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Trial registered on ANZCTR


Registration number
ACTRN12621000080820p
Ethics application status
Submitted, not yet approved
Date submitted
3/12/2020
Date registered
29/01/2021
Date last updated
29/01/2021
Date data sharing statement initially provided
29/01/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
A study to test the effect of different doses of BI 456906 in people with a liver disease called non-alcoholic steatohepatitis (NASH) and liver fibrosis
Scientific title
Multicenter, double-blind, parallel-group, randomised, 48 weeks, dose-ranging, placebo-controlled phase II trial to evaluate efficacy, safety and tolerability of multiple subcutaneous (s.c.) doses of BI 456906 in patients with non-alcoholic steatohepatitis (NASH) and fibrosis
Secondary ID [1] 302939 0
BI 1404-0043
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Non-alcoholic steatohepatitis 319967 0
Liver Fibrosis 320233 0
Condition category
Condition code
Metabolic and Endocrine 317901 317901 0 0
Metabolic disorders
Oral and Gastrointestinal 318168 318168 0 0
Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This trial is designed as a multi-centre, randomised, dose-ranging, double-blind, placebo controlled, parallel group trial for patients with non-alcoholic steatohepatitis (NASH). The patient will receive treatment with either BI 456906 or placebo for 48 weeks and the study drug will be administered as a subcutaneous injection once a week. Patients have an equal chance of being allocated to one of the following groups:
• Group 1 will receive BI 456906 and the dose will gradually increase from 0.3 mg to 2.4 mg and then remain at 2.4 mg per week from Week 16.
• Group 2 will receive BI 456906 and the dose will gradually increase from 0.3 mg to 4.8 mg and then remain at 4.8 mg per week from Week 20.
• Group 3 will receive BI 456906 and the dose will gradually increase from 0.3 mg to 6.0 mg and then remain at 6.0 mg per week from the Week 24.
• Group 4 will receive placebo during the entire treatment period.

Doses will be increased every 2 weeks until a participant reaches their target dose in their assigned group. Initially the dose will be increased 0.3mg in dose per fortnight. At Week 8, Group 1 will receive 1.8mg for 4 weeks, this will increase to 2.1mg at Weeks 12 and 13 and finally reach their target dose of 2.4mg at Week 16. At Week 8 Participants in Group 2 and 3 will have their dose increased by 0.6mg per fortnight until Group 2 reaches their target dose of 4.8mg at Week 18 and Group 3 will continue to increase by this increment until they reach their target dose of 6mg at Week 22.

Participants will receive two subcutaneous injections once weekly. When the participant attends the study site for their visit they will receive the injection from a site staff member however when the participant is at home for their designated visit the participant will either self-administer or designate this responsibility to a family/friend. The participant or designee will receive training on how to administer the pre-filled syringes. The participant will be required to keep a diary where they need to record the details of the drug administration and the administration will need to take place during study video call so that the study team can check that the injection is being made correctly.
Intervention code [1] 319225 0
Treatment: Drugs
Comparator / control treatment
Patients randomised to Group 4 will receive placebo which is a solution they will received by subcutaneous injection weekly. Commercially available isotonic saline solution in 10 mL polyethylene ampoules will be used as placebo solution for injection.
Control group
Placebo

Outcomes
Primary outcome [1] 325917 0
The primary endpoint is the improvement (yes/ no) from baseline in liver histological findings based on liver biopsy after 48 weeks of treatment in patients with NASH (NAS greater than or equal to 4, fibrosis F1-F3). NAFLD activity score (NAS) represents the sum of scores for steatosis (0-3), lobular inflammation (0-3) and ballooning (0-2).
Improvement in histological findings is defined as a composite of:
Improvement in NASH: Decrease of at least 2 points in NAS with at least 1 point decrease in NAS subscore of either lobular inflammation or ballooning
AND No worsening of fibrosis, defined as absence of any increase in the fibrosis stage.
Timepoint [1] 325917 0
Baseline (Visit 1a) and Week 48 post-intervention commencement.
Secondary outcome [1] 389498 0
Improvement of liver fat content (yes/ no) defined as at least 30% relative reduction in
liver fat content after 48 weeks of treatment compared to baseline assessed by magnetic
resonance imaging proton density fat fraction measurement (MRI-PDFF)
Timepoint [1] 389498 0
Baseline (Visit 1), Week 28 and Week 48 post-intervention commencement.
Secondary outcome [2] 389499 0
Absolute and relative change of liver fat content from baseline after 48 weeks of treatment assessed by MRI-PDFF. This is a composite endpoint.
Timepoint [2] 389499 0
Screening (Visit 1), Week 28 and Week 48 post-intervention commencement.
Secondary outcome [3] 389500 0
Improvement of fibrosis (yes/ no) defined as at least one stage decrease in fibrosis stage after 48 weeks of treatment assessed by liver biopsy. Assessment of liver biopsy specimens will be set-up in a blinded fashion. It will be based on the NAFLD scoring system (NAS), developed by the NASH clinical research network (CRN).
Timepoint [3] 389500 0
Screening (Visit 1a) and Week 48 post-intervention commencement.
Secondary outcome [4] 389501 0
Absolute change from baseline in NAFLD Activity Score (NAS) after 48 weeks of treatment assessed by liver biopsy
Timepoint [4] 389501 0
Screening (Visit 1a) and Week 48 post-intervention commencement.
Secondary outcome [5] 390266 0
Pharmacokinetic endpoints for BI 456906: Cpre,N (pre-dose concentration of the analyte in plasma immediately before dose N) assessed using serum assay.
Timepoint [5] 390266 0
Collected prior to administration of the study drug at Week 1, Week 2, Week 4, Week 6, Week 8, Week 10, Week 12, Week 16, Week 20, Week 24, Week 28, Week 36, Week 48 and at Week 52 post-intervention commencement.
Secondary outcome [6] 390267 0
Plasma concentration of BI 456906 will be used for the evaluation of dose-proportionality.
Timepoint [6] 390267 0
Blood collection prior to administration of study drug at Week 1, Week 2, Week 4, Week 6, Week 8, Week 10, Week 12, Week 16, Week 20, Week 24, Week 28, Week 36, Week 48 and at Week 52 post-intervention commencement.
Secondary outcome [7] 391132 0
Plasma concentration of BI 456906 will be used for the evaluation of attainment of steady state.
Timepoint [7] 391132 0
Blood collection prior to study drug administration at Week 1, Week 2, Week 4, Week 6, Week 8, Week 10, Week 12, Week 16, Week 20, Week 24, Week 28, Week 36, Week 48 and at Week 52 post-intervention commencement.
Secondary outcome [8] 391142 0
Overall safety as assessed from adverse events (AEs coded using the current version of the Medical Dictionary of Regulatory Activities (MedDRA)), vital signs assessed by clinical examination, safety laboratory parameters assessed by blood collection and cardiac health assessed by 12-lead ECG.
Timepoint [8] 391142 0
Overall safety will be assessed at various timepoints as outlined below.
Adverse Events: Assessed at every patient visit.
Vitals signs: Screening and Day 1, Day 8, Day 15, Day 22, Week4, Week 6, Week 8, Week 10, Week 12, Week 16, Week 20, Week 24, Week 28, Week 32, Week 36, Week 40, Week 44, Week 48 and Week 52 post-intervention commencement.
Laboratory tests and 12-lead ECG: Screening, Day 1, Day 15, Week 4, Week 6, Week 8, Week 10, Week 12, Week 16, Week 20, Week 24, Week 28, Week 32, Week 36, Week 40, Week 44, Week 48 and Week 52 post-intervention commencement.

Eligibility
Key inclusion criteria
1. Male or female patients greater than or equal to 18 years and less than or equal to 80 years of age at time of consent.
2. Diagnosis of NASH (NAS greater than or equal to 4, with at least 1 point in inflammation and ballooning each) and fibrosis stage F1–F3 proven by a biopsy conducted during the screening period or by a historical biopsy conducted within the last 6 months prior to randomization and stable body weight defined as less than 5% self-reported change in body weight between the historical biopsy and randomization, if a historical biopsy is used.
3. Liver fat fraction greater than or equal to 8% measured by MRI-PDFF and liver stiffness > 6.0 kPa measured by FibroScan® at screening visit (if biopsy is scheduled during the
screening period MRI-PDFF and FibroScan® assessments have to be performed prior to the biopsy).
4. Patients willing and able to undergo liver biopsies per protocol as judged by the Investigator.
5. BMI greater than or equal to 25 kg/m2 and a body weight greater than or equal to 70 kg at screening visit.
6. Signed and dated written informed consent in accordance with ICH-GCP and local legislation prior to admission to the trial.
7. Women of childbearing potential (WOCBP) must be willing and able to use two forms of effective contraception where at least one form is highly effective methods of birth control per ICH M3 that result in a low failure rate of less than 1% per year when used consistently and correctly. A list of contraception methods meeting these criteria is provided in the patient information.
Minimum age
18 Years
Maximum age
80 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Current or history of significant alcohol consumption (defined as intake of greater than 210 g/ week in males and greater than 140 g/ 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 within the last 5 years.
2. Intake of medications historically associated with liver injury, hepatic steatosis or steatohepatitis within 12 weeks prior to screening visit. Intake of restricted medications or any medications considered likely to interfere with the safe conduct of the trial.
3. History of other forms of chronic liver disease (e.g. viral hepatitis, autoimmune liver disease, primary biliary sclerosis, primary sclerosing cholangitis, Wilson’s disease, hemochromatosis, A1 At deficiency, history of liver transplantation). Hepatitis B and C testing will be done at screening visit.
4. Suspicion, diagnosis or history of hepatocellular carcinoma (HCC), or any documented active or suspected malignancy or history of malignancy with in 5 years prior to screening, except appropriately treated basal cell carcinoma of the skin or in situ carcinoma of uterine cervix.
5. Personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2, manifest hypo- or hyperthyroidism at screening visit.
6. History of chronic or acute pancreatitis or elevation of serum lipase/amylase > 2x ULN, or fasting serum triglyceride levels of > 500 mg/dL at screening visit.
7. Known history of HIV (Human Immunodeficiency Virus) infection and/or tuberculosis and/or acute SARS-CoV-2 infection at screening visit
8. Abnormal laboratory values as listed below:
a) Estimated Glomerular Filtration Rate (eGFR) < 30 ml/min/1.73 m2 at screening visit (Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] formula);
b) Platelet count < 150.000/ µL at screening visit;
c) Bilirubin level > 1.5x ULN at screening visit (except for known Gilbert’s disease with a conjugated bilirubin of < 0.3 mg/dL;
d) ALT and/or AST > 5x ULN at screening visit;
e) Glycosylated haemoglobin (HbA1c) greater to or equal than 9.5% at screening visit;
f) Calcitonin greater to or equal then 20pg/mL at screening visit.
9. 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 trial. Patients with an expected life expectancy of less than 2 years are also excluded.
10. Any suicidal behavior or history of major depressive disorder in the past 2 years before randomization, any suicidal ideation of type 4 or 5 in the C -SSRS in the past 3
months prior to screening visit.
11. Bariatric surgery, prior to or planned during trial conduct; except gastric-band surgery more than 2 years prior to screening (including adjustments) with a stable body
weight within the last 12 months. Any other major surgery (major according to Investigator’s assessment) performed within 12 weeks prior to randomization or planned during trial conduct.
12. Resting heart rate > 100 beats per minute (bpm) and/or blood pressure greater than or equal to 160/ 95 mmHg at screening visit.
13. A marked baseline prolongation of QT/ QTc interval (such as QTc intervals greater than 450 ms at screening visit) or any other abnormal clinically significant ECG finding at screening visit (e.g., type 2 second-degree AV block (Type Mobitz II) or third-degree AV block).
14. History of ventricular tachycardia, type 2 second-degree AV block (Type Mobitz II) or third-degree AV block.
15. Heart rhythm disturbances (e.g., bradycardia with baseline heart rate < 50 bpm, in the absence of heart rate lowering medications), tachycardia or tachyarrhythmia (e.g.,
atrial fibrillation, atrial flutter or ventricular tachycardia), considered by the Investigator indicative of relevant cardiac disease or with abnormalities that may
interfere with the interpretation of changes in ECG intervals at screening visit. Family history of long QT syndrome, use of prescription or over-the-counter medications
known to significantly prolong the QT/ QTc interval at screening visit.
16. Any of the following conditions or procedures within the last six months prior to screening visit: myocardial infarction, unstable angina (e.g. Canadian Cardiovascular Society (CCS) grading of Angina pectoris grade III and IV), artery bypass (e.g. coronary artery bypass graft, carotid bypass, peripheral artery bypass), percutaneous coronary intervention (diagnostic angiograms are permitted), transient ischaemic attack, cerebrovascular accident (stroke) or decompensated congestive heart failure.
17. Women who are pregnant, nursing, or who plan to become pregnant while in the trial.
18. Contraindication to magnetic resonance imaging including, but not limited to: severe claustrophobia, extensive tattoos, inner ear implant, pacemakers or other implanted cardiac rhythm management devices, intracranial aneurism clips incompatible with MRI, any other metallic, non-MR compatible implanted
devices (e.g. insulin pump, hip joint replacement), a history of intra-orbital metal fragments that have not been removed, and weight or girth that exceeds scanner capabilities.
19. Prior participation in an interventional trial during the previous 6 months or 5 times the half-life of the investigational drug, whichever is longer, before screening visit.
20. Any other clinical condition that, in the opinion of the Investigator, would jeopardize patient safety while participating in the trial.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Central randomisation by computer-based Interactive Web Response System will be performed at Visit 2.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
After the assessment of all in- and exclusion criteria, each eligible patient will be randomised to treatment groups according to a randomisation plan in a 1:1:1:1 ratio stratified based on:
Presence of any type of diabetes (Yes, No) and Country (Rest of World, China). Simple randomisation using a randomisation table created by computer software (i.e. computerised sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint/s
Efficacy
Statistical methods / analysis
The main trial objectives are to demonstrate a non-flat dose response curve, to evaluate the size of the treatment effect (using the absolute difference in proportions of patients with histological improvement between BI 456906 and placebo at Week 48), and to characterize the dose-response relationship. For this purpose, the primary analysis uses methodology for dose finding employing both multiple comparison procedures and modelling techniques (MCPMod).

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
4/05/2021
Actual
Date of last participant enrolment
Anticipated
30/11/2021
Actual
Date of last data collection
Anticipated
28/02/2023
Actual
Sample size
Target
240
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
QLD,WA,VIC
Recruitment outside Australia
Country [1] 23243 0
Austria
State/province [1] 23243 0
Country [2] 23244 0
Belgium
State/province [2] 23244 0
Country [3] 23245 0
Canada
State/province [3] 23245 0
Country [4] 23246 0
China
State/province [4] 23246 0
Country [5] 23247 0
Czech Republic
State/province [5] 23247 0
Country [6] 23248 0
France
State/province [6] 23248 0
Country [7] 23249 0
Germany
State/province [7] 23249 0
Country [8] 23250 0
Greece
State/province [8] 23250 0
Country [9] 23251 0
Hong Kong
State/province [9] 23251 0
Country [10] 23252 0
Hungary
State/province [10] 23252 0
Country [11] 23253 0
Ireland
State/province [11] 23253 0
Country [12] 23254 0
Israel
State/province [12] 23254 0
Country [13] 23255 0
Italy
State/province [13] 23255 0
Country [14] 23256 0
Japan
State/province [14] 23256 0
Country [15] 23257 0
Korea, Republic Of
State/province [15] 23257 0
Country [16] 23258 0
Malaysia
State/province [16] 23258 0
Country [17] 23259 0
Netherlands
State/province [17] 23259 0
Country [18] 23260 0
New Zealand
State/province [18] 23260 0
Country [19] 23261 0
Poland
State/province [19] 23261 0
Country [20] 23262 0
Portugal
State/province [20] 23262 0
Country [21] 23263 0
Singapore
State/province [21] 23263 0
Country [22] 23264 0
Spain
State/province [22] 23264 0
Country [23] 23265 0
Taiwan, Province Of China
State/province [23] 23265 0
Country [24] 23266 0
United Kingdom
State/province [24] 23266 0
Country [25] 23267 0
United States of America
State/province [25] 23267 0

Funding & Sponsors
Funding source category [1] 307362 0
Commercial sector/Industry
Name [1] 307362 0
Boehringer Ingelheim International GmbH
Country [1] 307362 0
Germany
Primary sponsor type
Commercial sector/Industry
Name
Boehringer Ingelheim International GmbH
Address
Binger Strasse 173 55216 Ingelheim am Rhein
Country
Germany
Secondary sponsor category [1] 308004 0
None
Name [1] 308004 0
Address [1] 308004 0
Country [1] 308004 0

Ethics approval
Ethics application status
Submitted, not yet approved
Ethics committee name [1] 307447 0
Melbourne Health HREC
Ethics committee address [1] 307447 0
300 Grattan St, Parkville VIC 3050
Ethics committee country [1] 307447 0
Australia
Date submitted for ethics approval [1] 307447 0
22/01/2021
Approval date [1] 307447 0
Ethics approval number [1] 307447 0

Summary
Brief summary
This trial is designed to evaluate safety, tolerability, PK and PD of BI 456906 in male and female patients with non-alcoholic steatohepatitis
(NASH) and liver fibrosis using multiple escalation schemes and doses, and will support dose selection for phase 3 clinical development of BI 456906 . Currently, no approved pharmacotherapy for NASH, the progressive form of NAFLD, is available, relying on treatment of the comorbidities of the
metabolic syndrome. Obesity is associated with a variety of medical conditions, including all components of the metabolic syndrome, cardiovascular, pulmonary, gastrointestinal, endocrine, joint and psychosocial disorders. Currently, the available weight loss medications lack sufficient efficacy, safety, tolerability and convenience to reduce body weight and improve its associated co-morbidities/ conditions.

This trial is a randomised, double-blind, placebo-controlled trial in which three dose regiments of BI 456906 will be compared to placebo over 48-week treatment period. Only approximately 60 patients out of total 240 patients will be randomised to receive placebo treatment. A placebo-control design is required for evaluation of evaluation of BI 456906 tolerability and safety. In addition, a placebo arm is needed in order to avoid potential confounding factors, such as placebo effect, potential investigator bias in safety and efficacy assessment or regression to the mean in endpoint scoring.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 107270 0
Dr Siddharth Sood
Address 107270 0
The Royal Melbourne Hospital - City Campus
Department of Gastroenterology & Hepatology
300 Grattan Street
Parkville VIC 3050
Country 107270 0
Australia
Phone 107270 0
+61393427470
Fax 107270 0
Email 107270 0
[email protected]
Contact person for public queries
Name 107271 0
Siddharth Sood
Address 107271 0
The Royal Melbourne Hospital - City Campus
Department of Gastroenterology & Hepatology
300 Grattan Street
Parkville VIC 3050
Country 107271 0
Australia
Phone 107271 0
+61393427470
Fax 107271 0
+61393427470
Email 107271 0
[email protected]
Contact person for scientific queries
Name 107272 0
Fiona Shepheard
Address 107272 0
Boehringer Ingelheim
Level 1, 78 Waterloo Rd, North Ryde, NSW 2113,
Country 107272 0
Australia
Phone 107272 0
+61288758744
Fax 107272 0
Email 107272 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
9965Clinical study report    A lay summary of the results of the clinical trial... [More Details]



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