Efficacy, Safety and Cardiovascular Protection of Mazdutide in Type 1 Diabetes

Type 1 Diabetes Intervention With Mazdutide for Efficacy, Safety and Cardiovascular Protection (The TIMES Trial Program-TIMES-EFFICACY & TIMES-CV

This study is a multicenter, randomized, double-blind, placebo-controlled clinical trial in patients with type 1 diabetes (T1D), conducted in two stages.

Stage 1 is the efficacy and safety assessment (TIMES-EFFICACY). A total of 182 T1D patients who meet the inclusion criteria will be randomized in a 1:1 ratio to two groups: one receiving mazdutide and the other receiving placebo. The follow-up period is 16 weeks. The primary clinical endpoint is the proportion of patients achieving time in range (TIR) >70% with time below range (TBR) <4%. An interim analysis will be performed at Week 8; if the absolute TBR in the mazdutide group increases by more than 5% relative to the placebo group, the subsequent study will be terminated.

Stage 2 is the cardiovascular protective effect assessment (TIMES-CV). During the Stage 1 efficacy and safety assessment, a pre-specified stratification method will ensure that 104 patients with high cardiovascular risk factors are randomized in a 1:1 ratio to the mazdutide group or the placebo group. After completing the 16-week efficacy and safety assessment, these 104 subjects will continue to receive randomized controlled treatment and enter the cardiovascular effect assessment stage, with a total follow-up duration of 52 weeks. The primary clinical endpoint is the change in non-calcified coronary artery plaque volume.

Study Overview

• Status: Not yet recruiting
• Conditions: Type 1 Diabetes
• Intervention / Treatment: Drug: Mazdutide; Drug: Placbo

• Study Type: Interventional
• Enrollment (Estimated): 182
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Chu Lin, M.D.; Phone Number: +86 18811792075; Email: chulin@bjmu.edu.cn
• Study Contact Backup: Name: Xiaoling Cai, M.D.; Phone Number: +86 13051396340; Email: dr_junel@sina.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Age ≥18 years at screening.

2. Patients with a clinical diagnosis of T1D for at least 12 months.

   Patients with T1D must satisfy all three of the following features:

   1. Clinical diagnosis of type 1 diabetes by a specialist physician;
   2. Any one of the following: age at onset <15 years; no overweight or obesity at onset; diabetic ketoacidosis at onset; peak stimulated C-peptide <200 pmol/L;
   3. Any one of the following: continuous insulin therapy since diagnosis (excluding pancreas or islet transplantation); one or more positive pancreatic islet autoantibodies (GADA / IAA / IA-2A / ZnT8).

3. Willingness to use once-weekly mazdutide.

4. HbA1c ≥7.0% and <10.0%.

5. Body mass index (BMI) ≥20 kg/m².

6. Continuous use of any of the following insulin regimens for at least 3 months prior to screening (no concomitant use of other oral glucose-lowering drugs or GLP-1RAs allowed), with a stable insulin dose for at least 2 weeks before enrollment:

   1. Multiple daily injections of basal insulin plus prandial insulin;
   2. Premixed insulin analog injected 2-3 times daily;
   3. Dual insulin analog (insulin degludec/aspart) injected twice daily;
   4. Continuous subcutaneous insulin infusion (CSII). Note: A stable insulin dose is defined as a daily insulin dose adjustment of no more than ±[value not specified in the source document].

7. Ability to provide informed consent prior to any study-related activity.

   • For participants enrolled in TIMES-CV, in addition to the above criteria, the following criteria must also be met: ***

1. Duration of type 1 diabetes ≥5 years. 2. Moderate or high 10-year atherosclerotic cardiovascular disease (ASCVD) risk (≥5.0%) as assessed by the China-PAR model.

3. Carotid atherosclerotic plaque confirmed by ultrasound.

Exclusion Criteria:

1. Other types of diabetes.
2. BMI <20 kg/m².
3. History of cardiovascular disease: previous myocardial infarction, unstable angina, coronary revascularization (PCI or CABG), stroke, transient ischemic attack (TIA), or symptomatic peripheral arterial disease.
4. Renal impairment: estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m² (based on the CKD-EPI equation).
5. Hepatic disease: known severe hepatic disease, or ALT/AST levels >3 times the upper limit of normal.
6. Personal or family history of medullary thyroid carcinoma, or multiple endocrine neoplasia syndrome type 2.
7. Pancreatic disease: history of acute or chronic pancreatitis.
8. Pregnancy and lactation: women who are pregnant, breastfeeding, or planning pregnancy and unwilling to use effective contraception.
9. Medications: use of GLP-1 receptor agonists, GIP or GCG receptor agonists, other non-insulin glucose-lowering drugs, or finerenone within 3 months prior to screening.
10. Requirement for long-term use of systemic glucocorticoids (topical/inhaled use permitted).
11. History of hypersensitivity to GLP-1 receptor agonists, mazdutide, or any of its excipients.
12. Moderate or more severe non-proliferative diabetic retinopathy or proliferative diabetic retinopathy.
13. Any other serious medical or psychiatric condition that, in the judgment of the investigator, may interfere with study assessments or endanger the safety of the subject.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: mazdutide group; Participants in the treatment group will receive mazdutide by subcutaneous injection once weekly. The dose will be escalated stepwise according to a pre-defined regimen from a safe starting dose to an effective maintenance dose (from 2 mg to 4 mg) over several weeks, with dose reduction permitted if needed.	Drug: Mazdutide; Mazdutide is a synthetic peptide analog of mammalian oxyntomodulin and a once-weekly dual agonist of the glucagon-like peptide-1 receptor (GLP-1R) and the glucagon receptor (GCGR), under development for the treatment of obesity and type 2 diabetes (T2D). Mazdutide has been shown to induce significant weight loss in patients with obesity and to help improve glycemic control in patients with T2D.
Placebo Comparator: placebo group; Participants in the control group will receive a placebo matched to mazdutide in appearance, packaging, and mode of administration, by subcutaneous injection once weekly.	Drug: Placbo; mazdutide matching placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of the participants achieving time in range (TIR)>70 and time below range (TBR)<4% (TIMES-EFFICACY)	The proportion of adult patients with T1D achieving the composite outcome of continuous glucose monitoring (CGM)-measured TIR >70% and TBR <4% at Week 16 in the mazdutide group versus the placebo group	From baseline to 16 weeks
Volume of non-calcified coronary artery plaque (TIMES-CV)	The absolute change in non-calcified coronary artery plaque volume in mm³ from baseline to Week 52, as measured by quantitative analysis of high-resolution coronary computed tomography angiography (CCTA)	From baseline to 52 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Level of HbA1c	Changes in HbA1c (%) from baseline to Week 16 and Week 52	From baseline to 52 weeks
Volume of coronary atherosclerotic plaque	Changes in total coronary atherosclerotic plaque volume, fibrous plaque volume, low-density plaque volume, and lipid-rich plaque volume in mm³	From baseline to 52 weeks
Thickness of carotid intima-media	Changes in carotid intima-media thickness (cIMT) in mm from baseline to Week 52	From baseline to 52 weeks
Time in range (TIR)	Changes in TIR (%) from baseline to Week 52	From baseline to 52 weeks
Time above range (TAR)	Changes in TAR (%) from the baseline to Week 52	From baseline to 52 weeks
Time below range (TBR)	Changes in TBR (%) from baseline to Week 52	From baseline to 52 weeks
Covariation (CV)	Changes in CV (%) assessed by continuous glucose monitoring from baseline to Week 52	From baseline to 52 weeks
Level of triglyceride (TG)	Changes in TG (mmol/L) from baseline to Week 52	From baseline to 52 weeks
Level of total cholesterol (TC)	Changes in TC (mmol/L) from baseline to Week 52	From baseline to 52 weeks
Level of low-density cholesterol (LDL-C)	Changes in LDL-C (mmol/L) from baseline to Week 52	From baseline to 52 weeks
Level of high-density cholesterol (HDL-C)	Changes in HDL-C (mmol/L) from baseline to Week 52	From baseline to 52 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
The level of urinary albumin/creatinine ratio	Changes in urinary albumin/creatinine ratio (mg/g) from baseline to Week 52	From baseline to 52 weeks
Change in hepatic fat content	Changes in hepatic fat content (%) from baseline to Week 52, assessed by MRI-PDFF	From baseline to 52 weeks
Levels of inflammation-related protein biomarkers	Changes in inflammation-related protein biomarkers (assessed by Olink) from baseline to Week 52	From baseline to Week 52

Collaborators and Investigators

• Sponsor: Peking University People's Hospital
• Collaborators: Qilu Hospital of Shandong University; Hebei General Hospital; Zhongnan Hospital; The First Affiliated Hospital of Henan University of Science and Technology; Shenzhen Second People's Hospital; Second Affiliated Hospital of Soochow University; Tianjin Medical University; Second Xiangya Hospital of Central South University; Heji Hospital affiliated to Changzhi Medical College; Tangshan Worker's Hospital; The Second Hospital of Shijiazhuang

Publications and helpful links

General Publications

• Pasqua MR, Tsoukas MA, Kobayati A, Aboznadah W, Jafar A, Haidar A. Subcutaneous weekly semaglutide with automated insulin delivery in type 1 diabetes: a double-blind, randomized, crossover trial. Nat Med. 2025 Apr;31(4):1239-1245. doi: 10.1038/s41591-024-03463-z. Epub 2025 Jan 10.
• Guo L, Zhang B, Xue X, Zhang X, Cai H, Jiang H, Zhang L, Jin P, Wang X, Cheng Z, Zhang S, Geng J, Guo Y, Hu H, Ma Q, Li L, Du H, Han-Zhang H, Xue F, Deng H, Qian L, Yang W; DREAMS-2 investigators. Mazdutide versus dulaglutide in Chinese adults with type 2 diabetes. Nature. 2026 Apr;652(8108):181-188. doi: 10.1038/s41586-025-10031-z. Epub 2025 Dec 17.
• Zhu D, Zhao J, Cai H, Chu X, Xiu S, Song C, Cheng Z, Cao H, Jiang H, Zhang L, Wang H, Shi B, Li Y, Liu M, Feng B, Xue F, Deng H, Li H, Li L, Li Y, Ma Q, Qian L. Mazdutide versus placebo in Chinese adults with type 2 diabetes. Nature. 2026 Apr;652(8108):174-180. doi: 10.1038/s41586-025-10026-w. Epub 2025 Dec 17.
• Gao L, Jiang H, Cai H, Tian J, Shi B, Qiu W, Huang C, Han J, Zhang S, Pang S, Bi Y, Chen L, Gu X, Han J, Ma Q, Deng H, Wang Y, Li L, Han-Zhang H, Qian L, Ji L; GLORY-2 Trial Investigators. Treatment With 9-mg Mazdutide for Weight Reduction in Chinese Adults With Obesity: The GLORY-2 Randomized Clinical Trial. JAMA. 2026 Aug 4;336(5):377-388. doi: 10.1001/jama.2026.8142.
• Ji L, Jiang H, Bi Y, Li H, Tian J, Liu D, Zhao Y, Qiu W, Huang C, Chen L, Zhong S, Han J, Zhang Y, Lian Q, Yang P, Lv L, Gu J, Liu Z, Deng H, Wang Y, Li L, Pei L, Qian L; GLORY-1 Investigators. Once-Weekly Mazdutide in Chinese Adults with Obesity or Overweight. N Engl J Med. 2025 Jun 12;392(22):2215-2225. doi: 10.1056/NEJMoa2411528. Epub 2025 May 25.
• Shirley M. Mazdutide: First Approval. Drugs. 2025 Dec;85(12):1621-1627. doi: 10.1007/s40265-025-02249-y. Epub 2025 Sep 30.

Study record dates

Study Major Dates

• Study Start (Estimated): January 1, 2027
• Primary Completion (Estimated): March 1, 2029
• Study Completion (Estimated): June 1, 2029

Study Registration Dates

• First Submitted: October 20, 2026
• First Submitted That Met QC Criteria: November 5, 2026
• First Posted (Actual): November 9, 2026

Study Record Updates

• Last Update Posted (Actual): November 9, 2026
• Last Update Submitted That Met QC Criteria: November 5, 2026
• Last Verified: November 1, 2026

More Information

Terms related to this study

• Keywords: type 1 diabetes; glucagon-like peptide-1 receptor agonist; glucagon receptor agonist; mazdutide
• Additional Relevant MeSH Terms: Endocrine System Diseases; Metabolic Diseases; Autoimmune Diseases; Immune System Diseases; Glucose Metabolism Disorders; Diabetes Mellitus; Nutritional and Metabolic Diseases; Diabetes Mellitus, Type 1; mazdutide
• Other Study ID Numbers: 2026PHD024-004; 3-SRA-2026-1955-M-B (Other Grant/Funding Number: Breakthrough T1D)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

IPD Plan Description

There is no plan to make individual participant data (IPD) collected in this study available to researchers outside the primary research group. The study data will be kept confidential by the sponsor and investigators in accordance with applicable regulations and the study protocol. Sharing of IPD is not planned due to considerations regarding participant confidentiality and data protection.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No