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Trial record 32 of 63 for:    "Bile Duct Disease" | "Anti-Infective Agents"

Combination Antiretroviral Therapy (cART) for PBC

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ClinicalTrials.gov Identifier: NCT03954327
Recruitment Status : Not yet recruiting
First Posted : May 17, 2019
Last Update Posted : October 3, 2019
Sponsor:
Collaborator:
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
University of Alberta

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.

Condition or disease Intervention/treatment Phase
Primary Biliary Cholangitis Drug: Emtricitabine (FTC)/Tenofovir Disoproxil (TDF) Drug: Raltegravir Drug: Placebo Oral Capsule [CEBOCAP] Phase 2

Detailed Description:

Primary endpoint:

Greater than 10% difference 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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 60 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: Double-blind
Primary Purpose: Treatment
Official Title: Randomized Controlled Trail (RCT) of Emtricitabine, Tenofovir Disoproxil and Raltegravir for Patients With Primary Biliary Cholangitis Unresponsive to Ursodeoxycholic Acid (UDCA)
Estimated Study Start Date : February 2020
Estimated Primary Completion Date : November 2022
Estimated Study Completion Date : November 2023


Arm Intervention/treatment
Experimental: Emtricitabine (FTC)/Tenofovir Disoproxil (TDF) & Raltegravir Drug: Emtricitabine (FTC)/Tenofovir Disoproxil (TDF)
Emtricitabine (FTC) 200 mg/Tenofovir Disoproxil (TDF) 300 mg by mouth once per day

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

Placebo Comparator: Placebo 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




Primary Outcome Measures :
  1. Change in alkaline phosphatase levels [ Time Frame: 12 months ]
    Mean changes in alkaline phosphatase levels after 12 months treatment with combination antiretroviral therapy or placebo.


Secondary Outcome Measures :
  1. Serial changes in alkaline phosphatase [ Time Frame: 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 levels with combination antiretroviral therapy or placebo.

  2. Serial changes in ALT [ Time Frame: 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 levels with combination antiretroviral therapy or placebo.

  3. Serial changes in bilirubin [ Time Frame: 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 levels with combination antiretroviral therapy or placebo.

  4. Achievement of the composite biochemistry endpoint [ Time Frame: 6 and 12 months ]
    (i) reduction of ALP to < 1.67 upper limit of normal, (ii) normalization of bilirubin within ULN and (iii) reduction of ALP by > 15%

  5. Human Betaretrovirus load in peripheral blood [ Time Frame: Evaluation baseline, 3 months, 6 months and end of RCT; then 3 months, 6 monthly to end of open label therapy ]
    Quantification of Human Betaretrovirus DNA or RNA levels in peripheral blood measured by Quantigene or polymerase chain reaction with therapy or placebo.

  6. Interferon gamma release to Human Betaretrovirus peptide stimulation [ Time Frame: Evaluation at baseline, 6 months and end of RCT; then 6 monthly to end of open label therapy ]
    Concentration of interferon gamma released from peripheral blood mononuclear cells stimulated by Human Betaretrovirus peptides in vitro in response to treatment or placebo.

  7. Liver histology [ Time Frame: Pretreatment biopsy and 24 month biopsy after initiation of study therapy ]
    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.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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,
  • 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, 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03954327


Contacts
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Contact: Andrew Mason, MD 780-492-8172 andrew.mason@ualberta.ca
Contact: Breanne Stewart, RN 780974-8606 breanne1@ualberta.ca

Locations
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Canada, Alberta
University of Alberta Not yet recruiting
Edmonton, Alberta, Canada, T6G 2R3
Contact: Andrew Mason, MD    780-492-8172    andrew.mason@ualberta.ca   
Contact: Breanne Stewart, RN    780-9748606    breanne1@ualberta.ca   
Sub-Investigator: Aldo Montano Loza, MD         
Sub-Investigator: Schokrollah Elahi, PhD         
Canada, British Columbia
University of British Columbia Not yet recruiting
Vancouver, British Columbia, Canada, V6Z 2C5
Contact: Eric Yoshida, MD       eric.yoshida@vch.ca   
Sub-Investigator: Vladimir Marquez, MD         
Sub-Investigator: Hin Hin Ko, MD         
Canada, Ontario
University of Toronto Not yet recruiting
Toronto, Ontario, Canada, M5S 1A1
Contact: Aliya Gulamhusein, MD       Aliya.Gulamhusein@uhn.ca   
Canada, Quebec
McGill University
Montréal, Quebec, Canada
University of Montreal Not yet recruiting
Montréal, Quebec, Canada
Contact: Catherine Vincent, MD       catherine.vincent@umontreal.ca   
Sponsors and Collaborators
University of Alberta
Merck Sharp & Dohme Corp.
Investigators
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Principal Investigator: Andrew Mason, MD University of Alberta

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Responsible Party: University of Alberta
ClinicalTrials.gov Identifier: NCT03954327     History of Changes
Other Study ID Numbers: Pro00082571
First Posted: May 17, 2019    Key Record Dates
Last Update Posted: October 3, 2019
Last Verified: October 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Bile Duct Diseases
Anti-Infective Agents
Cholangitis
Liver Cirrhosis, Biliary
Biliary Tract Diseases
Digestive System Diseases
Cholestasis, Intrahepatic
Cholestasis
Liver Diseases
Liver Cirrhosis
Tenofovir
Raltegravir Potassium
Emtricitabine
Antiviral Agents
Reverse Transcriptase Inhibitors
Nucleic Acid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-Retroviral Agents
Anti-HIV Agents
HIV Integrase Inhibitors
Integrase Inhibitors