CM-101 in PSC Patients -The SPRING Study

Study Overview
=================
Brief Summary
-----------------
This study is designed to assess the safety, tolerability and activity of the anti-human CCL24 monoclonal antibody CM-101 in adult subjects with Primary Sclerosing Cholangitis (PSC). At least 68 subjects at approximately 50 sites will be randomized to receive either CM-101 at doses of 10 mg/kg or 20 mg/kg or matching placebo.

Detailed Description
-----------------
This study will consist of a screening period, double-blind (DB) treatment period, open-label (OL) treatment period, and safety follow-up period. During the DB treatment period, subjects will receive 5 total dose administrations of study drug (investigational product - IP or placebo) once every 3 weeks (Q3W) for a coverage of 15 weeks. After completing the DB treatment period, subjects may elect to enroll in an OL treatment period. In the OL treatment period, subjects will receive a dose of IP Q3W for 11 administrations for a coverage of 33 weeks, resulting in a combined total coverage of up to 48 weeks. Subjects who do not elect to continue treatment in the OL dosing period will undergo an End of Treatment (EOT)-DB visit at Week 15 (Day 105), a Safety Follow-up Call at Week 21 (Day 147), and an End of Study (EOS) visit at Week 27. Eligible subjects who continue treatment in the OL treatment period will receive CM-101 at either a 10 mg/kg or 20 mg/kg dose commencing at Week 15 (OL Treatment 1), and the subjects will undergo an EOT-OL visit at Week 48 (Day 336), a Safety Follow-up Call at Week 54 (Day 378), and an EOS visit at Week 60 (Day 420).

Official Title
-----------------
A Phase 2a, Randomized, Double-Blind, Placebo-Controlled, Clinical Trial Evaluating the Safety and Efficacy of CM-101 in Subjects With Primary Sclerosing Cholangitis (The SPRING Study)

Conditions
-----------------
Primary Sclerosing Cholangitis

Intervention / Treatment
-----------------
* Biological: Anti-human CCL24 monoclonal antibody (CM-101)
* Other: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Subjects with diagnosis of large duct PSC of more than 24 weeks' duration Subjects that have no significant clinical concern for cholangiocarcinoma based on clinical, laboratory or imaging findings Subjects with serum Alkaline phosphatase (ALP) greater than 1.5 × Upper limit of normal (ULN) in Screening blood tests. Subjects receiving Ursodeoxycholic acid (UDCA) must receive a stable dose for ≥12 weeks prior to Screening Subjects with concomitant inflammatory bowel disease (IBD) is allowed but not required, and must meet the following stability criteria. Subjects with ulcerative colitis: Must be either in remission or have mild disease. Must have recent colonoscopy with biopsy confirming no dysplasia or colorectal cancer or history of colectomy. Subjects with Crohn's Disease must be in remission as defined by a Crohn's Disease Activity Index (CDAI) < 150. Subjects receiving concomitant medication for IBD, dose must be stable ≥12 weeks prior to screening and dose should remain stable during DB portion of the study Subjects receiving concomitant medication for their PSC must be on stable therapy ≥12 weeks prior to randomization and plan to remain on that stable dose during the DB portion of the study Female subjects of childbearing potential, must have a negative serum pregnancy test prior to starting study treatment and must have agree to highly effective method of contraception from the Screening Visit throughout the study period including 18 weeks post last dose Male subjects, if not vasectomized, must agree to use barrier contraception from screening through to study completion and for 90 days from the last dose of study drug Exclusion Criteria: Subjects with presence of documented secondary sclerosing cholangitis on prior clinical investigations Subjects with presence of competing etiology of liver disease. Subjects with possible overlap syndrome with autoimmune hepatitis are excluded if the Investigator considers autoimmune hepatitis as the predominant liver injury Subjects with small duct PSC in the absence of large duct disease Subjects with percutaneous biliary drain or bile duct stent or subjects who had required biliary drainage within 12 weeks of Screening Subjects that have undergone prior biliary surgery other than those who at the time of screening are more than 6 weeks after cholecystectomy without surgical complications Subjects with evidence of liver cirrhosis, as determined by local transient elastography values of ≥ 14.4 kPa obtained during the Screening period. In case of a fibrosis staging discrepancy between a recent (≤ 12 months) liver biopsy staging and the transient elastography results, eligibility will be based on the liver biopsy staging. History of cirrhosis and/or hepatic impairment (Child-Pugh classes A, B and C), and/or hepatic decompensation including ascites, encephalopathy, or variceal bleeding Subjects who have undergone or are planned for liver transplantation or with current model of end stage liver disease Subjects with Aspartate aminotransferase (AST) or Alanine aminotransferase (ALT) values > 5 × ULN as determined at Screening Subjects who show 'clinically significant' lab changes at Screening Subjects with serum total bilirubin values > 3 × ULN at Screening Subjects with known Gilbert's syndrome or a history of elevations in unconjugated (indirect) bilirubin >ULN Subjects with international normalized ratio (INR) >1.5 which does not correct on vitamin K replacement, in the absence of anticoagulants Subjects with serum creatinine > 1.4 mg/dL (123 μmol/L) and/or a platelet count < 100 × 109 /L Subjects with history of cholangiocarcinoma or a high clinical suspicion for cholangiocarcinoma Subjects with elevated cancer antigen 19-9 (Ca 19-9) value (> 129 U/mL) within 12 months prior to Screening unless Ca 19-9 levels have been stable and clinical evaluation and repeated Magnetic resonance imaging (MRI) within the same time period has not provided evidence of cholangiocarcinoma Subjects with a prior biliary stricture necessitating intervention should be stable for ≥ 24 weeks prior to randomization without intervention, or episode of cholangitis, and should show a low level of clinical suspicion of cholangiocarcinoma Subjects with current known portal hypertension with complications, including known gastric or large esophageal varices, poorly controlled or diuretic resistant ascites, history of variceal bleeds, or related therapeutic or prophylactic interventions Subjects with active malignancy (diagnosed and/or treated within 3 years of randomization), other than: adequately treated non-metastatic basal cell skin cancer squamous cell skin cancer that has been adequately treated and that has not recurred for at least 1 year prior to randomization history of cervical carcinoma in situ that has been adequately treated and that has not recurred. Subjects with a 'clinically significant' (as judged by the Investigator) unexplained weight loss during the 24 weeks prior to randomization Subjects showing deleterious effects of alcohol abuse or that consume excessive amounts of alcohol Subjects with known or suspected acute cholangitis in the 90 days prior to randomization, including cholangitis treated with antibiotics within the 90 days Subjects experiencing flare in colitis activity within 90 days of randomization requiring intensification of therapy beyond baseline maintenance treatment or use of oral prednisone > 10 mg/day (or equivalent), start or dose change of biologics ≤ 12 weeks before screening and or hospitalization for colitis within 90 days of randomization Subjects treated with or who are expected to begin treatment with fenofibrate or other fibrates or subjects who had a change in dose within 24 weeks of Screening, or subjects who are not planned to remain on a stable dose throughout the DB portion of the study Subjects that use any prohibited medication Subjects who have a known history of hypersensitivity reaction to CHO-derived antibodies, CM-101, or any of the formulation excipients Subjects with known chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection or that have positive hepatitis B surface antigen (HBSAg) at Screening Subjects with evidence of an active infection during the Screening period Subjects with any identified congenital or acquired immune-deficiency Subjects who have gone through major surgical procedure within 60 days of randomization or have had prior organ transplantation Subjects who have received a live/attenuated vaccine within 30 days of study randomization Female subjects who are pregnant or breast- feeding Subjects that have participated in an investigational trial of a drug or device either within 60 days of randomization; or where the study drug half-life is greater than 12 days, at least 5 half-lives need to have passed from the last dose of investigational drug prior to randomization Subjects with any other conditions, clinically significant disorders, or prior therapy that would make the subject unsuitable for the study or unable to comply with the dosing and study requirements

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Anti-human CCL24 monoclonal antibody (CM-101)<br>Anti-human CCL24 monoclonal antibody CM-101 Intravenous Infusion over 60 minutes (±5 minutes) | Biological: Anti-human CCL24 monoclonal antibody (CM-101)<br>* Anti-human CCL24 monoclonal antibody (CM-101) 100 mg Intravenous Infusion over 60 minutes (±5 minutes)<br>|
| Placebo Comparator: Placebo<br>Placebo - intravenous infusion | Other: Placebo<br>* Placebo - intravenous infusion<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety-related endpoints - number of participants with treatment-emergent adverse events (TEAEs) | Frequency and severity of treatment-emergent adverse events (TEAEs), including vital sign changes, changes in clinical safety laboratories and evaluation of infusion site reactions. | 15 week double-blind (DB) treatment period | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety-related endpoints - number of participants with abnormal vital sign changes | Frequency and severity of treatment-emergent adverse events (TEAEs), including abnormal vital sign changes. | 48 week double-blind (DB) and open-label (OL) treatment periods | 
| Safety-related endpoints - number of participants with abnormal changes in clinical safety laboratory test results | Frequency and severity of treatment-emergent adverse events (TEAEs), including changes in clinical safety laboratories. | 48 week double-blind (DB) and open-label (OL) treatment periods | 
| Safety-related endpoints - number of participants with infusion site reactions | Frequency and severity of treatment-emergent adverse events (TEAEs), including evaluation of infusion site reactions. | 48 week double-blind (DB) and open-label (OL) treatment periods | 
| Alkaline phosphate (ALP) levels | Serum ALP levels by treatment cohort | Change from baseline through Week 15 | 
| Enhanced Liver Fibrosis (ELF) score value | ECM marker set consisting of tissue inhibitor of metalloproteinases 1 (TIMP-1), amino-terminal propeptide of type III procollagen (PIIINP) and hyaluronic acid (HA) | Change from baseline through Week 15 | 
| ALP response rates | ALP response rates, defined as reduction of ALP to 1.3 x upper limit of normal (ULN), or a combination of ALP reduction to 1.5-1.3 x ULN with an at least 40% | Change from baseline through Week 15 | 
| Percent change in liver enzymes levels | Percent change in liver enzymes (alanine aminotransferase [ALT]), aspartate aminotransferase [AST], and gamma glutamyl transferase [GGT]) | Percent change from baseline through Week 15 | 
| Change in liver fibrosis markers | Liver fibrosis markers as measured by pro-peptide of type collagen (PRO-C3) and pro-peptide of type V collagen (PRO-C5) | Change from baseline through Week 15 | 
| Elucidation of the serum Pharmacokinetics (PK) Profile - C0 | Pre-dose plasma concentration | Up to 60 weeks | 
| Elucidation of the serum Pharmacokinetics (PK) Profile - Cmax | Observed maximum plasma concentration | Up to 60 weeks | 
| Elucidation of the serum Pharmacokinetics (PK) Profile - Tmax | Time to reach the observed maximum plasma concentration (Tmax) | Up to 60 weeks | 
| Elucidation of the serum Pharmacokinetics (PK) Profile - AUClast | Area under the plasma concentration-time curve from time of administration up to the last time point with a measurable concentration post dosing, calculated by linear up-logarithmic down trapezoidal summation. | Up to 60 weeks | 
| Elucidation of the serum Pharmacokinetics (PK) Profile - AUC∞ | Area under the plasma concentration-time curve extrapolated to infinity, calculated as: AUC∞ = AUClast + Clast/λz, where AUClast is the last measurable concentration. | Up to 60 weeks | 
| Elucidation of the serum Pharmacokinetics (PK) Profile - λz | Elimination rate constant, determined by linear regression of the terminal points of the ln-linear plasma concentration-time curve | Up to 60 weeks | 
| Elucidation of the serum Pharmacokinetics (PK) Profile - t½ | Terminal elimination half-life, defined as 0.693/λz | Up to 60 weeks | 
| Development of Anti-drug antibodies (ADAs) | Evaluation of the development of ADAs following repeated administration of anti-human CCL24 monoclonal antibody (CM-101) | 15 weeks | 
| Development of Anti-drug antibodies (ADAs) | Evaluation of the development of ADAs following repeated administration of anti-human CCL24 monoclonal antibody (CM-101) | 48 weeks | 
| Assessment of Pharmacodynamic (PD) parameters - Serum CCL24 levels | Serum CCL24 levels | Up to 60 weeks | 
| Assessment of Pharmacodynamic (PD) parameters - Inflammatory marker levels of cytokines | Inflammatory marker levels of cytokines | Up to 60 weeks | 
| Assessment of Pharmacodynamic (PD) parameters - Inflammatory marker levels of interleukins | Inflammatory marker levels of interleukins | Up to 60 weeks | 
| Assessment of Pharmacodynamic (PD) parameters - Single cell ribonucleic acid sequencing from whole blood samples | Single cell ribonucleic acid sequencing from whole blood samples | Up to 60 weeks | 
| Assessment of Pharmacodynamic (PD) parameters - IgG4 levels | IgG4 levels will be evaluated pre-dose | Up to 60 weeks | 
| Assessment of Pharmacodynamic (PD) parameters - IgG1 levels | IgG1 levels will be evaluated pre-dose | Up to 60 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Anti-fibrotic