Overweight and Obesity
Conditions
Keywords
AZD9550, AZD6234, Non-alcoholic Fatty Liver Disease, Non-alcoholic Steatohepatitis, Overweight, Obese, Obesity, Diabetes Mellitus, Type 2, Liver Glycogen, Adipose Tissue, Glucose, 3-Hydroxybutyric Acid, Subcutaneous Fat, Liver fat, Magnetic Resonance Imaging, Magnetic Resonance Spectroscopy, Weight Loss, Mixed Meal Tolerance Test
Brief summary
AZD9550, previously being developed for the treatment NASH, is a dual GCG and GLP-1 receptor agonist. AZD9550 is now being developed in combination with AZD6234, a SARA, for the treatment of overweight and obesity and its associated co-morbidities. Co-administration of AZD9550 and AZD6234 is currently being evaluated in participants living with obesity and overweight without T2DM in an ongoing Phase 2b study. The purpose of this study is to investigate the safety, tolerability, and effects of increasing doses of AZD9550 monotherapy in overweight and obese participants aged 18 through 65 years living with or without T2DM, and to investigate how AZD9550 is absorbed, distributed, and eliminated from the body (Parts A-D). In addition, the study will investigate the safety and tolerability of co-administration of AZD9550 and AZD6234 in participants living with T2DM with obesity or overweight aged 18 through 75 years (Part E).
Detailed description
This Phase I/II, randomised, single-blind, placebo-controlled, MAD study will assess the safety and tolerability of AZD9550 monotherapy and co-administration of AZD9550 and AZD6234 and will characterise the PK and PD of AZD9550 monotherapy and co-administration of AZD9550 and AZD6234 following SC administration to overweight and obese participants living with or without T2DM. Inclusion of participants receiving placebo is appropriate for benchmarking the safety and tolerability of AZD9550 and co-administration of AZD9550 and AZD6234. A randomised and single-blind study design has been chosen to minimise bias and includes a placebo to facilitate identification of effects related to the administration of the study intervention rather than the study procedures or situation.
Interventions
DRUGAZD9550
Part A: A constant dose Part B: Doses of AZD9550 that increase each week Part C: Doses of AZD9550 that increase every 2 weeks, then every 4 weeks Part D: Doses of AZD9550 that increase every 2 weeks, then every 4 weeks
DRUGPlacebo
Matching administration volumes for SC injection
DRUGAZD9550 and AZD6234
Part E: Doses of AZD9550 and AZD6234 that increase every 2 weeks, then every 4 weeks
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Masking description
This study is single-blind with regard to treatment (AZD9550 monotherapy, co-administered AZD9550 and AZD6234, or placebo). This means that the participant, investigator, Study Monitor, and the clinical unit staff will remain blinded during each part of the study and the randomisation code will only be available at each predefined decision point before the SRC meeting in order to review the data unblinded, if necessary. The sponsor will be unblinded throughout the study. AZD9550, AZD6234, and placebos will as far as possible be matched for appearance and volume. Participants randomised to placebo will receive the same volume of injection (SC cohorts) as participants on active treatment. In Part E, the number of injections per dosing occasion (ie, 2) will be the same in all treatment arms.
Intervention model description
The study will randomise approx. 120 participants and is devided in 5 parts (Part D conducted only in Japan): A: Approx. 45 participants will be screened to achieve 16 randomised. The study duration approx. 103 days. B: Approx. 90 participants will be screened to achieve 30 randomised. The study duration approx. 110 days. C: Approx. 90 participants will be screened to achieve 30 randomised. The study duration approx. 249 days. D: Approx. 35 participants will be screened to achieve 12 randomised. The study duration approx. 249 days. E: Approx. 80 participants will be screened to achieve approx. 28 randomised. The study duration approx. 249 days.
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
1. Males or females aged 18 through 65 years (Parts A-D) or 75 years (Part E) at the time of screening. 2. Parts A, B, C only: Participants with or without T2DM. If participants have a diagnosis of T2DM, the glucose control managed with diabetes diet and in addition to metformin treatment no more than two treatment options (with a stable dose 3 months prior to screening). Part D only: Participants who are diagnosed with T2DM, have inadequate glycaemic control with diet and exercise. Participants who are prescribed an oral anti-diabetic agent such as metformin, a DPP IV inhibitor, sulphonylurea, glinides, alphaglucosidase inhibitors, and an SGLT2 inhibitor may be eligible to enter the study following a washout of 4-weeks or 5-half lives (whichever is longer) washout period. Part E only: Participants are eligible to be included in the Part E only if they meet all of the following criteria at screening: 1. Diagnosed with T2DM. 2. Are treated with diet and exercise only, or any combination of OAD with stable doses in the 3 months prior to dosing. 3. Participants prescribed a DPP IV inhibitor or a GLP-1RA-containing medicine, alone or in combination with other OADs, may be eligible to enter the study if they have not been treated with any of these drugs for at least 35 days or 5 drug half-lives (whichever is longer) prior to randomisation. 3. Participants with a screening HbA1c value within the target range of • ≥ 42 to ≤ 86 mmol/mol (6% to 10%). 4. Body mass index from ≥27 (≥25 in Part D) to ≤39.9 kg/m2 (inclusive) (Part A-D) or ≥ 27 kg/m2 (Part E). 5. Contraceptive use by males or females should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. 6. Written informed consent and any locally required authorization (eg, European Union Data Privacy Directive) obtained from the participant prior to performing any protocol-related procedures, including screening evaluations 7. Ability to complete and meet all eligibility requirements for randomisation within 60 days after signing the ICF. 8. Venous access suitable for multiple cannulations. 9. Willing and able to self-administer weekly SC injections (Parts C, D and E only).
Exclusion criteria
1. Participants with T2DM treated with insulin. 2. Participants with T2DM treated with more than 3 anti-diabetic therapies (Parts A-D only). 3. Participants with or without T2DM treated with a GLP-1RA or GLP-1RA/GIPRA within 3 months of screening (Parts A to D only) or within 35 days of randomisation or five half-lives (whichever is shorter) of dosing (Part E only). 4. History of any clinically important disease or disorder which, in the opinion of the investigator, may either put the participant at risk because of participation in the study, or influence the results or the participant's ability to participate in the study. 5. Serum calcitonin suggestive of thyroid C-cell hyperplasia (calcitonin level \> 50 ng/L), medullary thyroid carcinoma, or history or family history of multiple endocrine neoplasia at screening. 6. History or presence of GI, renal, or hepatic disease (with the exception of Gilbert's syndrome), or any other condition known to interfere with absorption, distribution, metabolism, or excretion of drugs, as judged by the investigator. 7. History of cancer within the last 10 years, with the exception of non-melanoma skin cancer. 8. Any clinically important illness (apart from T2DM), as judged by the investigator. 9. Any medical/surgical procedure, or trauma within 4 weeks prior to screening, at the discretion of the investigator. 10. Symptoms of insulinopenia or poor blood glucose control (eg, significant thirst, nocturia, polyuria, polydipsia, or weight loss). 11. Positive hepatitis B or hepatitis C virus serology at screening. 12. Positive human immunodeficiency virus test at screening or participant taking antiretroviral medications as determined by medical history or participant's verbal report. 13. At screening blood tests, any of the following: * AST ≥ 1.5 × ULN * ALT ≥ 1.5 × ULN * TBL ≥ 1.5 × ULN (with the exception of Gilbert's syndrome) * Haemoglobin below the lower limit of the normal range or any other clinically significant haematological abnormality as judged by the investigator. * Total serum calcium, albumin-corrected calcium or ionised calcium \< LLN at screening (Part E). 14. Impaired renal function defined as estimated glomerular filtration rate (eGFR) ≤ 60 mL/minute/1.73m2 as defined by Chronic Kidney Disease Epidemiology Collaboration (2021) (Part A to D); or ≤ 45 mL/minute/1.73 m2 (Part E). 15. Any clinically important abnormalities in clinical chemistry, haematology, coagulation, or urinalysis results other than those specifically described as
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number and percentage of participants with any AE, SAEs, AEs leading to discontinuation of study intervention, AEs with outcome of death, and AEs leading to withdrawal from study. | Day - 35 to Day 205 | Applicable for Parts A, B, C, D, E. |
| Number and percentage of participants with clinically significant changes from baseline in Vital Sign Parameters. | Day - 35 to Day 205 | Applicable for Parts A, B, C, D, E. |
| Number and percentage of participants with clinically significant changes in ECG parameters. | Day - 35 to Day 205 | Applicable for Parts A, B, C, D, E. |
| Number and percentage of participants with clinically significant changes from baseline in Clinical Laboratory Parameters | Day - 35 to Day 205 | Applicable for Parts A, B, C, D, E. |
| Area Under Concentration-Time Curve of AZD9550 following repeat weekly SC doses | Day 1 to Day 65 | * AUC from 0 to the time of the last measured concentration (AUClast) at first dose and last dose * AUC over a dosing interval (AUCtau) at first dose and last dose. Applicable for Part A. |
| Maximum observed concentration of AZD9550 following repeat weekly SC doses | Day 1 to Day 65 | • Cmax at first dose and last dose Applicable for Part A. |
| Half life associated with terminal phase elimination rate constant of AZD9550 following repeat weekly SC doses | Day 1 to Day 65 | • t1/2λz at first dose and last dose Applicable for Part A. |
| Time to maximum observed concentration of AZD9550 following repeat weekly SC doses | Day 1 to Day 65 | • tmax at first dose and last dose Applicable for Part A. |
| Apparent oral clearance of AZD9550 following repeat weekly SC doses | Day 1 to Day 65 | • CL/F at first dose and last dose Applicable for Part A. |
| Apparent volume of distribution of AZD9550 following repeat weekly SC doses | Day 1 to Day 65 | • Vz/F at first dose and last dose Applicable for Part A. |
| Ratio for AUC of AZD9550 following repeat weekly SC doses | Day 1 to Day 65 | • Rac AUCtau at last dose Applicable for Part A. |
| Ratio for Cmax of AZD9550 following repeat weekly SC doses | Day 1 to Day 65 | • Rac Cmax at last dose Applicable for Part A. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in 7-day average glucose levels as measured by CGM | From baseline to Weeks 1, 2, 3, 4, 5, and 6 and during 14 days post last dose | Applicable for Part A (excluding during 14 days post last dose). Applicable for Part B (excluding from baseline to Week 6 and during 14 days post last dose). Applicable for Parts C and D. |
| Change in coefficient of variation of glucose levels as measured by CGM over 7 days | From baseline to Weeks 1, 2, 3, 4, 5, and 6, and during 14 days post last dose | Applicable for Part A (excluding during 14 days post last dose). Applicable for Part B (excluding from baseline to Week 6 and during 14 days post last dose). Applicable for Parts C and D. |
| Change in percentage time spent in hyperglycaemia (> 140 mg/dL), normoglycaemia (70 -140 mg/dL), and clinically significant hypoglycaemia (< 54 mg/dL) as measured by CGM over 24 hours | From baseline to Weeks 1, 2, 3, 4, 5, and 6, and during 14 days post last dose | Applicable for Part A (excluding during 14 days post last dose). Applicable for Part B (excluding from baseline to Week 6 and during 14 days post last dose). Applicable for Parts C and D. |
| Change in percentage time spent in hyperglycaemia (> 140 mg/dL), normoglycaemia (70 -140 mg/dL), and clinically significant hypoglycaemia (< 54 mg/dL) as measured by CGM over 7 days | From baseline to Weeks 1, 2, 3, 4, 5, and 6, and during 14 days post last dose | Applicable for Part A (excluding during 14 days post last dose). Applicable for Part B (excluding from baseline to Week 6 and during 14 days post last dose). Applicable for Parts C and D. |
| Percentage change in fasting hepatic glycogen concentration adjusted for liver volume as measured by MRS | From baseline to Week 5 | Applicable for Part B. |
| Change in fasting hepatic glycogen concentration unadjusted for liver volume as measured by MRS | From baseline to Week 5 | Applicable for Part B. |
| Percentage change in fasting hepatic glycogen concentration unadjusted for liver volume as measured by MRS | From baseline to Week 5 | Applicable for Part B. |
| Change in liver volume as measured by MRI | From baseline to Week 5 | Applicable for Part B. |
| Absolute change in body weight | From baseline to Week 5 | Applicable for Part B. |
| Percent change in body weight | From baseline to Week 5 | Applicable for Part B. |
| Proportion of participants achieving ≥ 5% body weight loss | From baseline to Week 5 | Applicable for Part B. |
| Proportion of participants achieving ≥ 10% body weight loss | From baseline to Week 5 | Applicable for Part B. |
| Change in liver volume, visceral and SC fat as measured by MRI | From baseline to Weeks 13 and 24 | Applicable for Part C. |
| Anti-AZD9550 antibody titre among participants with positive serum antibodies to AZD9550 | From Day 1 to 65 | • Titre of ADA to AZD9550 Applicable for Part A. |
| Maximum observed concentration of AZD9550 following repeat weekly SC doses | Day to Day 72 | • Cmax at the last dose Applicable for Part B. |
| Half life associated with terminal phase elimination rate constant of AZD9550 following repeat weekly SC doses | Day 1 to Day 72 | • t1/2λz at the last dose Applicable for Part B. |
| Time to maximum observed concentration of AZD9550 following repeat weekly SC doses | Day 1 to Day 72 | • tmax at the last dose Applicable for Part B. |
| Apparent oral clearance of AZD9550 following repeat weekly SC doses | Day 1 to day 72 | • CL/F at the last dose Applicable for Part B. |
| Apparent volume of distribution of AZD9550 following repeat weekly SC doses | Day 1 to Day 72 | • Vz/F at the last dose Applicable for Part B. |
| The effect of AZD9550 on hepatic fat fraction versus placebo after 13 and 24 weeks of treatment | From baseline to Weeks 13 and 24 | * Change in hepatic fat fraction as measured by MRI-PDFF * Percent change in hepatic fat fraction as measured by MRI-PDFF Applicable for Part C. |
| PD effect of AZD9550 on glucose metabolism compared to placebo | From baseline to Week 4 | • Percent change in fasting glucose, fasting insulin, fasting c-peptide, and HbA1c Applicable for Part A. |
| PD effect of AZD9550 on fasting insulin compared to placebo | From baseline to Week 4 | • Absolute change in fasting insulin Applicable for Part A. |
| PD effect of AZD9550 on fasting c-peptide compared to placebo | From baseline to Week 4 | • Absolute change in fasting c-peptide Applicable for Part A. |
| Absolute change in percentage body fat | From baseline to Week 5 | Applicable for Part B. |
| PD effect of AZD9550 on HbA1c compared to placebo | From baseline to Week 4 | • Absolute change in HbA1c Applicable for Part A. |
| Prevalence, incidence, and titres of ADAs to AZD9550 and AZD6234 in combination | After 24 weeks | • To assess the immunogenicity profile of co-administered AZD9550 and AZD6234 in combination. Applicable for Part E. |
| Change in visceral and subcutaneous fat as measured by MRI | From baseline to week 5 | Applicable for Part B. |
| PD effect of AZD9550 on fasting glucose compared to placebo | From baseline to Week 4 | • Absolute change in fasting glucose Applicable for Part A. |
| PD effect of AZD9550 on fasting lipid profile compared to placebo | From baseline to Week 4 | • Absolute and percentage change in total cholesterol, high-density lipoprotein, low-density lipoprotein, triglycerides, and BHB Applicable for Part A. |
| Absolute and percentage change in body weight from baseline | From baseline to Week 4 | Applicable for Part A. |
| Incidence of anti-AZD9550 antibodies | From Day 1 to Day 65 | • Incidence of ADA to AZD9550 Applicable for Part A. |
| Absolute change in percentage body fat from baseline | From baseline to Week 4 | Applicable for Part A. |
| Effect of AZD9550 on hepatic fat fraction versus placebo at Week 5 | From baseline to Week 5 | * Change in hepatic fat fraction as measured by MRI-PDFF * Percent change in hepatic fat fraction as measured by MRI-PDFF Applicable for Part B. |
| PD effect of AZD9550 on glucose metabolism following an MMTT compared to placebo | From baseline to Week 5 | * Percent change in glucose AUC(0-4h) measured by MMTT * Percent change in insulin AUC(0-4h) measured by MMTT * Percent change in c-peptide AUC(0-4h) measured by MMTT Applicable for Part B. |
| Area Under concentration-time Curve of AZD9550 following repeat weekly SC doses | Day 1 to Day 72 | * AUC from 0 to the time of the last measured concentration (AUClast) at the last dose * AUC over a dosing interval (AUCtau) at first dose and last dose Applicable for Part B. |
| Effects of AZD9550 compared to placebo on body weight | From baseline to Week 24 | * Change in body weight * Percent change in body weight • Proportion of participants achieving ≥ 5% body weight loss • Proportion of participants achieving ≥ 10% body weight loss * Absolute change in percentage body fat Applicable for Parts C and D. |
| Change in daily (24 hours) average glucose levels as measured by CGM | From baseline to Day 176 | Applicable for Parts C and D. |
| Change in fasting hepatic glycogen concentration adjusted for liver volume as measured by MRS | From baseline to Weeks 13 and 24 | Applicable for Part C. |
Countries
Austria, Canada, Germany, Japan, Sweden
Outcome results
None listed