| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| PRIMARY SCLEROSING CHOLANGITIS (PSC) |
|
| E.1.1.1 | Medical condition in easily understood language |
| PRIMARY SCLEROSING CHOLANGITIS (PSC) |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Digestive System Diseases [C06] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10036732 |
| E.1.2 | Term | Primary sclerosing cholangitis |
| E.1.2 | System Organ Class | 10019805 - Hepatobiliary disorders |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.0 |
| E.1.2 | Level | HLT |
| E.1.2 | Classification code | 10004607 |
| E.1.2 | Term | Bile duct infections and inflammations |
| E.1.2 | System Organ Class | 10019805 - Hepatobiliary disorders |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.0 |
| E.1.2 | Level | SOC |
| E.1.2 | Classification code | 10019805 |
| E.1.2 | Term | Hepatobiliary disorders |
| E.1.2 | System Organ Class | 10019805 - Hepatobiliary disorders |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10008609 |
| E.1.2 | Term | Cholangitis sclerosing |
| E.1.2 | System Organ Class | 10019805 - Hepatobiliary disorders |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.0 |
| E.1.2 | Level | HLGT |
| E.1.2 | Classification code | 10004606 |
| E.1.2 | Term | Bile duct disorders |
| E.1.2 | System Organ Class | 10019805 - Hepatobiliary disorders |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| • 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. |
|
| E.2.2 | Secondary objectives of the trial |
• 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 |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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 CA19-9 > 130 U/mL may be enrolled if they have two results a minimum 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 consistent use of one of the following methods of birth control in addition to a male partner using a condom from Screening to 30 days after the last dose of study drug:
1. hormone-containing contraceptive
2. intrauterine device with a failure rate < 1% per year
3. cervical cap or diaphragm with spermicidal agent
4. tubal sterilization
5. vasectomy in male partner
7. Male subjects must agree to consistently and correctly use a condom in combination with one of the above methods of birth control from date of consent to 30 days after the last dose of study drug.
8. Subjects must be able to comply with the SC self-administration instructions for study drug and be able to complete the study schedule of procedures. |
|
| E.4 | Principal 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 regmin 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 MRI 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 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 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 squamous or non-invasive basal cell skin cancers is permitted; cervical carcinoma in situ is allowed if appropriately treated prior to Screening); subjects under evaluation for malignancy are not eligible.
13. Clinically-relevant drug or alcohol abuse within 12 months of screening. A positive drug screen will exclude subjects unless it can be explained by a prescribed medication.
14. Use of any prohibited concomitant medications as described in Section 5.7 within 4 weeks of Day 1 visit
15. Patients with severe allergic or anaphylactic reactions to recombinant therapeutic proteins, fusion proteins, or chimeric, human, or humanized antibodies
16. Participation in a study of another investigational agent within 4 weeks or
five half-lives of the investigational drug (whichever is longer) prior to Screening
17. History of clinically significant unstable or untreated illness or any other major
medical disorder that may interfere with subject treatment, assessment, or compliance with the protocol
18. Any acute or chronic condition or other disease that, in the opinion of the
Investigator, would limit the patient’s ability to complete and/or participate in this clinical study
19. Presence of any other conditions (e.g., geographic or social), actual or projected, that the investigator feels would restrict or limit the patient’s participation for the duration of the study
20. Employment by NGM, participating contract research organization (CRO), or study site (permanent, temporary contract worker, or designee responsible for the conduct of the study) or are immediate family of an NGM employee, participating CRO, or study-site employee (hence, conflict of interest issues). Immediate family is defined as a spouse, parent, child, or sibling, whether biological or legally adopted.
The Investigator has discretion to repeat assessments/procedures if he/she believes there is a good chance the results were spurious and do not accurately represent the subject’s true values. Repeat assessments/procedures must be conducted within the 6-week Screening Period, prior to randomization, and a subject may only be rescreened for these labs a single time. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy endpoint is the mean change in ALP from Baseline at Week 12. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 12 weeks compared to baseline |
|
| E.5.2 | 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 |
|
| E.5.2.1 | 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. |
|
| 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 | Yes |
| 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 | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| 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 | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 27 |
| 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 |
| France |
| Netherlands |
| United Kingdom |
| United States |
|
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | 2 |
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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