Simtuzumab (GS-6624) in the Prevention of Progression of Liver Fibrosis in Adults With Primary Sclerosing Cholangitis (PSC)

Primary Sclerosing Cholangitis (PSC) Clinical Trial

Official title:

A Phase 2b, Dose-Ranging, Randomized, Double-Blind, Placebo-Controlled Trial Evaluating the Safety and Efficacy of GS-6624, a Monoclonal Antibody Against Lysyl Oxidase Like 2 (LOXL2) in Subjects With Primary Sclerosing Cholangitis (PSC)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01672853
• Other study ID #: GS-US-321-0102
• Secondary ID: 2012-002473-61
• Status: Completed
• Phase: Phase 2
• Start date: March 4, 2013
• Est. completion date: August 24, 2016

Study information

• Verified date: October 2019
• Source: Gilead Sciences
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to evaluate whether simtuzumab (GS-6624) is effective at preventing the progression of liver fibrosis in adults with primary sclerosing cholangitis (PSC).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 235
• Est. completion date: August 24, 2016
• Est. primary completion date: August 8, 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 70 Years

Eligibility

Key Inclusion Criteria:

• Adult Individuals (aged 18-70) with chronic cholestatic liver disease of at least 6 months.

• Liver biopsy consistent with PSC: If a liver biopsy has been performed within 3 months of the screening visit, tissue from that biopsy may be used as the screening biopsy. Slides would be re-cut from the existing tissue block and submitted for central reader assessment. Some individuals with PSC may have a normal liver biopsy, in the event of a normal liver biopsy, the individual must have an abnormal magnetic resonance cholangiopancreatography (MRCP).

• MRCP consistent with PSC: Some individuals with PSC may have a normal MRCP; in the event of a normal MRCP, the individual must have an abnormal liver biopsy.

• Exclusion of other causes of liver disease including viral hepatitis ,alcoholic liver disease,primary biliary cirrhosis and secondary sclerosing cholangitis

• Must have aspartate aminotransferase (AST) and alanine aminotransferase (ALT) = 10 x the Central Laboratory Upper Limit of Normal (clULN)

• Must have serum creatinine < 2.0 mg/dL

• A negative serum pregnancy test is required for female individuals of childbearing potential

• All sexually active female individuals of childbearing potential must agree to use a protocol recommended method of contraception during heterosexual intercourse throughout the study and for 90 days following the last dose of study medication

• Lactating females must agree to discontinue nursing before starting study treatment

• Males if not vasectomized, are required to use barrier contraception (condom plus spermicide) during intercourse from the screening through the study completion and for 90 days following the last dose of study drug

Key Exclusion Criteria:

• Pregnant or breast feeding

• Evidence of hepatic decompensation present, including ascites, episodes of hepatic encephalopathy, variceal bleeding or a prolonged prothrombin time/international normalized ratio (PT/INR)

• Positive for hepatitis C virus (HCV) RNA

• Positive for HBsAg

• Positive for anti-mitochondrial antibody

• Alcohol consumption greater than 21oz/week for males or 14oz/week for females

• Moderately active ulcerative colitis (UC) defined as either a partial Mayo score of > 4, bleeding score of >1, or current use of oral corticosteroid therapy and/or any inhibitor of Tumor necrosis factor-a (TNF-a) or a4ß7 integrin antagonist

• Positive urine screen for amphetamines, cocaine or opiates (i.e. heroin, morphine) at screening. Individuals on stable methadone or buprenorphine maintenance treatment for at least 6 months prior to screening may be included in the study. Individuals with a positive urine drug screen due to prescription opioid-based medication are eligible if the prescription and diagnosis are reviewed and approved by the investigator

• Clinically significant cardiac disease

• History of cholangiocarcinoma

• History of other cancers,other than non-melanomatous skin cancer, within 5 years prior to screening

• Ascending cholangitis within 60 days of screening

• Presence of a percutaneous drain or bile duct stent

• Known hypersensitivity to the investigation product or any of its formulation excipients

• History of bleeding diathesis within 6 months of screening

• Unavailable for follow-up assessment or concern for individual's compliance with the protocol procedures;

• Participation in an investigational trial of a drug or device within 30 days prior to screening

• Major surgical procedure within 30 days prior to screening or the presence of an open wound

Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Related Conditions & MeSH terms

• Cholangitis
• Cholangitis, Sclerosing
• Primary Sclerosing Cholangitis (PSC)

Intervention

Biological:
• Simtuzumab
Subcutaneous injections weekly for a total of 96 injections
• Placebo
Subcutaneous injections weekly for a total of 96 injections

Locations

Country	Name	City	State
Belgium	Hôpital Erasme	Brussels
Belgium	Université Catholique de Louvain	Bruxelles
Belgium	UZ Antwerpen	Edegem
Belgium	UZ Gent	Gent
Belgium	UZ Leuven	Leuven
Canada	University of Calgary	Calgary	Alberta
Canada	University of Alberta	Edmonton	Alberta
Canada	Dalhousie University	Halifax	Nova Scotia
Canada	London Health Science Center	London	Ontario
Canada	Toronto Liver Centre	Toronto	Ontario
Canada	University of Manitoba	Winnepeg	Manitoba
Denmark	Århus Universitetshospital, Århus Sygehus	Århus C
Denmark	Hvidovre Hospital	Hvidovre
Denmark	Rigshospitalet	Kobenhavn O
Germany	Klinikum der Johann Wolfgang Goethe Universitat	Frankfurt
Germany	Medizinische Hochschule Hannover	Hannover
Germany	Gastroenterologisch Hepatologisches Zentrum Kiel	Kiel
Germany	EUGASTRO GmbH	Leipzig
Italy	Azienda Ospedaliera San Camillo Forlanini	Roma
Italy	Istituto Clinico Humanitas	Rozzano	Milano
Italy	Azienda Ospedaliera Città della Salute e della Scienza di Torino	Torino
Netherlands	Eramus MC	Rotterdam
Spain	Hospital Universitario Vall d'Hebron	Barcelona	Cataluna
Spain	Hospital Universitario Puerta de Hierro	Majadahonda
Spain	Hospital Donostia	San Sebastian
Sweden	Avd för invärtesmedicin och klinisk nutrition	Goteborg
United Kingdom	New Queen Elizabeth Hospital	Birmingham
United Kingdom	John Radcliffe Hospital	Headington
United Kingdom	Imperial College Healthcare NHS Trust- St. Mary's Hospital	London
United Kingdom	University College London	London
United Kingdom	Norfolk and Norwich University Hospital	Norwich
United Kingdom	University of Nottingham	Nottingham
United States	University of Colorado Denver	Aurora	Colorado
United States	Walter Reed National Military Medical Center	Bethesda	Maryland
United States	Beth Israel Deaconess Medical Center	Boston	Massachusetts
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	University of Virginia Health Center	Charlottesville	Virginia
United States	Northwestern University	Chicago	Illinois
United States	Southern California Liver Center	Chula Vista	California
United States	Cleveland Clinic	Cleveland	Ohio
United States	University Hospitals Case Medical Center	Cleveland	Ohio
United States	Iowa Digestive Disease Center	Clive	Iowa
United States	Southern California Liver Centers	Coronado	California
United States	UT Southwestern Medical Center	Dallas	Texas
United States	Duke Clinical Research Institute	Durham	North Carolina
United States	Brooke Army Medical Center	Fort Sam Houston	Texas
United States	St. Luke Episcopal Hospital	Houston	Texas
United States	Indiana University	Indianapolis	Indiana
United States	Indianapolis Gastroenterology Research Foundation	Indianapolis	Indiana
United States	Scripps Clinic	La Jolla	California
United States	University of Louisville	Louisville	Kentucky
United States	University of Miami Center for Liver Diseases	Miami	Florida
United States	Intermountain Medical Center	Murray	Utah
United States	Vanderbilt University Medical Center	Nashville	Tennessee
United States	Tulane University Health Sciences Center	New Orleans	Louisiana
United States	Mount Sinai Hospital	New York	New York
United States	Weill Cornell Medical College	New York	New York
United States	Liver Institute of Virginia	Newport News	Virginia
United States	Digestive and Liver Disease Specialists	Norfolk	Virginia
United States	Verterans Adminstration Hospital	Palo Alto	California
United States	University of Pennsylvania	Philadelphia	Pennsylvania
United States	Mayo Clinic Hospital	Phoenix	Arizona
United States	University Gastroenterology	Providence	Rhode Island
United States	Bon Secours Richmond Health System	Richmond	Virginia
United States	Virginia Commonwealth University Health System	Richmond	Virginia
United States	UC Davis Medical Center	Sacramento	California
United States	St. Louis University	Saint Louis	Missouri
United States	Minnesota Gastroenterology, PA	Saint Paul	Minnesota
United States	University of Utah	Salt Lake City	Utah
United States	Alamo Medical Research	San Antonio	Texas
United States	University of San Diego Medical Center	San Diego	California
United States	University of California San Francisco	San Francisco	California
United States	University of Washington	Seattle	Washington
United States	Virginia Mason Medical Center	Seattle	Washington
United States	University of Arizona Health Sciences Center	Tucson	Arizona

Sponsors (1)

Lead Sponsor	Collaborator
Gilead Sciences

Countries where clinical trial is conducted

United States,  Belgium,  Canada,  Denmark,  Germany,  Italy,  Netherlands,  Spain,  Sweden,  United Kingdom, 

References & Publications (13)

Bowlus CL, Montano-Loza AJ, Invernizzi P, Chazouilleres O, Hirschfield G, Metselaar HJ, et al. Liver stiffness measurement by transient elastography for the prediction of fibrosis in patients with primary sclerosing cholangitis in a randomized trial of si

Bowlus CL, Patel K, Chuha IN, Chapman RW, Chazouilleres O, Chalasani NP, et al. Validation of serum fibrosis marker panels in patients with primary sclerosing cholangitis (PSC) in a randomized trial of simtuzumab. Hepatol 2015; 62 (1): 519A.

Bowlus CL, Patel K, Hirschfield G, Guha I, Chapman R, Chazouilleres O, et al. Prospective validation of the Enhanced Liver Fibrosis test for the prediction of disease progression in a randomized trial of patients with primary sclerosing cholangitis. J Hep

French D, Goodman ZD, Huntzicker EG, Newstrom D, Karnik S, Smith V, et al. Expression of matrix metalloproteinase 9 (MMP9) and the apoptosis signal-regulating kinase 1 (ASK1) pathway activation marker, phospho-P38 (p-P38), in primary sclerosing cholangiti

French D, Huntzicker EG, Goodman ZD, Shea PR, Ding D, Aguilar Schall, RE, et al. Hepatic expression of lysyl oxidase-like-2 (LOXL2) in primary sclerosing cholangitis (PSC). Hepatol 2016; 64 (1): 194A.

Goodman Z, Patel K, Guha I, Hameed B, Kowdley K, Alaparthi L, et al. Correlations between hepatic morphometric collagen content, histologic fibrosis stage, and serum markers in patients with primary sclerosing cholangitis (PSC). J Hepatol 2016; 64 (2): S6

Levy C, Eksteen B, Shiffman M, Janssen H, Montano-Loza A, Ding D, et al. Prospective validation of serum alkaline phosphatase for the prediction of disease progression in a randomized trial of patients with primary sclerosing cholangitis. J Hepatol 2017;

Levy C, Shiffman M, Caldwell S, Luketic V, Invernizzi P, Minuk G, et al. Serum fibroblast growth factor 19, 7a-Hydroxy-4-Cholesten-3-one, and bile acids and their associations with clinical characteristics in primary sclerosing cholangitis. J Hepatol 2017

Manns MP, Eksteen B, Shiffman ML, Levy C, Kowdley KV, Montano-Loza AJ, et al. Association between elevated serum IgG4 (sIgG4) concentrations and the phenotype of patients with primary sclerosing cholangitis (PSC). Hepatol 2015; 62 (1): 515A.

Muir A, Goodman Z, Levy C, Janssen H, Montano-Loza A, Bowlus C, et al. Efficacy and safety of simtuzumab for the treatment of primary sclerosing cholangitis: results of a phase 2b, dose-ranging, randomized, placebo-controlled trial. J Hepatol 2017; 66 (1)

Muir AJ, Goodman Z, Bowlus CL, Caldwell S, Invernizzi P, Luketic V, et al. Serum lysyl oxidase-like-2 (SLOXL2) levels correlate with disease severity in patients with primary sclerosing cholangitis. J Hepatol 2016; 64 (2): S428.

Shea P, Hirschfield G, Shiffman M, McColgan B, Goodman Z, Myers, R, et al. Common variation near glial-derived neurotrophic factor is associated with progression of hepatic collagen content in a genome-wide association study of liver fibrosis phenotypes i

Shea PR, Eksteen B, Hirschfield GM, Shiffman ML, Janssen HLA, Montano-Loza AJ, et al. Genome-wide association study (GWAS) of liver fibrosis phenotypes in patients with primary sclerosing cholangitis (PSC) reveals common genetic variation influencing seru

* Note: There are 13 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change From Baseline in MQC on Liver Biopsy at Week 96		Baseline; Week 96
Secondary	Percentage of Participants Who Permanently Discontinued Any Study Drug Due to an Adverse Event		First dose date up to Week 96
Secondary	Study Drug Exposure	The average SIM exposure was summarized.	First dose date up to Week 96
Secondary	Percentage of Participants Experiencing Any Treatment-Emergent Laboratory Abnormality	A treatment-emergent graded laboratory abnormality was defined as an increase of at least 1 abnormality grade from the predose assessment and occurring after the predose visit and on or before the date of the administration of study drug plus 30 days. The most severe graded abnormality from all tests was counted for each participant [Grade 1 (mild); Grade 2 (moderate); Grade 3 (severe); Grade 4 (life-threatening)].	First dose date up to Week 96 plus 30 days