Combination Antiretroviral Therapy (cART) for PBC

Randomized Controlled Trail (RCT) of Emtricitabine, Tenofovir Disoproxil and Raltegravir for Patients With Primary Biliary Cholangitis Unresponsive to Ursodeoxycholic Acid (UDCA)

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.

Study Overview

• Status: Completed
• Conditions: Primary Biliary Cholangitis
• Intervention / Treatment: Drug: Emtricitabine (FTC)/Tenofovir Disoproxil (TDF); Drug: Raltegravir; Drug: Placebo Oral Capsule [CEBOCAP]

Detailed 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.

• Study Type: Interventional
• Enrollment (Actual): 37
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Andrew Mason, MD; Phone Number: 780-492-8172; Email: andrew.mason@ualberta.ca
• Study Contact Backup: Name: Breanne Stewart, RN; Phone Number: 780974-8606; Email: breanne1@ualberta.ca

Study Locations

• Canada
  • Alberta
    • Edmonton, Alberta, Canada, T6G 2R3
      • University of Alberta
  • British Columbia
    • Vancouver, British Columbia, Canada, V6Z 1Y6
      • St Paul's Hospital, University of British Columbia
    • Vancouver, British Columbia, Canada, V6Z 1Z4
      • Vancouver General Hospital, University of Brittish Columbia
  • Ontario
    • Toronto, Ontario, Canada, M5S 1A1
      • University of Toronto
  • Quebec
    • Montréal, Quebec, Canada
      • University of Montreal
  • Saskatchewan
    • Saskatoon, Saskatchewan, Canada, S7N 0W8
      • Royal University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Emtricitabine (FTC)/Tenofovir Disoproxil (TDF) & Raltegravir; one Emtricitabine 200mg and Tenofovir Disoproxil 300mg tablet two Raltegravir 600mg tablets	Drug: Emtricitabine (FTC)/Tenofovir Disoproxil (TDF); Emtricitabine (FTC) 200 mg/Tenofovir Disoproxil (TDF) 300 mg by mouth once per day; Other Names: Truvada; Drug: Raltegravir; Raltegravir (RTF) 600 mg two tablets by mouth once per day; Other Names: Isentress
Placebo Comparator: Placebo; Identical tablets resembling one Emtricitabine 200mg and Tenofovir Disoproxil 300mg tablet two Raltegravir 600mg tablets	Drug: Placebo Oral Capsule [CEBOCAP]; Two capsules identical to Raltegravir and one capsule identical to Truvada with no active ingredients by mouth once per day; Other Names: placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in alkaline phosphatase levels	Mean changes in alkaline phosphatase levels after 12 months treatment with combination antiretroviral therapy or placebo.	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Serial changes in alkaline phosphatase	Serial changes in alkaline phosphatase levels with combination antiretroviral therapy or placebo.	Evaluation baseline, 3 months, 6 months and end of RCT; then 3 months, 6 monthly to end of open label therapy]
Serial changes in ALT	Serial changes in ALT levels with combination antiretroviral therapy or placebo.	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	Serial changes in bilirubin levels with combination antiretroviral therapy or placebo.	Evaluation baseline, 3 months, 6 months and end of RCT; then 3 months, 6 monthly to end of open label therapy]
Achievement of the composite biochemistry endpoint	(i) reduction of ALP to < 1.67 upper limit of normal, (ii) normalization of bilirubin within ULN and (iii) reduction of ALP by > 15%	6 and 12 months
Human Betaretrovirus load in peripheral blood	Quantification of Human Betaretrovirus DNA or RNA levels in peripheral blood measured by Quantigene or polymerase chain reaction with therapy or placebo.	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	Concentration of interferon gamma released from peripheral blood mononuclear cells stimulated by Human Betaretrovirus peptides in vitro in response to treatment or placebo.	Evaluation at baseline, 6 months and end of RCT; then 6 monthly to end of open label therapy
Liver histology	Liver histology will be measured in a scale for staging and grading disease using the Nakanuma scoring system. Scores for fibrosis, bile duct loss, and chronic cholestasis will be combined for staging: stage 1, total score of 0; stage 2, score 1-3; stage 3, score 4-6; and stage 4, score 7-9. Cholangitis activity and hepatitis activity will be graded as 0-3, respectively.	Pretreatment biopsy and 24 month biopsy after initiation of study therapy

Collaborators and Investigators

• Sponsor: University of Alberta
• Collaborators: Merck Sharp & Dohme LLC
• Investigators: Principal Investigator: Andrew Mason, MD, University of Alberta

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2021
• Primary Completion (Actual): October 1, 2022
• Study Completion (Actual): January 1, 2024

Study Registration Dates

• First Submitted: May 7, 2019
• First Submitted That Met QC Criteria: May 16, 2019
• First Posted (Actual): May 17, 2019

Study Record Updates

• Last Update Posted (Actual): February 16, 2024
• Last Update Submitted That Met QC Criteria: February 15, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Liver Diseases; Fibrosis; Biliary Tract Diseases; Bile Duct Diseases; Cholestasis, Intrahepatic; Cholestasis; Liver Cirrhosis; Cholangitis; Liver Cirrhosis, Biliary; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; HIV Integrase Inhibitors; Integrase Inhibitors; Tenofovir; Emtricitabine; Raltegravir Potassium
• Other Study ID Numbers: Pro00082571

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No