The testing of NGM282 for 12 weeks in patients with Primary Sclerosing Cholangitis (PSC)

• Register: EUCTR
• Last refreshed on: 30 April 2019
• Main ID: EUCTR2015-003392-30-GB
• Date of registration: 14/12/2015
• Prospective Registration: Yes
• Primary sponsor: NGM Biopharmaceuticals, Inc.
• Public title: The testing of NGM282 for 12 weeks in patients with Primary Sclerosing Cholangitis (PSC)
• Scientific title: A PHASE 2, RANDOMIZED, DOUBLE BLIND, PLACEBO CONTROLLED, PARALLEL GROUP, MULTIPLE CENTER STUDY TO EVALUATE THE SAFETY, TOLERABILITY, AND EFFICACY OF NGM282 ADMINISTERED FOR 12 WEEKS IN PATIENTS WITH PRIMARY SCLEROSING CHOLANGITIS (PSC)
• Date of first enrolment: 18/04/2016
• Target sample size: 60
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2015-003392-30
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes; Randomised: yes; Open: no; Single blind: no; Double blind: yes; Parallel group: yes; Cross over: no; Other: no; If controlled, specify comparator, Other Medicinial Product: no; Placebo: yes; Other: no; Number of treatment arms in the trial: 3
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

France, Netherlands, United Kingdom, United States

Contacts

• Name: Clinical Department
• Affiliation: NGM

• Name: Clinical Department
• Affiliation: NGM

Key inclusion & exclusion 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 < 5 × ULN
d. Serum creatinine < 2 mg/dL or creatinine clearance > 60 mL/min by Cockroft-Gault calculation
e. Platelets < 100 K/uL
f. International Normalized Ratio (INR) = 1.3 (in the absence of warfarin or other anticoagulant therapy)
g. Carbohydrate antigen 19-9 (CA19-9) = 130 U/mL
Patients with a CA 19-9 > 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 < 27 mg/kg/day
b. Minimum of 12 weeks of treatment
c. No significant dosage changes during 8 weeks prior to Screening
d. Minimum of 12 weeks washout period prior to Screening if UDCA is stopped

5. Patients with concomitant IBD are allowed to enroll upon meeting the following criteria:
a. A colonoscopy within 12 months of Screening with no evidence of dysplasia
b. No episode of an IBD flare or IBD flare–related bloody diarrhea within 6 months of Screening and through Day 1
c. Stable doses of biologic treatments, immunosuppressive, or systemic corticosteroids (< 10 mg/day) for > 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:
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

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

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 - Hepatobiliary disorders
MedDRA version: 19.0 Level: SOC Classification code 10019805 Term: Hepatobiliary disorders System Organ Class: 10019805 - Hepatobiliary disorders
MedDRA version: 19.0 Level: PT Classification code 10008609 Term: Cholangitis sclerosing System Organ Class: 10019805 - Hepatobiliary disorders
MedDRA version: 19.0 Level: HLGT Classification code 10004606 Term: Bile duct disorders System Organ Class: 10019805 - Hepatobiliary disorders

Therapeutic area: Diseases [C] - Digestive System Diseases [C06]

Intervention(s)

Product Name: NGM282
Pharmaceutical Form: Solution for injection in pre-filled syringe
INN or Proposed INN: engineered recombinant human FGF19
CAS Number: 1616639-03-2
Current Sponsor code: NGM282
Other descriptive name: rec-h-FGF19
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 1-
Pharmaceutical form of the placebo: Solution for injection in pre-filled syringe
Route of administration of the placebo: Subcutaneous use

Product Name: NGM282
Pharmaceutical Form: Solution for injection in pre-filled syringe
INN or Proposed INN: engineered recombinant human FGF19
CAS Number: 1616639-03-2
Current Sponsor code: NGM282
Other descriptive name: rec-h-FGF19
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 3-
Pharmaceutical form of the placebo: Solution for injection in pre-filled syringe
Route of administration of the placebo: Subcutaneous use

Primary Outcome(s)

Timepoint(s) of evaluation of this end point: 12 weeks compared to baseline

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.

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 Outcome(s)

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.

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

Secondary ID(s)

119,471

15-0106

Source(s) of Monetary Support

NGM Biopharmaceuticals, Inc.

Ethics review

Status: Approved
Approval date:
Contact:

Results

• Results available: Yes
• Date Posted: 15/07/2018
• Date Completed: 07/06/2017
• URL: https://www.clinicaltrialsregister.eu/ctr-search/trial/2015-003392-30/results