Clinical trial NCT03954327: Combination Antiretroviral Therapy (cART) for PBC
Official title: Randomized Controlled Trail (RCT) of Emtricitabine, Tenofovir Disoproxil and Raltegravir for Patients With Primary Biliary Cholangitis Unresponsive to Ursodeoxycholic Acid (UDCA)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Primary Biliary Cholangitis
Lead sponsor: University of Alberta
Sponsor class: OTHER
Collaborators: name: Merck Sharp & Dohme LLC
First posted: 2019-05-17
Enrollment: 37
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Change in alkaline phosphatase levels
timeFrame: 12 months
Secondary outcomes:
measure: Serial changes in alkaline phosphatase
timeFrame: Evaluation baseline, 3 months, 6 months and end of RCT; then 3 months, 6 monthly to end of open label therapy]
measure: Serial changes in ALT
timeFrame: Evaluation baseline, 3 months, 6 months and end of RCT; then 3 months, 6 monthly to end of open label therapy]
measure: Serial changes in bilirubin
timeFrame: Evaluation baseline, 3 months, 6 months and end of RCT; then 3 months, 6 monthly to end of open label therapy]
measure: Achievement of the composite biochemistry endpoint
timeFrame: 6 and 12 months
measure: Human Betaretrovirus load in peripheral blood
timeFrame: Evaluation baseline, 3 months, 6 months and end of RCT; then 3 months, 6 monthly to end of open label therapy
measure: Interferon gamma release to Human Betaretrovirus peptide stimulation
timeFrame: Evaluation at baseline, 6 months and end of RCT; then 6 monthly to end of open label therapy
measure: Liver histology
timeFrame: Pretreatment biopsy and 24 month biopsy after initiation of study therapy
Other outcomes:
Locations:
city: Edmonton
country: Canada
facility: University of Alberta
state: Alberta
city: Vancouver
country: Canada
facility: St Paul's Hospital, University of British Columbia
state: British Columbia
city: Vancouver
country: Canada
facility: Vancouver General Hospital, University of Brittish Columbia
state: British Columbia
city: Toronto
country: Canada
facility: University of Toronto
state: Ontario
city: Montréal
country: Canada
facility: University of Montreal
state: Quebec
city: Saskatoon
country: Canada
facility: Royal University Hospital
state: Saskatchewan
Study officials:
affiliation: University of Alberta
name: Andrew Mason, MD
role: PRINCIPAL_INVESTIGATOR
References: