Clinical trial NCT04771273: A Study to Test Safety and Efficacy of Survodutide (BI456906) in Adults With Non-alcoholic Steatohepatitis (NASH) and Fibrosis (F1-F3)
Official title: Multicenter, Double-blind, Parallel-group, Randomized, 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.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Non-alcoholic Steatohepatitis (NASH)
Lead sponsor: Boehringer Ingelheim
Sponsor class: INDUSTRY
First posted: 2021-02-25
Enrollment: 295
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study is open for men and women with a liver disease called nonalcoholic steatohepatitis (NASH) and liver fibrosis. The purpose of the study is to find out whether a medicine called BI 456906 helps patients with NASH and liver fibrosis. The study tests 3 different doses of BI 456906 to find the dose that helps best. Participants are put into 4 groups randomly, which means by chance. There are 3 groups that each receive a different dose of BI 456906 and there is 1 group that receives placebo. BI 456906 and placebo are given as an injection under the skin once per week. The placebo injection looks like the BI 456906 injection but does not contain any medicine.

Participants are in the study for a little over 1 year (60 weeks). During this time, they visit the study site several times and have some video calls in addition. At the visits, the study doctors take different measurements. To see whether the treatment works, the doctors take a very small sample of liver tissue (biopsy) from each participant at the start and at the end of the study. They also examine the liver by ultrasound and MRI. The doctors also regularly check the general health of the participants.


Eligibility criteria: Inclusion Criteria:

1. Male or female patients ≥ 18 years (or who are of legal age in countries where that is greater than 18 years) and ≤ 80 years of age at time of consent.
2. Diagnosis of non-alcoholic steatohepatitis (NASH) (Non-alcoholic Fatty Liver Disease (NAFLD) Activity Score (NAS) ≥ 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 ≥ 8% measured by Magnetic Resonance Imaging (MRI)-Proton Density Fat Fraction (PDFF) and liver stiffness \> 6.0 kPa measured by FibroScan® at Visit 1 (if biopsy is scheduled during the screening period MRI-PDFF and FibroScan® assessments have to be performed prior to the biopsy). However, the diagnosis of NASH and fibrosis at liver biopsy (including historical biopsy) is the primary assessment to establish patient eligibility.
4. Patients willing and able to undergo liver biopsies per protocol as judged by the Investigator.
5. Signed and dated written informed consent in accordance with ICH-GCP and local legislation prior to admission to the trial.
6. Women of childbearing potential (WOCBP)1 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 International Council on Harmonisation (ICH) M3 (R2) 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.

Further inclusion criteria apply.

Exclusion Criteria:

1. Current or history of significant alcohol consumption (defined as intake of \> 210 g/ week in males and \> 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 Visit 1. 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, Alpha-1 Antitrypsin (A1At) deficiency, history of liver transplantation). Hepatitis B and C testing will be done at Visit 1. Patients with positive Hepatitis B surface antigen (HBsAg) should be excluded. Patients treated for hepatitis C must have a negative RNA test at screening and also be Hepatitis C Virus (HCV) RNA negative for at least 3 years prior to screening in order to be eligible for the trial.
4. Suspicion, diagnosis, or history of hepatocellular carcinoma (HCC), or 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.
5. Personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2, manifest hypo- or hyperthyroidism at Visit 1.
6. History of chronic or acute pancreatitis or elevation of serum lipase/amylase \> 2x ULN or fasting serum triglyceride levels of \> 500 mg/dL (\> 5.65 mmol/L) at screening.
7. Known history of HIV (Human Immunodeficiency Virus) infection and/or tuberculosis and/or an acute COVID-19 infection at Visit 1 (confirmed by SARS CoV-2 RT-PCR test). Further exclusion criteria apply.

Primary outcomes:
measure: Improvement (Yes/ no) From Baseline in Liver Histological Findings Based on Liver Biopsy After 48 Weeks of Treatment in Patients With NASH (NAS ≥ 4, Fibrosis F1-F3) - Actual Maintenance Treatment
timeFrame: At baseline and at 48 weeks.
measure: Improvement (Yes/ no) From Baseline in Liver Histological Findings Based on Liver Biopsy After 48 Weeks of Treatment in Patients With NASH (NAS ≥ 4, Fibrosis F1-F3) - Planned Maintenance Treatment
timeFrame: At baseline and after 48 weeks of treatment.
Secondary outcomes:
measure: 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 MRI-PDFF - Actual Maintenance Treatment
timeFrame: At baseline and after 48 weeks.
measure: 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 MRI-PDFF - Planned Maintenance Treatment
timeFrame: At baseline and at 48 weeks.
measure: Absolute Change of Liver Fat Content From Baseline After 48 Weeks of Treatment Assessed by MRI-PDFF - Actual Maintenance Treatment
timeFrame: MMRM included measurements from baseline and at Week 28 and at Week 48 after first drug administration. MMRM estimates of absolute change from baseline to Week 48 is reported.
measure: Absolute Change of Liver Fat Content From Baseline After 48 Weeks of Treatment Assessed by MRI-PDFF - Planned Maintenance Treatment
timeFrame: MMRM included measurements from baseline and at Week 28 and at Week 48 after first drug administration. MMRM estimates of absolute change from baseline to Week 48 is reported.
measure: Percent Change of Liver Fat Content From Baseline After 48 Weeks of Treatment Assessed by MRI-PDFF - Actual Maintenance Treatment
timeFrame: MMRM included measurements from baseline and at Week 28 and at Week 48 after first drug administration. MMRM estimates of percent change from baseline to Week 48 is reported.
measure: Percent Change of Liver Fat Content From Baseline After 48 Weeks of Treatment Assessed by MRI-PDFF - Planned Maintenance Treatment
timeFrame: MMRM included measurements from baseline and at Week 28 and at Week 48 after first drug administration. MMRM estimates of percent change from baseline to Week 48 is reported.
measure: Improvement of Fibrosis (Yes/ no) Defined as at Least One Stage Decrease in Fibrosis Stage After 48 Weeks of Treatment Assessed by Liver Biopsy - Actual Maintenance Treatment
timeFrame: At baseline and after 48 weeks of treatment.
measure: Improvement of Fibrosis (Yes/ no) Defined as at Least One Stage Decrease in Fibrosis Stage After 48 Weeks of Treatment Assessed by Liver Biopsy - Planned Maintenance Treatment
timeFrame: At baseline and after 48 weeks of treatment.
measure: Absolute Change From Baseline in NAS After 48 Weeks of Treatment Assessed by Liver Biopsy - Actual Maintenance Treatment
timeFrame: At baseline and 48 weeks of treatment.
measure: Absolute Change From Baseline in NAS After 48 Weeks of Treatment Assessed by Liver Biopsy - Planned Maintenance Treatment
timeFrame: At baseline and 48 weeks of treatment.
Other outcomes:
Locations:
city: Huntsville
country: United States
facility: North Alabama Health Research, LLC
state: Alabama
city: Coronado
country: United States
facility: Southern California Research Center
state: California
city: Huntington Park
country: United States
facility: Velocity Clinical Research
state: California
city: Panorama City
country: United States
facility: Velocity Clinical Research
state: California
city: San Francisco
country: United States
facility: Quest Clinical Research
state: California
city: Colorado Springs
country: United States
facility: Peak Gastroenterology Associates
state: Colorado
city: Doral
country: United States
facility: Integrity Clinical Research, LLC
state: Florida
city: Fort Myers
country: United States
facility: Covenant Metabolic Specialists, LLC
state: Florida
city: Miami
country: United States
facility: Optimus U Corporation
state: Florida
city: Miami
country: United States
facility: Sanchez Clinical Research ,Inc
state: Florida
city: Ocala
country: United States
facility: Ocala GI Research
state: Florida
city: Orlando
country: United States
facility: Omega Research Orlando, LLC
state: Florida
city: Sarasota
country: United States
facility: Covenant Metabolic Specialists, LLC
state: Florida
city: Marietta
country: United States
facility: Gastrointestinal Specialists of Georgia
state: Georgia
city: South Bend
country: United States
facility: Digestive Research Alliance of Michiana
state: Indiana
city: Iowa City
country: United States
facility: University of Iowa Hospitals and Clinics
state: Iowa
city: Bastrop
country: United States
facility: Delta Research Partners, LLC
state: Louisiana
city: Lake Charles
country: United States
facility: Centex Studies, Inc.
state: Louisiana
city: Marrero
country: United States
facility: Tandem Clinical Research
state: Louisiana
city: Fall River
country: United States
facility: NECCR PrimaCare Research, LLC
state: Massachusetts
city: Biloxi
country: United States
facility: National Diabetes and Obesity Research Institute
state: Mississippi
city: Flowood
country: United States
facility: Gastrointestinal Associates
state: Mississippi
city: Florham Park
country: United States
facility: AIG Digestive Disease Research
state: New Jersey
city: Concord
country: United States
facility: Northeast GI Research Division
state: North Carolina
city: Morehead City
country: United States
facility: Lucas Research, Inc.
state: North Carolina
city: Greenwood
country: United States
facility: Digestive Diseases Research Center
state: South Carolina
city: Summerville
country: United States
facility: Palmetto Clinical Research
state: South Carolina
city: Hermitage
country: United States
facility: Digestive Health Research, LLC
state: Tennessee
city: Arlington
country: United States
facility: Texas Clinical Research Institute, LLC
state: Texas
city: Austin
country: United States
facility: Texas Liver Institute
state: Texas
city: Brownsville
country: United States
facility: South Texas Research Institute
state: Texas
city: Edinburg
country: United States
facility: South Texas Research Institute
state: Texas
city: Houston
country: United States
facility: Houston Methodist Hospital
state: Texas
city: San Antonio
country: United States
facility: American Research Corporation at the Texas Liver Institute
state: Texas
city: San Antonio
country: United States
facility: Pinnacle Clinical Research
state: Texas
city: Richmond
country: United States
facility: Virginia Commonwealth University
state: Virginia
city: Southport
country: Australia
facility: Gold Coast University Hospital
state: Queensland
city: Clayton
country: Australia
facility: Monash Medical Centre
state: Victoria
city: Parkville
country: Australia
facility: Royal Melbourne Hospital
state: Victoria
city: Graz
country: Austria
facility: Medical University of Graz State Hospital - University Hospital Graz
city: Innsbruck
country: Austria
facility: Medical University of Innsbruck
city: Linz
country: Austria
facility: Ordensklinikum Linz GmbH - Barmherzige Schwestern
city: Edegem
country: Belgium
facility: Edegem - UNIV UZ Antwerpen
city: London
country: Canada
facility: University Hospital (LHSC)
state: Ontario
city: Toronto
country: Canada
facility: Toronto Liver Centre
state: Ontario
city: Chicoutimi
country: Canada
facility: Ecogene-21
state: Quebec
city: Beijing
country: China
facility: Beijing Ditan Hospital Capital Medical University
city: Beijing
country: China
facility: Beijing Tsinghua Changgung Hospital
city: Beijing
country: China
facility: Peking University People's Hospital
city: Beijing
country: China
facility: Beijing Friendship Hospital
city: Changchun
country: China
facility: The First Hospital of Jilin University
city: Guangzhou
country: China
facility: The First Afiliated Hospital, Sun Yet-sen University
city: Guangzhou
country: China
facility: NanFang Hosptial
city: Hangzhou
country: China
facility: Sir Run Run Shaw Hospital, Zhejiang University, School of Medicine
city: Kunming
country: China
facility: First People's hospital of Yunann Province
city: Nanjing
country: China
facility: The Second Hospital of Nanjing
city: Shanghai
country: China
facility: Shanghai Public Health Clinical Center
city: Tianjin
country: China
facility: Tianjin Third Central Hospital
city: Wenxzhou
country: China
facility: The First Affiliated Hospital of Wenzhou Med College
city: Liberec
country: Czechia
facility: Regional Hospital Liberec
city: Prague
country: Czechia
facility: General Faculty Hospital, Prague
city: Nice
country: France
facility: HOP l'Archet
city: Paris
country: France
facility: HOP La Pitié Salpêtrière
city: Pessac
country: France
facility: HOP Haut-Lévêque
city: Strasbourg
country: France
facility: HOP Civil
city: Aachen
country: Germany
facility: Universitätsklinikum Aachen, AöR
city: Berlin
country: Germany
facility: Synexus Clinical Research GmbH
city: Bochum
country: Germany
facility: Universitätsklinikum Knappschaftskrankenhaus Bochum GmbH
city: Düsseldorf
country: Germany
facility: Universitätsklinikum Düsseldorf
city: Frankfurt
country: Germany
facility: Synexus Clinical Research GmbH
city: Leipzig
country: Germany
facility: Synexus Clinical Research GmbH
city: Mainz
country: Germany
facility: Universitätsmedizin der Johannes Gutenberg-Universität Mainz
city: Mannheim
country: Germany
facility: Universitätsklinikum Mannheim GmbH
city: Ulm
country: Germany
facility: Universitätsklinikum Ulm
city: Haidari-Athens
country: Greece
facility: Attikon University Hospital
city: Thessaloniki
country: Greece
facility: General Hospital of Thessaloniki "Hippokrateio"
city: Hong Kong
country: Hong Kong
facility: Prince of Wales Hospital
city: Hong Kong
country: Hong Kong
facility: Queen Mary Hospital
city: Budapest
country: Hungary
facility: Synexus Hungary Healthcare Service Ltd.
city: Budapest
country: Hungary
facility: Fed.St. Istvan&Szent Laszlo Hospital
city: Gyula
country: Hungary
facility: Synexus Hungary Healthcare Service Ltd
city: Jerusalem
country: Israel
facility: Shaare Zedek Medical Center, Jerusalem 91031
city: Nahariya
country: Israel
facility: Western Galilee Hospital
city: Petach Tikva
country: Israel
facility: Rabin Medical Center Beilinson
city: Tel Aviv
country: Israel
facility: Sourasky Medical Center
city: Tel-Hashomer
country: Israel
facility: The Chaim Sheba Medical Center
city: Baggiovara (MO)
country: Italy
facility: Ospedale Civile di Baggiovara
city: Palermo
country: Italy
facility: A.O. Univ. Policlinico "Paolo Giaccone"
city: Roma
country: Italy
facility: Poli Univ A. Gemelli
city: Rozzano (MI)
country: Italy
facility: Istituto Clinico Humanitas
city: SAN Giovanni Rotondo (FG)
country: Italy
facility: IRCCS Ospedale "Casa Sollievo della Sofferenza"
city: Torino
country: Italy
facility: AO Città della Salute e Scienza
city: Ehime, Toon
country: Japan
facility: Ehime University Hospital
city: Fukui, Fukui
country: Japan
facility: Fukuiken Saiseikai Hospital
city: Fukuoka, Kurume
country: Japan
facility: Kurume University Hospital
city: Gifu, Ogaki
country: Japan
facility: Ogaki Municipal Hospital
city: Hokkaido, Sapporo
country: Japan
facility: Japan Community Health Care Organization Hokkaido Hospital
city: Kagawa, Kita-gun
country: Japan
facility: Kagawa University Hospital
city: Kagawa, Takamatsu
country: Japan
facility: Kagawa Prefectural Central Hospital
city: Kanagawa, Kawasaki
country: Japan
facility: St. Marianna University Hospital
city: Kanagawa, Sagamihara
country: Japan
facility: Kitasato University Hospital
city: Kanagawa, Yokohama
country: Japan
facility: Yokohama City University Hospital
city: Kanagawa, Yokohama
country: Japan
facility: National Hospital Organization Yokohama Medical Center
city: Kumamoto, Kumamoto
country: Japan
facility: Kumamoto University Hospital
city: Kyoto, Kyoto
country: Japan
facility: University Hospital Kyoto Prefectural University of Medicine
city: Nagano, Matsumoto
country: Japan
facility: Shinshu University Hospital
city: Nagano, Nagano
country: Japan
facility: Nagano Municipal Hospital
city: Nara, Kashihara
country: Japan
facility: Nara Medical University Hospital
city: Osaka, Suita
country: Japan
facility: Suita Hospital
city: Saga, Saga
country: Japan
facility: Saga University Hospital
city: Shizuoka, Hamamatsu
country: Japan
facility: Hamamatsu University Hospital
city: Shizuoka, Izunokuni
country: Japan
facility: Juntendo University Shizuoka Hospital
city: Tokyo, Bunkyo-ku
country: Japan
facility: Tokyo Medical and Dental University Hospital
city: Busan
country: Korea, Republic of
facility: Pusan National Univ. Hosp
city: Daegu
country: Korea, Republic of
facility: Keimyung University Dongsan Hospital
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Kelantan
country: Malaysia
facility: Universiti Sains Malaysia Hospital
city: Kuala Lumpur
country: Malaysia
facility: University of Malaya Medical Centre
city: Selangor
country: Malaysia
facility: Hospital Selayang
city: Amsterdam
country: Netherlands
facility: Amsterdam UMC, location VUMC
city: Leiden
country: Netherlands
facility: Leids Universitair Medisch Centrum (LUMC)
city: Rotterdam
country: Netherlands
facility: Sint Franciscus, Locatie Vlietland
city: Auckland
country: New Zealand
facility: New Zealand Clinical Research (NZCR)
city: Papatoetoe
country: New Zealand
facility: Middlemore Clinical Trials
city: Bydgoszcz
country: Poland
facility: INTERCORE Medical Center
city: Czestochowa
country: Poland
facility: Synexus Poland, Branch in Czestochowa
city: Elblag
country: Poland
facility: Private health care facility "Your Health EL" LLC
city: Gdansk
country: Poland
facility: Synexus Polska SCM Sp. z o.o. Gdansku, Gdansk
city: Gdynia
country: Poland
facility: Synexus Polska Sp. z o.o. Oddzial w Gdyni, Gdynia
city: Katowice
country: Poland
facility: University Clinical Center Professor Gibinskiego
city: Krakow
country: Poland
facility: University Hospital in Krakow
city: Oswiecim
country: Poland
facility: Medicome Limited Liability Company
city: Warszawa
country: Poland
facility: Centrum Medyczne Synexus
city: Wroclaw
country: Poland
facility: Synexus Poland, Branch in Wroclaw
city: Zamosc
country: Poland
facility: ETG Zamosc
city: Lisboa
country: Portugal
facility: ULS de Santa Maria, E.P.E
city: Porto
country: Portugal
facility: Centro Hospitalar Universitário São João,EPE
city: Singapore
country: Singapore
facility: National University Hospital
city: Singapore
country: Singapore
facility: Singapore General Hospital
city: Barcelona
country: Spain
facility: Hospital Vall d'Hebron
city: Majadahonda
country: Spain
facility: Hospital Puerta de Hierro
city: Pontevedra
country: Spain
facility: Hospital de Montecelo
city: Santander
country: Spain
facility: Hospital Universitario Marqués de Valdecilla
city: Sevilla
country: Spain
facility: Hospital Virgen del Rocío
city: Valencia
country: Spain
facility: Hospital General Universitario de Valencia
city: ChiaYi
country: Taiwan
facility: Chia Yi Christian Hospital
city: Kaohsiung
country: Taiwan
facility: Kaohsiung Medical University Chung-Ho Memorial Hospital
city: Tainan
country: Taiwan
facility: National Chen Kung University, Dept of Neurology
city: Taoyuan County
country: Taiwan
facility: Chang Gung Memorial Hospital(Linkou)
city: Birmingham
country: United Kingdom
facility: Queen Elizabeth Hospital
city: Hexham
country: United Kingdom
facility: Synexus - Hexham
city: Liverpool
country: United Kingdom
facility: Aintree University Hospital
city: London
country: United Kingdom
facility: King's College Hospital
city: Nottingham
country: United Kingdom
facility: Queen's Medical Centre
Study officials:
References: