| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Non-alcoholic steatohepatitis |
|
| E.1.1.1 | Medical condition in easily understood language |
| Non-alcoholic liver inflammation and damage caused by a buildup of fat in the liver |
|
| E.1.1.2 | Therapeutic area | Body processes [G] - Metabolic Phenomena [G03] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10076331 |
| E.1.2 | Term | Steatohepatitis |
| E.1.2 | System Organ Class | 10019805 - Hepatobiliary disorders |
|
| 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 |
The primary objective of this study is the proof of mechanism and
support of dose finding, together with the safety evaluation in patients
with clinical evidence of NASH. |
|
| E.2.2 | Secondary objectives of the trial |
Effect of BI 1467335 on reduction of secondary biomarker endpoints
(ALT, AST, AP, Gamma-GT and CK18 fragments). Safety will be assessed
throughout the study to provide key information regarding the use of BI
1467335 in patients with NASH. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Clinical evidence of NASH defined as
a. histological evidence of NASH (no more than 3 years prior to
screening)
OR
b. clinical imaging results suggestive of NASH (no more than 3 years
prior to
screening OR within the screening phase, imaging procedures performed
as per local standard)
i. evidence of hepatic steatosis >5% measured by the MRI-PDFF or
assessed as
steatosis (raised echogenicity of the liver parenchyma) by ultrasound
AND
ii. evidence of liver fibrosis defined as mean stiffness > 3.64 kPa as
measured by
the MRE protocol or mean stiffness > 7.2 kPa as measured by ultrasound
based
transient elastography (Fibroscan®)
2. Increased ALT defined as
a. ALT >1.5 ULN at screening and ALT >1.25 ULN in a local lab within 1
week to 3 months prior screening
OR
b. Historic ALT > 1.25 ULN more than 3 months prior to screening and
two consecutive ALT > 1.5xULN must be confirmed at least 1 week apart
within the screening period
3. Age ≥ 18 and ≤75 years at screening
4. BMI ≥25kg/m2 and <45kg/m2 at screening
5. Stable body weight defined as less than 5% change in body weight in
the 3 months
prior to screening while being treated with the standard of care and not
treated with
anti-obesity medication at screening.
6. Treatment with Antidiabetic concomitant medication including any
insulin regimen needs to be stable for 3 months, and treatment with vitamin E needs to be stable for 6 months prior to informed consent and expected to be stable throughout the trial. All other concomitant medication has to be stable for at least 4 weeks prior screening.
Concomitant medications taken to treat acute conditions (e.g. headache,
sinusitis) for a short period (< 7 days) are permissible, if not otherwise prohibited.
For restricted medications please refer to section 4.2.2.1.
7. For female patients: Women of childbearing potential* can be
randomized after a negative pregnancy test and under adequate contraception with two methods, of which at least one is highly effective, during the trial.
* A woman is considered of childbearing potential (WOCBP), i.e. fertile,
following menarche and until becoming post-menopausal unless permanently
sterile.
Permanent sterilisation methods include hysterectomy, bilateral
salpingectomy and
bilateral oophorectomy. Tubal ligation is NOT a method of permanent
sterilisation.
A postmenopausal state is defined as no menses for 12 months without
an alternative
medical cause.
8. Signed and dated written informed consent in accordance with GCP
and local
legislation prior to admission to the trial. |
|
| E.4 | Principal exclusion criteria |
1. Current or history of significant alcohol consumption (defined as intake of >210g/week in males and >140g/week in females on average over a consecutive period of more than 3 months) or inability to reliably quantify alcohol consumption based on investigator judgement.
2. Prior participation in an interventional NASH trial 6 months before baseline or 5 times halflife of the investigational drug, whichever is longer.
3. Prior or planned bariatric surgery during study conduct, except gastric-band surgery more than 2 years prior to screening (including adjustments) with a stable body weight within the last 12 months.
4. Use of drugs historically associated with liver injury, hepatic steatosis or steatohepatitis in the 4 weeks prior to screening; please refer to section 4.2.2.
5. History of liver cirrhosis (fibrosis stage 4), or hepatic decompensation (e.g. ascites, hepatic encephalopathy, variceal bleeding, etc.) or history of other forms of chronic liver disease (for example Hepatitis B, Hepatitis C, autoimmune liver disease, primary biliary sclerosis, primary sclerosing cholangitis, Wilsons disease, hemochromatosis, A1At deficiency, history of liver transplantation).
6. Active known chronic or relevant acute infections, such as HIV (Human Immunodeficiency Virus), \viral hepatitis, or tuberculosis. QuantiFERON® TB test and HBs Ag test will be performed during screening. Patients with a positive test result may participate in the study if further work up (according to local practice/guidelines) establishes conclusively that the patient has no evidence of active infection.
7. Solid liver lesions other than haemangiomas. a. Suspicion or diagnosis or history of hepatocellular carcinoma (HCC)
8. eGFR <60ml/min/1.73m2 at screening (CKD-EPI formula).
9. ALT >5.0 ULN at screening.
10. Platelet count < 150.000/μL
11. Bilirubin level > ULN (except for known Gilbert´s disease with a conjugated bilirubin of < 0.3 mg/dL))
12. Uncontrolled diabetes defined as an HbA1c ≥9.5% in the 3 months prior to or at screening.
13. Diagnosis of a serious or unstable disease including hepatic (other than NASH), renal, gastroenterologic, respiratory, cardiovascular (including ischemic heart disease), endocrinologic, neurologic , psychiatric, immunologic, or hematologic disease and other conditions that, in the clinical judgment of the investigator, are likely to interfere with the analyses of safety and efficacy in this study. Patients with an expected life expectancy of less than 2 years are also excluded.
14. Major surgery (major according to the investigator’s assessment) performed within 12 weeks prior to randomisation or planned during study conduct, e.g. hip replacement.
15. Any documented active or suspected malignancy or history of malignancy within 5 years prior to screening, except appropriately treated basal cell carcinoma of the skin or in situ carcinoma of uterine cervix.
16. Patients who must or wish to continue the intake of restricted medications (see section 4.2.2.1) or any drug considered likely to interfere with the safe conduct of the trial
17. Previous randomisation in this trial.
18. Currently enrolled in another investigational device or drug study, or less than 30 days since ending another investigational device or drug study(s), or receiving other investigational treatment(s).
19. Chronic drug abuse or any condition that, in the investigator’s opinion, makes them an unreliable study subject or unlikely to complete the trial.
20. Women who are pregnant, nursing, or who plan to become pregnant while in the trial.
21. Patients with Wolff-Parkinson-White Syndrome, baseline QTc > 450 ms, family history of long QT, or on medication prolonging QT time at screening or planned initiation during the trial.
22. Any other clinical condition that, in the opinion of the investigator, would jeopardize patient safety while participating in this clinical trial.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| 1) Plasma amine oxidase copper-containing 3 (AOC3) activity relative to baseline in %, 24 h post dose, after 12 weeks of treatment. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
1) Percentage of subjects with adverse reactions.
2) relative ALT change from baseline
3) relative AST change from baseline
4) relative AP change from baseline
5) relative Gamma-GT change from baseline
6) relative caspase cleaved cytokeratin 18 (M30) change from baseline
7) relative total cytokeratin 18 (M65) change from baseline |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1) 16 weeks
2) 12 weeks
3) 12 weeks
4) 12 weeks
5) 12 weeks
6) 12 weeks
7) 12 weeks |
|
| 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 | 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 | 5 |
| 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 | 8 |
| 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 |
| Belgium |
| Canada |
| France |
| Germany |
| Ireland |
| Netherlands |
| Spain |
| United Kingdom |
| United States |
|
| 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
|
|
| 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 | 2 |
| E.8.9.1 | In the Member State concerned days | 20 |
| 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 | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 14 |
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