| Participants are eligible to be included in the study only if all the following criteria apply:
Age
1 Participant must be of the legal age of consent and at least 18 years of age at the time of signing informed consent.
Type of Participant and Disease Characteristics
Study 1
2 At the screening visit:
(a) BMI ≥ 30 kg/m2 or
(b) 25 kg/m2 ≤ BMI < 30 kg/m2 (participants with 25 kg/m2 ≤ BMI < 27 kg/m2 must also have a waist-to-height ratio ≥ 0.5) with at least one of the following weight-related comorbidities (treated or untreated):
(i) Hypertension
(ii) Prediabetes (Note: For this study, the diagnosis of prediabetes should be supported by a historical laboratory value not older than 180 days, fitting the definition of prediabetes according to ADA guidelines [ADA Professional Practice Committee 2025a])
(iii) Dyslipidemia
(iv) Cardiovascular disease
(v) Obstructive sleep apnea.
Study 2
2 At the screening visit, BMI ≥ 25 kg/m2 (participants with 25 kg/m2 ≤ BMI < 27 kg/m2 must also have a waist-to-height ratio ≥ 0.5) and T2DM defined as below:
(a) Established diagnosis of T2DM as per ADA or local diagnostic standards. T2DM may be treated with diet/exercise alone or any glucose-lowering medications except GLP-1 RA containing medications within 90 days prior to the screening visit or during the screening period.
OR
(b) Without established diagnosis of T2DM and HbA1c ≥ 6.5% (48 mmol/mol) at the screening visit confirmed by post screening retesting prior to randomization. Participants with T2DM detected at screening and a HbA1c ≥ 8.5% (69 mmol/mol) or overt signs/symptoms of hyperglycemia must be rescreened after a 90-day period, during which they should receive standard of care glucose management except GLP-1 RA containing medications. Participants with HbA1c < 8.5% (69 mmol/mol) may proceed with randomization, provided all other eligibility criteria are met.
Note: Participant’s assignment to Study 1 or Study 2 based on T2DM-related inclusion criteria is depicted in Figure |
Participants are excluded from the study if any of the following criteria apply:
Diabetes
Study 1
1 Any of the following medical history or laboratory values:
(a) Established diagnosis of T1DM or T2DM. History of gestational diabetes is not an exclusion criterion per se.
(b) HbA1c ≥ 6.5% (48 mmol/mol) at the screening visit (one repeat test allowed).
Study 2
1 Any of the following medical history, laboratory values, or complications related to diabetes:
(a) T1DM, secondary forms of diabetes (including congenital forms), or history of ketoacidosis or hyperosmolar coma within 180 days prior to the screening visit or during the screening period.
(b) HbA1c ≥ 10% (86 mmol/mol) at the screening visit (one repeat test allowed).
(c) Currently receiving, or anticipated to receive, therapeutic intervention for diabetic retinopathy and/or macular edema. Fundus photography or dilated fundoscopic exam will be performed as per the SoA (Section 1.3) by an ophthalmologist/optometrist or according to local practice to confirm eligibility.
(d) Have had more than one episode of severe hypoglycemia, as defined by the occurrence of neuroglycopenic symptoms requiring the assistance of another person for recovery, within 180 days prior to the screening visit or during the screening period, or has a history of hypoglycemia unawareness or poor recognition of hypoglycemic symptoms as per Investigator judgment.
Weight
2 Any of the following that are related to medical reasons or planned/previous changes in weight (see further details in Section 5.3.5 and Appendix I):
(a) Obesity induced by other endocrine disorders such as Cushing’s syndrome or monogenic or syndromic obesity such as Prader-Willi syndrome.
(b) Received any medication for weight loss, including GLP-1 RAs, within 90 days prior to the screening visit or during the screening period.
(c) Previous or planned (within study period) bariatric surgery or fitting of a weight loss device (eg, gastric balloon or duodenal barrier).
(d) Planned to start a targeted weight loss program during the study other than dietary and lifestyle considerations outlined in the protocol.
(e) Initiated therapy with, or altered the dosage of, medications associated with significant weight gain within 365 days prior to the screening visit or during the screening period (see Section 6.9.2.1 for details).
Gastrointestinal/Liver
3 Known clinically significant condition affecting the upper GI tract that may affect gastric emptying, drug absorption, or the interpretation of safety and tolerability data (eg, gastroparesis or gastric outlet obstruction, severe disease, or surgery).
4 Participants with history of any of the below conditions:
(a) Cirrhosis or hepatic decompensation (including ascites, hepatic encephalopathy, or variceal bleeding)
(b) Liver transplant or current placement on a liver transplant list
(c) Clinically significant liver disease of any etiology as judged by the Investigator, including but not limited to alcoholic steatohepatitis, drug-induced, viral, or autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, hemochromatosis, alpha-1 antitrypsin deficiency, and Wilson’s disease
Exceptions include: participants with metabolic dysfunction-associated steatotic liver disease or metabolic dysfunction associated steatohepatitis.
5 Any of the following results at the screening visit:
(a) ALT ≥ 3 × ULN
(b) AST ≥ 3 × ULN
(c) ALP ≥ 1.5 × ULN
(d) TBIL ≥ 1.5 × ULN (unless known history of Gilbert’s syndrome, where up to 3 mg/dL [51 μmol/L] is acceptable if DBIL is < ULN).
6 Participants with active hepatitis B or C disease defined as
(a) Positive for HBcAb and with positive/detectable HBV DNA and/or positive HBsAg.
(b) Positive for anti-HCV antibody and HCV RNA positive.
7 Any positive results for serum HIV antibody.
8 History of acute (unless due to previously resolved gallstone pancreatitis and post cholecystectomy) or chronic pancreatitis.
Cardiovascular/Renal
9 Cardiac arrhythmia or ECG morphology abnormalities, as considered by the Investigator, that may interfere with interpretation of QTc interval, including ST wave morphology.
(a) Second or third degree atrial ventricular block or sinus node dysfunction with clinically significant pause, not treated with pacemaker.
(b) Ventricular arrhythmia requiring treatment.
(c) Atrial fibrillation/flutter with confirmed ventricular rate > 100 bpm at rest.
(d) QT interval corrected (ECG interval measured from the onset of the QRS complex to the end of the T wave) using Fridericia’s formula QTcF > 450 msec or a family history of congenital long QT syndrome.
10 Any of the following conditions within 90 days prior to the screening visit or during the screening period: acute MI, unstable angina, transient ischemic attack or stroke, percutaneous coronary intervention, or a coronary artery bypass graft.
11 Severe congestive heart failure (New York Heart Association Class IV).
12 Impaired renal function defined as eGFR < 20 mL/min/1.73 m2 (GFR estimated according to 2021 CKD-EPI calculation, using creatinine) at the screening visit.
Mental Health
13 History of significant active or unstable major depressive disorder or other severe psychiatric disorder (eg, schizophrenia, bipolar disorder, suicidal ideation or behavior, or other serious mood or anxiety disorder) within the last 2 years.
Note: Participants with major depressive disorder or generalized anxiety disorder whose disease state is considered stable and expected to remain stable throughout the course of the study, in the opinion of the Investigator, may be considered for inclusion if they are not on excluded medications.
14 Any lifetime history of suicide attempt.
Endocrine
15 Uncontrolled thyroid disease, defined as TSH > 6.0 mIU/L or < 0.4 mIU/L at the screening visit.
16 History/family history (first degree biologic relatives) of medullary thyroid cancer or multiple endocrine neoplasia type 2 or basal calcitonin level of ≥ 35 ng/L or pg/mL at the screening visit.
Malignancy
17 History of active malignancy within 5 years prior to the screening visit. Exceptions include: adequately treated basal and squamous cell skin cancers, as well as in situ cancer (eg, cervical cancer, or in situ or Grade 1 [for example, Gleason 6 or lower] prostate cancer).
Other
18 Any hematological condition that may interfere with HbA1c measurement (eg, hemoglobinopathy, hemolytic anemia, history of red blood cell transfusion within 90 days prior to the screening visit).
19 Known or suspected history of drug abuse, or history of alcohol abuse or excessive intake of alcohol, likely to impact participant safety or compliance with study procedures as judged by the Investigator.
20 Major surgery planned to take place during the study period, identified at the screening visit or any point prior to randomization at Visit 2 (excluding minor surgical procedures).
Sex and Contraceptive Barrier Requirements
21 Lactating, breastfeeding or pregnant females or females who intend to become pregnant or begin breastfeeding anytime from initiation of screening until 5 days following the last dose of study intervention.
Prior/Concomitant Therapy
22 Chronic use (> 14 consecutive days) of medications that can lead to alterations in gastric motility or emptying within 90 days prior to the screening visit or during the screening period.
23 Concomitant use of strong or moderate CYP3A4 inhibitors or inducers, or of drugs with a narrow therapeutic index that are sensitive substrates of CYP3A4, BCRP, P-gp, or CYP2C8. For specific details and exceptions on restricted and prohibited concomitant medications, see Section 6.9.2.
24 Currently on a lower dose of statin medication due to a history of statin intolerance to high-intensity dosing (eg, atorvastatin 40 or 80 mg, rosuvastatin 20 or 40 mg).
25 History of allergy/hypersensitivity or previous severe GI intolerance, as judged by the Investigator, to GLP-1 RA or excipients.
Study-related
26 History of, or any existing condition that, in the opinion of the Investigator, would interfere with the evaluation of the study intervention, put the participant at risk, influence the participant’s ability to participate, or affect the interpretation of the results of the study.
27 Judgment 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.
28 Any participant who has received another study intervention as part of a clinical study within 30 days or 5 half-lives of the drug (whichever is longer) prior to the screening visit or during the screening period.
29 Concurrent participation in another interventional study of any kind or previous randomization in the present study.
30 Any AstraZeneca or study site employee directly involved with the planning and/or conduct of the study.
31 A study within this master protocol that the participant is eligible for is closed to randomization or a prespecified cap has been reached in the IRT system.
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Adult: 18 Year(s)-44 Year(s) |
18 Year(s) |
105 Year(s) |
Both |