Non-cirrhotic Non-alcoholic Steatohepatitis With Fibrosis
Conditions
Keywords
NASH, fatty liver disease, non-alcoholic fatty liver, NAS, liver fibrosis, Non-alcoholic steatohepatitis
Brief summary
The purpose of this study is to evaluate the safety and efficacy of cotadutide in participants with non-cirrhotic NASH with fibrosis.
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.
Interventions
DRUGCotadutide
Cotadutide administered subcutaneously once daily
DRUGPlacebo
Placebo administered subcutaneously once daily
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events (AEs). | First dose on Day 1 until the follow-up period, 28 days post last dose, up to approximately 52 weeks. | To assess safety and tolerability of Cotadutide. Occurrence of AEs and serious AEs, including AEs leading to dose reduction, and AEs of special interest. |
| Number of Participants With Abnormal Vital Signs. | First dose on Day 1 until the follow-up period, 28 days post last dose, up to approximately 52 weeks. | To assess safety and tolerability of Cotadutide. |
| Number of Participants With Abnormal Laboratory Assessments | First dose on Day 1 until the follow-up period, 28 days post last dose, up to approximately 52 weeks. | To assess safety and tolerability of Cotadutide. |
| Number of Participants With Treatment Emergent Abnormality in 12-lead Electrocardiogram (ECG). | First dose on Day 1 until the follow-up period, 28 days post last dose, up to approximately 52 weeks. | To assess safety and tolerability of Cotadutide. |
| Number of Treatment-induced Anti-Drug Antibody (ADA) Participants | First dose on Day 1 until the follow-up period, 28 days post last dose, up to approximately 52 weeks. | To assess the immunogenicity of Cotadutide |
| Titer of Treatment-induced Anti-Drug Antibody (ADA) | From first dose on Day 1 until the follow-up period, 28 days post last dose (from randomization up to approximately 52 weeks). | To assess the immunogenicity of cotadutide. Titers represent a dilution and are therefore unitless. Summary statistics are based on the maximum observed titer for each ADA positive subject within the time frame. |
Countries
Argentina, Australia, Austria, Canada, France, Germany, Greece, Israel, Italy, Japan, Malaysia, New Zealand, South Africa, South Korea, Spain, Taiwan, Thailand, Turkey (Türkiye), United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Cotadutide 300 ug Cotadutide 300 ug QD | 17 |
| Cotadutide 600 ug Cotadutide 600 ug QD | 18 |
| Placebo 600 ug Placebo 600 ug QD | 9 |
| Placebo 300 ug Placebo 300 ug QD | 10 |
| Total | 54 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 2 | 1 | 0 |
| Overall Study | Discontinued | 1 | 0 | 0 | 0 |
| Overall Study | Lost to Follow-up | 1 | 0 | 0 | 0 |
| Overall Study | study terminated by sponsor (reason as collected in database, study was not terminated) | 0 | 1 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 1 | 3 | 2 |
Baseline characteristics
| Characteristic | Cotadutide 300 ug | Cotadutide 600 ug | Placebo 600 ug | Placebo 300 ug | Total |
|---|---|---|---|---|---|
| Age, Continuous Mean(standard Deviation) | 54.4 Years STANDARD_DEVIATION 12.4 | 53 Years STANDARD_DEVIATION 12.6 | 56.4 Years STANDARD_DEVIATION 9.4 | 56.9 Years STANDARD_DEVIATION 11.6 | 54.7 Years STANDARD_DEVIATION 11.7 |
| Age, Customized >=50 - <65 years | 7 Participants | 7 Participants | 5 Participants | 4 Participants | 23 Participants |
| Age, Customized < 50 years | 6 Participants | 7 Participants | 2 Participants | 3 Participants | 18 Participants |
| Age, Customized >= 65 years | 4 Participants | 4 Participants | 2 Participants | 3 Participants | 13 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized Asian | 5 Participants | 9 Participants | 2 Participants | 2 Participants | 18 Participants |
| Race/Ethnicity, Customized Black or African American | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Multiple | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Not Reported | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Other | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized White | 11 Participants | 8 Participants | 6 Participants | 7 Participants | 32 Participants |
| Sex: Female, Male Female | 11 Participants | 10 Participants | 6 Participants | 4 Participants | 31 Participants |
| Sex: Female, Male Male | 6 Participants | 8 Participants | 3 Participants | 6 Participants | 23 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 17 | 0 / 18 | 0 / 9 | 0 / 10 |
| other Total, other adverse events | 16 / 17 | 17 / 18 | 5 / 9 | 8 / 10 |
| serious Total, serious adverse events | 1 / 17 | 0 / 18 | 0 / 9 | 0 / 10 |
Outcome results
Primary
Number of Participants With Abnormal Laboratory Assessments
To assess safety and tolerability of Cotadutide.
Time frame: First dose on Day 1 until the follow-up period, 28 days post last dose, up to approximately 52 weeks.
Population: Although there are two placebo arms for blinding purposes, the safety and efficacy analyses in the (abbreviated) CSR pooled the two placebo arms and analyzed them as a single group as prespecified in the SAP.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cotadutide 300 ug | Number of Participants With Abnormal Laboratory Assessments | 16 Participants |
| Cotadutide 600 ug | Number of Participants With Abnormal Laboratory Assessments | 17 Participants |
| Placebo | Number of Participants With Abnormal Laboratory Assessments | 19 Participants |
Primary
Number of Participants With Abnormal Vital Signs.
To assess safety and tolerability of Cotadutide.
Time frame: First dose on Day 1 until the follow-up period, 28 days post last dose, up to approximately 52 weeks.
Population: Although there are two placebo arms for blinding purposes, the safety and efficacy analyses in the (abbreviated) CSR pooled the two placebo arms and analyzed them as a single group as prespecified in the SAP.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cotadutide 300 ug | Number of Participants With Abnormal Vital Signs. | 13 Participants |
| Cotadutide 600 ug | Number of Participants With Abnormal Vital Signs. | 14 Participants |
| Placebo | Number of Participants With Abnormal Vital Signs. | 17 Participants |
Primary
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.
Time frame: First dose on Day 1 until the follow-up period, 28 days post last dose, up to approximately 52 weeks.
Population: Although there are two placebo arms for blinding purposes, the safety, immunogenicity, and efficacy analyses in the (abbreviated) CSR pooled the two placebo arms and analyzed them as a single group as prespecified in the SAP.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cotadutide 300 ug | Number of Participants With Adverse Events (AEs). | 16 Participants |
| Cotadutide 600 ug | Number of Participants With Adverse Events (AEs). | 16 Participants |
| Placebo | Number of Participants With Adverse Events (AEs). | 13 Participants |
Primary
Number of Participants With Treatment Emergent Abnormality in 12-lead Electrocardiogram (ECG).
To assess safety and tolerability of Cotadutide.
Time frame: First dose on Day 1 until the follow-up period, 28 days post last dose, up to approximately 52 weeks.
Population: Although there are two placebo arms for blinding purposes, the safety and efficacy analyses in the (abbreviated) CSR pooled the two placebo arms and analyzed them as a single group as prespecified in the SAP.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cotadutide 300 ug | Number of Participants With Treatment Emergent Abnormality in 12-lead Electrocardiogram (ECG). | 4 Participants |
| Cotadutide 600 ug | Number of Participants With Treatment Emergent Abnormality in 12-lead Electrocardiogram (ECG). | 2 Participants |
| Placebo | Number of Participants With Treatment Emergent Abnormality in 12-lead Electrocardiogram (ECG). | 6 Participants |
Primary
Number of Treatment-induced Anti-Drug Antibody (ADA) Participants
To assess the immunogenicity of Cotadutide
Time frame: First dose on Day 1 until the follow-up period, 28 days post last dose, up to approximately 52 weeks.
Population: Although there are two placebo arms for blinding purposes, the safety and efficacy analyses in the (abbreviated) CSR pooled the two placebo arms and analyzed them as a single group as prespecified in the SAP.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cotadutide 300 ug | Number of Treatment-induced Anti-Drug Antibody (ADA) Participants | 7 Participants |
| Cotadutide 600 ug | Number of Treatment-induced Anti-Drug Antibody (ADA) Participants | 11 Participants |
| Placebo | Number of Treatment-induced Anti-Drug Antibody (ADA) Participants | 0 Participants |
Primary
Titer of Treatment-induced Anti-Drug Antibody (ADA)
To assess the immunogenicity of cotadutide. Titers represent a dilution and are therefore unitless. Summary statistics are based on the maximum observed titer for each ADA positive subject within the time frame.
Time frame: From first dose on Day 1 until the follow-up period, 28 days post last dose (from randomization up to approximately 52 weeks).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cotadutide 300 ug | Titer of Treatment-induced Anti-Drug Antibody (ADA) | 240 titer |
| Cotadutide 600 ug | Titer of Treatment-induced Anti-Drug Antibody (ADA) | 60 titer |