| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| NON-ALCOHOLIC STEATOHEPATITIS |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10053219 |
| E.1.2 | Term | Non-alcoholic steatohepatitis |
|
| 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 |
To evaluate the efficacy of 20 mg QD and 5 mg QD of CP-945,598 given for 48 weeks in the treatment of NASH.
|
|
| E.2.2 | Secondary objectives of the trial |
To evaluate the safety and tolerability of 20 mg QD and 5 mg QD of CP-945,598 given for 48 weeks in the treatment of NASH.
To evaluate the effect of CP-945,598 in subjects with NASH on circulating biomarkers and validate their relationship with histological changes over time.
To assess the population PK of CP-945,598 in subjects with NASH following multiple doses of 20 mg QD and 5 mg QD for 48 weeks in order to develop a PK/PD model for efficacy and safety endpoints. The influence of CYP3A5 polymorphisms on the PK/PD of CP-945,598 will also be assessed with the PK/PD model.
To evaluate the effect of CP-945,598 on health-related QoL in subjects with NASH. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Male or female subjects between 18 and 65 years of age inclusive (of minimum adult legal age, according to local laws for signing the informed consent document).
2.Evidence of a personally signed and dated informed consent document indicating that the subject (or a legally acceptable representative) has been informed of all pertinent aspects of the trial.
3.Subjects with BMI of 25-40 kg/m2.
4.Subjects with biopsy evidence of NASH (confirmed by central review) in the 24 weeks prior to the first screening visit or a protocol biopsy at Visit 2. All subjects should have:
a.A diagnosis of steatohepatitis by the local histopathologist.
b.NAS of greater (or equal) to 4 – to include a score of at least >1 on ballooning (confirmed by central histopathology review).
c.Fibrosis Stage 1 to 3 excluding stage 4 (cirrhosis)Note: Guidance for those who fulfill all other criteria for selection and who require biopsy for the purpose of the protocol – subjects with at least 2 risk factors of the Metabolic Syndrome (Age >50 years, BMI >30 kg/m2, glucose intolerance and hypertension) are more likely to have features of NASH.
5.Hemoglobin greater (or equal) to11g/dL, platelet count greater (or equal) to100,000 cells/mm3, neutrophil count greater (or equal) to 1500 cells/mm3.
6.For women of childbearing potential (WOCBP), a negative serum pregnancy test will be required prior to randomization. Female subjects must be surgically sterile or postmenopausal or must agree to use adequate and effective contraception during the study.
a.Even women who are using oral, implanted or injectable contraceptive hormones or mechanical products (intrauterine devices; barrier methods) to prevent pregnancy; who are practicing abstinence; or who have a partner that is sterile (eg, vasectomy) should be considered to be of child bearing potential.
b.Willingness to utilize adequate contraception for WOCBP from screening to at least 4 Weeks after the study.
Note: Oral contraceptive use is permitted if used for at least 3 months before starting study medication.
Note: The definition of effective contraception will be based on the judgment of the Investigator or a designated associate.
7.Subjects who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other trial procedures.
|
|
| E.4 | Principal exclusion criteria |
Subjects with a known history of, or presenting with, any of the following will not be
included in the trial:
1. Known history chronic liver disease:
a. Chronic infections with Hepatitis B virus (HBV), Hepatitis C virus (HCV), Ebstein Barr Virus (EBV) and Cytomegalovirus (CMV) or other chronic infection known to cause liver disease – eg, Human Immunodeficiency Virus (HIV), schistosomiasis etc.
b. Auto-immune hepatitis.
c. Auto-immune cholestatic disease.
d. Genetic liver diseases including Wilson’s, α-1-antitrypsin deficiency (A1AT), Haemachromatosis or secondary iron overload.
e. Drug induced liver disease defined on the basis of typical exposure and history of ingestion of drugs known to produce hepatic injury including but not limited to highdose estrogens, tetracycline, tamoxifen or amiodarone in the previous 24 weeks.
f. Cholestatic liver disease.
2. Known history or presence of decompensated or severe liver disease is defined by one or more of the following criteria:
a. Prior liver biopsy showing cirrhosis.
b. Abnormal INR (Normal value 0.8-1.2) in the absence of anticoagulants.
c. Direct (conjugated) bilirubin of ≥ 0.6 mg/dL.
d. Serum albumin below laboratory normal range.
e. ALT ≥ 250 IU/L during the screening visits.
f. Evidence of portal hypertension including splenomegaly, ascites, encephalopathy, and/or esophageal varices.
g. Child-Pugh score >7 (Appendix 9).
h. Hospitalization for liver disease in the 60 days prior to screening (except if it has been for performing a liver biopsy).
3. Women who are pregnant or lactating, or who have a positive serum or urine pregnancy test or are planning to become pregnant.
4. Subjects with clinically significant abnormalities identified during the screening process.
Specific exclusions include but are not limited to the following:
a. CV:
i. Subjects with blood pressure (BP) systolic BP ≥ 155 and/or diastolic BP ≥ 95 mm Hg (confirmed by repeated measurement) or BP requiring new pharmacological treatment or change in current treatment according to local guidelines.
b. Neurological and Psychiatric:
i. Subjects with a history of CNS disorder including:
• A mood disturbance that meets the criteria for a Major Depressive Disorder according to the Diagnostic and Statistical Manual of Mental Disorders Fourth Edition – Text Revision (DSM-IV TR) criteria within the last 2 years prior to screening defined as:
• Requiring hospitalization, or
• Two or more episodes of a major depressive disorder, or
• Any previous suicide attempt.
• PHQ-9 and C-SSRS results (administered on the day of screening and at randomization visit).
• Positive score to PHQ-9 item 9 addressing suicidal ideas and/or;
• PHQ score ≥15.
• Any positive response to the C-SSRS that indicates potential suicidality.
ii. Subjects with severe psychiatric disorders such as psychotic conditions (eg, schizophrenia, bipolar disorder) or on antipsychotic pharmacotherapy.
iii. Subjects with seizure disorders whoare not controlled by current antiepileptic treatment, and/or are taking antiepileptic drugs that may increase the risk for a drug-drug interaction. See exclusion criteria #9 below.
iv. Subjects with neurological disorders that are acute, chronic relapsing, progressive or have an unpredictable course.
c. Renal impairment (creatinine >1.5 x ULN) or history of hepatorenal syndrome. Any history of nephrotic syndrome; subjects with significant proteinuria on urine dipstick should have an evaluation to rule out nephrotic syndrome prior to randomization.
d. Gastrointestinal (GI) bypass surgery and other weight reducing surgical treatments for morbid obesity and NASH.
e. Patients with diabetes (Type 1 or 2) who are on insulin or who have an HbA1c of ≥ 9%.
f. Clinical laboratory tests outside the pre-specified exclusionary limits as defined by the central/affiliate laboratory considered significant in the judgment of the investigator.
g. History of pancreatitis or spontaneous bacterial peritonitis or any other active systemic infection at the time of entry into the study.
5. Malignancy:
a. Hepatocellular carcinoma (HCC) at entry into the study (AFP levels greater than 200 ng/ml and/or liver mass on imaging study that is suggestive of liver cancer).
b. Subjects with any prior history of malignancy except for Basal cell carcinoma of the skin curatively treated or other malignancies (regardless of site) that have been cancer-free for greater than 5 years prior to screening.
6. Suspected excessive alcohol consumption OR a history of excess alcohol ingestion, averaging more than 20 gm/day (2 drinks per day) for males; 10 gm/day (1 drink per day) for females in the previous one year.
7. History of HIV infection or use of antiretroviral agents.
8. Contraindications to liver biopsy. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Change from baseline in liver histology as measured by the NAS at 48 weeks of the study. A response will be defined as ≥ 2-point improvement in NAS from baseline, with a 1-point improvement in the hepatocellular ballooning component of the NAS, and an additional total 1-point improvement in the lobular inflammation and steatosis components of the NAS, with no worsening in fibrosis, at 48 weeks of the study. |
|
| 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 | Information not present in EudraCT |
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
| Tolerability and Quality of Life |
|
| 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.8.3 |
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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 18 |
| 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 | Information not present in EudraCT |
| 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 |
|
| 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 | 1 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | 21 |
| 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 | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 21 |
Print
