A Study to Evaluate the Safety and Efficacy of Cotadutide Given by Subcutaneous Injection in Adult Participants With Non-cirrhotic Non-alcoholic Steatohepatitis With Fibrosis (PROXYMO-ADV)

A Phase II Randomized, Double-blind, Placebo-controlled, Proof-of-Concept Study to Evaluate the Safety and Efficacy of Cotadutide in Participants With Non-cirrhotic Non-alcoholic Steatohepatitis With Fibrosis

The purpose of this study is to evaluate the safety and efficacy of cotadutide in participants with non-cirrhotic NASH with fibrosis.

Study Overview

• Status: Active, not recruiting
• Conditions: Non-cirrhotic Non-alcoholic Steatohepatitis With Fibrosis
• Intervention / Treatment: Drug: Cotadutide; Drug: Placebo

Detailed Description

A Phase 2, randomized, double-blind, placebo-controlled study to evaluate the safety and efficacy of two different doses of cotadutide at 300 and 600 μg in participants with non-cirrhotic non-alcoholic steatohepatitis with fibrosis.

• Study Type: Interventional
• Enrollment (Actual): 54
• Phase: Phase 2

Contacts and Locations

Study Locations

• Argentina
  • Caba, Argentina, C1056ABJ
    • Research Site
• Australia
  • Heidelberg, Australia, 3084
    • Research Site
  • Kogarah, Australia, 2217
    • Research Site
  • Meadowbrook, Australia, 4131
    • Research Site
  • Melbourne, Australia, 3004
    • Research Site
  • Westmead, Australia, 2145
    • Research Site
• Austria
  • Wien, Austria, 1130
    • Research Site
  • Wien, Austria, 1030
    • Research Site
• Canada
  • Ontario
    • London, Ontario, Canada, N6A 5A5
      • Research Site
  • Quebec
    • Terrebonne, Quebec, Canada, J6X 4P7
      • Research Site
• France
  • Montpellier Cedex 5, France, 34090
    • Research Site
  • Paris, France, 75651
    • Research Site
• Germany
  • Dresden, Germany, 01307
    • Research Site
  • Konstanz, Germany, 78464
    • Research Site
• Greece
  • Athens, Greece, 12462
    • Research Site
  • Ioannina, Greece, 45500
    • Research Site
• Israel
  • Haifa, Israel, 34362
    • Research Site
  • Jerusalem, Israel, 91031
    • Research Site
  • Nahariya, Israel, 22100
    • Research Site
  • Petach-Tikva, Israel, 49100
    • Research Site
  • Tel Aviv, Israel, 64239
    • Research Site
  • Tel Hashomer, Israel, 52621
    • Research Site
• Italy
  • Catania, Italy, 95100
    • Research Site
  • Foggia, Italy, 71100
    • Research Site
  • Milano, Italy, 20127
    • Research Site
  • Roma, Italy, 00161
    • Research Site
  • Roma, Italy, 00100
    • Research Site
  • Rozzano, Italy, 20089
    • Research Site
  • San Giovanni Rotondo, Italy, 71013
    • Research Site
• Japan
  • Chiba-shi, Japan, 260-8677
    • Research Site
  • Fukui-shi, Japan, 918-8503
    • Research Site
  • Gifu-shi, Japan, 500-8513
    • Research Site
  • Hiroshima-shi, Japan, 734-8551
    • Research Site
  • Kawasaki-shi, Japan, 216-8511
    • Research Site
  • Kawasaki-shi, Japan, 215-0026
    • Research Site
  • Kure-shi, Japan, 737-0023
    • Research Site
  • Osaka, Japan, 637086
    • Research Site
  • Saga-shi, Japan, 849-8501
    • Research Site
  • Sapporo-shi, Japan, 062-0921
    • Research Site
  • Sendai-shi, Japan, 980-0873
    • Research Site
  • Shinjuku-ku, Japan, 160-0023
    • Research Site
  • Suita-shi, Japan, 564-0013
    • Research Site
  • Takasaki-shi, Japan, 370-0829
    • Research Site
  • Toon-shi, Japan, 791-0281
    • Research Site
  • Yokohama-shi, Japan, 236-0004
    • Research Site
  • Yokohama-shi, Japan, 245-8575
    • Research Site
• Korea, Republic of
  • Busan, Korea, Republic of, 49241
    • Research Site
  • Gangwon-do, Korea, Republic of, 26426
    • Research Site
  • Jung-gu, Korea, Republic of, 41944
    • Research Site
  • Seoul, Korea, Republic of, 03080
    • Research Site
  • Seoul, Korea, Republic of, 06351
    • Research Site
  • Seoul, Korea, Republic of, 04763
    • Research Site
• Malaysia
  • Kuala Lumpur, Malaysia, 59100
    • Research Site
  • Kuala Lumpur, Malaysia, 56000
    • Research Site
  • Melaka, Malaysia, 75400
    • Research Site
  • Seremban, Malaysia, 70300
    • Research Site
• New Zealand
  • Auckland, New Zealand, 2025
    • Research Site
  • Christchurch, New Zealand, 8011
    • Research Site
  • Grafton, New Zealand, 1023
    • Research Site
• South Africa
  • Plumstead, South Africa, 7800
    • Research Site
• Spain
  • A Coruña, Spain, 15006
    • Research Site
  • Almería, Spain, 04009
    • Research Site
  • Lérida, Spain, 25198
    • Research Site
  • Madrid, Spain, 28046
    • Research Site
  • Malaga, Spain, 29010
    • Research Site
  • Sevilla, Spain
    • Research Site
• Taiwan
  • Kaohsiung, Taiwan, 80756
    • Research Site
  • Tainan City, Taiwan, 70403
    • Research Site
  • Taipei City, Taiwan, 114
    • Research Site
  • Taipei City, Taiwan, 110
    • Research Site
  • Taipei City, Taiwan, 11217
    • Research Site
• Thailand
  • Bangkok, Thailand, 10330
    • Research Site
  • Bangkok, Thailand, 10400
    • Research Site
  • Bangkok, Thailand, 10700
    • Research Site
  • Hat Yai, Thailand, 90110
    • Research Site
  • Khon Kaen, Thailand, 40002
    • Research Site
• Turkey
  • Ankara, Turkey, 06800
    • Research Site
  • Istanbul, Turkey, 34093
    • Research Site
• United Kingdom
  • Aberdeen, United Kingdom, AB25 2ZN
    • Research Site
  • Glasgow, United Kingdom, G51 4LB
    • Research Site
  • Ipswich, United Kingdom, IP4 5PD
    • Research Site
  • Liverpool, United Kingdom, L1 9ED
    • Research Site
  • London, United Kingdom, EN1 1LJ
    • Research Site
  • Preston, United Kingdom, PR2 9QB
    • Research Site
  • Rochdale, United Kingdom, OL11 4AU
    • Research Site
  • Sheffield, United Kingdom, S2 5FX
    • Research Site
• United States
  • Arizona
    • Tucson, Arizona, United States, 85712
      • Research Site
  • California
    • Canoga Park, California, United States, 91303
      • Research Site
    • Gilroy, California, United States, 95020
      • Research Site
    • Sacramento, California, United States, 95821
      • Research Site
  • Colorado
    • Englewood, Colorado, United States, 80113
      • Research Site
  • Florida
    • Bradenton, Florida, United States, 34208
      • Research Site
    • Jacksonville, Florida, United States, 32216
      • Research Site
    • Miami, Florida, United States, 33176
      • Research Site
    • Miami, Florida, United States, 33175
      • Research Site
    • Miami, Florida, United States, 33256
      • Research Site
    • Winter Park, Florida, United States, 32789
      • Research Site
  • Indiana
    • Munster, Indiana, United States, 46321
      • Research Site
  • Louisiana
    • Houma, Louisiana, United States, 70363
      • Research Site
    • Marrero, Louisiana, United States, 70072
      • Research Site
    • Marrero, Louisiana, United States, 70006
      • Research Site
    • Shreveport, Louisiana, United States, 71105
      • Research Site
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • Research Site
  • Nevada
    • Las Vegas, Nevada, United States, 89109
      • Research Site
    • Las Vegas, Nevada, United States, 89104
      • Research Site
  • New Jersey
    • Lawrence Township, New Jersey, United States, 08648
      • Research Site
    • Warren, New Jersey, United States, 07059
      • Research Site
  • North Carolina
    • Morehead City, North Carolina, United States, 28557
      • Research Site
  • Tennessee
    • Chattanooga, Tennessee, United States, 37421
      • Research Site
  • Texas
    • Arlington, Texas, United States, 76012
      • Research Site
    • Austin, Texas, United States, 78745
      • Research Site
    • Dallas, Texas, United States, 75230
      • Research Site
    • Lewisville, Texas, United States, 75057
      • Research Site
    • San Antonio, Texas, United States, 78215
      • Research Site
  • Utah
    • Ogden, Utah, United States, 84403
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Provision of informed consent
2. Males and female participants ≥ 18 to ≤ 75 years of age (inclusive) at the time of signing the informed consent.

3. Histologically confirmed non-alcoholic steatohepatitis (NASH) per NASH Clinical Research Network (CRN) criteria as diagnosed by histology from a liver biopsy performed ≤ 180 days from randomization and fulfilling all of the following histological criteria:

   1. NAS (Non-alcoholic Fatty Liver Disease Activity Score) ≥ 4 with a score of ≥ 1 for each component: steatosis, lobular inflammation, and ballooning
   2. Presence of fibrosis stage F2 or F3
4. Women of childbearing potential, non-pregnant and nonbreastfeeding and using appropriate birth control to avoid pregnancy throughout the study and for up to 4 weeks after the last dose of study intervention.

Exclusion Criteria:

1. Chronic liver disease of other etiologies.
2. History of cirrhosis and/or hepatic decompensation, including evidence of portal hypertension (e.g. low platelet count, splenomegaly, ascites, history of hepatic encephalopathy, esophageal varices, or variceal bleeding).
3. Clinically significant cardiovascular or cerebrovascular disease within 90 days prior to screening, including but not limited to, myocardial infarction, acute coronary syndrome, unstable angina pectoris, transient ischemic attack, or stroke, or participants who have undergone percutaneous coronary intervention or a coronary artery bypass graft within the past 90 days or who are due to undergo these procedures at the time of screening
4. History of malignant neoplasms within 5 years prior to screening, except for adequately treated basal cell, squamous cell skin cancer, or any in situ carcinoma.
5. Participation in another clinical study with an investigational product administered within the last 30 days or 5 half-lives of the therapy (whichever is longer) at the time of screening or the time of the historical biopsy or concurrent participation in another interventional study of any kind or prior randomization in this study.
6. Severe allergy/hypersensitivity to any of the proposed study treatments or excipients
7. Contraindication to liver biopsy (eg, bleeding diathesis, such as hemophilia, suspected hemangioma, or suspected echinococcal infection) or inability to safely obtain a liver biopsy as determined by the investigator
8. Severely uncontrolled hypertension defined as SBP ≥ 180 mmHg or DBP ≥ 110 mmHg on the average of 2 seated BP measurements after being at rest for at least 10 minutes at screening or randomization 9 Any positive results for human immunodeficiency virus infection, positive results for hepatitis B surface antigen or hepatitis C antibody test along with a positive HCV RNA test.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cotadutide 300μg	Drug: Cotadutide; Cotadutide administered subcutaneously once daily
Placebo Comparator: Placebo 300μg	Drug: Placebo; Placebo administered subcutaneously once daily
Experimental: Cotadutide 600μg	Drug: Cotadutide; Cotadutide administered subcutaneously once daily
Placebo Comparator: Placebo 600μg	Drug: Placebo; Placebo administered subcutaneously once daily

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of participants with adverse events (AEs).	To assess safety and tolerability of Cotadutide. Occurrence of AEs and serious AEs, including AEs leading to dose reduction, and AEs of special interest.	From first dose on Day 1 until the follow-up period, 28 days post last dose
Number of participants with abnormal vital signs.	To assess safety and tolerability of Cotadutide.	From first dose on Day 1 until the follow-up period, 28 days post last dose
Number of participants with abnormal laboratory assessments	To assess safety and tolerability of Cotadutide.	From first dose on Day 1 until the follow-up period, 28 days post last dose
Number of participants with treatment emergent abnormality in 12-lead electrocardiogram (ECG).	To assess safety and tolerability of Cotadutide.	From first dose on Day 1 until the follow-up period, 28 days post last dose
Number of Treatment-induced Anti-Drug Antibody (ADA) participants	To assess the immunogenicity of Cotadutide	From first dose on Day 1 until the follow-up period, 28 days post last dose
Titer of Treatment-induced Anti-Drug Antibody (ADA)	To assess the immunogenicity of cotadutide	Time Frame: From first dose on Day 1 until the follow-up period, 28 days post last dose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part A: Proportion of participants with improvement of liver fibrosis by at least one stage without worsening of NASH	To assess the effect of cotadutide versus placebo on improvement in fibrosis by at least one stage without worsening of NASH	Week 48
Part A: Proportion of participants with ≥ 2-point improvement from baseline in NAS based on biopsy	To assess the effect of cotadutide versus placebo on ≥ 2-point improvement in NAS	Week 48
Part A: Proportion of participants with both resolution of NASH and improvement in fibrosis by at least one stage	To assess the effect of cotadutide versus placebo on resolution of NASH and improvement in fibrosis	Week 48
Part A: Proportion of participants with improvement in fibrosis by at least one stage based on biopsy	To assess the effect of cotadutide versus placebo on improvement in fibrosis by at least one stage	Week 48
Part A: Absolute change from baseline in body weight	To determine whether cotadutide is superior to placebo for weight reduction	Week 48
Part A: Change from baseline in HbA1c in participants with T2DM	To determine whether cotadutide is superior to placebo for glycemic control in participants with T2DM	Week 48
Part A: Percent change from baseline in triglycerides	To assess the effect of cotadutide versus placebo on triglycerides	Week 48
Part B: Proportion of participants with ≥ 2-point improvement from baseline in NAS based on biopsy	To assess the effect of cotadutide versus placebo on ≥ 2-point improvement in NAS	Week 84
Part B: Proportion of participants with both resolution of NASH and improvement in fibrosis by at least one stage	To assess the effect of cotadutide versus placebo on resolution of NASH and improvement in fibrosis	Week 84
Part B: Proportion of participants with progression to cirrhosis based on biopsy	To assess the effect of cotadutide versus placebo on progression to cirrhosis	Week 84
Part B: Proportion of participants with improvement in fibrosis by at least one stage based on biopsy	To assess the effect of cotadutide versus placebo on improvement in fibrosis by at least one stage	Week 84
Part B: Absolute change from baseline in body weight	To determine whether cotadutide is superior to placebo for weight reduction	Week 84
Part B: Change from baseline in HbA1c in participants with T2DM	To determine whether cotadutide is superior to placebo for glycemic control in participants with T2DM	Week 84
Part B: Percent change from baseline in triglycerides	To assess the effect of cotadutide versus placebo on triglycerides	Week 84

Collaborators and Investigators

• Sponsor: AstraZeneca

Study record dates

Study Major Dates

• Study Start (Actual): July 14, 2022
• Primary Completion (Estimated): April 24, 2024
• Study Completion (Estimated): April 24, 2024

Study Registration Dates

• First Submitted: May 4, 2022
• First Submitted That Met QC Criteria: May 4, 2022
• First Posted (Actual): May 6, 2022

Study Record Updates

• Last Update Posted (Actual): April 4, 2024
• Last Update Submitted That Met QC Criteria: April 3, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: NASH; liver fibrosis; fatty liver disease; NAS; Non-alcoholic steatohepatitis; non-alcoholic fatty liver
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Liver Diseases; Fibrosis; Fatty Liver; Non-alcoholic Fatty Liver Disease
• Other Study ID Numbers: D5671C00006; 2021-005484-53 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment:

https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

• IPD Sharing Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• IPD Sharing Access Criteria: When a request has been approved AstraZeneca will provide access to the deidentified individual patient-level data in an approved sponsored tool . Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

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