Different Doses of BI 1467335 Compared to Placebo in Patients With Clinical Evidence of NASH

NCT ID: NCT03166735

Last Updated: 2020-06-11

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 114 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-06-06
• Study Completion Date: 2019-06-14

Brief Summary

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, γ-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.

Conditions

Non-alcoholic Fatty Liver Disease

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

BI 1467335 dose 1

Group Type: EXPERIMENTAL

BI 1467335

Intervention Type: DRUG

once daily

BI 1467335 dose 2

Group Type: EXPERIMENTAL

BI 1467335

Intervention Type: DRUG

once daily

BI 1467335 dose 3

Group Type: EXPERIMENTAL

BI 1467335

Intervention Type: DRUG

once daily

BI 1467335 dose 4

Group Type: EXPERIMENTAL

BI 1467335

Intervention Type: DRUG

once daily

Placebo

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

once daily

Interventions

BI 1467335

once daily

Intervention Type: DRUG

Placebo

once daily

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• 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 moderate to severe 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®)
• 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
• Age ≥ 18 and ≤75 years at screening
• BMI ≥25kg/m2 and <45kg/m2 at screening
• 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.
• 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 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.
• Signed and dated written informed consent in accordance with GCP and local legislation prior to admission to the trial.

Exclusion Criteria

• 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.
• Prior participation in an interventional NASH trial 6 months before baseline or 5 times halflife of the investigational drug, whichever is longer.
• 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.
• Use of drugs historically associated with liver injury, hepatic steatosis or steatohepatitis in the 4 weeks prior to screening.
• 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).
• 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.
• Solid liver lesions other than haemangiomas.

-- Suspicion or diagnosis or history of hepatocellular carcinoma (HCC)

• eGFR <60ml/min/1.73m2 at screening (CKD-EPI formula).
• ALT >5.0 ULN at screening.
• Platelet count < 150.000/μL
• Bilirubin level > ULN (except for known Gilbert´s disease with a conjugated bilirubin of < 0.3 mg/dL))
• Uncontrolled diabetes defined as an HbA1c ≥9.5% in the 3 months prior to or at screening.
• 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.
• 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.
• 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.
• Patients who must or wish to continue the intake of restricted medications or any drug considered likely to interfere with the safe conduct of the trial.
• Previous randomisation in this trial.
• 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).
• Chronic drug abuse or any condition that, in the investigator's opinion, makes them an unreliable study subject or unlikely to complete the trial.
• Women who are pregnant, nursing, or who plan to become pregnant while in the trial.
• 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.
• Any other clinical condition that, in the opinion of the investigator, would jeopardize patient safety while participating in this clinical trial.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Boehringer Ingelheim

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

Southern California Research Center

Coronado, California, United States

University of California San Diego

La Jolla, California, United States

eStudySite

La Mesa, California, United States

National Research Institute

Los Angeles, California, United States

National Research Institute

Los Angeles, California, United States

Quest Clinical Research

San Francisco, California, United States

Florida Research Institute

Lakewood Rch, Florida, United States

Genoma Research Group, Inc

Miami, Florida, United States

Rutgers Robert Wood Johnson Medical School

New Brunswick, New Jersey, United States

Northwell Health

Manhasset, New York, United States

The University of North Carolina at Chapel Hill

Chapel Hill, North Carolina, United States

Duke University Medical Center

Durham, North Carolina, United States

Diabetes and Endocrinology Consultants, PC

Morehead City, North Carolina, United States

Dallas Diabetes and Endocrine Center

Dallas, Texas, United States

Pinnacle Clinical Research

Live Oak, Texas, United States

American Research Corporation at the Texas Liver Institute

San Antonio, Texas, United States

Virginia Commonwealth University

Richmond, Virginia, United States

Edegem - UNIV UZ Antwerpen

Edegem, , Belgium

AZ Maria Middelares

Ghent, , Belgium

UZ Leuven

Leuven, , Belgium

Centre Hospitalier Universitaire de Liège

Liège, , Belgium

University of Calgary

Calgary, Alberta, Canada

Toronto Liver Centre

Toronto, Ontario, Canada

HOP Claude Huriez

Lille, , France

HOP La Pitié Salpêtrière

Paris, , France

Universitätsklinikum Aachen, AöR

Aachen, , Germany

Universitätsklinikum Köln (AöR)

Cologne, , Germany

Universitätsklinikum Frankfurt

Frankfurt am Main, , Germany

Universitätsklinikum Leipzig

Leipzig, , Germany

Universitätsmedizin der Johannes Gutenberg-Universität Mainz

Mainz, , Germany

Universitätsklinikum Würzburg

Würzburg, , Germany

St James's Hospital

Dublin, , Ireland

Amsterdam UMC, Locatie AMC

Amsterdam, , Netherlands

Maastricht Universitair Medisch Centrum

Maastricht, , Netherlands

Radboud Universitair Medisch Centrum

Nijmegen, , Netherlands

Hospital Vall d'Hebron

Barcelona, , Spain

Hospital Virgen de la Victoria

Málaga, , Spain

Hospital Universitario Marqués de Valdecilla

Santander, , Spain

Hospital Virgen del Rocío

Seville, , Spain

Hospital General Universitario de Valencia

Valencia, , Spain

Queen Elizabeth Hospital

Birmingham, , United Kingdom

Aintree University Hospital

Liverpool, , United Kingdom

Manchester Royal Infirmary

Manchester, , United Kingdom

Royal Stoke University Hospital

Stoke-on-Trent, , United Kingdom

Countries

United States; Belgium; Canada; France; Germany; Ireland; Netherlands; Spain; United Kingdom

References

Newsome PN, Sanyal AJ, Neff G, Schattenberg JM, Ratziu V, Ertle J, Link J, Mackie A, Schoelch C, Lawitz E; BI 1467335 NASH Phase IIa trial team. A randomised Phase IIa trial of amine oxidase copper-containing 3 (AOC3) inhibitor BI 1467335 in adults with non-alcoholic steatohepatitis. Nat Commun. 2023 Nov 6;14(1):7151. doi: 10.1038/s41467-023-42398-w.

Reference Type: DERIVED

PMID: 37932258 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Related Links

https://trials.boehringer-ingelheim.com/

Related Info

Other Identifiers

2016-000499-83

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

1386-0004

Identifier Type: -

Identifier Source: org_study_id