Combination Antiretroviral Therapy (cART) for PBC

University of Alberta

Status and phase: Completed; Phase 2

Conditions: Primary Biliary Cholangitis

Treatments: Drug: Emtricitabine (FTC)/Tenofovir Disoproxil (TDF); Drug: Raltegravir; Drug: Placebo Oral Capsule [CEBOCAP]

Study type: Interventional

Funder types: Other; Industry

Identifiers

NCT03954327

Pro00082571

Details and patient eligibility

About

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.

Full description

Primary endpoint:

Change in mean percentage of alkaline phosphatase (ALP) reduction in cART vs. placebo at 6 and 12 months.

Secondary endpoints:

1. Serum biochemistries bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT) and gamma-glutamyltransferase (GGT) will be studied as continuous variables.
2. 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.
3. 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.
4. 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].
5. Serial human betaretrovirus measurement in peripheral blood and cellular immune response to viral peptides.

Enrollment: 37 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• 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.

Exclusion criteria

• 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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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37 participants in 2 patient groups, including a placebo group

Emtricitabine (FTC)/Tenofovir Disoproxil (TDF) & Raltegravir

Experimental group

Description:

one Emtricitabine 200mg and Tenofovir Disoproxil 300mg tablet two Raltegravir 600mg tablets

Treatment:

Drug: Raltegravir

Drug: Emtricitabine (FTC)/Tenofovir Disoproxil (TDF)

Placebo

Placebo Comparator group

Description:

Identical tablets resembling one Emtricitabine 200mg and Tenofovir Disoproxil 300mg tablet two Raltegravir 600mg tablets

Treatment:

Drug: Placebo Oral Capsule [CEBOCAP]