response rate at EOT in patients who receive LNF 50 mg/RTV 100 mg BID with PEG IFN-alfa-2a 180 mcg QW vs patients who receive placebo.
时间窗: 48 weeks
To compare the composite virologic and biochemical response rate at end-of-treatment (EOT) in patients who receive LNF 50 mg/RTV 100 mg BID vs patients who receive placebo.
时间窗: 48 weeks
次要结局
- To compare the histologic response rate at EOT in patients who receive LNF 50 mg/RTV 100 mg BID vs patients who receive placebo.(48 weeks)
- To compare the histologic response rate at EOT in patients who receive LNF 50 mg/RTV 100 mg BID with PEG IFN-alfa-2a 180 mcg QW vs patients who receive placebo.(48 weeks)
- To evaluate the health-related quality of life (HRQL) over a 48-week treatment period in patients who receive LNF 50 mg/RTV 100 mg BID vs placebo.(48 weeks)
- To evaluate the HRQL over a 48-week treatment period in patients who receive LNF 50 mg/RTV 100 mg BID/PEG IFN-alfa-2a 180 mcg QW vs placebo.(48 weeks)
- To evaluate the Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] over a 48-week treatment period in patients who receive LNF 50 mg/RTV 100 mg BID/PEG IFN-alfa-2a 180 mcg QW vs placebo.(48 weeks)
- To evaluate the Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] over a 48-week treatment period in patients who receive LNF 50 mg/RTV 100 mg BID vs placebo.(48 weeks)