Research Study on Whether a Combination of 2 Medicines (NNC0194 0499 and Semaglutide) Works in People With Non-alcoholic Steatohepatitis (NASH)

Efficacy and Safety Investigation of NNC0194-0499 Co-administered With Semaglutide in Subjects With Non-alcoholic Steatohepatitis: a Dose-ranging, Placebo Controlled Trial

This study is being done to see if a combination of 2 medicines (called NNC0194-0499 and semaglutide) can reduce liver damage in patients with non alcoholic steatohepatitis (NASH).

NNC0194-0499 is a new medicine which works in the liver. Semaglutide is a well-known medicine, which is already used by doctors to treat type 2 diabetes in many countries. It also helps with weight loss and may reduce liver damage, and so prevent future liver complications. It works in a different way to NNC0194 0499. The 2 medicines may work better together than on their own.

The study will also look at a combination of semaglutide and another weight-loss medicine called NNC0174-0833, which may be another treatment option for NASH.

Each week, participants will get 2 injections. These could be 2 of the 3 medicines OR 1 of the medicines and a placebo OR 2 placebo injections. Which treatment participants get is decided by chance. A placebo is a dummy medicine which looks like the real medicine but doesn't contain any active medicine.

The study will last for about 19 months. Participants will have 14 clinic visits and 9 phone calls with the study doctor.

Participants will have 1 or 2 liver biopsies (tiny pieces of liver tissue) - one at the start (if participants have not had a biopsy recently) and one at the end of the study treatment.

Women: Women cannot take part if pregnant, breast-feeding or planning to become pregnant during the study period.

Study Overview

• Status: Active, not recruiting
• Conditions: Non-alcoholic Steatohepatitis
• Intervention / Treatment: Drug: NNC0194 0499 50 mg/mL; Drug: Semaglutide 3 mg/mL; Drug: Placebo (NNC0194-0499); Drug: Semaglutide placebo; Drug: NNC0174 0833 10 mg/mL; Drug: NNC0174 0833 placebo

• Study Type: Interventional
• Enrollment (Estimated): 672
• Phase: Phase 2

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Broadmeadow, New South Wales, Australia, 2292
      • Genesis Research Services
    • Darlinghurst, New South Wales, Australia, 2010
      • St Vincent's Hospital
    • Kingswood, New South Wales, Australia, 2747
      • Nepean Hospital
    • Westmead, New South Wales, Australia, 2145
      • Westmead Hospital
  • South Australia
    • Adelaide, South Australia, Australia, 5000
      • Royal Adelaide Hospital - Hepatology- 5E291
  • Victoria
    • Clayton, Victoria, Australia, 3168
      • Monash Health Department of Gastroenterology
    • Fitzroy, Victoria, Australia, 3065
      • St Vincent's Hospital (Melbourne)
    • Heidelberg, Victoria, Australia, 3084
      • Austin Health
    • Melbourne, Victoria, Australia, 3004
      • The Alfred Centre - Gastroenterology
  • Western Australia
    • Murdoch, Western Australia, Australia, 6150
      • Fiona Stanley Hospital - Hepatology
• Belgium
  • Bruxelles, Belgium, 1070
    • CUB Hôpital Erasme_Brussels_0
  • Bruxelles, Belgium, 1200
    • Cliniques Universitaires Saint-Luc - Serv. Hépato-gastroentérology
  • Edegem, Belgium, 2650
    • UZA
  • Gent, Belgium, 9000
    • UZ Gent - Department Gastro-enterology
• Bulgaria
  • Sofia, Bulgaria, 1407
    • "Acibadem City Clinic MHAT Tokuda"
  • Sofia, Bulgaria, 1431
    • UMHAT "Sv. Ivan Rilski", Clinic of Gastroenterology
  • Sofia, Bulgaria, 1618
    • "DCC XX - Sofia" EOOD
• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 4Z6
      • University of Calgary Liver Unit-(HMRC)
  • British Columbia
    • Vancouver, British Columbia, Canada, V6Z 2K5
      • GI Research Institute
  • Ontario
    • Toronto, Ontario, Canada, M6H 3M1
      • Toronto Liver Centre
• Czechia
  • Liberec, Czechia, 460 01
    • Krajská nemocice Liberec, a.s
• Denmark
  • Hvidovre, Denmark, 2650
    • Hvidovre Hospital
  • København NV, Denmark, 2400
    • Abdominal Center K, Research Unit
  • Odense C, Denmark, 5000
    • Odense University Hospital
• France
  • Angers, France, 49100
    • Centre Hospitalier Universitaire D'Angers-1
  • Clichy, France, 92110
    • Ap-Hp-Hopital Beaujon
  • Lille, France, 59037
    • Centre Hospitalier Universitaire de Lille-Hopital Claude Huriez
  • Lyon Cedex 4, France, 69317
    • Hospices Civils de Lyon-Hopital de La Croix Rousse
  • Nice, France, 06200
    • Centre Hospitalier Universitaire de Nice-Hopital de L'Archet 2
  • Paris, France, 75013
    • Aphp-Hopital La Pitie Salpetriere-4
  • Saint Herblain, France, 44800
    • Centre Hospitalier Universitaire de Nantes-Hopital Nord Laennec-1
  • Venissieux, France, 69200
    • Groupe Hospitalier Mutualiste Des Portes Du Sud
• Germany
  • Essen, Germany, 45147
    • Klinik für Endokrinologie, Diabetologie und Stoffwechsel
  • Lübeck, Germany, 23562
    • Universitätsklinikum Schleswig-Holstein
  • Mainz, Germany, 55131
    • Universitätsmedizin der Johannes-Gutenberg-Universität Mainz
  • Würzburg, Germany, 97080
    • Universitätsklinikum Würzburg, ZIM
• Greece
  • Athens, Greece, GR-11527
    • Gen Hospital of Athens Ippokrateio,B' Uni Clinic of Inte Med
  • Athens, Greece, GR-11527
    • Gen Hospital of Athens Laiko,1st Dpt. of Propaedeutic Inter
  • Goudi, Athens, Greece, GR-115 27
    • General Hospital of Athens "LAIKO"
  • Thessaloniki, Greece, GR-54621
    • "AHEPA" University Hospital of Thessaloniki
  • Thessaloniki, Greece, GR-54642
    • General Hospital of Thessaloniki "Ippokrateio"
• India
  • New Delhi, India, 110070
    • Institute of liver and Biliary Sciences
  • Andhra Pradesh
    • Secunderabad, Andhra Pradesh, India, 500003
      • Yashoda Hospital
  • Gujarat
    • Surat, Gujarat, India, 395002
      • Surat Institute of Digestive Science
    • Surat, Gujarat, India, 395009
      • BAPS Pramukh Swami Hospital
  • Haryana
    • Gurugram, Haryana, India, 122001
      • Medanta - The Medicity Multi-Speciality Hospital, Gurugram
  • Karnataka
    • Mangalore, Karnataka, India, 575001
      • Kasturba Medical College Hospitals (KMC Hospitals), Mangalore
  • Karnatka
    • Belgaum, Karnatka, India, 590010
      • KLES & Prabhakar Kore Hospital and Research Centre
  • Maharashtra
    • Mumbai, Maharashtra, India, 400012
      • Seth GS medical college and KEM Hospital
    • Mumbai, Maharashtra, India, 400012
      • Global Hospitals Superspeciality and Transplant center
    • Nagpur, Maharashtra, India, 441108
      • Midas Multispeciality Hospital
  • New Delhi
    • New Dehli, New Delhi, India, 110029
      • All India Institute of medical Sciences
  • Punjab
    • Chandigarh, Punjab, India, 160012
      • Post Graduate Institute of Medical Education & Research_Chandigarh
    • Chandigarh,, Punjab, India, 160062
      • Fortis Heart Institute and Multispeciality Hospital
    • Ludhiana, Punjab, India, 141001
      • Dayanand Medical College & Hospital
  • Rajasthan
    • Jaipur, Rajasthan, India, 302001
      • S.R.Kalla Memorial Gastro & General Hospital
  • Telagana
    • Hyderabad, Telagana, India, 500012
      • Osmania General Hospital
  • Telangana
    • Hyderabad, Telangana, India, 500072
      • Ramdev Rao Hospital
• Italy
  • Ancona, Italy, 60126
    • Azienda Ospedaliero Universitaria Ospedali Riuniti di Ancona
  • Bergamo, Italy, 24127
    • Azienda Socio Sanitaria Territoriale (ASST) Papa Giovanni XXIII
  • Bologna, Italy, 40138
    • Azieda Ospedaliero-Universitaria, Policlinico S. Orsola-Malp
  • Firenze, Italy, 50134
    • AOU Careggi Padiglione 16 San Luca, 3° piano
  • Padova, Italy, 35128
    • Azienda Ospedaliera di Padova Clin.Med.3
  • Pisa, Italy, 56124
    • AOU Pisana Stabilimento di Cisanello EDIFICIO 6, Piano 5
  • Roma, Italy, 00168
    • Fondazione Policlinico Universitario Agostino Gemelli IRCCS
  • Rome, Italy, 00128
    • Policlinico Università Campus Biomedico di Roma
• Japan
  • Chiba-shi, Chiba, Japan, 260-8677
    • Chiba University Hospital_Chiba-shi, Chiba
  • Fukui-shi, Fukui, Japan, 918-8503
    • Fukui-ken Saiseikai Hospital, Internal Medicine
  • Hamamatsu-shi, Shizuoka, Japan, 431-3192
    • Hamamatsu University Hospital
  • Hatsukaichi-shi, Hiroshima, Japan, 783-8503
    • JA Hiroshima General Hospital
  • Kamigyo-ku, Kyoto, Japan, 602-8566
    • University Hospital Kyoto Prefectual University of Medicine
  • Kawasaki-shi, Kanagawa, Japan, 216-8511
    • St. Marianna University School of Medicine Hospital
  • Kumamoto-shi, Kumamoto, Japan, 862-8655
    • Kumamoto Shinto General Hospital
  • Minato-ku, Tokyo, Japan, 105-8470
    • Toranomon Hospital, Hepatology
  • Okayama-shi, Okayama, Japan, 700-8505
    • Kawasaki Medical School General Medical Center
  • Saga-shi, Saga, Japan, 849-8501
    • Saga University Hospital_Liver Center
  • Sendai-shi, Miyagi, Japan, 980-0873
    • Sendai Kousei Hospital
  • Suita-shi, Osaka, Japan, 564-0013
    • Saiseikai Suita Hospital, Gastroenterology
  • Toon-shi, Ehime, Japan, 791-0295
    • Ehime University Hospital
  • Wakayama-shi, Wakayama, Japan, 640-8158
    • Saiseikai Wakayama Hospital
  • Yokohama-shi, Kanagawa, Japan, 236-0004
    • Yokohama City University Hospital, Gastrointestinal Medicine
• Korea, Republic of
  • Daegu, Korea, Republic of, 41944
    • Kyungpook National University Hospital
  • Daegu, Korea, Republic of, 42601
    • Keimyung University Dongsan Medical Center
  • Daegu, Korea, Republic of, 42415
    • Yeungnam Univ. Medical Center
  • Gangwon-do, Korea, Republic of, 26426
    • Wonju Severance Christian Hospital
  • Seoul, Korea, Republic of, 03722
    • Severance Hospital, Yonsei University Health System
  • Seoul, Korea, Republic of, 08308
    • Korea University Guro Hospital
  • Seoul, Korea, Republic of, 07061
    • SMG-SNU Boramae Medical Center
  • Gyeonggi-do
    • Ansan, Gyeonggi-do, Korea, Republic of, 15355
      • Korea University Ansan Hospital
• Malaysia
  • Batu Caves, Malaysia, 68100
    • Hospital Selayang
  • Kelantan
    • Kota Bharu, Kelantan, Malaysia, 16150
      • Hospital Universiti Sains Malaysia
  • Wilayah Persekutuan Kuala Lumpur
    • Kuala Lumpur, Wilayah Persekutuan Kuala Lumpur, Malaysia, 59100
      • University Malaya Medical Centre
• Poland
  • Bydgoszcz, Poland, 85-605
    • Spolka Lekarzy Intercor Sp. z o.o.
  • Katowice, Poland, 40-156
    • Clinical Medical Research Korfantego - Ambulatoryjna Opieka
  • Katowice, Poland, 40-752
    • Uniwersyteckie Centrum Kliniczne im. Prof. K. Gibińskiego Śl
  • Krakow, Poland, 31-501
    • Krakowskie Centrum Medyczne Sp. z o.o.
  • Kraków, Poland, 31-156
    • "LANDA" Katarzyna Agata Landa
  • Rzeszow, Poland, 35-326
    • Centrum Medyczne Medyk Sp. z o.o.
  • Staszow, Poland, 28-200
    • Ko-Med Nova Sp.zo.o. STASZOW
  • Wroclaw, Poland, 50-220
    • EMC Instytut Medyczny S.A.
  • Wroclaw, Poland, 51-162
    • Centrum Badan Klinicznych
  • Wroclaw, Poland, 53-673
    • FutureMeds Sp. z o.o.
  • Malopolskie
    • Mysłowice, Malopolskie, Poland, 41-400
      • ID Clinic Arkadiusz Pisula
• Portugal
  • Lisboa, Portugal, 1649-035
    • Centro Hospitalar Lisboa Norte
  • Matosinhos, Portugal, 4464-513
    • Unidade Local de Saúde de Matosinhos
• Puerto Rico
  • San Juan, Puerto Rico, 00927
    • FDI Clinical Research
• Russian Federation
  • Penza, Russian Federation, 440052
    • Penza Regional Clinical Hospital named after N.N. Burdenko
• Singapore
  • Singapore, Singapore, 169608
    • Singapore General Hospital
  • Singapore, Singapore, 529889
    • Changi General Hospital
  • Singapore, Singapore, 119228
    • National University Hospital_TBD
• Spain
  • Barcelona, Spain, 08035
    • Hospital Vall d'Hebron
  • Majadahonda, Spain, 28222
    • Hospital Universitario Puerta de Hierro Majadahonda
  • Pontevedra, Spain, 36004
    • Complejo Hospitalario de Pontevedra - Hospital de Montecelo
  • Santander, Spain, 39008
    • Hospital Universitario Marques de Valdecilla
  • Sevilla, Spain, 41013
    • Hospital Virgen Del Rocio
  • Valladolid, Spain, 47010
    • Hospital Clínico de Valladolid
• Taiwan
  • Chiayi City, Taiwan, 600
    • Ditmanson Medical Foundation Chia-Yi Christian Hospital
  • Kaoshiung, Taiwan, 807
    • Kaohsiung Medical University Chung-Ho Memorial Hospital
  • Tainan, Taiwan, 704
    • National Cheng Kung University Hospital
  • Taipei, Taiwan, 100
    • National Taiwan University Hospital
• Turkey
  • Adana, Turkey, 01000
    • T.C. Saglık Bakanlıgı Adana Sehir Egitim ve Arastirma Hastan
  • Ankara, Turkey, 06500
    • Gazi University Medical Faculty
  • Ankara, Turkey, 06230
    • Hacettepe Universitesi Tıp Fakültesi- Gastroenteroloji
  • Istanbul, Turkey, 34093
    • Bezmialem Vakif Universitesi Tip Fakultesi Hastanesi-Gastroe
  • Istanbul, Turkey, 34899
    • Marmara Univ. Pendik Gastroenterology
  • Kocaeli, Turkey, 41000
    • Kocaeli Universitesi Tıp Fakültesi Gastroenteroloji ve Hepat
• United Kingdom
  • Exeter, United Kingdom, EX2 5DW
    • Royal Devon & Exeter NHS Foundation Trust
• United States
  • Alabama
    • Huntsville, Alabama, United States, 35801
      • North AL Health Res, LLC
  • Arizona
    • Chandler, Arizona, United States, 85224
      • The Institute for Liver Health
    • Peoria, Arizona, United States, 85381
      • Inst-Liver Hlth dba AZ Liver H
    • Tucson, Arizona, United States, 85715
      • Del Sol Research Management, LLC
  • California
    • La Jolla, California, United States, 92037
      • UCSD NAFLD Research Center
    • Lancaster, California, United States, 93534
      • Om Research LLC
    • Redwood City, California, United States, 94063
      • Stanford Medicine
    • Sacramento, California, United States, 95817
      • UC Davis Hlth -Midtwn Ambu Cen
  • Colorado
    • Colorado Springs, Colorado, United States, 80907
      • Peak Gastro Assoc-Col Springs
  • Connecticut
    • Hartford, Connecticut, United States, 06106
      • Hartford Hsptl_Hartford
  • Florida
    • Doral, Florida, United States, 33122
      • Integrity Clinical Research, LLC
    • Hialeah, Florida, United States, 33012
      • Miguel Rebollar PA
    • Inverness, Florida, United States, 34452
      • Nature Coast Clinical Research_Inverness
    • Jacksonville, Florida, United States, 32224
      • UF Hepatology Jacksonville
    • Lakewood Ranch, Florida, United States, 34211
      • Florida Research Institute, LLC
    • Miami, Florida, United States, 33135
      • Optimus U, Corp
    • Miami, Florida, United States, 33136
      • Univ of Miami/Schiff Ctr
    • Sarasota, Florida, United States, 34240
      • Covenant Metabolic Specialists LLC
    • Zephyrhills, Florida, United States, 33542
      • Florida Medical Clinic, LLC
  • Georgia
    • Atlanta, Georgia, United States, 30309
      • Piedmont Healthcare
    • Atlanta, Georgia, United States, 30327
      • Digestive Healthcare of Georgia
    • Macon, Georgia, United States, 31201
      • Gastroenterology Assoc_ CGA
    • Marietta, Georgia, United States, 30060
      • Gastroint Spec of Georgia
  • Indiana
    • South Bend, Indiana, United States, 46635
      • Digestive Research Alliance of Michiana
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • University Of Kansas Hospital
    • Topeka, Kansas, United States, 66606
      • Kansas Medical Clinic, PA
  • Louisiana
    • Houma, Louisiana, United States, 70363
      • Tandem Clinical Research - Houma
    • Marrero, Louisiana, United States, 70072
      • Tandem Clinical Research
    • Shreveport, Louisiana, United States, 71105
      • Louisiana Research Center, LLC
  • Maryland
    • Baltimore, Maryland, United States, 21202
      • Mercy Medical Center, GI Research
    • Bethesda, Maryland, United States, 20889
      • Walter Reed Nat Mil Md Ctr
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Henry Ford Hospital_Detroit
  • Missouri
    • Kansas City, Missouri, United States, 64131
      • Kansas City Research Institute
  • New Jersey
    • Florham Park, New Jersey, United States, 07932
      • AIG Digestive Disease Research
  • New York
    • New York, New York, United States, 10016
      • NYU Grossman School of Med
    • New York, New York, United States, 10065
      • Weill Cornell Med Coll-NYPH
  • Ohio
    • Cleveland, Ohio, United States, 44106
      • Univ Hosp Cleveland Med Ctr
    • Columbus, Ohio, United States, 43210
      • Ohio State Univ Wexner Med Ctr
    • Springboro, Ohio, United States, 45066
      • DSI Research,LLC
  • Pennsylvania
    • Danville, Pennsylvania, United States, 17822-2111
      • Geisinger Clinic
    • Hershey, Pennsylvania, United States, 17033
      • Pennsylvania State University
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania Hospital
    • Philadelphia, Pennsylvania, United States, 19107-5244
      • Thomas Jefferson University Hospital
    • Pittsburgh, Pennsylvania, United States, 15213
      • UPMC Center for Liver Diseases
    • Pittsburgh, Pennsylvania, United States, 15213
      • UPMC_Center for Liver Care
  • Tennessee
    • Hermitage, Tennessee, United States, 37076
      • Digestive Health Res-TSMC
    • Nashville, Tennessee, United States, 37211
      • Quality Medical Research
  • Texas
    • Arlington, Texas, United States, 76012
      • Texas Clin Res Inst, LLC
    • Dallas, Texas, United States, 75203
      • Liver Ins@ Mthdist DTX Med Cen
    • Houston, Texas, United States, 77030
      • Liver Specialists of Texas
    • Round Rock, Texas, United States, 78681
      • Texas Diabetes & Endocinology
    • San Antonio, Texas, United States, 78215
      • Amer. Rrsch Corp-TX Liver Inst
    • Waco, Texas, United States, 76710
      • Impact Research
    • Wichita Falls, Texas, United States, 76301
      • Digestive Hlth Res of N Texas
  • Virginia
    • Falls Church, Virginia, United States, 22042
      • Inova Fairfax Medical Campus
    • Richmond, Virginia, United States, 23226
      • Bon Secours Richmond Community Hospital LLC
    • Roanoke, Virginia, United States, 24014
      • Gastroent Consult of SW VA
  • Washington
    • Seattle, Washington, United States, 98104
      • Swedish med ctr org trans-lvr ctr
    • Seattle, Washington, United States, 98105
      • Liver Institute NW

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Aged greater than or equal to 18 years at the time of signing informed consent. In Republic of Korea, subjects must be aged greater than or equal to 19 years. In Japan, subjects must be aged greater than or equal to 20 years. In Singapore, subjects must be aged greater than or equal to 21 years.
• Histological evidence of NASH based on a central pathologist evaluation of the baseline liver biopsy. The baseline liver biopsy can be a historical biopsy obtained within 180 days prior to Visit 1.
• Histological evidence of fibrosis stage 2, 3 or 4 according to the NASH CRN classification based on a central pathologist evaluation of the baseline liver biopsy.
• Histological non-alcoholic fatty liver disease (NAFLD) activity score (NAS) greater than or equal to 4 for subjects with F2/F3 or greater than or equal to 3 for subjects with F4 based on a central pathologist evaluation of the baseline liver biopsy. All subjects must have a score of 1 or more in steatosis, lobular inflammation and hepatocyte ballooning.

Exclusion Criteria:

• Documented causes of chronic liver disease other than NAFLD.
• Positive HBsAg, positive anti-HIV, positive HCV RNA at screening (V2A) or any known presence of HCV RNA or HBsAg within 2 years of screening (V2A).
• Presence or history of ascites more than grade 1, variceal bleeding, hepatic encephalopathy, spontaneous bacterial peritonitis or liver transplantation at V2A.
• For subjects with F4, presence or history of gastro-oesophageal varices more than or equal to grade 2 at V3. An oesophagogastroduodenoscopy performed no more than 52 weeks prior to V3 must be available at V3.
• Known or suspected excessive consumption of alcohol (more than 20 g/day for women or more than 30 g/day for men) or alcohol dependence (assessed by the Alcohol Use Disorders Identification Test (AUDIT questionnaire)).
• Treatment with vitamin E (at doses more than or equal to 800 IU/day) or pioglitazone or medications approved for the treatment of NASH which has not been at a stable dose in the opinion of the investigator in the period from 90 days prior to V2A. In addition, for subjects with a historical liver biopsy taken more than 90 days prior to V2A, treatment should be at a stable dose in the opinion of the investigator from time of biopsy until V2A.
• Treatment with GLP-1 RAs within 90 days prior to V2A. Subjects with a historical liver biopsy taken more than 90 days prior to V2A are excluded if they receive treatment with GLP-1 RAs from time of biopsy until V2A.
• Treatment with glucose-lowering agent(s) (other than GLP-1 RAs), lipid-lowering medication or weight loss medication not stable in the opinion of the investigator in the period from 90 days prior to V2A. In addition, for subjects with a historical liver biopsy taken more than 90 days prior to V2A, treatment should be at a stable dose in the opinion of the investigator from time of biopsy until V2A.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

10

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: NNC0194-0499 7.5 mg + semaglutide 2.4 mg; Each subject will receive two subcutaneous injections once weekly, consisting of two active drugs or one active drug and one placebo or two placebo injections.	Drug: NNC0194 0499 50 mg/mL; Patients will receive subcutaneous (s.c., under the skin) injections of NNC0194-0499 once weekly The study will last for about 19 months; Drug: Semaglutide 3 mg/mL; Patients will receive subcutaneous (s.c., under the skin) injections of semaglutide once weekly The study will last for about 19 months
Placebo Comparator: Placebo (NNC0194-0499) 7.5 mg + semaglutide placebo 2.4 mg; Each subject will receive two subcutaneous injections once weekly, consisting of two active drugs or one active drug and one placebo or two placebo injections.	Drug: Placebo (NNC0194-0499); Patients will receive subcutaneous (s.c., under the skin) injections of placebo once weekly The study will last for about 19 months; Drug: Semaglutide placebo; Patients will receive subcutaneous (s.c., under the skin) injections of semaglutide placebo once weekly The study will last for about 19 months
Experimental: NNC0194-0499 15 mg + semaglutide 2.4 mg; Each subject will receive two subcutaneous injections once weekly, consisting of two active drugs or one active drug and one placebo or two placebo injections.	Drug: NNC0194 0499 50 mg/mL; Patients will receive subcutaneous (s.c., under the skin) injections of NNC0194-0499 once weekly The study will last for about 19 months; Drug: Semaglutide 3 mg/mL; Patients will receive subcutaneous (s.c., under the skin) injections of semaglutide once weekly The study will last for about 19 months
Placebo Comparator: Placebo (NNC0194-0499) 15 mg + semaglutide placebo 2.4 mg; Each subject will receive two subcutaneous injections once weekly, consisting of two active drugs or one active drug and one placebo or two placebo injections.	Drug: Placebo (NNC0194-0499); Patients will receive subcutaneous (s.c., under the skin) injections of placebo once weekly The study will last for about 19 months; Drug: Semaglutide placebo; Patients will receive subcutaneous (s.c., under the skin) injections of semaglutide placebo once weekly The study will last for about 19 months
Experimental: NNC0194-0499 30 mg + semaglutide 2.4 mg; Each subject will receive two subcutaneous injections once weekly, consisting of two active drugs or one active drug and one placebo or two placebo injections.	Drug: NNC0194 0499 50 mg/mL; Patients will receive subcutaneous (s.c., under the skin) injections of NNC0194-0499 once weekly The study will last for about 19 months
Experimental: NNC0194-0499 30 mg + semaglutide placebo 2.4 mg; Each subject will receive two subcutaneous injections once weekly, consisting of two active drugs or one active drug and one placebo or two placebo injections.	Drug: NNC0194 0499 50 mg/mL; Patients will receive subcutaneous (s.c., under the skin) injections of NNC0194-0499 once weekly The study will last for about 19 months; Drug: Semaglutide placebo; Patients will receive subcutaneous (s.c., under the skin) injections of semaglutide placebo once weekly The study will last for about 19 months
Active Comparator: Placebo (NNC0194-0499) 30 mg + semaglutide 2.4 mg; Each subject will receive two subcutaneous injections once weekly, consisting of two active drugs or one active drug and one placebo or two placebo injections.	Drug: Semaglutide 3 mg/mL; Patients will receive subcutaneous (s.c., under the skin) injections of semaglutide once weekly The study will last for about 19 months; Drug: Placebo (NNC0194-0499); Patients will receive subcutaneous (s.c., under the skin) injections of placebo once weekly The study will last for about 19 months
Placebo Comparator: Placebo (NNC0194-0499) 30 mg + semaglutide placebo 2.4 mg; Each subject will receive two subcutaneous injections once weekly, consisting of two active drugs or one active drug and one placebo or two placebo injections.	Drug: Placebo (NNC0194-0499); Patients will receive subcutaneous (s.c., under the skin) injections of placebo once weekly The study will last for about 19 months; Drug: Semaglutide placebo; Patients will receive subcutaneous (s.c., under the skin) injections of semaglutide placebo once weekly The study will last for about 19 months
Experimental: NNC0174-0833 2.4 mg + semaglutide 2.4 mg; Each subject will receive two subcutaneous injections once weekly, consisting of two active drugs or one active drug and one placebo or two placebo injections.	Drug: Semaglutide 3 mg/mL; Patients will receive subcutaneous (s.c., under the skin) injections of semaglutide once weekly The study will last for about 19 months; Drug: NNC0174 0833 10 mg/mL; Patients will receive subcutaneous (s.c., under the skin) injections of NNC0174-0833 once weekly The study will last for about 19 months
Placebo Comparator: Placebo (NNC0174-0833) 2.4 mg + semaglutide placebo 2.4 mg; Each subject will receive two subcutaneous injections once weekly, consisting of two active drugs or one active drug and one placebo or two placebo injections.	Drug: Semaglutide placebo; Patients will receive subcutaneous (s.c., under the skin) injections of semaglutide placebo once weekly The study will last for about 19 months; Drug: NNC0174 0833 placebo; Patients will receive subcutaneous (s.c., under the skin) injections of NNC0174-0833 placebo once weekly The study will last for about 19 months

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Improvement in liver fibrosis and no worsening of NASH (Yes/No)	Count of subjects Improvement in fibrosis is defined as greater than or equal to 1 grade improvement on the NASH CRN fibrosis scale	From baseline (week 0) to week 52

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Resolution of steatohepatitis and no worsening of liver fibrosis (Yes/No)	Count of subjects Resolution of steatohepatitis is defined as a NAS of 0-1 for inflammation, 0 for ballooning and any value for steatosis according to NASH CRN52. Fibrosis is graded on the NASH CRN (Non-Alcoholic Steatohepatitis Clinical Research Network) fibrosis scale from 0 to 4.	From baseline (week 0) to week 52
Improvement in steatohepatitis with at least a 2-point reduction in NAS and no worsening of fibrosis (Yes/No)	Count of subjects The 2-point reduction must include at least a 1-point reduction in either lobular inflammation or hepatocellular ballooning.	From baseline (week 0) to week 52
Change in histology-assessed liver collagen proportionate area	Ratio to baseline	From baseline (week 0) to week 52
Resolution of steatohepatitis and improvement in liver fibrosis (Yes/No)	Count of subjects Resolution of steatohepatitis is defined as an NAS score of 0-1 for inflammation, 0 for ballooning and any value for steatosis (according to NASH CRN). Improvement in fibrosis is defined as greater than or equal to 1 grade improvement on the NASH CRN fibrosis scale	From baseline (week 0) to week 52
Improvement in liver fibrosis (Yes/No)	Count of subjects Improvement in fibrosis is defined as greater than or equal to 1 grade improvement on the NASH CRN fibrosis scale	From baseline (week 0) to week 52
Progression of liver fibrosis (Yes/No)	Count of subjects For subjects with fibrosis stage 2 or 3 at baseline	From baseline (week 0) to week 52
Worsening in steatohepatitis (Yes/No)	Count of subjects Worsening in steatohepatitis is defined as increase in NAS score for ballooning, inflammation or steatosis	From baseline (week 0) to week 52
Improvement in ballooning (Yes/No)	Count of subjects	From baseline (week 0) to week 52
Improvement in inflammation (Yes/No)	Count of subjects	From baseline (week 0) to week 52
Improvement in steatosis (Yes/No)	Count of subjects	From baseline (week 0) to week 52
Change in ALT (alanine aminotransferase)	Ratio to baseline	From baseline (week 0) to week 52
Change in AST (aspartate aminotransferase)	Ratio to baseline	From baseline (week 0) to week 52
Change in inflammation assessed by HsCRP (high sensitivity C-reactive protein)	Ratio to baseline	From baseline (week 0) to week 52
Change in ELF (Enhanced Liver Fibrosis) score	Logarithm	From baseline (week 0) to week 52
Change in HbA1c. For subjects with type 2 diabetes	%-points (absolute change)	From baseline (week 0) to week 52
Change in triglycerides	Ratio to baseline	From baseline (week 0) to week 52
Change in free fatty acids	Ratio to baseline	From baseline (week 0) to week 52
Change in LDL (low density lipoprotein) cholesterol	Ratio to baseline	From baseline (week 0) to week 52
Change in HDL (high density lipoprotein) cholesterol	Ratio to baseline	From baseline (week 0) to week 52
Relative change in body weight	Percentage	From baseline (week 0) to week 52
Change in SF-36 (36-item Short Form Survey) bodily pain	Points	From baseline (week 0) to week 52
Change in NASH-CHECK (patient-reported outcome measure for non-alcoholic steatohepatitis)pain	Points	From baseline (week 0) to week 52
Change in PROMIS (Patient-Reported Outcomes Measurement Information System) Fatigue score	Points	From baseline (week 0) to week 52
Number of treatment emergent adverse events (TEAEs)	Count	From baseline (week 0) to week 59

Collaborators and Investigators

• Sponsor: Novo Nordisk A/S
• Investigators: Study Director: Clinical Transparency (dept. 1452), Novo Nordisk A/S

Study record dates

Study Major Dates

• Study Start (Actual): August 31, 2021
• Primary Completion (Estimated): May 8, 2024
• Study Completion (Estimated): March 12, 2025

Study Registration Dates

• First Submitted: August 18, 2021
• First Submitted That Met QC Criteria: August 18, 2021
• First Posted (Actual): August 23, 2021

Study Record Updates

• Last Update Posted (Actual): May 7, 2024
• Last Update Submitted That Met QC Criteria: May 6, 2024
• Last Verified: May 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases; Fatty Liver; Non-alcoholic Fatty Liver Disease; Hypoglycemic Agents; Physiological Effects of Drugs; Glucagon-Like Peptide-1 Receptor Agonists; Semaglutide
• Other Study ID Numbers: NN9500-4656; U1111-1255-5551 (Other Identifier: World Health Organization (WHO)); 2020-003566-39 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: According to the Novo Nordisk disclosure commitment on novonordisk-trials.com

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No