E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Treatment of Primary Sclerosing Cholangitis |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10036732 |
E.1.2 | Term | Primary sclerosing cholangitis |
E.1.2 | System Organ Class | 100000004871 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective is to determine the activity of the anti-human CCL24 monoclonal antibody CM-101, administered over 12 weeks, in male and female adult subjects with primary sclerosing cholangitis, as measured by a decrease in alkaline phosphatase (ALP) levels. |
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E.2.2 | Secondary objectives of the trial |
To evaluate the safety, tolerability, pharmacokinetic (PK) and pharmacodinamic (PD) profiles, ADA development, biochemical response (liver enzyme levels) and a panel of biomarkers to monitor disease progression in PSC. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Subjects must meet all inclusion criteria to be eligible for the study: 1. Males and females, Age 18 Years to 75 Years, both inclusive 2. Subjects with diagnosis of large duct PSC (intrahepatic and/or extrahepatic), of more than 6 months duration, based on the EASL 2009 cholestatic guidelines definition (cholestatic liver function tests with consistent magnetic resonance cholangiopancreatography (MRCP) or endoscopic retrograde cholangiopancreatography (ERCP) showing sclerosing cholangitis, +/- a liver biopsy consistent with PSC once secondary causes of sclerosing cholangitis have been excluded). Note: Subjects must have cholangiographic changes showing sclerosing cholangitis in order to be eligible for the study. 3. Subjects must have a recent (within 12 months of Day 0) imaging surveillance that is interpreted by the investigator as low risk for cholangiocarcinoma. The minimum imaging requirement is a transabdominal ultrasound however other imaging modalities such as CT or MR are also accepted. Note: Subjects that do not have such imaging will have a transabdominal ultrasound done as part of the screening procedures. 4. Subjects with serum ALP greater than 1.5 × upper limit of normal (ULN) as determined by the mean of the Screening and Baseline values 5. Subjects receiving Ursodeoxycholic acid (UDCA), must have been stable for ≥3 months prior to, and including, Day 0 and must not have exceeded 20 mg/kg/day during this time. 6. For subjects with concomitant IBD: a. Colonoscopy or other appropriate endoscopic procedure within 12-18 months of Day 0 confirming no dysplasia or colorectal cancer b. Subjects with Crohn’s Disease (CD) must be in remission as defined by a Crohn’s Disease Activity Index (CDAI) <150 c. Subjects with ulcerative colitis (UC) must either be in remission or have mild disease. Remission is defined as a partial Mayo score of ≤2 with no individual sub-score exceeding 1. Mild disease is defined as a partial Mayo score ≤3 with no individual sub-score exceeding 1 point. 7. Subjects receiving concomitant medications need to be on stable therapy for > 3 months prior to study Day 0 8. Female subjects of childbearing potential must have a negative serum/urine pregnancy test prior to starting study treatment. Sexually active women of childbearing potential must agree to use an effective method of contraception from the Screening Visit throughout the study period including the 15 weeks post last dose follow-up period. Effective methods of contraception are considered to be those listed below: • Barrier method, i.e., (a) condom (male or female) with spermicide or (b) diaphragm with spermicide; or • Intrauterine device; or • Vasectomy (partner), or • Hormonal (e.g., contraceptive pill, patch, intramuscular implant or injection) • Abstinence, if in line with the preferred and usual lifestyle of the subject [where abstinence is defined as refraining from heterosexual intercourse during the trial duration (from first administration of investigational product until the end of the 15 weeks post last dose follow-up period)] 9. Male subjects, if not vasectomized, must agree to use barrier contraception (condom plus spermicide) during heterosexual intercourse from screening through to study completion and for 60 days from the last dose of study investigational medicinal product. 10. Subjects able to understand and sign a written informed consent form (ICF) |
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E.4 | Principal exclusion criteria |
Subjects must not meet any exclusion criteria to be eligible for the study: 1. Subjects with presence of documented secondary sclerosing cholangitis on prior clinical investigations. 2. Subjects with presence of competing etiology of liver disease including, but not limited to, viral hepatitis, alcoholic liver disease, non-alcoholic steatohepatitis, primary biliary cirrhosis etc. 3. Subjects with evidence of autoimmune immunoglobin (Ig) IgG4-associated cholangitis, 4. Subjects with small duct cholangitis in the absence of large duct disease. 5. Subjects with percutaneous biliary drain or bile duct stent 6. Subjects that have undergone prior biliary surgery (laparoscopic or open surgery) other than those who at the time of screening are more than 6 weeks after cholecystectomy without surgical complications 7. Subjects with evidence of cirrhosis, as determined by local transient elastography taken within 6 months of study screening. 8. History of cirrhosis and/or hepatic impairment (Child-Pugh classes A, B and C) and/or hepatic decompensation including ascites, encephalopathy or variceal bleeding 9. Subjects who have undergone or are planned for liver transplantation or current model of end stage liver disease 10. Subjects with Aspartate aminotransferase (AST) and alanine aminotransferase (ALT); above the allowed cut-offs, 11. Subjects with Total Bilirubin > 2 x ULN 12. Subjects with International Normalized Ratio (INR) > 1.3 in the absence of anticoagulants 13. Subjects with serum creatinine >1.4 mg/dL (123 μmol/L) and/or platelet count <50 x 109/L 14. Subjects with history of cholangiocarcinoma or a high suspicion of cholangiocarcinoma, as indicated by clinical judgment, a functional dominant stricture (Bilirubin <2x ULN) or an elevated Ca 19-9 value (>129 U/mL) at screening. 15. Subjects with a prior dominant biliary stricture necessitating biliary intervention should have been stable (Bilirubin <2x ULN) for the previous 6 months without intervention and a low level of clinic suspicion of cholangiocarcinoma. 16. Subjects with active malignancy (within 3 years of diagnosis), other than: a) adequately treated nonmetastatic basal cell skin cancer; b) squamous cell skin cancer that has been adequately treated and that has not recurred for at least 1 year prior to first study treatment; and 17. history of cervical carcinoma in situ that has been adequately treated and that has not recurred for at least 3 years prior to first study treatment. Subjects that lost > 10% of their body weight during the 6 months prior to screening 18. Subjects that consume alcohol greater than 21 units/week for males or 14 units/week for females 19. Subjects experiencing cholangitis within last 90 days or ongoing need for prophylactic antibiotics 20. Subjects experiencing flare in colitis activity within 90 days of screening requiring intensification of therapy beyond baseline maintenance treatment 21. Subjects treated with the following medications ≤6 months of study Day 0 and throughout the trial: fenofibrate or other fibrates and potentially hepatotoxic medications 22. Subjects with known chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection or that has positive hepatitis B core antibody (anti-HBc) at screening 23. Subjects with evidence of an active infection during the Screening Period 24. Subjects with any identified congenital or acquired immune-deficiency 25. Subjects who went through major surgical procedure within 30 days of screening or prior organ transplantation 26. Subjects which have received a live vaccine within 30 days of planned start of study therapy. 27. Females subjects who are pregnant or breastfeeding 28. Subjects that have participated in an investigational trial of a drug or device either within 60 days of screening or 5 half-life’s of the last dose of investigational drug, where the study drug half-life is greater than 12 days 29. Subjects with any other clinically significant disorders or prior therapy that, in the opinion of the investigator, would make the subject unsuitable for the study or unable to comply with the dosing and protocol requirements |
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E.5 End points |
E.5.1 | Primary end point(s) |
The Study primary objective is to determine the activity of the anti-human CCL24 monoclonal antibody CM-101, administered over 12 weeks, in male and female adult subjects with primary sclerosing cholangitis, as measured by a decrease in alkaline phosphatase (ALP) levels.
1. Percent change from baseline through Week 15 in serum alkaline phosphatase |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
To evaluate the safety, tolerability, pharmacokinetic (PK) and pharmacodinamic (PD) profiles, ADA development, biochemical response (liver enzyme levels) and a panel of biomarkers to monitor disease progression in PSC.
Incidence and characteristics of adverse events (AEs) occurring following repeated administrations of CM-101 2. Elucidate the Serum PK profile of repeated administrations of CM-101. The following parameters and others will be calculated: - Maximum CM-101 plasma concentration (Cmax) - Time to Cmax (tmax) - Area under the curve (AUC) to the final concentration limit of quantitation (LOQ), AUC(0-t) and to infinity AUCinf - Terminal elimination rate constant (λz) - Terminal elimination half-life (T½) Additional parameters may be also calculated as deemed necessary 2. Evaluation of the development of anti-drug antibodies (ADA) following repeated administrations of CM-101 3. Percent change from baseline over time in liver enzymes (ALT, AST and GGT) 4. Change from baseline through Week 15 in markers of liver fibrosis- such as ELF™ Blood Test, PRO-C3 and PRO-C5 |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 5 |
E.8.9.1 | In the Member State concerned days | 30 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 5 |
E.8.9.2 | In all countries concerned by the trial days | 30 |