E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Primary biliary cirrhosis |
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E.1.1.1 | Medical condition in easily understood language |
Disease of the liver marked by the slow progressive destruction of the small bile ducts within the liver |
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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 | 14.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10036680 |
E.1.2 | Term | Primary biliary cirrhosis |
E.1.2 | System Organ Class | 10019805 - Hepatobiliary disorders |
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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 |
To investigate the efficacy of multiple doses of NI 0801 on hepatic function
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E.2.2 | Secondary objectives of the trial |
To evaluate the safety and tolerability of multiple doses of NI-0801 in primary biliary cirrhosis patients
To characterize the pharmacokinetic and pharmacodynamic profile of multiple doses of NI 0801
To assess immunogenicity of NI 0801 |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Male or female, 18 years or older
2. Proven PBC, as demonstrated by the presence of at least 2 of the following 3 diagnostic factors:
− History of increased ALP levels for at least 6 months
− Positive serum AMA titer (>1:40)
− Liver biopsy consistent with PBC
3. Incomplete response to UDCA defined as failure to normalise ALP levels or to reduce ALP levels by more than 40% after 1 year of therapy with UDCA according to the local recommended dose.
4. Stable dose of UDCA for at least 6 months prior to screening
5. Screening ALP > 1.5 ULN
6. Screening ALT or AST > 1.5 ULN
7. Female patients must be postmenopausal, surgically sterile, or willing to use 2 methods of effective contraception with all sexual partners until 3 months after having received the last dose of study medication
8. Male patients who agree to take the appropriate precautions to avoid fathering a child until 3 months after having received the last dose of study medication
9. Have given written informed consent |
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E.4 | Principal exclusion criteria |
1. Screening bilirubin > 2.9 mg/dL (50 μmol/L)
2. Screening creatinine clearance < 80 ml/min
3. History or presence of hepatic decompensation
4. History or presence of other concomitant liver diseases including hepatitis due to hepatitis B or C virus (HCV, HBV), primary sclerosing cholangitis (PSC), alcoholic liver disease, definite autoimmune liver disease (AIH) and biopsy proven nonalcoholic steatohepatitis (NASH)
5. Positive serology result for Human Immunodeficiency Virus (HIV), Hepatitis B or C
6. Average alcohol ingestion >21 units/week (male) / >14 units/week (female)
7. Have received any immunosuppressants, steroids or peroxisome proliferator activation receptor (PPAR) activators at any time during the 3 months prior to screening for the study
8. Known or previous diagnosis of malignancy
9. Presence of any active infection
10. Presence or history of multiple allergic reactions to drugs
11. Previous history of active TB within 12 months of screening
12. Pregnant or breastfeeding women
13. Have received or plan to receive any vaccines within 6 weeks prior to receiving study drug and throughout the study period |
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E.5 End points |
E.5.1 | Primary end point(s) |
Change in liver enzyme measurements from baseline to Week 12 (SD85) |
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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) |
PBC-related exploratory assessments
• Biochemical markers of liver function
• Mayo risk score (MRS)
• Liver stiffness measurement (LSM) with Transient Elastography (Fibroscan™)
• Enhanced Liver Fibrosis (ELF) test
• Quality-of-Life assessment: PBC-40
Pharmacokinetic characterisation
Pharmacodynamic measurements
• The evolution over time of total circulating CXCL10 levels will be measured
Extent of the NI 0801 inhibition on CXCL10 chemotactic activity by in vitro chemotaxis
• Serum cytokines and chemokines
• FACS analysis for the quantification of leukocytes and subsets and CXCR3 expression on these subsets
Safety and tolerability
• All emerging AEs
• The number of subjects withdrawing from the study for safety related reasons
• Vital signs and any changes revealed by medical examination.
• Laboratory abnormalities in Safety Hematology parameters, Safety Blood Chemistry parameters and Urinalysis parameters
Immunogenicity
• The presence of anti-drug antibodies
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
ELF, Fibroscan, PBC-40: SD1, SD85, W18
PK, blood samples: SD1, SD5, SD15, SD29, SD43, SD57, SD71, SD75, SD85, W18, W24
Chemokines/cytokines: SD1, SD5, SD15, SD29, SD43, SD57, SD71, SD75, SD85, W18, W24
FACS: SD1, SD85
Immunogenicity: SD1, SD15, SD29, SD43, SD57, SD71, W24
Vital signs, hematology and biochemistry blood samples, AEs recording & concomittant medications: SD1, SD5, SD15, SD29, SD43, SD57, SD71, SD75, SD85, W18, W24
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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 | Yes |
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
| 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 | 12 |
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 | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
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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The date of the last visit of the last patient undergoing the study. |
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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 | 1 |
E.8.9.1 | In the Member State concerned days | 30 |