Proxymo-Advance (NASH)

PHRR220803-004916

D5671C00006

2022-CT0688

A Phase lib/III Randomized, Double-blind, Placebo controlled Study to Evaluate the Safety and Efficacy of Cotadutide 111 Participants with Non-cirrhotic Nonalcoholic Steatohepatitis with Fibrosis

This 2-part Phase IIb/III study will evaluate the safety and efficacy of cotadutide in adults with biopsy-proven non-cirrhotic NASH with fibrosis stage F2 or F3. GLP-1 receptor mono-agonists reduce liver fat and improve histological features of NASH (Armstrong et al 2016, Petit et al 2017, Newsome et al 202). Cotadutide, an oxyntomodulin-like peptide with targeted balanced GLP-1 and glucagon receptor activity, has been associated with robust improvements in body weight, glucose and insulin homeostasis, markers of hepatic health, lipid lowering, collagen turnover, liver fibrosis profile, and renoprotection in a number of animal models of NASH, CKD, obesity, and T2DM. Importantly, cotadutide has demonstrated robust and significant histologic benefits, including reduction in NASH disease activity and improvement in fibrosis in animal models (Boland et al 2020). In obese patients with T2DM, cotadutide had a robust and significant treatment effect on HFF (Ambery et al 2018) and other non-invasive measures of NAFLD (Nahra et al 2021). In patients with biopsy-proven non-cirrhotic NASH with fibrosis (F1, F2, F3), cotadutide has demonstrated robust and significant improvements in HFF, liver enzymes, and non-invasive markers of NASH and fibrosis.

The primary goal of this study is to evaluate the safety and efficacy of cotadutide in participants with non-cirrhotic NASH with fibrosis. Part A will examine the safety, tolerability, and efficacy of 2 different doses of cotadutide. Week 48 data from Part A will be used to guide possible dose adaptations for the ongoing Part B of the study. Part B will examine the effects of cotadutide on safety, histology, and other efficacy endpoints following 84 weeks of treatment.

Start Date Duration in Months Target Completion Date Actual Completion Date
2022-09-12 36 2025-09-12 0000-00-00

Pending

Pending IRB approval and contract execution

Institution Classification Region LTO #
AstraZeneca AB Private Business Sweden LTO-3000002234602
Institution Classification Region LTO #
NA None NCR
Institution Region
AstraZeneca AB Sweden
Name E-Mail Institution and Institution Address
Samia Necesito-Dungao samia.necesito@astrazeneca.com 16th Floor, Inoza Tower, 40th Street, Bonifacio Global City, Taguig, Metro Manila
Name E-Mail Institution and Institution Address
Samia Necesito-Dungao samia.necesito@astrazeneca.com 16th Floor, Inoza Tower, 40th Street, Bonifacio Global City, Taguig, Metro Manila
Name Expertise Affiliation
Janus P Ong Internal Medicine/ Gastroenterology The Medical City
Madalinee Eternity Labio, MD Internal Medicine/ Gastroenterology Makati Medical Center
Olivert Gomez, MD Diabetology Docbebet Diabetes Clinic
Name of Trial Site Address Principal Investigator Research Ethics Committee
NAME EXPERTISE REC Name Status of Approval
The Medical City The Medical City The Medical City - Institutional Review Board Janus P Ong Internal Medicine/ Gastroenterology
Makati Medical Center Makati Medical Center Makati Medical Center Institutional Review Board Madalinee Eternity Labio, MD Internal Medicine/ Gastroenterology
Docbebet Diabetes Clinic Doc Bebet Diabetes Clinic, Pampanga Baguio General Hospital and Medical Center Ethics Review Committee Olivert Gomez, MD Diabetology
Project Location Institutional Ethics Review Board
The Medical City The Medical City - Institutional Review Board
Makati Medical Center Makati Medical Center Institutional Review Board
Docbebet Diabetes Clinic Baguio General Hospital and Medical Center Ethics Review Committee

Clinical Trial

Unspecified

Non-cirrhotic Non-alcoholic Steatohepatitis with Fibrosis

Proportion of participants with resolution of NASH without worsening of liver fibrosis based on biopsy at Week 48

  • Proportion of participants with improvement of liver fibrosis by at least one stage without worsening of NASH based on biopsy at Week 48
  • Proportion of participants with ≥ 2-point improvement from baseline in NAS based on biopsy at Week 48
  • Proportion of participants with both resolution of NASH and improvement in fibrosis by at least one stage based on biopsy at Week 48
  • Proportion of participants with improvement in fibrosis by at least one stage based on biopsy at Week 48
  • Absolute change from baseline in body weight at Week 48
  • Change from baseline in HbA1c in participants with T2DM at Week 48
  • Percent change from baseline in triglycerides at Week 48

Pending

  • Argentina
  • Australia
  • Austria
  • Brazil
  • Canada
  • China
  • Colombia
  • France
  • Germany
  • Greece
  • Hong Kong
  • Israel
  • Italy
  • Japan
  • Malaysia
  • Mexico
  • New Zealand
  • Peru
  • Russia
  • Singapore
  • South Africa
  • South Korea
  • Spain
  • Switzerland
  • Taiwan
  • Thailand
  • Turkey
  • United Kingdom
  • United States
  • Vietnam

D5671C00006

20220426094103

2022-07-08

0000-00-00

Protocol Code Number D5671C00006
Protocol Version Unspecified
Date of Protocol Version Unspecified

24

Unspecified

Unspecified

Unspecified

0000-00-00

Inclusion

Age

1 Participant must be ≥ 18 to ≤ 75 years of age at the time of signing the informed consent.

Type of Participant and Disease Characteristics

2 Histologically confirmed NASH per NASH Clinical Research Network criteria as diagnosed by liver biopsy within 90 days of screening (no more than 180 days from randomization) fulfilling all of the following histological criteria, read by a central pathology review committee:

(a)NAS ≥ 4 with a score of ≥ 1 for each component: steatosis, lobular inflammation, and ballooning

(b)Presence of fibrosis stage F2 or F3 OR

(c)Willingness to undergo a liver biopsy at screening, result of which should fulfill the above histological criteria Investigators should determine eligibility for liver biopsy on participants who are found to be eligible with respect to all other criteria, based on local procedures and clinical judgment, including the use of non-invasive techniques (such as FibroScan, FIB-4, and other clinical and laboratory-based measures).

3 HbA1c ≤ 10.5% in patients with T2DM managed on a stable dose of antidiabetic medication and/or diet for at least 90 days prior to screening. HbA1c testing may be repeated once.

Sex

4 Male or female (non-pregnant and non-breastfeeding)

Reproduction and Contraception: Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.

5 Female participants of childbearing potential must use at least one highly effective form of birth control. A highly effective method of contraception is defined as one that can achieve a failure rate of less than 1% per year when used consistently and correctly. Women of childbearing potential who are sexually active with a non-sterilized male partner must agree to use one highly effective method of birth control, as defined below, from enrolment throughout the study and until at least 4 weeks after last dose of study intervention. Cessation of contraception after this point should be discussed with a responsible physician. All women of child-bearing potential must have a negative serum pregnancy test result at Visit 1.

(a) Women not of childbearing potential are defined as women who are either permanently sterilized (hysterectomy, bilateral oophorectomy, or bilateral salpingectomy), or who are postmenopausal. Women will be considered postmenopausal if they have been amenorrhoeic for 12 months prior to the planned date of randomization without an alternative medical cause. The following age-specific requirements apply:

•Women < 50 years old would be considered postmenopausal if they have been amenorrhoeic for 12 months or more following cessation of exogenous hormonal treatment and follicle stimulating hormone levels in the postmenopausal range.

•Women ≥ 50 years old would be considered postmenopausal if they have been amenorrhoeic for 12 months or more following cessation of all exogenous hormonal treatment.

(b) Highly effective birth control methods include sexual abstinence, a vasectomized partner, Implanon®, bilateral tubal occlusion, intrauterine device/levonorgestrel intrauterine system, Depo-Provera™ injections, oral contraceptive, and Evra Patch™, Xulane™, or NuvaRing®. Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and lactational amenorrhea method are not acceptable methods of contraception. Female condom and male condom should not be used together, and neither is considered to be a highly effective birth control method.

6 Female participants must refrain from egg cell donation and breastfeeding while on study and for 4 weeks after the final dose of study intervention.

Informed Consent

7 Capable of giving signed informed consent as described in Appendix A, which includes compliance with the requirements and restrictions listed in the ICF and in this protocol

8 Provision of signed and dated written Optional Genetic Research Information informed consent prior to collection of samples for optional genetic research that supports Genomic Initiative

9 Part B only: Provision of signed and dated written Optional MRE/MRI informed consent prior to optional MRE/MRI imaging

 

Exclusion

Participants are excluded from the study if any of the following criteria apply:

Medical Conditions

1 History of, or any existing condition that, in the opinion of the investigator, would interfere with evaluation of the study intervention, put the participant at risk, influence the participant’s ability to participate, or affect the interpretation of the results of the study

2 Liver disease of other etiologies (eg, alcoholic steatohepatitis; drug-induced, viral, or autoimmune hepatitis; primary biliary cirrhosis; primary sclerosing cholangitis; hemochromatosis; alpha 1 antitrypsin deficiency; Wilson's disease). Participants cured of HCV infection less than 2 years prior to the Screening visit are not eligible

3 History of cirrhosis and/or hepatic decompensation, including ascites, hepatic encephalopathy, or variceal bleeding

4 Prior or planned liver transplantation

5 Prior or planned bariatric surgery

6 Alcohol consumption > 21 units (1 unit = 14 g pure alcohol) per week (21 standard drinks per week) for men and > 14 units per week (14 standard drinks per week) for women on average within 2 years prior to baseline liver biopsy (historical or at screening). Evidence of alcohol dependence as assessed by the AUDIT questionnaire at screening

7 Type 1 diabetes mellitus, a history of diabetic ketoacidosis, or symptoms of acutely decompensated blood glucose control (eg, thirst, polyuria, weight loss)

8 History of acute pancreatitis (unless previously resolved gallstone pancreatitis and post cholecystectomy), or current chronic pancreatitis

9 Clinically significant inflammatory bowel disease, gastroparesis, or other severe disease or surgery affecting the upper gastrointestinal tract (including bariatric surgery) that may affect gastric emptying or could affect the interpretation of the safety and tolerability data

10 History of any of the following that in the opinion of the investigator is not stable in the period from 90 days prior to the screening visit:

(a)> 5% weight loss (self-reported or documented)

(b)Treatment with glucose-lowering agent(s)

(c)Treatment with lipid-lowering agent(s)

(d)Pharmacologic or non-pharmacologic weight loss medication(s) (approved and/or off-label use)

(e)Participation in weight loss programs

11 Clinically significant CV 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

12 Cardiac arrhythmia

(a)Second or third degree atrial ventricular block or sinus node dysfunction with clinically significant pause, not treated with pacemaker

(b)Ventricular arrhythmia requiring treatment

(c)Participants with atrial fibrillation/flutter with ventricular rate (> 100 bpm at rest)

13 Severe congestive heart failure (New York Heart Association Class IV)

14 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

15 History of substance dependence or positive screen for drugs of abuse at screening or psychiatric disorder likely to impact participant safety or compliance with study procedures, at the discretion of the investigator

Prior/Concomitant Therapy

16 Recent (within 90 days of screening biopsy or historical biopsy through screening) use of therapies associated with development of NAFLD (eg, methotrexate, tamoxifen, amiodarone, or long-term use of tetracyclines or systemic corticosteroids [inhaled, nasal, topical are allowed])

17 Recent (within 180 days of screening biopsy or historical biopsy through screening) use of obeticholic acid or other therapy under investigation for NASH

18 Pioglitazone or high dose vitamin E (> 400 IU) unless on a stable dose for at least 180 days prior to the baseline biopsy (either screening or historical) and not initiated after the biopsy was taken

19 Recent (within 90 days of screening biopsy or historical biopsy through screening) use of GLP-1 receptor agonist or GLP-1 receptor agonist containing therapies

Prior/Concurrent Clinical Study Experience

20 Participation in another clinical study with an IP 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, not covered under exclusion criteria 16 or 17

21 Concurrent participation in another interventional study of any kind or prior randomization in this study

22 Severe allergy/hypersensitivity to any of the proposed study treatments or excipients

Diagnostic Assessments

23 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 

24 Participants with serum triglyceride concentrations above 1000 mg/dL (11 mmol/L) at screening

25 Abnormal laboratory values at screening, including any of the following:

(a)AST or ALT > 5 × ULN

(b)Alkaline phosphatase > 2 × ULN

(c)Impaired renal function defined as eGFR≤ 30 mL/minute/1.73 m2 at screening(estimated according to the CKD Epidemiology collaboration) (Inker et al 2021)

(d)Albumin < 3.5 g/dL

(e)International normalized ratio≥ 1.3

(f)TBL ≥ 1.3 mg/dL in the absence of known Gilbert’s disease

(g)Platelet count < 150,000/mm3

(h)Any other clinically significant abnormalities in serum chemistry, hematology, or urinalysis results as judged by the investigator

26 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

27 Basal calcitonin level≥ 50 ng/L (ie, ≥ 50 pg/mL) at screening, or history/family history of medullary thyroid carcinoma or multiple endocrine neoplasia type 1 or multiple endocrine neoplasia type 2

28 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

Other Exclusions

29 Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site)

30 Judgment by the investigator that the participant should not participate in the study if the participant is unlikely to comply with study procedures, restrictions, and requirements31Fibrosis stage F2 if the cap has been reached on F2 participants or fibrosis stage F3 if the cap has been reached on F3 participants

Interventional

Cotadutide

Cotadutide has shown potent agonism of both the GLP-1 receptor and glucagon receptor in human and animal in vitro assays. In vivo, this has translated into the anticipated pharmacological effects on body weight reduction, improved glucose and insulin homeostasis, improvements in markers of hepatic health, lipid lowering, reduced collagen turnover, an improved liver fibrosis profile, and renoprotective effects in a number of animal models of NASH, CKD, obesity, and T2DM. For a summary of nonclinical pharmacology and toxicology studies.

None

Method of Allocation

Randomized

Masking or Blinding

Double Blind

Masking Details

Unspecified

Control

Unspecified

Assignment

Single

Phase

Phase II/III

Purpose of the Study

Non-alcoholic steatohepatitis has a prevalence of approximately 2% to 3% in the general population and can lead to cirrhosis, hepatocellular carcinoma, and end-stage liver disease. It has been previously demonstrated that GLP-1 receptor mono-agonists reduce liver fat and improve histological features of NASH (Armstrong et al 2016, Petit et al 2017, Newsome et al 202). Cotadutide, an oxyntomodulin-like peptide with targeted balanced GLP-1 and glucagon receptor activity, has been associated with improvements i n body weight, glucose and insulin homeostasis, markers of hepatic health, lipid lowering, collagen turnover, liver fibrosis profile, and renoprotection in a number of animal models of NASH, CKD, obesity, and T2DM. Importantly, cotadutide has demonstrated robust and significant histologic benefit to reduce NASH disease activity leading to NASH resolution and on improvement in fibrosis in animal models of NASH with fibrosis (Boland et al 2020). In 2 separate studies in obese patients with T2DM, cotadutide had a significant treatment effect on HFF, and treatment with cotadutide for 54 weeks in obese T2DM led to significant treatment effects on non-invasive measures of NAFLD as well as effects on body weight, glucose lowering, and lipid profile parameters(Ambery et al 2018, Nahra et al 2021).

In a Phase II randomized, double-blind, placebo-controlled study (D5671C00002; PROXYMO) in overweight/obese participants (n = 74) with biopsy-proven non-cirrhotic NASH with fibrosis, treatment with cotadutide at 300 and 600 μg doses for 52 weeks was generally safe and well-tolerated. The AE profile was consistent with the incretin class, and the majority of events were mild-to-moderate in severity. Cotadutide demonstrated dose- and time-dependent improvements in HFF and other measures of NASH. Dose-dependent reductions in liver enzymes were observed, with robust and significant treatment effects on ALT and ALT in the 600 μg group. Additionally, improvements in biomarkers of NASH and fibrosis were observed. This Phase IIb/III study will evaluate the safety and efficacy of 300 and 600 μg cotadutide in adults with biopsy-proven non-cirrhotic NASH with fibrosis stage F2 or F3.

Detailed purpose of the study

Unspecified

Plan to Share IPD

Unspecified

IPD Description

Unspecified

Date of posting of result summaries

Unspecified

Date of the first journal publication of results

Unspecified

URL hyperlinks related to results and publications

Unspecified

URL link to protocol files(s) with version and data

Unspecified

Baseline Characteristics

Unspecified

Participant Flow

Unspecified

Adverse Events

Unspecified

Outcome Measures

Unspecified

Brief Summary

Unspecified

Utilization Utilization Info
Publication
Oral Presentation
Drug Literature
Posters
Others
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