PRIMARY SCLEROSING CHOLANGITIS (PSC) MedDRA version: 19.0 Level: LLT Classification code 10036732 Term: Primary sclerosing cholangitis System Organ Class: 10019805 - Hepatobiliary disorders MedDRA version: 19.0 Level: HLT Classification code 10004607 Term: Bile duct infections and inflammations System Organ Class: 10019805 - Hepatobili
Conditions
Interventions
Product Name: NGM282
Pharmaceutical Form: Solution for injection in pre-filled syringe
INN or Proposed INN: engineered recombinant human FGF19
CAS Numbe
Sponsors
NGM Biopharmaceuticals, Inc.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Patients who meet the following criteria may be included in the study: 1. Males and females between 18 and 75 years of age inclusive who are able to comprehend instructions and follow the study procedures, and are willing to sign an Informed Consent Form (ICF). 2. Confirmed diagnosis of PSC based any two of the following three criteria: a. Historical evidence of an elevated ALP > ULN from any laboratory b. Liver biopsy consistent with PSC Patients with small-duct PSC on liver biopsy must also have a concurrent diagnosis of IBD c. Abnormal cholangiography consistent with PSC as measured by MRCP, ERCP, or percutaneous transhepatic cholangiography 3. Subjects must have certain additional laboratory parameters in specified ranges at Screening, as follows: a. ALP > 1.5 × ULN b. Total bilirubin = 2.5 mg/dL c. ALT and AST 60 mL/min by Cockroft-Gault calculation e. Platelets 130 U/mL may be enrolled if they have two results a mínimum of 4 weeks but not greater than 1 year apart and not more than 50 U/mL difference between the two results 4. Patients taking UDCA will be allowed to enroll if meeting the following criteria: a. Total daily dose of 12 weeks prior to Screening and through Day 1 Vedolizumab is an excluded biologic treatment 6. Female patients are eligible for the study if they meet the following criteria: a. Are not pregnant or nursing b. Of non-childbearing potential defined as women who have had a hysterectomy, bilateral oophorectomy, medically documented ovarian failure, or are documented postmenopausal (follicle-stimulating hormone > 40 mIU/mL) OR Of childbearing potential defined as including women < 55 years of age with 2 years of amenorrhea and both the following criteria: i. Both a negative serum pregnancy test at Screening and urine pregnancy test prior to Randomization ii. Correct and consist
Exclusion criteria
Exclusion criteria: Any of the following will exclude potential subjects from the study: 1. Clinically significant acute or chronic liver disease of an etiology other than PSC. a. Patients with stable treated overlapping PSC and autoimmune hepatitis (AIH) will be allowed to enroll into the study. i. Stable treated overlapping PSC/AIH is defined as on a consistent regimen of immunosuppressive therapy for a minimum of 12 weeks and no evidence of a hepatic flare during that time period. 2. Secondary or IgG4-related sclerosing cholangitis 3. Presence of a dominant stricture of clinical concern on MRCP at Screening. a. Patients with dominant stricture can be enrolled if the investigator feels there is no evidence on magnetic resonance imaging or cholangiography indicative of cholangiocarcinoma or that the stricture will not result in significant fluctuations in ALP during Screening or Study period. b. Patients with a dominant stricture must have a total bilirubin of = 2.5 mg/dL for at least 6 months prior to Screening. 4. Placement of a bile-duct stent or percutaneous bile-duct drain within 3 months of Screening a. Patients who have undergone a balloon dilation procedure of a stricture will be allowed to enroll into the study after a minimum of 4 weeks post-procedure. 5. History, evidence, or high suspicion of cholangiocarcinoma or other hepatobiliary malignancy based on imaging, screening laboratory values, and/or clinical symptoms 6. Acute cholangitis within 12 weeks of Screening and through Day 1. a. Chronic preventive antibiotics for the prevention or presumptive treatment of cholangitis will be allowed in the study. b. Intermittent courses of antibiotics for the presumptive treatment of cholangitis are allowed if outside the 12-week window prior to Screening. 7. Evidence of decompensated cirrhosis (Child-Pugh B or C) based on histology, relevant medical complications, or laboratory parameters. a. Patients with compensated cirrhosis will be allowed to enroll into the study. b. Patients with pre-sinusoidal esophageal varices with no history or evidence of bleeding may be enrolled as long as there is no other evidence of hepatic decompensation. 8. Prior liver transplantation 9. Any contraindication or inability to obtain a screening MRCP or colonoscopy (only in patients with concomitant IBD, if historical colonoscopy within the 12-month window is not available) 10. Screening electrocardiogram (ECG) with clinically significant abnormalities as determined by the Investigator 11. Positive for HBsAg, HCV-RNA, or anti-HIV 12. History of malignancy diagnosed or treated within 2 years (recent localized treatment of squ
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: • Evaluate the treatment effect of NGM282 as measured by the mean change in alkaline phosphatase (ALP) from Baseline to Week 12 in patients with PSC.; Secondary Objective: • Assess the safety and tolerability of NGM282 in patients with PSC with 12 weeks of treatment. • Evaluate the percentage change from Baseline at Week 12 in ALP. • Evaluate the absolute and percentage changes from Baseline at Week 12 of the following: o Alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin (total, direct), and GGT o Total cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides o 7 alpha hydroxy 4 cholesten 3 one (C4) and serum bile acids o Bile mediated absorption as measured by fat soluble vitamins and fecal fat content • Evaluate changes in pruritus and fatigue • Compare NM282 versus placebo with respect to the incidence and severity of: o IBD associated intestinal symptoms during the study period o Acute cholangitis during the study period • Evaluate the exposure of 1 mg and 3 mg of NGM282 in patients with PSC • Compare the dose related changes in safety, tolerability, and pharmacodynamic (PD) parameters ;Primary end point(s): The primary efficacy endpoint is the mean change in ALP from Baseline at Week 12.;Timepoint(s) of evaluation of this end point: 12 weeks compared to baseline | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): The secondary efficacy and PD endpoints are the following: ? Percent change from Baseline at Week 12 in ALP ? Absolute and percent changes from Baseline at Week 12 in the following: o ALT, AST, bilirubin (total, direct), and GGT o C4 and serum bile acids o Total cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides ? Bile-mediated absorption as measured by fat-soluble vitamins and fecal fat content ? Changes in pruritus and fatigue, as measured by the weekly mean of the daily pruritusand fatigue NRS assessments ? Incidence and severity of IBD-associated intestinal symptoms ? Incidence and severity of acute cholangitis ; Timepoint(s) of evaluation of this end point: For each NGM282 treatment group, the LS mean rate of change in ALP during Weeks 1–4 will be compared to that during Weeks 5–12; the changes in slopes will be estimated. This estimation will be performed using a MMRM similar to that of the primary efficacy analysis. It will also be repeated using percent change in ALP. Categorical secondary efficacy endpoints (reflecting incidence and severity of IBD-associated symptoms and acute cholangitis) will be analyzed using confidence intervals of differences of population treatment proportions. | — |
Countries
France, Netherlands, United Kingdom, United States
Contacts
Public ContactClinical Department
NGM
Outcome results
None listed