Evaluation of AZD9550 Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics in Overweight and Obese Patients with Non-alcoholic Steatohepatitis
- Trial ID
- 2023-504215-32-00
- Protocol
- D8460C00002
- Sponsor
- AstraZeneca AB
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **safety** and **tolerability** of AZD9550 in overweight and obese participants with or without Type 2 Diabetes Mellitus. This is assessed through repeat subcutaneous (SC) doses in Part A, multiple ascending SC doses in Part B, and up to a maximum tolerated SC dose in Part C over 24 weeks. Understanding the safety and tolerability of AZD9550 is crucial for determining its potential as a therapeutic agent for managing conditions such as Non-alcoholic steatohepatitis (NASH), which is associated with metabolic disorders.
Secondary objectives include:
- Characterizing the pharmacodynamic (PD) effect of AZD9550 on glucose metabolism and fasting lipid profile compared to placebo across different parts of the study.
- Assessing the effects of AZD9550 on glucose levels, body weight, and body fat, as well as hepatic glycogen and fat fraction, compared to placebo.
- Evaluating the immunogenicity profile of AZD9550 and its pharmacokinetics (PK) following repeat weekly SC doses.
These secondary objectives aim to provide a comprehensive understanding of the metabolic effects and potential therapeutic benefits of AZD9550 in the target population.
Participants
The clinical trial involves a total of **12 participants** diagnosed with **non-alcoholic steatohepatitis (NASH)**. The study population comprises both male and post-menopausal female subjects, aged between 18 and 65 years. Participants may have type 2 diabetes mellitus (T2DM), provided their glucose levels are managed through diet and metformin, with no more than two additional treatment options, maintaining a stable dose for at least three months prior to screening. The trial includes individuals with a body mass index ranging from 27 to 39.9 kg/m². Participants are required to have a screening HbA1c value within specified target ranges, depending on their T2DM status. The selection process ensures that participants have suitable venous access for multiple cannulations and are willing and able to self-administer weekly subcutaneous injections, where applicable. The trial does not include vulnerable populations, and all participants have provided written informed consent in accordance with local regulations.
Plans and Procedures
The clinical trial is designed as a **randomized**, 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**. The trial is divided into three parts: Part A, Part B, and Part C, each with specific objectives related to the evaluation of AZD9550 compared to placebo. The study is expected to run until June 30, 2025, with recruitment starting on September 21, 2023.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, body mass index, and glucose control. The trial includes multiple follow-up visits to monitor safety and efficacy endpoints, such as adverse events, vital signs, and laboratory assessments. The end-of-study visit will conclude the participant's involvement, ensuring all data is collected and any necessary follow-up care is arranged.
The expected length of participant involvement varies depending on the part of the study they are enrolled in, with Part C extending up to 24 weeks of dosing. Participants may be terminated early from the study if they experience significant adverse events, fail to comply with study procedures, or withdraw consent. The trial aims to provide comprehensive data on the effects of AZD9550, contributing to the understanding of its potential benefits and risks in the target population.
Treatment
The clinical trial involves the administration of several treatments, including both experimental and non-experimental medications. The primary experimental medication is **AZD9550**, a protein-based solution for injection, administered subcutaneously. The dosing schedule involves repeat weekly subcutaneous doses, with the aim of evaluating safety, tolerability, pharmacokinetics, and pharmacodynamics in overweight and obese participants, with or without Type 2 Diabetes Mellitus. The sponsor product code for AZD9550 is AZD9550, and it is developed by AstraZeneca AB.
In addition to AZD9550, the trial includes a **placebo** to match AZD9550, also administered subcutaneously. The placebo is used to provide a control for evaluating the effects of the experimental drug. The pharmaceutical form and active substance details for the placebo are not applicable, as it is designed to mimic the appearance and administration route of AZD9550 without containing the active substance.
Other non-experimental treatments used in the study include **Glucose**, administered intravenously, and **Dapagliflozin**, administered orally. Glucose is classified under the ATC code V04CA02, while Dapagliflozin is classified under A10BK01. These treatments are used as auxiliary medications to support the trial's objectives.
Additional non-experimental treatments include **Glucagon**, administered via nasal use, and **Metformin**, administered orally. Glucagon is classified under the ATC code H04AA01, and Metformin under A10BA02. These medications are included to manage specific conditions or symptoms that may arise during the trial.
Other medications involved in the trial are **Ondansetron** and **Cyclizine Hydrochloride**, both administered orally. Ondansetron is classified under the ATC code A04AA01, and Cyclizine Hydrochloride under R06AE03. These medications are used to manage nausea and vomiting, which may be side effects of the trial treatments.
Lastly, **Insulin Degludec** is administered parenterally. It is classified under the ATC code A10AE06 and is used to manage blood glucose levels in participants with Type 2 Diabetes Mellitus. The trial ensures participant compliance through regular monitoring and adherence checks, although specific compliance measures are not detailed in the provided data.
Efficacy
Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoints include the evaluation of adverse events (AEs) and serious adverse events (SAEs), vital signs, electrocardiograms (ECG), and clinical laboratory assessments across Parts A, B, and C of the study. Additionally, pharmacokinetic (PK) parameters such as AUClast, AUCtau, Cmax, t1/2λz, tmax, CL/F, and Vz/F will be measured at the first and last dose levels in Part A.
Secondary endpoints will focus on various metabolic and physiological parameters. In Part A, changes from baseline to Week 4 in fasting glucose, fasting insulin, fasting c-peptide, and **HbA1c** will be measured, along with changes in lipid profiles and body weight. Part B will extend these assessments to Week 5, including hepatic fat fraction changes measured by MRI-PDFF and glucose levels measured by CGM. Part C will further evaluate these parameters up to Week 24, with additional focus on hepatic glycogen concentration and body fat percentage. The incidence and titre of anti-drug antibodies (ADA) to AZD9550 will also be monitored throughout the study.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Males or females aged 18 through 65 years (Parts A-C) or 75 years (Part E-F) at the time of screening.
- Parts A, B, C only: Participants with or without T2DM. If participants have a diagnosis of T2DM, the glucose control is 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 E only: Participants are eligible to be included in the Part E only if they meet all of the following criteria at screening: a) Diagnosed with T2DM. b) Are treated with diet and exercise only, or any combination of OAD with stable doses in the 3 months prior to dosing. c) 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.
- Participants with a screening HbA1c value within the target range of: • ≥ 42 to ≤ 75 mmol/mol (6% to 9%). • Part F: < 48 mmol/mol (6.5%).
- Body mass index from ≥ 27 to ≤ 39.9 kg/m2 (inclusive) (Part A-C) or ≥ 27 kg/m2 (Part E), or ≥ 30 kg/m2 (Part F).
- Contraceptive use by males or females should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
- Written informed consent and any locally required authorisation (eg, European Union Data Privacy Directive) obtained from the participant prior to performing any protocol-related procedures, including screening evaluations.
- Ability to complete and meet all eligibility requirements for randomisation within 60 days after signing the ICF.
- Venous access suitable for multiple cannulations.
- Willing and able to "route of administration" weekly SC injections (Parts C, D, E, and F only).
Exclusion Criteria
- Participants with T2DM (Part F) and participants with T2DM treated with insulin (Parts A-E).
- 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.
- Participants with implantable cardiac defibrillator or a permanent pacemaker, and participants with symptomatic tachy- or brady-arrhythmias.
- Participants with T2DM treated with more than 3 anti-diabetic therapies (Parts A-C only).
- 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.
- In Parts A-C: History of hospitalisation caused by heart failure or a diagnosis of heart failure. In Part E, severe congestive heart failure (New York Heart Association Class III or IV) or recent (< 6 months) hospitalisation due to heart failure.
- Known or suspected history of drug abuse within the past 3 years as judged by the investigator (Parts A-F) and/or a positive screen for drugs of abuse at screening (Parts A-C only).
- History of severe allergy/hypersensitivity or ongoing clinically important allergy/hypersensitivity as judged by the investigator.
- 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.
- History of psychosis or bipolar disorder.
- History of lactic acidosis.
- Symptoms of insulinopenia or poor blood glucose control (eg, significant thirst, nocturia, polyuria, polydipsia, or weight loss).
- 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.
- Use of drugs with enzyme inducing properties such as St John’s Wort within 3 weeks prior to the first administration of study intervention.
- 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 half-lives 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 previous AZD9550, AZD6234, or AZD9550/AZD6234 combination studies, are not excluded from Part E.
- Treatment with GLP-1RA or GLP-1RA/GIPRA within 3 months of screening (Parts A to C only) or within 35 days of randomisation or five half-lives (whichever is shorter) of dosing (Parts E and F only).
- Previous enrolment or randomisation in the present study.
- Concurrent participation in another study of any kind is prohibited.
- 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.
- 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) (Part A-C only).
- Excessive intake of caffeine-containing drinks or food (eg, coffee, tea, Coca-Cola/Pepsi or similar drink type, chocolate) as judged by the investigator (Part A-C only)..
- Current smokers or those who have smoked or used nicotine products (including e-cigarettes) within the previous 3 months prior to screening (Part A-C only).
- Positive hepatitis B or hepatitis C virus serology at screening.
- 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).
- The participant is an employee, or close relative of an employee, of AstraZeneca, the Service Provider, or the study site, regardless of the employee’s role.
- 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.
- 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).
- History of any clinically important disease or disorder which 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.
- 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.
- 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.
- History of cancer within the last 10 years, with the exception of non-melanoma skin cancer.
- Any clinically important illness (apart from T2DM), as judged by the investigator.
- Any medical/surgical procedure, or trauma within 4 weeks prior to screening, at the discretion of the investigator.
- Positive human immunodeficiency virus test at screening or participant taking antiretroviral medications as determined by medical history or participant’s verbal report.
- Serum triglyceride concentrations > 500 mg/dL (5.6 mmol/L) at screening or any other metabolic condition judged by the investigator as likely to precipitate acute pancreatitis (Part E only).
- History of use of marijuana or THC-containing products within 3 months prior to screening or unwillingness to abstain from marijuana or THC-containing products use during the study (Parts E and F only).
- 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).
- Impaired renal function defined as eGFR ≤ 60 mL/minute/1.73 m2 as defined by Chronic Kidney Disease Epidemiology Collaboration (2021) (Part A to C); or ≤ 45 mL/minute/1.73 m2 (Parts E and F).
- 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.
- 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.
- 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.
- History of major depressive disorder within the 2 years prior to screening or depression, where the participant is deemed to be clinically unstable as judged by the investigator.
- Previous hospitalisation for any psychiatric reason.
- Questionnaire score ≥ xx within the x years prior to screening or at screening (Parts E and F only).
- Active suicidal ideation defined as Category 4 (Active Suicidal Ideation with Some Intent to Act, without Specific Plan) or Category 5 (Active Suicidal Ideation with Specific Plan and Intent) on the C-SSRS at any time prior to the study.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Austria | Not Recruiting | 21 Sept 2023 | 12 |
 Germany | Not Yet Recruiting | 21 Sept 2023 | 70 |
 Sweden | Not Recruiting | 21 Sept 2023 | 26 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
CALCIUM CARBONATE | Other | PHF00169MIG | ORAL | — | — | SCP1155079 |
DAPAGLIFLOZIN | Other | PHF00082MIG | ORAL | — | — | SCP153586 |
AZD6234 | Test | SOLUTION FOR INJECTION | SUBCUTANEOUS USE | — | — | PRD10501952 |
Placebo to match AZD9550 | Placebo | N/A | SUBCUTANEOUS | — | — | N/A |
ONDANSETRON | Other | PHF00230MIG | ORAL | — | — | SCP15701768 |
GLUCAGON | Other | PHF00231MIG | NASAL USE | — | — | SCP54118154 |
CALCIUM CITRATE | Other | PHF00082MIG | ORAL | — | — | SCP2004265 |
CALCIUM GLUCONATE | Other | PHF00231MIG | INFUSION | — | — | SCP101859404 |
Placebo to match AZD6234 | Placebo | N/A | — | — | — | N/A |
CYCLIZINE | Other | PHF00245MIG | ORAL | — | — | SCP135358 |