Clinical trial NCT06151964: A Trial to Learn How Safe AZD9550 is in People With or Without Type 2 Diabetes Who Are Overweight or Obese
Official title: A Phase I/II, Randomised, Single-blind, Placebo-controlled, Multiple-ascending-dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of AZD9550 in Overweight and Obese Participants With or Without Type 2 Diabetes Mellitus
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
PHASE2
Conditions: Non-alcoholic Steatohepatitis (NASH)
Keywords: AZD9550
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
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
First posted: 2023-11-30
Enrollment: 88
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: The study will randomise approximately 90 participants and will be conducted in 4 parts (A to D). Part D will be conducted exclusively in Japan. Part A: Approximately 45 participants will be screened to achieve 16 randomised to study intervention: Cohort 1 (n = 8) and Cohort 2 (n = 8). The study duration will be approximately 103 days.

Part B: Approximately 90 participants will be screened to achieve 30 randomised to study intervention. The study duration will be approximately 110 days. Part C: Approximately 90 participants will be screened to achieve 30 randomised to study intervention: Cohort 1 (n = 12) and Cohort 2 (n = 18). The study duration will be approximately 249 days.

Part D: Approximately 35 participants will be screened to achieve 12 randomised to study intervention. The study duration will be approximately 249 days.
Primary purpose: TREATMENT

Brief summary: AZD9550 is in early development for the treatment of NASH, a type of liver disease that commonly affects overweight and obese participants living with or without T2DM.

The purpose of this study is to investigate the safety, tolerability, and effects of increasing doses of AZD9550 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.

Detailed description: This Phase I/II, randomised, single-blind, placebo-controlled, MAD study will assess the safety and tolerability of AZD9550 and characterise the PK and PD of AZD9550 following SC administration to overweight and obese participants living with or without T2DM, including men and post-menopausal women. Inclusion of participants receiving placebo is appropriate for benchmarking the safety and tolerability of AZD9550. A randomised and single-blind study design has been chosen to minimise bias and includes placebo to facilitate identification of effects related to administration of study intervention rather than the study procedures or situation.

Eligibility criteria: Inclusion Criteria:

1. Males or post-menopausal females aged 18 through 65 years 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.
3. Participants with a screening HbA1c value within the target range of

   * ≥ 42 to ≤ 75 mmol/mol (6% to 9%) for T2DM patients
   * \< 48 mmol/mol (\< 6.5%) for participants without T2DM
4. Body mass index from ≥27 (≥25 in Part D) to ≤39.9 kg/m2 (inclusive).
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 and D only).

Exclusion Criteria:

1. Participants with T2DM treated with insulin.
2. Participants with T2DM treated with more than 3 anti-diabetic therapies.
3. Participants with or without T2DM treated with a GLP-1RA within 3 months of screening.
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.
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).
15. Any clinically important abnormalities in clinical chemistry, haematology, coagulation, or urinalysis results other than those specifically described as exclusion criteria herein, as judged by the investigator.
16. Significant late diabetic complications (macroangiopathy with symptoms of congestive heart disease or peripheral arterial disease, microangiopathy with symptoms of neuropathy, gastroparesis, retinopathy requiring treatment, nephropathy) detected in laboratory results or in clinical history/documentation as judged by the investigator.
17. Abnormal vital signs, after 10 minutes of supine rest, defined as any of the following:

    * Systolic BP \< 90 mmHg or ≥ 150 mmHg
    * Diastolic BP \< 50 mmHg or ≥ 90 mmHg
    * HR \< 50 or \> 85 bpm at resting state
    * Participants may be re-tested for the vital signs criteria only once if, in the investigator's judgement, they are not representative of the participant.
18. Any clinically important abnormalities in rhythm, conduction, or morphology of the resting ECG and any abnormalities in the 12-lead ECG that, as considered by the investigator, may interfere with the interpretation of QTc interval changes, including abnormal ST-T-wave morphology or left ventricular hypertrophy.
19. Participants with implantable cardiac defibrillator or a permanent pacemaker, and participants with symptomatic tachy- or brady-arrhythmias.
20. Participants with unstable angina pectoris or stable angina pectoris classified higher than Canadian Cardiovascular Society class II or an acute coronary syndrome/acute myocardial infarction or coronary intervention with percutaneous coronary intervention or coronary artery bypass grafting or stroke within 6 months.
21. History of hospitalisation caused by heart failure or a diagnosis of heart failure.
22. Known or suspected history of drug abuse within the past 3 years as judged by the investigator and /or a positive screen for drugs of abuse at screening.
23. History of severe allergy/hypersensitivity or ongoing clinically important allergy/hypersensitivity as judged by the investigator.
24. Whole blood or red blood cell donation, or any blood loss \> 500 mL (or \> 400 mL in Part D) during the 3 months prior to screening.
25. Psychiatric illness such that participants have been committed to an institution by way of official or judicial order.
26. History of lactic acidosis or ketoacidosis.
27. Use of any of the following medicinal products:

    * Use of systemic corticosteroids within 28 days prior to screening.
    * Use of compounds known to prolong the QTc interval.
    * Use of any herbal preparations or medicinal products licensed for control of body weight or appetite within 3 months prior to screening.
28. Use of drugs with enzyme inducing properties such as St John's Wort within 3 weeks prior to the first administration of study intervention.
29. Received another new chemical entity (defined as a compound that has not been approved for marketing), or has participated in any other clinical study that included drug treatment within at least 30 days or 5 half-lives prior to the first administration of study intervention in this study (whichever is longer). The period of exclusion to begin 30 days or 5 halflives of IMP after the final dose, or after the last visit, whichever is longest. Participants consented and screened, but not randomised into this study or a previous Phase 1 study, are not excluded.
30. Previous enrolment or randomisation in the present study.
31. Concurrent participation in another study of any kind is prohibited.
32. Ongoing weight loss diet (hypocaloric diet) or use of weight loss agents, unless the diet or treatment has been stopped at least 3 months prior to screening and the participant has had a stable body weight (± 5%) during the 3 months prior to screening.
33. Participants who are vegans, ones with medical dietary restrictions, or participants who are willingly conducting any diet likely to increase ketone levels (Atkins or any similar diet based on increased protein consummation or low carbohydrate content).
34. Excessive intake of caffeine-containing drinks or food (eg, coffee, tea, Coca-Cola/Pepsi or similar drink type, chocolate) as judged by the investigator.
35. Current smokers or those who have smoked or used nicotine products (including e-cigarettes) within the previous 3 months prior to screening.
36. Participants who cannot communicate reliably with the investigator or vulnerable participants (eg, kept in detention, protected adults under guardianship, trusteeship, or committed to an institution by governmental or juridical order).
37. The participant is an employee, or close relative of an employee, of AstraZeneca, the CRO, or the study site, regardless of the employee's role.
38. Judgement by the investigator that the participant should not participate in the study if the participant is unlikely to comply with study procedures, restrictions, and requirements.
39. Contra-indication to MRI: such as participants with pacemakers, metallic cardiac valves, magnetic material such as surgical clips, implanted electronic infusion pumps or other conditions that would preclude proximity to a strong magnetic field; participants with history of extreme claustrophobia or participant cannot fit inside the MRI scanner cavity (Parts B and C only).

Primary outcomes:
measure: 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.
timeFrame: Day - 35 to Day 205
measure: Number and percentage of participants with clinically significant changes from baseline in Vital Sign Parameters.
timeFrame: Day - 35 to Day 205
measure: Number and percentage of participants with clinically significant changes in ECG parameters.
timeFrame: Day - 35 to Day 205
measure: Number and percentage of participants with clinically significant changes from baseline in Clinical Laboratory Parameters
timeFrame: Day - 35 to Day 205
measure: Area Under Concentration-Time Curve of AZD9550 following repeat weekly SC doses
timeFrame: Day 1 to Day 65
measure: Maximum observed concentration of AZD9550 following repeat weekly SC doses
timeFrame: Day 1 to Day 65
measure: Half life associated with terminal phase elimination rate constant of AZD9550 following repeat weekly SC doses
timeFrame: Day 1 to Day 65
measure: Time to maximum observed concentration of AZD9550 following repeat weekly SC doses
timeFrame: Day 1 to Day 65
measure: Apparent oral clearance of AZD9550 following repeat weekly SC doses
timeFrame: Day 1 to Day 65
measure: Apparent volume of distribution of AZD9550 following repeat weekly SC doses
timeFrame: Day 1 to Day 65
measure: Ratio for AUC of AZD9550 following repeat weekly SC doses
timeFrame: Day 1 to Day 65
measure: Ratio for Cmax of AZD9550 following repeat weekly SC doses
timeFrame: Day 1 to Day 65
Secondary outcomes:
measure: PD effect of AZD9550 on fasting glucose compared to placebo
timeFrame: From baseline to Week 4
measure: PD effect of AZD9550 on fasting lipid profile compared to placebo
timeFrame: From baseline to Week 4
measure: Absolute and percentage change in body weight from baseline
timeFrame: From baseline to Week 4
measure: Incidence of anti-AZD9550 antibodies
timeFrame: From Day 1 to Day 65
measure: Absolute change in percentage body fat from baseline
timeFrame: From baseline to Week 4
measure: PD effect of AZD9550 on fasting glucose compared to placebo
timeFrame: From baseline to Week 5
measure: PD effect of AZD9550 on fasting lipid profile compared to placebo
timeFrame: From baseline to Week 5
measure: Effect of AZD9550 on hepatic fat fraction versus placebo at Week 5
timeFrame: From baseline to Week 5
measure: PD effect of AZD9550 on glucose metabolism following an MMTT compared to placebo
timeFrame: From baseline to Week 5
measure: Area Under concentration-time Curve of AZD9550 following repeat weekly SC doses
timeFrame: Day 1 to Day 72
measure: Incidence of anti-AZD9550 antibodies
timeFrame: Day 1 to Day 72
measure: PD effect of AZD9550 on fasting glucose compared to placebo
timeFrame: From baseline to Week 24
measure: PD effect of AZD9550 on fasting lipid profile compared to placebo
timeFrame: From baseline to Week 24
measure: The effect of AZD9550 on hepatic fat fraction versus placebo after 13 and 24 weeks of treatment
timeFrame: From baseline to Weeks 13 and 24
measure: Effects of AZD9550 compared to placebo on body weight
timeFrame: From baseline to Week 24
measure: Change in daily (24 hours) average glucose levels as measured by CGM
timeFrame: From baseline to Day 176
measure: Change in fasting hepatic glycogen concentration adjusted for liver volume as measured by MRS
timeFrame: From baseline to Weeks 13 and 24
measure: Area Under concentration-time Curve of AZD9550 following repeat weekly SC doses
timeFrame: Day 1 to Day 169
measure: Incidence of anti-AZD9550 antibodies
timeFrame: Day 1 to Day 205
measure: Change in daily (24 hours) average glucose levels as measured by CGM
timeFrame: From baseline to Weeks 1, 2, 3, 4, 5, and 6, and during 14 days post last dose
measure: Change in 7-day average glucose levels as measured by CGM
timeFrame: From baseline to Weeks 1, 2, 3, 4, 5, and 6 and during 14 days post last dose
measure: Change in coefficient of variation of glucose levels as measured by CGM over 7 days
timeFrame: From baseline to Weeks 1, 2, 3, 4, 5, and 6, and during 14 days post last dose
measure: 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
timeFrame: From baseline to Weeks 1, 2, 3, 4, 5, and 6, and during 14 days post last dose
measure: 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
timeFrame: From baseline to Weeks 1, 2, 3, 4, 5, and 6, and during 14 days post last dose
measure: Change in fasting hepatic glycogen concentration adjusted for liver volume as measured by MRS
timeFrame: From baseline to Week 5
measure: Percentage change in fasting hepatic glycogen concentration adjusted for liver volume as measured by MRS
timeFrame: From baseline to Week 5
measure: Change in fasting hepatic glycogen concentration unadjusted for liver volume as measured by MRS
timeFrame: From baseline to Week 5
measure: Percentage change in fasting hepatic glycogen concentration unadjusted for liver volume as measured by MRS
timeFrame: From baseline to Week 5
measure: Change in liver volume as measured by MRI
timeFrame: From baseline to Week 5
measure: Absolute change in body weight
timeFrame: From baseline to Week 5
measure: Percent change in body weight
timeFrame: From baseline to Week 5
measure: Proportion of participants achieving ≥ 5% body weight loss
timeFrame: From baseline to Week 5
measure: Proportion of participants achieving ≥ 10% body weight loss
timeFrame: From baseline to Week 5
measure: Change in 7-day average glucose levels as measured by CGM
timeFrame: From baseline to Day 176
measure: Change in coefficient of variation of glucose levels as measured by CGM over 7 days
timeFrame: From baseline to Day 176 and during 14 days post last dose
measure: 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
timeFrame: From baseline to Day 176
measure: 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
timeFrame: From baseline to Day 176 and during 14 days post last dose
measure: Percentage change in fasting hepatic glycogen concentration adjusted for liver volume as measured by MRS
timeFrame: From baseline to Weeks 13 and 24
measure: Change in fasting hepatic glycogen concentration unadjusted for liver volume as measured by MRS
timeFrame: From baseline to Weeks 13 and 24
measure: Percentage change in fasting hepatic glycogen concentration unadjusted for liver volume as measured by MRS
timeFrame: From baseline to Weeks 13 and 24
measure: Change in liver volume, visceral and SC fat as measured by MRI
timeFrame: From baseline to Weeks 13 and 24
measure: Anti-AZD9550 antibody titre among participants with positive serum antibodies to AZD9550
timeFrame: From Day 1 to 65
measure: Maximum observed concentration of AZD9550 following repeat weekly SC doses
timeFrame: Day to Day 72
measure: Half life associated with terminal phase elimination rate constant of AZD9550 following repeat weekly SC doses
timeFrame: Day 1 to Day 72
measure: Time to maximum observed concentration of AZD9550 following repeat weekly SC doses
timeFrame: Day 1 to Day 72
measure: Apparent oral clearance of AZD9550 following repeat weekly SC doses
timeFrame: Day 1 to day 72
measure: Apparent volume of distribution of AZD9550 following repeat weekly SC doses
timeFrame: Day 1 to Day 72
measure: Anti-AZD9550 antibody titre among participants with positive serum antibodies to AZD9550
timeFrame: Day 1 to Day 72
measure: Maximum observed concentration of AZD9550 following repeat weekly SC doses
timeFrame: Day 1 to Day 169
measure: Half life associated with terminal phase elimination rate constant of AZD9550 following repeat weekly SC doses
timeFrame: Day 1 to Day 169
measure: Time to maximum observed concentration of AZD9550 following repeat weekly SC doses
timeFrame: Day 1 to Day 169
measure: Apparent oral clearance of AZD9550 following repeat weekly SC doses
timeFrame: Day 1 to Day 169
measure: Apparent volume of distribution of AZD9550 following repeat weekly SC doses
timeFrame: Day 1 to day 169
measure: Anti-AZD9550 antibody titre among participants with positive serum antibodies to AZD9550
timeFrame: Day 1 to Day 205
measure: Change in visceral and subcutaneous fat as measured by MRI
timeFrame: From baseline to week 5
measure: PD effect of AZD9550 on glucose metabolism compared to placebo
timeFrame: From baseline to Week 4
measure: PD effect of AZD9550 on glucose metabolism compared to placebo
timeFrame: From baseline to Week 5
measure: PD effect of AZD9550 on glucose metabolism compared to placebo
timeFrame: From baseline to Week 24
measure: PD effect of AZD9550 on fasting insulin compared to placebo
timeFrame: From baseline to Week 4
measure: PD effect of AZD9550 on fasting c-peptide compared to placebo
timeFrame: From baseline to Week 4
measure: PD effect of AZD9550 on fasting insulin compared to placebo
timeFrame: From baseline to Week 24
measure: PD effect of AZD9550 on fasting c-peptide compared to placebo
timeFrame: From baseline to Week 24
measure: PD effect of AZD9550 on fasting insulin compared to placebo
timeFrame: From baseline to Week 5
measure: PD effect of AZD9550 on fasting c-peptide compared to placebo
timeFrame: From baseline to Week 5
measure: Absolute change in percentage body fat
timeFrame: From baseline to Week 5
measure: PD effect of AZD9550 on glucose metabolism following an MMTT compared to placebo
timeFrame: From baseline to Week 13 and Week 24
measure: PD effect of AZD9550 on fasting lipid profile compared to placebo
timeFrame: From baseline to week 24
measure: PD effect of AZD9550 on HbA1c compared to placebo
timeFrame: From baseline to Week 4
measure: PD effect of AZD9550 on HbA1c compared to placebo
timeFrame: From baseline to Week 5
measure: PD effect of AZD9550 on HbA1c compared to placebo
timeFrame: From baseline to Week 24
Other outcomes:
Locations:
city: Graz
country: Austria
facility: Research Site
city: Vienna
country: Austria
facility: Research Site
city: Magdeburg
country: Germany
facility: Research Site
city: Neu-Ulm
country: Germany
facility: Research Site
city: Neuss
country: Germany
facility: Research Site
city: Fukuoka-shi
country: Japan
facility: Research Site
city: Shinjuku-ku
country: Japan
facility: Research Site
city: Suita-shi
country: Japan
facility: Research Site
city: Uppsala
country: Sweden
facility: Research Site
Study officials:
References: