Mazdutide for Remission of Type 2 Diabetes: Multicentre, Double Blind, Randomised, Placebo Controlled Trial

Mazdutide for Remission of Type 2 Diabetes: Multicentre, Double Blind, Randomised, Placebo Controlled Trial

The purpose of this study is to investigate and efficacy of Mastitide for diabetes remission in Chinese type 2 diabetic subjects with poor glycemic control on diet or exercise therapy alone or metformin/sodium-glucose cotransporter (SGLT2) inhibitor monotherapy.

This study is a 44-week, multicenter, randomized, double-blind, placebo-controlled clinical trial. A total of 249 type 2 diabetes patients with overweight or obesity are randomized 2:1 to either the active treatment group (receiving subcutaneous injections of mazdutide weekly, with stepwise dose escalation to a maintenance dose per protocol) or the placebo group (receiving matched placebo injections). The primary objective is to evaluate the potential diabetes remission effects of mazdutide on cognitive dysfunction in type 2 diabetes.

Inclusion Criteria:

1.T2D was diagnosed according to WHO standards in 1999. 2.18 years to 70years when signing the informed consent form. 3.Diet and exercise intervention alone before screening, or stable metformin (≥500 mg/ day and ≤2000mg/ day for at least 4 weeks), or a stable dose of SGLT2 inhibitor (minimum maintenance dose: Empagliflozin 10 mg/ day, dapagliflozin 5 mg/ day, canagliflozin 100 mg/ day, constant agliflozin 5 mg/ day, and etoagliflozin 5 mg/ day for at least 4 weeks) were still not well controlled after monotherapy, and the local laboratory test at screening was 6.5%≤HbA1c≤9.0%.

4.Duration of type 2 diabetes ≤5 years at screening. 5.BMI≥24 kg/m2 at screening. 6.A stable diet and exercise lifestyle could be maintained during the study period.

7.Subjects voluntarily sign informed consent and agree to strictly follow the requirements of this protocol.

Exclusion Criteria:

1. Subjects who are considered by the investigator to be potentially allergic to the components of the study drug or to the drug in the same class.

2.Weight change > 5% in 12 weeks before screening (chief complaint). 3. Use of any of the following drugs or treatments before screening:

1. Use of a GLP-1R agonist or GLP-1R/GCGR (glucagon receptor) agonist or GIPR (glucose-dependent insulinotropic polypeptide) within 2 months before screening receptor) /GLP-1R agonist or GIPR/GLP-1R/GCGR agonist; Participants who discontinued a drug more than 2 months before screening because of lack of efficacy or intolerance were also excluded.
2. Oral antidiabetic drugs other than background medications within 2 months before screening.
3. Use of insulin for diabetes control within 3 months before screening, except for short-term use of insulin in acute conditions (cumulative ≤14 days), such as acute illness, hospitalization, or elective surgery. The interval between the last insulin treatment and screening day was less than 14 days.
4. Weight-loss medications used within 1 month before screening or planned to be used during the trial, such as semaglutide, benaglutide, liraglutide, orlistat, sibutramine hydrochloride, phenylpropanolamine, chlorbendazole, phenylbutamine, lorcaserin hydrochloride, phentermine, phentermine/topiramate, bupropion, and naltrexone/bupropion.
5. Use of Chinese herbal medicine, other traditional medicines and health products with hypoglycemic effect within 2 months before screening.
6. were receiving chronic (> 2 weeks) systemic glucocorticoids or had received glucocorticoids within 4 weeks before screening (topical, intraocular, intranasal, or inhaled administration were excluded).
7. current use of central nervous system stimulants, excluding caffeinated beverages, at the time of screening.
8. have participated in another clinical trial and received a trial drug within 3 months before screening.
9. History of alcohol and drug abuse at screening. Mean weekly alcohol intake: more than 21 units for men and 14 units for women (1 unit = 360 ml of beer, or 150 ml of red wine, or 45 ml of distilled/liquor).

4. There is a history or evidence of any of the following diseases:

1. Previously diagnosed with type 1 diabetes (including latent autoimmune diabetes in adults, LADA), or positive for glutamic acid decarboxylase antibody (GADA) and other islet-related antibodies.
2. Complications of diabetes occurred within 30 days before screening (ketosis acidosis, hyperosmolar diabetic state, or lactic acidosis).
3. History of severe hypoglycemic episodes within 30 days before screening, defined as presenting with neurological hypoglycemic symptoms and requiring assistance from others to recover, or having no awareness of hypoglycemia or insufficient understanding of hypoglycemic symptoms in the past. Subjects who the researchers consider unable to communicate and understand hypoglycemic symptoms and appropriate treatment should also be excluded from this study.
4. Previous history of acute or chronic pancreatitis, or blood amylase or lipase > 2.0×upper limit of normal value (ULN) during the screening period, or fasting triglycerides ≥ 5.64 mmol/L (500 mg/dl).
5. Previous history of gastroparesis or bariatric surgery, or clinically significant gastric emptying abnormalities as determined by the researcher.
6. Previous proliferative diabetic retinopathy, or diabetic macular edema, or rapid progression of non-proliferative diabetic retinopathy or requiring urgent treatment.
7. Acute or chronic hepatitis (except chronic hepatitis B), symptoms and signs of other liver diseases, or ALT > 3.0×ULN (ALT > 5.0×ULN for non-alcoholic fatty liver disease), or AST > 3.0×ULN, or total bilirubin (TBIL) > 2.0×ULN.
8. Previous personal or family history of medullary thyroid carcinoma, patients with multiple endocrine neoplasia type 2, or serum calcitonin ≥ 50 ng/L (pg/mL), or thyroid function-related indicators TSH > 6 mIU/L or < 0.4 mIU/L.
9. Hyperthyroidism or hypothyroidism confirmed by clinical assessment and/or abnormal thyroid stimulating hormone (TSH) as determined by clinical evaluation, except for subjects on stable thyroid hormone replacement therapy for at least 2 months with normal thyroid function and expected unchanged dosage throughout the study period.
10. Previously diagnosed with autonomic neuropathy, manifested as urinary retention, resting tachycardia, orthostatic hypotension, or diabetic diarrhea.
11. Had a severe cardiovascular or cerebrovascular event within 3 months before screening.
12. 12-lead ECG at screening shows a heart rate < 50 beats/min or > 100 beats/min, ECG indicates active heart disease, or the researcher considers the ECG abnormality at screening would interfere with the interpretation of ECG results during the subsequent follow-up, especially excluding QTcF > 500 ms.
13. Poorly controlled hypertension, systolic blood pressure ≥ 160 mmHg or diastolic blood pressure ≥ 100 mmHg; or had adjusted antihypertensive drugs (dose or type) within 30 days before screening; evidence of renal artery stenosis, or unstable blood pressure (including orthostatic hypotension, etc.).
14. Had active or untreated malignant tumors within 5 years before screening, or in a clinical remission period (skin basal cell carcinoma and squamous cell carcinoma, cervical carcinoma in situ, prostate carcinoma in situ, or papillary thyroid carcinoma with no recurrence after surgery, except for subjects without recurrence) during the screening period. 15) During the screening process, if the estimated glomerular filtration rate (eGFR) is less than 45 mL/min/1.73 m2, it is calculated using the CKD-EPI formula (see Appendix 2).

16) A history of atopic reactions (clinical manifestations of severe or multiple allergies), or a clinically significant history of multiple or severe drug allergies, or intolerance to topical glucocorticoids, or severe post-treatment hypersensitivity reactions (including but not limited to erythema multiforme, linear immunoglobulin A dermatitis, toxic epidermal necrolysis, allergic reactions, angioedema or exfoliative dermatitis).

17) Evidence of previous or during the screening period human immunodeficiency virus (HIV) infection or positive HIV antibody, or hepatitis B (HBV) antibody, or hepatitis C (HCV) antibody, or positive syphilis antibody.

18) History of organ transplantation (except corneal transplantation), or preparing for organ transplantation.

19) During the screening process, the investigator considers that there is a serious active and uncontrolled physical condition or history that may place the participant at risk during the use of the study drug or interfere with the interpretation of the efficacy and safety data of this study.

20) A history of mental illness during the past or during the screening period, and the investigator considers that the participant is not suitable to participate in this study.

21) Within the previous 3 months, the blood donation volume and/or blood loss volume was ≥ 450 mL or there was bone marrow donation, blood transfusion or severe blood loss, or there was hemoglobinopathy, hemolytic anemia, sickle cell anemia, or the blood hemoglobin was < 110g/L (for males) or < 100g/L (for females) during the screening, or there were any other known factors that may interfere with the HbA1c test results; 5. Pregnant or lactating women, or men or women with reproductive capacity who are unwilling to use contraception throughout the study period until 8 weeks after the end of the study.

6. The investigator considers that the subject has any other factors that may affect the efficacy or safety evaluation of this study and is not suitable to participate in this study.