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

NCT03166735 | Completed Phase 2 Results FDA Drug

• 2 other identifiers: 1386-00042016-000499-83
• Study Type: interventional
• Target: 114
• Locations: 9 countries
• Sites: 44

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

Outcome Measures

Primary Outcomes (1)

• Plasma Amine Oxidase Copper-containing 3 (AOC3) Activity After 12 Weeks of Treatment, Relative to Baseline in Percent

  The patient-specific plasma AOC3 activity at time t (24 hours after the last dose in week 12) relative to baseline in percentage was calculated as follows: %AOC3at = \[(AOC3at - AOC3at,back) ⁄ (AOC3abase - AOC3abase,back)\]\*100 With AOC3at the AOC3 activity measured at time t, AOC3at,back the background noise at time t, AOC3abase the AOC3 activity measured at baseline and AOC3abase,back the background noise at baseline. A dose-response relationship was analysed using a non-linear regression model to estimate the daily dosage needed to reach 10% of AOC3 activity (i.e. 90% inhibition) 12 weeks after treatment.

  Day 1 (baseline), day 15, 29, 43, 57 and 85 (time t) 24 hours after the last dose of BI 1467335.

Secondary Outcomes (7)

• Percentage of Participants With Drug-related Adverse Events (AEs)

  Start of treatment till end of treatment + 28 days, up to 113 days.

• Alanine Aminotransaminase (ALT) After 12 Weeks of Treatment, Relative to Baseline in Percent

  Day 1 (baseline), day 15, 29, 43, 57 and 85 (time t) 24 hours after the last dose of BI 1467335.

• Aspartate Aminotransferase (AST) After 12 Weeks of Treatment, Relative to Baseline in Percent

  Day 1 (baseline), day 15, 29, 43, 57 and 85 (time t) 24 hours after the last dose of BI 1467335.

• Alkaline Phosphatase (AP) After 12 Weeks of Treatment, Relative to Baseline in Percent

  Day 1 (baseline), day 15, 29, 43, 57 and 85 (time t) 24 hours after the last dose of BI 1467335.

• Gamma-glutamyltransferase (GGT) After 12 Weeks of Treatment, Relative to Baseline in Percent

  Day 1 (baseline), day 15, 29, 43, 57 and 85 (time t) 24 hours after the last dose of BI 1467335.

Study Arms (5)

BI 1467335 dose 1

EXPERIMENTAL

Drug: BI 1467335

BI 1467335 dose 2

EXPERIMENTAL

Drug: BI 1467335

BI 1467335 dose 3

EXPERIMENTAL

Drug: BI 1467335

BI 1467335 dose 4

EXPERIMENTAL

Drug: BI 1467335

Placebo

PLACEBO COMPARATOR

Drug: Placebo

Interventions

BI 1467335 DRUG

once daily

BI 1467335 dose 1; BI 1467335 dose 2; BI 1467335 dose 3; BI 1467335 dose 4

Placebo DRUG

once daily

Placebo

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Boehringer Ingelheim: lead

Study Sites (44)

Southern California Research Center

Coronado, California, 92118, United States

Location

University of California San Diego

La Jolla, California, 92037, United States

Location

eStudySite

La Mesa, California, 91942, United States

Location

National Research Institute

Los Angeles, California, 90057, United States

Location

National Research Institute

Los Angeles, California, 90255, United States

Location

Quest Clinical Research

San Francisco, California, 94115, United States

Location

Florida Research Institute

Lakewood Rch, Florida, 34211, United States

Location

Genoma Research Group, Inc

Miami, Florida, 33165, United States

Location

Rutgers Robert Wood Johnson Medical School

New Brunswick, New Jersey, 08901, United States

Location

Northwell Health

Manhasset, New York, 11030, United States

Location

The University of North Carolina at Chapel Hill

Chapel Hill, North Carolina, 27599, United States

Location

Duke University Medical Center

Durham, North Carolina, 27710, United States

Location

Diabetes and Endocrinology Consultants, PC

Morehead City, North Carolina, 28557, United States

Location

Dallas Diabetes and Endocrine Center

Dallas, Texas, 75230, United States

Location

Pinnacle Clinical Research

Live Oak, Texas, 78233, United States

Location

American Research Corporation at the Texas Liver Institute

San Antonio, Texas, 78215, United States

Location

Virginia Commonwealth University

Richmond, Virginia, 23298, United States

Location

Edegem - UNIV UZ Antwerpen

Edegem, 2650, Belgium

Location

AZ Maria Middelares

Ghent, 9000, Belgium

Location

UZ Leuven

Leuven, 3000, Belgium

Location

Centre Hospitalier Universitaire de Liège

Liège, 4000, Belgium

Location

University of Calgary

Calgary, Alberta, T2N 4Z6, Canada

Location

Toronto Liver Centre

Toronto, Ontario, M6H 3M1, Canada

Location

HOP Claude Huriez

Lille, 59037, France

Location

HOP La Pitié Salpêtrière

Paris, 75651, France

Location

Universitätsklinikum Aachen, AöR

Aachen, 52074, Germany

Location

Universitätsklinikum Köln (AöR)

Cologne, 50937, Germany

Location

Universitätsklinikum Frankfurt

Frankfurt am Main, 60590, Germany

Location

Universitätsklinikum Leipzig

Leipzig, 04103, Germany

Location

Universitätsmedizin der Johannes Gutenberg-Universität Mainz

Mainz, 55131, Germany

Location

Universitätsklinikum Würzburg

Würzburg, 97080, Germany

Location

St James's Hospital

Dublin, 8, Ireland

Location

Amsterdam UMC, Locatie AMC

Amsterdam, 1105 AZ, Netherlands

Location

Maastricht Universitair Medisch Centrum

Maastricht, 6229 HX, Netherlands

Location

Radboud Universitair Medisch Centrum

Nijmegen, 6525 GA, Netherlands

Location

Hospital Vall d'Hebron

Barcelona, 08035, Spain

Location

Hospital Virgen de la Victoria

Málaga, 29010, Spain

Location

Hospital Universitario Marqués de Valdecilla

Santander, 39008, Spain

Location

Hospital Virgen del Rocío

Seville, 41013, Spain

Location

Hospital General Universitario de Valencia

Valencia, 46014, Spain

Location

Queen Elizabeth Hospital

Birmingham, B15 2TH, United Kingdom

Location

Aintree University Hospital

Liverpool, L9 7AL, United Kingdom

Location

Manchester Royal Infirmary

Manchester, M13 9WL, United Kingdom

Location

Royal Stoke University Hospital

Stoke-on-Trent, ST4 6QG, United Kingdom

Location

Related Publications (1)

• 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.

  PMID: 37932258 DERIVED

Related Links

• Related Info

MeSH Terms

Conditions

Non-alcoholic Fatty Liver Disease

Condition Hierarchy (Ancestors)

Fatty Liver; Liver Diseases; Digestive System Diseases

Limitations and Caveats

Global Amendment 5 (dated 12 Sep 2018): Sample size reduction from 147 to 108 randomised patients due to a lower expected variability for ALT based on new external and blinded internal data.

Results Point of Contact

• Title: Boehringer Ingelheim, Call Center
• Organization: Boehringer Ingelheim

clintriage.rdg@boehringer-ingelheim.com

1-800-243-0127

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 24, 2017
• First Posted: May 25, 2017
• Study Start: June 6, 2017
• Primary Completion: June 14, 2019
• Study Completion: June 14, 2019
• Last Updated: June 11, 2020
• Results First Posted: June 11, 2020

Record last verified: 2020-05

Locations

DE (6); ES (5); CA (2); FR (2); IE (1); BE (4); NL (3); GB (4); US (17)