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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 (PROXYMO-ADVANCE)

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-ADVANCE)

54

Participants were randomized in a 2:1:2:1 ration to receive cotadutide 300 microgram, placebo matching cotadutide 300 microgram, cotadutide 600 microgram, or placebo matching cotadutide 600 micogram. Participants uderwent dose titration steps every 4 weeks to reach the target dose of 300 microgram or 600 microgram once dailry. Participants were 18 or more to 75 or less years of age (inclusive) with biopsy-proven NASH (historical biopsy prformed 180 days or less from randomization or on-study biopsy) demonstrating NAS 4 more or (with a score of at least 1 for each component: steatosis, lobular inflammation, and ballooning) and liver fibrosis stage F2 or F3. 1860 paritipants were originally planning to be randmly assigned to study intervention, however, this study has permaturely stopped randomization as the cotadutide program was discontinued. 54 participants were totally randomizaed and got the study intervention (Cotadutide 300 mirogram grooup: 17, Placebo matching cotadutide 300 microgram: 10, Cotadutide 600 mirogram grooup: 18, Placebo matching cotadutide 600 microgram: 9) The backgroud of randomized patients is as follow: - Mean age Cotadutide 300 microgram group: 54.4 years, Placebo matching cotadutide 300 microgram: 56.9 years, Cotadutide 600 mirogram group: 53 years, Placebo matching cotadutide 600 microgram: 56.4 years. - Sex Cotadutide 300 microgram group: female: 11 (64.7%), male: 6 (35.3%), Placebo matching cotadutide 300 microgram: female: 4 (40.0%), male: 6 (60.0%), Cotadutide 600 mirogram group: female: 10 (55.6%), male: 8 (44.4%), Placebo matching cotadutide 600 microgram: female: 6 (66.7%), male: 3 (33.3%). - Race Cotadutide 300 microgram group:Asian: 5, Not reported: 1, White: 11, Placebo matching cotadutide 300 microgram: American Indian or Alaska Native: 1, Asian: 2, White: 7, Cotadutide 600 mirogram group: Asian: 9, Black or African American: 1 White: 8, Placebo matching cotadutide 600 microgram: American Indian or Alaska Native: 1, Asian: 2 White: 6.

The study was discontinued prematurely and recruitment was terminated due to a strategic decision to stop the cotadutide development program in NASH. The participant disposition was similar across the treatment groups. In total, 586 patients were enrolled, 54 participants were randomized, 36 (66.7%) participants were assessed for post-baseline biopsy, and 41 (75.9%) participants completed the study. Demographics, baseline participant characteristics, and use of concomitant medications were generally similar across treatment groups.

The safety set comprised 54 participants who received at least one dose of IP. Mean duration of exposure was similar across the treatment groups. The proportion of participants who experienced at least 1 adverse event was numerically greater in the cotadutide total group (93.4%) than in the placebo group (68.4%). Serioud adverse events were reported in 1 participant (cotadutide 300 microgram group). There were no deaths reproted.Only 3 participants (2 in the cotadutide 600 microgram group and 1 in the placebo group) experienced an adverse event leading to withdrawal from the study.

In the full analysis set, the proportion of participants with resolution of NASH without worsening of liver fibrosis was 35.3%, 44.4% and 26.3% in cotadutide 300 microgram, cotadutide 600 microgram, and placebo groups, respectively. Treatment with cotadutide 300 microgram was associated with a response difference of 18.1% (95% confidence interval [CI] -13.0, 46.4, p=0.257) compared to the placebo group. The proportion of participants in the full analysis set with improvement in liver fibrosis by at least one stage without worsening of NASH was 5.9%, 61.1%, and 21.1%, in the cotadutide 300 microgram, cotadutide 600 microgram, and placebo groups, respectively. Teatment with cotadutide 600 microgram was associated with a response difference of 40.1% (95% CI 8.1, 64.8, p=0.022) compared to the placebo group.

- Safety and tolerability of cotadutide 300 and 600 microgram administered subcutaneous once daily in adults with non-cirrhotic NASH with fibrosis were generally consistent with the known safety profile for cotadutide. - Cotadutide treatment at both doses demonstrated numerical improvements in resolution of NASH without worsning of liver fibrosis.

Oct. 01, 2025

No

https://jrct.mhlw.go.jp/latest-detail/jRCT2051220031

Ageishi Yuji

Astrazeneka K.K

3-1, Ofuka-cho, Kita-ku, Osaka-shi, Osaka

RD-clinical-information-Japan@astrazeneca.com

Ageishi Yuji

Astrazeneka K.K

3-1, Ofuka-cho, Kita-ku, Osaka-shi, Osaka

+81-6-4802-3533

RD-clinical-information-Japan@astrazeneca.com

Complete

June. 30, 2022

Interventional

randomized controlled trial

double blind

placebo control

parallel assignment

treatment purpose

1. Provision of informed consent

2. Males and female participants more or 18 to less or equal 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 less than or equal to 180 days from randomization and fulfilling all of the following histological criteria:

a. NAS (Non-alcoholic Fatty Liver Disease Activity Score) more or equal to 4 with a score of less or equal to 1 for each component: steatosis, lobular inflammation, and ballooning

b. 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.

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 within90 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 more or equal to 180 mmHg or DBP more or equal to 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.

Both

Non-Small Cell Lung Cancer

Cotadutide is administered subcutaneously once daily in increasing doses from 50ug to 300ug or 600ug.

Safety and tolerability will be evaluated in terms of AEs, vital signs, clinical and laboratory assessments, and ECG.
Incidence of ADAs to cotadutide and titer during treatment and follow-up

+81-6-6382-1521

May. 09, 2022

Austria/France/Greece/Italy/Malaysia/New Zealand/South Africa/Korea/Spain/Taiwan/United Kingdom/United States/Thailand