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. To gain further insight into clinical effects of AOC3 inhibition on NASH…
ID
Source
Brief title
Condition
- Other condition
- Hepatic and hepatobiliary disorders
Synonym
Health condition
NASH (niet alcoholische steatose hepatitis)
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary endpoint is the plasma amine oxidase copper-containing 3 (AOC3)
activity relative to baseline in %, 24 h post dose, after 12 weeks of
treatment. The baseline is defined as the last AOC3 activity measurement prior
to administration of any randomised study medication.
Secondary outcome
Safety and tolerability will be assessed based on the number (%) of subjects
with adverse reactions.
The secondary biomarker endpoints will be assessed based on the:
- relative ALT change from baseline after 12 weeks of treatment
- relative AST change from baseline after 12 weeks of treatment
- relative AP change from baseline after 12 weeks of treatment
- relative gamma-GT change from baseline after 12 weeks of treatment
- relative caspase cleaved cytokeratin 18 (M30) change from baseline after 12
weeks of treatment
- relative total cytokeratin 18 (M65) change from baseline after 12 weeks of
treatment
Background summary
To date, no approved therapy for liver fibrosis or effective disease modifying
regimen for NASH is available. The current standard of care for NASH is weight
loss through diet and exercise to improve insulin resistance and lower fat
mass, which is a clinically challenging goal to achieve and therefore only
affects a minor proportion of the patients. Persistent inflammation in response
to liver injury is the critical factor that drives progression to fibrosis,
cirrhosis, and hepatocellular carcinoma. Inflammation at any site, including
the liver, is the result of an accumulation of leukocytes organized into an
inflammatory infiltrate. For this to occur, leukocytes must be recruited from
the circulation by interactions with the endothelium and positioned within the
tissue. A key protein in promoting the recruitment of leukocytes in liver
tissue is AOC3, which is
constitutively expressed on human hepatic endothelium. BI 1467335 is an
irreversible AOC3 inhibitor with anti-inflammatory and anti-oxidative stress
activities that is currently under development for the treatment of chronic
liver disease secondary to Non-alcoholic Steatohepatitis (NASH).
This first study in NASH patients is performed to support the proof of
mechanism and to allow further insights into the dose-response relationship of
BI 1467335.
Please also refer to protocol section 1.1.
Study objective
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.
To gain further insight into clinical effects of AOC3 inhibition on NASH
further exploratory analyses of biomarkers related to NASH and liver fibrosis
will be performed. This will include the 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.
Additional objectives include investigation of PK and further PD
parameters/biomarkers after repeated dosing of BI 1467335 in patients with NASH.
Please also refer to protocol section 2.2.
Study design
Please also refer to protocol section 3.1.
Intervention
Multiple doses of BI 1467335 and/or Placebo to match BI 1467335 will be
administered.
For details, refer to protocol section 4.1.1. - 4.1.4.
Study burden and risks
This is a newly developed drug at an early stage of testing and therefore an
individual benefit cannot be guaranteed, nonetheless inhibiting AOC3 enzymatic
activity might be beneficial for patients with steatohepatitis.
Total duration of the study for a patient is maximal 20 weeks. 1-4 week
screening period (1 visit), 12 week treatment period (6 site visits and 2 phone
call visits) and a 4 week follow-up period (1 visit). The end of treatment
visits is two days. Total duration of these visits is 42,5 hours.
Procedures that are done during the study are: height 1x, weight waist and hip
circumference 8x, vital signs 8x, ECG 8x, pregnancy test (if applicable 8x,
standard blood drawing 8x, PK blood samling 37x, PK urine collection 3x,
PG-sampling 1x, PD-sampling 7x. During the 12-week treatment period, patients
must complete a (paper) diary in which the date and time of intake of
studymedication is to be written down.
Patients have a risk on (unknown) side effects, an allergic reaction to the
study medication, catheter site pain and Erythema (redness) or skin reaction at
ECG electrode site.
Please also refer to protocol section 2.3.
Comeniusstraat 6
Alkmaar 1817 MS
NL
Comeniusstraat 6
Alkmaar 1817 MS
NL
Listed location countries
Age
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)
i. evidence of hepatic steatosis > 5% measured by the MRI-PDFF protocol ) or assessed as moderate to severe steatosis (raised echogenicity) 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. ALT > 1.5 ULN at screening and ALT > 1.25 ULN in a local lab within 1 week to 3 months prior screening;;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 site 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;;Further criteria apply, see protocol section 3.3.2.
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;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/*L ;Further criteria apply, see protocol section 3.3.3.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2016-000499-83-NL |
| ClinicalTrials.gov | NCT03166735 |
| CCMO | NL60270.056.17 |