Primary Sclerosing Cholangitis (PSC)
Conditions
Keywords
PSC, Sclerosis, Monoclonal antibody, LOXL2, Simtuzumab, Primary sclerosing cholangitis, Liver fibrosis, Liver disease, MRCP, MRE, Liver biopsy
Brief 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).
Interventions
BIOLOGICALSimtuzumab
Subcutaneous injections weekly for a total of 96 injections
BIOLOGICALPlacebo
Subcutaneous injections weekly for a total of 96 injections
Sponsors
Gilead Sciences
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
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-α (TNF-α) or α4β7 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/
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Change From Baseline in MQC on Liver Biopsy at Week 96 | Baseline; Week 96 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Permanently Discontinued Any Study Drug Due to an Adverse Event | First dose date up to Week 96 | — |
| Study Drug Exposure | First dose date up to Week 96 | The average SIM exposure was summarized. |
| Percentage of Participants Experiencing Any Treatment-Emergent Laboratory Abnormality | First dose date up to Week 96 plus 30 days | 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 \[Grade 1 (mild); Grade 2 (moderate); Grade 3 (severe); Grade 4 (life-threatening)\]. |
Countries
Belgium, Canada, Denmark, Germany, Italy, Netherlands, Spain, Sweden, United Kingdom, United States
Participant flow
Recruitment details
Participants were enrolled at study sites in North America and Europe. The first participant was screened on 4 March 2013. The last study visit occurred on 24 August 2016.
Pre-assignment details
298 participants were screened.
Participants by arm
| Arm | Count |
|---|---|
| SIM 75 mg SIM 75 mg subcutaneous injections weekly for 96 weeks | 79 |
| SIM 125 mg SIM 125 mg subcutaneous injections weekly for 96 weeks | 77 |
| Placebo Placebo subcutaneous injections weekly for 96 weeks | 78 |
| Total | 234 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 4 | 6 | 8 |
| Overall Study | Investigator's Discretion | 1 | 0 | 0 |
| Overall Study | Lost to Follow-up | 0 | 1 | 0 |
| Overall Study | Pregnancy | 0 | 1 | 0 |
| Overall Study | Protocol Specified Criteria for Withdraw | 0 | 4 | 0 |
| Overall Study | Randomized but Never Treated | 0 | 0 | 1 |
| Overall Study | Withdrew Consent | 5 | 5 | 5 |
Baseline characteristics
| Characteristic | SIM 75 mg | Total | Placebo | SIM 125 mg |
|---|---|---|---|---|
| Age, Continuous | 45 years STANDARD_DEVIATION 11.3 | 44 years STANDARD_DEVIATION 11.5 | 44 years STANDARD_DEVIATION 12.8 | 43 years STANDARD_DEVIATION 10.1 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 6 Participants | 1 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 78 Participants | 228 Participants | 77 Participants | 73 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Morphometric Quantitative Collagen (MQC) | 5.6 percentage of MQC STANDARD_DEVIATION 5.09 | 5.4 percentage of MQC STANDARD_DEVIATION 4.19 | 5.1 percentage of MQC STANDARD_DEVIATION 3.98 | 5.6 percentage of MQC STANDARD_DEVIATION 3.36 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 0 Participants | 4 Participants | 3 Participants | 1 Participants |
| Race/Ethnicity, Customized Black | 7 Participants | 21 Participants | 8 Participants | 6 Participants |
| Race/Ethnicity, Customized Other | 1 Participants | 7 Participants | 4 Participants | 2 Participants |
| Race/Ethnicity, Customized White | 71 Participants | 201 Participants | 62 Participants | 68 Participants |
| Region of Enrollment Belgium | 1 Participants | 3 Participants | 1 Participants | 1 Participants |
| Region of Enrollment Canada | 16 Participants | 45 Participants | 12 Participants | 17 Participants |
| Region of Enrollment Denmark | 5 Participants | 8 Participants | 0 Participants | 3 Participants |
| Region of Enrollment France | 1 Participants | 7 Participants | 2 Participants | 4 Participants |
| Region of Enrollment Germany | 3 Participants | 10 Participants | 5 Participants | 2 Participants |
| Region of Enrollment Italy | 3 Participants | 10 Participants | 5 Participants | 2 Participants |
| Region of Enrollment Netherlands | 2 Participants | 5 Participants | 2 Participants | 1 Participants |
| Region of Enrollment Spain | 0 Participants | 5 Participants | 2 Participants | 3 Participants |
| Region of Enrollment Sweden | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Region of Enrollment United Kingdom | 5 Participants | 20 Participants | 6 Participants | 9 Participants |
| Region of Enrollment United States | 42 Participants | 120 Participants | 43 Participants | 35 Participants |
| Sex: Female, Male Female | 27 Participants | 85 Participants | 33 Participants | 25 Participants |
| Sex: Female, Male Male | 52 Participants | 149 Participants | 45 Participants | 52 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 79 | 0 / 77 | 0 / 78 |
| other Total, other adverse events | 71 / 79 | 72 / 77 | 75 / 78 |
| serious Total, serious adverse events | 16 / 79 | 23 / 77 | 21 / 78 |
Outcome results
Primary
Change From Baseline in MQC on Liver Biopsy at Week 96
Time frame: Baseline; Week 96
Population: Participants in the Full Analysis Set (participants who were randomized into the study and received at least 1 dose of study drug) with available data were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| SIM 75 mg | Change From Baseline in MQC on Liver Biopsy at Week 96 | -0.5 percentage of MQC | Standard Deviation 5.78 |
| SIM 125 mg | Change From Baseline in MQC on Liver Biopsy at Week 96 | 0.5 percentage of MQC | Standard Deviation 6.94 |
| Placebo | Change From Baseline in MQC on Liver Biopsy at Week 96 | 0.0 percentage of MQC | Standard Deviation 4.76 |
Comparison: A mixed-effect model for repeated measures (MMRM) with an unstructured variance-covariance matrix for each participant was used to calculate a point estimate and a 95% confidence interval (CI) for the treatment difference between each treatment arm and placebo in least squares mean (LSMean) change from baseline in MQC at Week 96. With MMRM setting, all participants with available data from the 3 treatment groups with change in MQC at Week 48 and/or Week 96 contributed to the overall model.95% CI: [-2.3, 1.6]
Comparison: A MMRM with an unstructured variancecovariance matrix for each participant was used to calculate a point estimate and a 95% CI for the treatment difference between each treatment arm and placebo in LSMean change from baseline in MQC at Week 96. With MMRM setting, all participants with available data from the 3 treatment groups with change in MQC at Week 48 and/or Week 96 contributed to the overall model.95% CI: [-1, 3]
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 \[Grade 1 (mild); Grade 2 (moderate); Grade 3 (severe); Grade 4 (life-threatening)\].
Time frame: First dose date up to Week 96 plus 30 days
Population: Participants in the Safety Analysis Set with at least one post-baseline measurement were analyzed.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| SIM 75 mg | Percentage of Participants Experiencing Any Treatment-Emergent Laboratory Abnormality | Grade 1 | 11.4 percentage of participants |
| SIM 75 mg | Percentage of Participants Experiencing Any Treatment-Emergent Laboratory Abnormality | Grade 2 | 26.6 percentage of participants |
| SIM 75 mg | Percentage of Participants Experiencing Any Treatment-Emergent Laboratory Abnormality | Grade 3 | 48.1 percentage of participants |
| SIM 75 mg | Percentage of Participants Experiencing Any Treatment-Emergent Laboratory Abnormality | Grade 4 | 11.4 percentage of participants |
| SIM 125 mg | Percentage of Participants Experiencing Any Treatment-Emergent Laboratory Abnormality | Grade 4 | 13.0 percentage of participants |
| SIM 125 mg | Percentage of Participants Experiencing Any Treatment-Emergent Laboratory Abnormality | Grade 1 | 16.9 percentage of participants |
| SIM 125 mg | Percentage of Participants Experiencing Any Treatment-Emergent Laboratory Abnormality | Grade 3 | 46.8 percentage of participants |
| SIM 125 mg | Percentage of Participants Experiencing Any Treatment-Emergent Laboratory Abnormality | Grade 2 | 20.8 percentage of participants |
| Placebo | Percentage of Participants Experiencing Any Treatment-Emergent Laboratory Abnormality | Grade 4 | 7.7 percentage of participants |
| Placebo | Percentage of Participants Experiencing Any Treatment-Emergent Laboratory Abnormality | Grade 2 | 25.6 percentage of participants |
| Placebo | Percentage of Participants Experiencing Any Treatment-Emergent Laboratory Abnormality | Grade 3 | 48.7 percentage of participants |
| Placebo | Percentage of Participants Experiencing Any Treatment-Emergent Laboratory Abnormality | Grade 1 | 17.9 percentage of participants |
Secondary
Percentage of Participants Who Permanently Discontinued Any Study Drug Due to an Adverse Event
Time frame: First dose date up to Week 96
Population: The Safety Analysis Set included participants who received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SIM 75 mg | Percentage of Participants Who Permanently Discontinued Any Study Drug Due to an Adverse Event | 5.1 percentage of participants |
| SIM 125 mg | Percentage of Participants Who Permanently Discontinued Any Study Drug Due to an Adverse Event | 7.8 percentage of participants |
| Placebo | Percentage of Participants Who Permanently Discontinued Any Study Drug Due to an Adverse Event | 10.3 percentage of participants |
Secondary
Study Drug Exposure
The average SIM exposure was summarized.
Time frame: First dose date up to Week 96
Population: Participants in the Safety Analysis Set were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| SIM 75 mg | Study Drug Exposure | 92.0 weeks | Standard Deviation 15.33 |
| SIM 125 mg | Study Drug Exposure | 83.8 weeks | Standard Deviation 26.12 |
| Placebo | Study Drug Exposure | 87.4 weeks | Standard Deviation 22.35 |