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Combination Antiretroviral Therapy (cART) for PBC

Primary Purpose

Primary Biliary Cholangitis

Status

Active

Phase

Phase 2

Locations

Canada

Study Type

Interventional

Intervention

Emtricitabine (FTC)/Tenofovir Disoproxil (TDF)

Raltegravir

Placebo Oral Capsule [CEBOCAP]

About this trial

This is an interventional treatment trial for Primary Biliary Cholangitis

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept 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.

Sites / Locations

University of Alberta
St Paul's Hospital, University of British Columbia
Vancouver General Hospital, University of Brittish Columbia
University of Toronto
University of Montreal
Royal University Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

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

Placebo

Arm Description

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

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

Outcomes

Primary Outcome Measures

Change in alkaline phosphatase levels

Mean changes in alkaline phosphatase levels after 12 months treatment with combination antiretroviral therapy or placebo.

Secondary Outcome Measures

Serial changes in alkaline phosphatase

Serial changes in alkaline phosphatase levels with combination antiretroviral therapy or placebo.

Serial changes in ALT

Serial changes in ALT levels with combination antiretroviral therapy or placebo.

Serial changes in bilirubin

Serial changes in bilirubin levels with combination antiretroviral therapy or placebo.

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%

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.

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.

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.

Full Information

NCT ID

NCT03954327

First Posted

May 7, 2019

Last Updated

March 24, 2023

Sponsor

University of Alberta

Collaborators

Merck Sharp & Dohme LLC

1. Study Identification

Unique Protocol Identification Number

NCT03954327

Brief Title

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

2. Study Status

Record Verification Date

March 2023

Overall Recruitment Status

Active, not recruiting

Study Start Date

March 1, 2021 (Actual)

Primary Completion Date

October 1, 2022 (Actual)

Study Completion Date

January 1, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

University of Alberta

Collaborators

Merck Sharp & Dohme LLC

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

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: 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Primary Biliary Cholangitis

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Masking Description

Double-blind

Allocation

Randomized

Enrollment

37 (Actual)

8. Arms, Groups, and Interventions

Arm Title

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

Arm Type

Experimental

Arm Description

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

Arm Title

Placebo

Arm Type

Placebo Comparator

Arm Description

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

Intervention Type

Drug

Intervention Name(s)

Emtricitabine (FTC)/Tenofovir Disoproxil (TDF)

Other Intervention Name(s)

Truvada

Intervention Description

Emtricitabine (FTC) 200 mg/Tenofovir Disoproxil (TDF) 300 mg by mouth once per day

Intervention Type

Drug

Intervention Name(s)

Raltegravir

Other Intervention Name(s)

Isentress

Intervention Description

Raltegravir (RTF) 600 mg two tablets by mouth once per day

Intervention Type

Drug

Intervention Name(s)

Placebo Oral Capsule [CEBOCAP]

Other Intervention Name(s)

placebo

Intervention Description

Two capsules identical to Raltegravir and one capsule identical to Truvada with no active ingredients by mouth once per day

Primary Outcome Measure Information:

Title

Change in alkaline phosphatase levels

Description

Mean changes in alkaline phosphatase levels after 12 months treatment with combination antiretroviral therapy or placebo.

Time Frame

12 months

Secondary Outcome Measure Information:

Title

Serial changes in alkaline phosphatase

Description

Serial changes in alkaline phosphatase levels with combination antiretroviral therapy or placebo.

Time Frame

Evaluation baseline, 3 months, 6 months and end of RCT; then 3 months, 6 monthly to end of open label therapy]

Title

Serial changes in ALT

Description

Serial changes in ALT levels with combination antiretroviral therapy or placebo.

Time Frame

Evaluation baseline, 3 months, 6 months and end of RCT; then 3 months, 6 monthly to end of open label therapy]

Title

Serial changes in bilirubin

Description

Serial changes in bilirubin levels with combination antiretroviral therapy or placebo.

Time Frame

Evaluation baseline, 3 months, 6 months and end of RCT; then 3 months, 6 monthly to end of open label therapy]

Title

Achievement of the composite biochemistry endpoint

Description

(i) reduction of ALP to < 1.67 upper limit of normal, (ii) normalization of bilirubin within ULN and (iii) reduction of ALP by > 15%

Time Frame

6 and 12 months

Title

Human Betaretrovirus load in peripheral blood

Description

Quantification of Human Betaretrovirus DNA or RNA levels in peripheral blood measured by Quantigene or polymerase chain reaction with therapy or placebo.

Time Frame

Evaluation baseline, 3 months, 6 months and end of RCT; then 3 months, 6 monthly to end of open label therapy

Title

Interferon gamma release to Human Betaretrovirus peptide stimulation

Description

Concentration of interferon gamma released from peripheral blood mononuclear cells stimulated by Human Betaretrovirus peptides in vitro in response to treatment or placebo.

Time Frame

Evaluation at baseline, 6 months and end of RCT; then 6 monthly to end of open label therapy

Title

Liver histology

Description

Time Frame

Pretreatment biopsy and 24 month biopsy after initiation of study therapy

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Andrew Mason, MD

Organizational Affiliation

University of Alberta

Official's Role

Principal Investigator

Facility Information:

Facility Name

University of Alberta

City

Edmonton

State/Province

Alberta

ZIP/Postal Code

T6G 2R3

Country

Canada

Facility Name

St Paul's Hospital, University of British Columbia

City

Vancouver

State/Province

British Columbia

ZIP/Postal Code

V6Z 1Y6

Country

Canada

Facility Name

Vancouver General Hospital, University of Brittish Columbia

City

Vancouver

State/Province

British Columbia

ZIP/Postal Code

V6Z 1Z4

Country

Canada

Facility Name

University of Toronto

City

Toronto

State/Province

Ontario

ZIP/Postal Code

M5S 1A1

Country

Canada

Facility Name

University of Montreal

City

Montréal

State/Province

Quebec

Country

Canada

Facility Name

Royal University Hospital

City

Saskatoon

State/Province

Saskatchewan

ZIP/Postal Code

S7N 0W8

Country

Canada

12. IPD Sharing Statement

Plan to Share IPD

Learn more about this trial

Combination Antiretroviral Therapy (cART) for PBC

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