Randomized Controlled Trail (RCT) of Emtricitabine, Tenofovir Disoproxil and Raltegravir for Patients With Primary Biliary Cholangitis Unresponsive to Ursodeoxycholic Acid (UDCA)
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 37
- 试验地点
- 6
- 主要终点
- Change in alkaline phosphatase levels
研究概览
简要总结
Placebo Controlled, double-blind randomized controlled trial (RCT) with 12 months Tenofovir Disoproxil and Raltegravir for primary biliary cholangitis (PBC) patients unresponsive to Ursodeoxycholic Acid (UDCA). Placebo patients will be offered 12 months open label therapy at unblinding. All patients will be offered an additional 12 months open label therapy. Observational, open label study will be performed in parallel using Emtricitabine (FTC)/Tenofovir Disoproxil (TDF) & Raltegravir in liver transplant recipients meeting all entry criteria except for use of immunosuppression.
详细描述
Primary endpoint:
Change in mean percentage of alkaline phosphatase (ALP) reduction in cART vs. placebo at 6 and 12 months.
Secondary endpoints:
- Serum biochemistries bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT) and gamma-glutamyltransferase (GGT) will be studied as continuous variables.
- Composite endpoint used for the POISE study [A Placebo-Controlled Trial of Obeticholic Acid in Primary Biliary Cholangitis]: (i) reduction of ALP to < 1.67 upper limit of normal, (ii) normalization of bilirubin within upper limit of normal (ULN) and (iii) reduction of ALP by > 15% at 6 and 12 months.
- Symptomatic evaluation performed using the PBC-40 to assess five symptom domains relating to fatigue, itch, cognitive symptoms, social and emotional symptoms, and other symptoms.
- Histological change in grade and stage of PBC using the Nakanuma scoring system for a subgroup of patients undergoing liver biopsy [liver biopsy not compulsory for study].
- Serial human betaretrovirus measurement in peripheral blood and cellular immune response to viral peptides.
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)
盲法说明
Double-blind
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
- •over 18 years old of either sex,
- •Anti-mitochondrial antibody +ve or liver histology compatible with PBC,
- •stable UDCA dose of 13-15 mg/kg for > 12 months or intolerant to UDCA,
- •ALP at least 1.67 x ULN or abnormal bilirubin less than 2x ULN
- •able to read and sign informed consent form.
排除标准
- •subjects with baseline total bilirubin > 2 x ULN,(patients meeting inclusion criteria stabilized on second line therapies including obeticholic acid or bezafibrate over 12 months or more may be enrolled).
- •use of non-standard or experimental therapy within the last 6 months,
- •advanced liver disease: INR > 1.2 ULN, Albumin < 35 g/L lower limit of normal, platelets < 120,000/microL unless varices with risk of bleeding excluded by endoscopy within the last 6 months, Childs Pugh class B or C cirrhosis, presence of grade 2 varices or previous variceal hemorrhage, encephalopathy, ascites or need for liver transplantation within the next two years;
- •secondary diagnosis such as HIV, viral hepatitis, drug induced liver injury, extrahepatic biliary obstruction, primary sclerosing cholangitis, metabolic liver - regular use of > 30g alcohol/day in the last year;
- •a predicted survival of less than 3 years from malignant or other life threatening disease;
- •hepatic mass consistent with hepatocellular carcinoma ;
- •previous allergic reaction to study medications;
- •Glomerular Filtration Rate less than < 30 mL/min as measured Cockcroft-Gault formula;
- •pregnancy, breast-feeding or pre-menopausal patients not using contraception.
研究组 & 干预措施
Emtricitabine (FTC)/Tenofovir Disoproxil (TDF) & Raltegravir
one Emtricitabine 200mg and Tenofovir Disoproxil 300mg tablet two Raltegravir 600mg tablets
干预措施: Emtricitabine (FTC)/Tenofovir Disoproxil (TDF) (Drug)
Emtricitabine (FTC)/Tenofovir Disoproxil (TDF) & Raltegravir
one Emtricitabine 200mg and Tenofovir Disoproxil 300mg tablet two Raltegravir 600mg tablets
干预措施: Raltegravir (Drug)
Placebo
Identical tablets resembling one Emtricitabine 200mg and Tenofovir Disoproxil 300mg tablet two Raltegravir 600mg tablets
干预措施: Placebo Oral Capsule [CEBOCAP] (Drug)
结局指标
主要结局
Change in alkaline phosphatase levels
时间窗: 12 months
Mean changes in alkaline phosphatase levels after 12 months treatment with combination antiretroviral therapy or placebo.
次要结局
- Serial changes in ALT(Evaluation baseline, 3 months, 6 months and end of RCT; then 3 months, 6 monthly to end of open label therapy])
- Serial changes in bilirubin(Evaluation baseline, 3 months, 6 months and end of RCT; then 3 months, 6 monthly to end of open label therapy])
- Serial changes in alkaline phosphatase(Evaluation baseline, 3 months, 6 months and end of RCT; then 3 months, 6 monthly to end of open label therapy])
- Human Betaretrovirus load in peripheral blood(Evaluation baseline, 3 months, 6 months and end of RCT; then 3 months, 6 monthly to end of open label therapy)
- Interferon gamma release to Human Betaretrovirus peptide stimulation(Evaluation at baseline, 6 months and end of RCT; then 6 monthly to end of open label therapy)
- Achievement of the composite biochemistry endpoint(6 and 12 months)
- Liver histology(Pretreatment biopsy and 24 month biopsy after initiation of study therapy)