ADJUnct Semaglutide Treatment in Type 1 Diabetes (ADJUST-T1D)

• ClinicalTrials.gov Identifier: NCT05537233
• Recruitment Status: Active, not recruiting
• First Posted: September 13, 2022
• Last Update Posted: April 15, 2024
• Sponsor: Viral N. Shah
• Collaborator: Juvenile Diabetes Research Foundation
• Information provided by (Responsible Party): Viral N. Shah, Indiana University

Study Description

Brief Summary:

The purpose of this study is to assess the use of once weekly semaglutide injection in inadequately controlled obese adults with type 1 diabetes (T1D) using FDA-approved hybrid closed-loop therapies.

Condition or disease	Intervention/treatment	Phase
Type 1 Diabetes; Obesity	Drug: Semaglutide; Drug: Placebo	Phase 2

Detailed Description:

After being informed about the study and potential risks, all patients given written informed consent will undergo a 2-week screening period to determine eligibility for study entry. At week 0, patients who meet the eligibility requirements will be randomized in a double-blind manner using computer generated randomization scheme to receive either semaglutide or placebo (1:1 ratio) for 26 weeks.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 115 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Efficacy and Safety of Once Weekly Semaglutide in Adults With Obesity and Inadequately Controlled Type 1 Diabetes Using Hybrid Closed-Loop System.
• Actual Study Start Date: April 11, 2023
• Estimated Primary Completion Date: August 15, 2024
• Estimated Study Completion Date: August 15, 2024

Arms and Interventions

Arm	Intervention/treatment
Experimental: Semaglutide; Participants in this group will receive semaglutide once weekly injection in addition to their standard closed-loop therapy	Drug: Semaglutide; Semaglutide up to 1 mg per week in addition to standard closed-loop therapy
Placebo Comparator: Control; Participants in this group will receive placebo once weekly injection in addition to their standard closed-loop therapy	Drug: Placebo; Injection placebo up to 1 mg per week in addition to standard closed-loop therapy

Outcome Measures

Primary Outcome Measures :

1. Proportion of adults with T1D achieving composite outcome (CGM-measured time in range (TIR)>70% with time below range (TBR) of <4% and reduction in body weight by 5%) at 26 weeks in the semaglutide group compared to placebo group [ Time Frame: 26 weeks ]
   The primary endpoint (differences in proportion of patients achieving composite outcomes) will be compared, including the proportion of study participants achieving a reduction in body weight of 5% or more between 4 and 26 weeks and achieving TIR >70% and TBR of <4% at 26 weeks. This comparison between the proportion meeting the composite endpoint will be examined while adjusting for pre-specified covariates, baseline A1c and BMI. Baseline A1c is known to affect TIR (better improvement in TIR in those with higher A1c). Similarly, higher BMI may affect weight loss. Therefore, the investigator decided to use these covariates for adjustment. Sustain 7 post hoc analysis suggested that efficacy of semaglutide on glycemic control and weight loss remains the same regardless of baseline age, diabetes duration or sex. Therefore, the investigator did not include those variables in the pre-specified adjustment.

Secondary Outcome Measures :

1. Change in HbA1c [ Time Frame: 26 weeks ]
   HbA1c will be measured at a central laboratory and change in Hba1c from 4 weeks to 26 weeks will be compared by randomization group using intention to treat (ITT) analysis.
2. Change in mean glucose [ Time Frame: 26 weeks ]
   Mean glucose (mg/dL) will be obtained by CGM and change in mean CGM glucose from 4 weeks to 26 weeks will be compared by randomization group using intention to treat (ITT) analysis.weeks will be compared by randomization group using intention to treat (ITT) analysis.
3. Percent time spent in CGM-measured glucose range of 70-140 mg/dL (time in tight target range; TTIR) [ Time Frame: 26 weeks ]
   Percent of time spent in tight glucose range (70-140 mg/dL) will be obtained by CGM and change in percent time in range from 4 weeks to 26 weeks will be compared by randomization group using intention to treat (ITT) analysis.
4. Percent time spent in CGM-measured glucose >180 mg/dL [ Time Frame: 26 weeks ]
   Percent of time spent in glucose range >180 mg/dL will be obtained by CGM and change in mean CGM glucose from 4 weeks to 26 weeks will be compared by randomization group using intention to treat (ITT) analysis.
5. Percent time spent in CGM-measured glucose >250mg/dL [ Time Frame: 26 weeks ]
   Percent of time spent in glucose range >250 mg/dL will be obtained by CGM and change in mean CGM glucose from 4 weeks to 26 weeks will be compared by randomization group using intention to treat (ITT) analysis.
6. Percent time spent in CGM-measured glucose <70mg/dL [ Time Frame: 26 weeks ]
   Percent of time spent in glucose range <70 mg/dL will be obtained by CGM and change in mean CGM glucose from 4 weeks to 26 weeks will be compared by randomization group using intention to treat (ITT) analysis.
7. Percent time spent in CGM-measured glucose <54 mg/dL [ Time Frame: 26 weeks ]
   Percent of time spent in glucose range <54 mg/dL will be obtained by CGM and change in mean CGM glucose from 4 weeks to 26 weeks will be compared by randomization group using intention to treat (ITT) analysis.
8. Differences in CGM metrics (mean glucose, TIR, TAR, TBR and CV) by daytime vs nighttime [ Time Frame: 26 weeks ]
   CGM metrics (TIR, TBR, TAR) during the day (6am - midnight) compared to at night (>midnight to <6am) will be compared by randomization group using an ITT analysis.
9. Change in CGM measured glycemic variability (coefficient of variation) [ Time Frame: 26 weeks ]
   Glucose coefficient of variation (mg/dL) will be obtained by CGM and change in glucose CV from 4 weeks to 26 weeks will be compared by randomization group using intention to treat (ITT) analysis.
10. Percentage of patients achieving HbA1c <7% [ Time Frame: 26 weeks ]
    The proportion of patients achieving HbA1c <7% at 26 weeks will be compared by randomization group using an ITT analysis
11. Percentage of patients achieving TIR >70% [ Time Frame: 26 weeks ]
    The proportion of patients achieving TIR >70% at 26 weeks will be compared by randomization group using an ITT analysis
12. Change in patient reported quality of life [ Time Frame: 26 weeks ]
    Patient reported quality of life will be measured using a validated instrument (ADDQOL) and the change in score from 4 to 26 weeks will be compared by randomization group using an ITT analysis.
13. Change in insulin dose (total daily dose, units/kg of body weight) [ Time Frame: 26 weeks ]
    The change in total daily dose of insulin per kg of body weight from 4 to 26 weeks will be compared by randomization group using an ITT analysis.
14. Change in weight [ Time Frame: 26 weeks ]
    The change in kg of body weight from 4 to 26 weeks will be compared by randomization group using an ITT analysis.
15. Change in BMI (Kg/m2) [ Time Frame: 26 weeks ]
    Change in body mass index (BMI) calculated as kg body weight per meter squared of height from 4 to 26 weeks will be compared by randomization group using an ITT analysis.
16. Change in modifiable HCL settings [ Time Frame: 26 weeks ]
    Example, basal-rate, insulin to carb ratio and correction factors for Tandem control-IQ, insulin to carb ratio and active insulin time for Medtronic 670 G/770G and target glucose level, insulin to carb ratio, correction factor and active insulin time for Omnipod 5.
17. Severe hypoglycemia and diabetic ketoacidosis episodes [ Time Frame: 26 weeks ]
    The number of severe hypoglyemia and diabetic ketoacidosis events during the study period will be compared by randomization group using an ITT analysis.
18. Change in blood pressure (systolic, diastolic, mean and pulse pressure) [ Time Frame: 26 weeks ]
    The change in blood metric metrics (systolic, diastolic, mean arterial pressure and pulse pressure) from 4 weeks to 26 weeks will be compared by randomization group using an ITT analysis.
19. Change in brachial arterial distensibility (Brach D), augmentation index by radial artery tonometry [pulse wave analysis [PWA]), pulse wave velocity (PWV)], and carotid atherosclerosis by carotid intima media thickness (cIMT) [ Time Frame: 26 weeks ]
    Changes in arterial stiffness measures (BrachD, PWV, PWA) and carotid IMT from 4 weeks to 26 weeks will be compared by randomization group using an ITT analysis.
20. Change in lipid parameters [ Time Frame: 26 weeks ]
    Changes in fasting lipids (total cholesterol, triglyceride, LDL-C and HDL-C) from 4 to 26 weeks will be compared by randomization group using an ITT analysis.
21. Change in albumin to creatinine ratio (ACR) [ Time Frame: 26 weeks ]
    Changes in renal function as measured by urinary ACR from 4 to 26 weeks will be compared by randomization group using an ITT analysis.
22. Change in estimated glomerular filtration rate (eGFR) [ Time Frame: 26 weeks ]
    Changes in renal function as measured by eGFR from 4 to 26 weeks will be compared by randomization group using an ITT analysis.
23. Change in NAFLD biomarkers [ Time Frame: 26 weeks ]
    Changes in NAFLD biomarkers, HSI and FIB-4 from 4 to 26 weeks will be compared by randomization group using an ITT analysis.

Other Outcome Measures:

1. Change in cardiac and aortic structure and function measured by cardiac magnetic resonance (CMR) [ Time Frame: 26 weeks ]
   Changes in cardiac and aortic structure and function measured by cardiac magnetic resonance imaging from 4 to 26 weeks will be compared by randomization group using an ITT analysis.
2. Change in ectopic fat volumes in the abdomen and around the heart [ Time Frame: 26 weeks ]
   Changes in fat volume around the heart and in the abdomen from 4 to 26 weeks will be compared by randomization group using an ITT analysis.
3. Changes in liver stiffness and hepatic steatosis [ Time Frame: 26 weeks ]
   Changes in liver stiffness and hepatic steatosis measured by MRE and PDFF

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 65 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

For an eligible subject, all inclusion criteria must be answered "yes"

1. Age >18 years at screening
2. Patients with clinical diagnosis of T1D diagnosed for at least 12 months
3. Patient is on FDA- approved hybrid closed-loop system for ≥ 3 months
4. Willing to use once weekly semaglutide
5. Willing to share devices (HCL system) data uploads
6. Point-of-care HbA1c >7.0% and <10.0%
7. Body mass index ≥30 kg/m2
8. Has current glucagon product to treat severe hypoglycemia
9. Has current ketone meters to check ketones
10. Ability to provide informed consent before any trial-related activities

Exclusion Criteria:

1. Age <18 years and >65 years
2. HbA1c ≤7.0 % or ≥ 10.0% at screening
3. Less than 12 months of insulin treatment
4. Use of unapproved insulin for HCL system. E.g. use of Fiasp in the Tandem Control-IQ system
5. Not willing to share the devices (HCL system) data uploads
6. Non compatible devices (e.g. pump, CGM or smart phones) for data transfer
7. Current use of multiple daily injection or inhaled insulin (Afrezza)
8. Patients with T1D using any glucose lowering medications other than insulin at the time of screening
9. Pregnancy, breast feeding, and positive pregnancy test during screening
10. Women of childbearing age wanting to become pregnant
11. Unwilling to use acceptable contraceptive methods (for both men and women) during the trial period
12. Current use (≥ 2 weeks of continuous use) of any steroidal medication, or anticipated long-term steroidal treatment (>4 weeks continuously), during the study period
13. Use of GLP-1RA or weight loss medications in the past 3 month
14. Clinical diagnosis/history of gastroparesis or gastric motility disorders
15. Serum triglycerides >500 mg/dL
16. Planning for bariatric surgery during the study period
17. eGFR below 45 ml/min/1.73 m^2 using CKD-EPI formula
18. History of severe hypoglycemia in the previous 3 months
19. History of diabetic ketoacidosis requiring hospitalization in the past 3 months
20. History of allergy to any form of insulin, GLP-1RA or its excipients
21. History of any form of pancreatitis
22. History of stroke, myocardial infarction in the past 3 months
23. History of congestive heart failure class III or IV
24. History of acute or chronic liver disease
25. History of malignancy requiring chemotherapy, surgery or radiation in previous 5 years
26. Personal or family history of multiple endocrine neoplasia type 2 (MEN-2) or familial thyroid carcinoma or non-familial medullary thyroid carcinoma
27. Have a pacemaker, metal implants, or aneurysm clips (exclusion only if doing MRI and CT scan)
28. Use of investigational drugs within 5 half-lives prior to screening
29. Participation to other intervention trials during the study period
30. Any comorbidities or medical conditions such as severe psychiatric disorder that make a person unfit for the study at the discretion of the investigators

Contacts and Locations

Locations

United States, Colorado

Barbara Davis Center for Diabetes

Aurora, Colorado, United States, 80045

United States, Iowa

Iowa Diabetes Research Center

West Des Moines, Iowa, United States, 50265

United States, Michigan

Henry Ford Hospital

Detroit, Michigan, United States, 48202

United States, Oregon

Harold Schnitzer Diabetes Health Center

Portland, Oregon, United States, 97239

Sponsors and Collaborators

Viral N. Shah

Juvenile Diabetes Research Foundation

Investigators

• Principal Investigator: Viral N Shah, MD; Indiana University

  Study Documents (Full-Text)

Documents provided by Viral N. Shah, Indiana University:

Study Protocol and Statistical Analysis Plan  [PDF] February 6, 2023

More Information

• Responsible Party: Viral N. Shah, Visiting Professor of Medicine, Indiana University
• ClinicalTrials.gov Identifier: NCT05537233
• Other Study ID Numbers: 22388
• First Posted: September 13, 2022
• Last Update Posted: April 15, 2024
• Last Verified: April 2024

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: IPD will be available once the study is completed.
• Supporting Materials: Study Protocol
• Time Frame: Study protocol is available
• Access Criteria: Anyone can access the protocol

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Viral N. Shah, Indiana University:

Type 1 diabetes; Obesity; HbA1c; Time-in-range; Weight loss; Cardiovascular risk

Additional relevant MeSH terms:

Diabetes Mellitus; Obesity; Diabetes Mellitus, Type 1; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Overweight; Overnutrition; Nutrition Disorders; Body Weight; Autoimmune Diseases; Immune System Diseases; Semaglutide; Glucagon-Like Peptide-1 Receptor Agonists; Hypoglycemic Agents; Physiological Effects of Drugs