Obesity in Diabetes, Obesity/Therapy, Type 1 Diabetes Mellitus (T1DM), Insulin Sensitivity/Resistance, Semaglutide, Lipidomics, Metabolomics, Weight Loss, Glycemic Control for Diabetes Mellitus
Conditions
Keywords
Semaglutide, Obesity, Type 1 Diabetes, Obese Type 1 Diabetics, Insulin sensitivity, Insulin resistance, Weight loss, GLP1-RA, GLP1, Wegovy
Brief summary
The goal of this clinical trial is to investigate the efficacy of semaglutide on body weight, insulin dose requirements and improvements in glucose control and safety aspects in regards to risk of hypoglycemia and diabetic ketoacidosis for patients with established Type 1 Diabetes.
Detailed description
This is a multicentre, randomised, double-blinded, placebo-controlled and investigator-initiated trial aimed to investigate the efficacy of semaglutide in patients with Type 1 Diabetes. Patients from all included diabetes care centres will at routine visits be screened for eligibility for the trial and offered participation. If accepted, the patients will be randomised to one of two intervention arms and undergo a series of different examinations prior to start of the intervention. The two arms consist of treatment with subcutaneous semaglutide injections or subcutaneous injections with semaglutide placebo. The baseline examinations entail documentation of insulin doses, dietary patterns, diabetes distress and treatment satisfaction questionnaires, anthropoimetric data (height, weight and calculation of BMI, waist circumference, waist-hip-ratio), blood work (HbA1c, fasting glucose, fasting c-peptide, lipids, liver and kidney markers incl. Fib-4-scoring, hematology, hsCRP), ECG, capturing of data from continuous/flash glucose monitors. The first 40 included in the study from the centres of SDCA and NOH will further be examined through hyperinsulinemic euglycemic clamps to determine their insulin sensitivity and asses their transcriptome through muscle and fat cell biopsies in relation to the clamp and also be assessed through DXA scans to look at body composition and bone density. Patients will then be handed out their trial drug-pens and start the uptitration proces. The efficacy of semaglutide will be evaluated through the above mentioned array of different investigations by comparing parameters prior to trial drug start, during (throughout the study period), at the end of the drug and at a 6 week post-study followup in an intention-to-treat analysis primarily and secondarily a per-protocol analysis. The safety will be assessed through evaluation of standardized adverse event reporting (including hypoglycemic events and diabetic ketoacidosis).
Interventions
The active comparator of the intervention is s.c. Semaglutide injection once a week in increasing doses every month from 0.25 mg to 0.5 mg to 1.0 mg to 1.7 mg to 2.4 mg and the placebo comparator is s.c. injection with a visually identical and same label pen as described for the active comparator
Visually identical and same label as the active comparator intervention
Sponsors
Steno Diabetes Center Copenhagen
Steno Diabetes Center Odense
Zealand University Hospital
Steno Diabetes Center Aarhus (SDCA), Aarhus University Hospital
Nordsjaellands Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
Randomised, double-blinded, placebo-controlled.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Type 1 Diabetes for more than 3 years * BMI ≥ 30 or ≥ 27 and atleast one comorbidity (hypertension, hypercholesterolemia, microalbuminuria, ischemic heart disease, history of stroke, atherosclerosis or arthrosis
Exclusion criteria
* Treated with GLP1-RAs within last 6 months * Known intolerance for semaglutide * Other forms of diabetes * Pregnant or nursing women * Fertile women not using chemical (hormonal) or mechanical (spiral) contraceptives * Liver disease with elevated plasma alanine aminotransferase (ALT) \> five times and plasma aspartate aminotransferase (AST) \> five times the upper limit of normal (measured at visit 0 with the possibility of one repeat analysis within a week, and the last measured value as being conclusive) * Acute or chronic pancreatitis * Cancer, unless in complete remission for \> 5 years or unless basocellular carcinomas * History of thyroid adenoma or carcinoma * Alcohol/drug abuse * Other concomitant disease or treatment that according to the investigator's assessment makes the patient unsuitable for study participation * Receipt of an investigational drug within 30 days prior to visit 0 / Simultaneous participation in any other clinical intervention trial
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Body weight | 74 weeks | Body weight will be measured both prior to and following treatment for 68 weeks with either semaglutide or placebo. Changes in body weight will be compared for the two intervention arms, before, throughout and at the end of treatment and then at followup 6 weeks later. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Bone density (through bone mineral content) | 68 weeks | For a subgroup consisting of the first 40 patients from two specified sites: Bone density (through bone mineral content) is measured by DXA scan at randomisation and at end-of-treatment. |
| Omics / Metabolome | 74 weeks | For a subgroup consisting of the first 40 patients from two specified sites: Blood samples will be analyzed to assess metabolomic profile (entailing both lipidome and proteome) before treatment and evaluated for changes throughout the 68-week regimen, at its conclusion, and again six weeks post-treatment during follow-up |
| Muscle tissue biopsy | 68 weeks | For a subgroup consisting of the first 40 patients from two specified sites: Muscle tissue biopsies will be taken to assess changes in transcriptome at randomisation and at end-of-treatment. |
| Fat tissue biopsy | 68 weeks | For a subgroup consisting of the first 40 patients from two specified sites: Fat tissue biopsies will be taken to assess changes in transcriptome at randomisation and at end-of-treatment. |
| Electrocardiogram | 68 weeks | Electrocardiograms (ECG) will be recorded at initiation and end of treatment period to assess and evaluate if any rhytm changes occur. |
| Systolic blood pressure | 74 weeks | Systolic blood pressure will be assessed at randomization and evaluated for changes throughout, at the end of treatment and at followup 6 weeks later. |
| Diastolic blood pressure | 74 weeks | Diastolic blood pressure will be assessed at randomization and evaluated for changes throughout, at the end of treatment and at followup 6 weeks later. |
| Resting heart rate | 74 weeks | Systolic blood pressure will be assessed at randomization and evaluated for changes throughout, at the end of treatment and at followup 6 weeks later. |
| Waist circumference | 74 weeks | Waist circumference will be assessed and evaluated for changes during and after treatment for 68 weeks with semaglutide compared to before treatment. |
| Hip-waist-ratio | 74 weeks | Hip-waist-ratio will be assessed and evaluated for changes during and after treatment for 68 weeks with semaglutide compared to before treatment. |
| Hemoglobin | 74 weeks | Blood samples will be analyzed to assess hemoglobin before treatment and evaluated for changes throughout the 68-week regimen, at its conclusion, and again six weeks post-treatment during follow-up. |
| Leucocytes | 74 weeks | Blood samples will be analyzed to assess leucocytes levels before treatment and evaluated for changes throughout the 68-week regimen, at its conclusion, and again six weeks post-treatment during follow-up. |
| Thrombocytes | 74 weeks | Blood samples will be analyzed to assess thrombocytes levels before treatment and evaluated for changes throughout the 68-week regimen, at its conclusion, and again six weeks post-treatment during follow-up. |
| HbA1c | 74 weeks | Blood samples will be analyzed to assess HbA1c before treatment and evaluated for changes throughout the 68-week regimen, at its conclusion, and again six weeks post-treatment during follow-up. |
| Fasting plasma-glucose | 74 weeks | Blood samples will be analyzed to assess fasting plasma-glucose before treatment and evaluated for changes throughout the 68-week regimen, at its conclusion, and again six weeks post-treatment during follow-up. |
| Fasting c-peptide | 74 weeks | Blood samples will be analyzed to assess fasting c-peptide before treatment and evaluated for changes throughout the 68-week regimen, at its conclusion, and again six weeks post-treatment during follow-up. |
| Total cholesterol | 74 weeks | Blood samples will be analyzed to assess total cholesterol before treatment and evaluated for changes throughout the 68-week regimen, at its conclusion, and again six weeks post-treatment during follow-up. |
| HDL cholesterol | 74 | Blood samples will be analyzed to assess HDL cholesterol before treatment and evaluated for changes throughout the 68-week regimen, at its conclusion, and again six weeks post-treatment during follow-up. |
| LDL cholesterol | 74 weeks | Blood samples will be analyzed to assess LDL cholesterol before treatment and evaluated for changes throughout the 68-week regimen, at its conclusion, and again six weeks post-treatment during follow-up. |
| VLDL cholesterol | 74 weeks | Blood samples will be analyzed to assess VLDL cholesterol before treatment and evaluated for changes throughout the 68-week regimen, at its conclusion, and again six weeks post-treatment during follow-up. |
| Triglycerides | 74 weeks | Blood samples will be analyzed to assess triglycerides levels before treatment and evaluated for changes throughout the 68-week regimen, at its conclusion, and again six weeks post-treatment during follow-up. |
| non-HDL cholesterol | 74 weeks | Blood samples will be analyzed to assess non-HDL cholesterol before treatment and evaluated for changes throughout the 68-week regimen, at its conclusion, and again six weeks post-treatment during follow-up. |
| Sodium | 74 weeks | Blood samples will be analyzed to assess sodium before treatment and evaluated for changes throughout the 68-week regimen, at its conclusion, and again six weeks post-treatment during follow-up. |
| Potassium | 74 weeks | Blood samples will be analyzed to assess potassium before treatment and evaluated for changes throughout the 68-week regimen, at its conclusion, and again six weeks post-treatment during follow-up. |
| Creatinine/eGFR | 74 weeks | Blood samples will be analyzed to assess creatinine levels to calculate estimated Glomerular Filtration Rates (eGFR, based on sex, age and creatinine leve) before treatment and evaluated for changes throughout the 68-week regimen, at its conclusion, and again six weeks post-treatment during follow-up. |
| Alanine transaminase (ALT) | 74 weeks | Blood samples will be analyzed to assess alanine transaminase (ALT) before treatment and evaluated for changes throughout the 68-week regimen, at its conclusion, and again six weeks post-treatment during follow-up. |
| Aspartate transaminase (AST) | 74 weeks | Blood samples will be analyzed to assess aspartate transaminase (AST) before treatment and evaluated for changes throughout the 68-week regimen, at its conclusion, and again six weeks post-treatment during follow-up. |
| Fibrosis-4-score (Fib-4) | 74 weeks | Blood samples will be analyzed for fibrosis-4-scores (based on age, thrombocytes, ALT and AST) before treatment and evaluated for changes throughout the 68-week regimen, at its conclusion, and again six weeks post-treatment during follow-up. |
| Amylase | 74 weeks | Blood samples will be analyzed to assess pancreatic amylase before treatment and evaluated for changes throughout the 68-week regimen, at its conclusion, and again six weeks post-treatment during follow-up. |
| Lipase | 74 weeks | Blood samples will be analyzed to assess pancreatic lipase before treatment and evaluated for changes throughout the 68-week regimen, at its conclusion, and again six weeks post-treatment during follow-up. |
| High sensitivity C-reactive protein (hsCRP) | 74 weeks | Blood samples will be analyzed to assess high sensitivity C-reactive protein (hsCRP) before treatment and evaluated for changes throughout the 68-week regimen, at its conclusion, and again six weeks post-treatment during follow-up. |
| Albumin | 74 weeks | Blood samples will be analyzed to assess serum albumin before treatment and evaluated for changes throughout the 68-week regimen, at its conclusion, and again six weeks post-treatment during follow-up. |
| Ketones | 74 weeks | Blood samples will be analyzed to assess total serum ketones before treatment and evaluated for changes throughout the 68-week regimen, at its conclusion, and again six weeks post-treatment during follow-up |
| CGM data - Time in range (TIR) | 68 weeks | Data from CGMs will be analyzed to asses time in range (TIR) before treatment and evaluated for changes in TIR throughout the 68-week regimen and at its conclusion. |
| CGM data - Time in tight range (TITR) | 68 weeks | Data from CGMs will be analyzed to asses time in tight range (TITR) before treatment and evaluated for changes in TITR throughout the 68-week regimen and at its conclusion. |
| CGM data - Time above range (TAR) | 68 weeks | Data from CGMs will be analyzed to asses time above range (TAR) before treatment and evaluated for changes in TAR throughout the 68-week regimen and at its conclusion. |
| CGM data - Time below range (TBR) | 68 weeks | Data from CGMs will be analyzed to asses time in range (TBR) before treatment and evaluated for changes in TBR throughout the 68-week regimen and at its conclusion. |
| CGM data - coefficient of variation (CV) | 68 weeks | Data from CGMs will be analyzed to asses coefficient of variation (CV) before treatment and evaluated for changes in CV throughout the 68-week regimen and at its conclusion. |
| Total daily dose of insulin | 74 weeks | Total daily dose will be assessed at randomization and evaluated for changes throughout treatment regimen, at the end of study and at six weeks followup through the use of insulin dose diaries. |
| Insulin sensitivity | 68 weeks | For a subgroup consisting of the first 40 patients from two specified sites: Insulin sensitivity will be assessed through the golden standard hyperinsulinemic euglycemic clamping method. This will be done before treatment and at the end of treatment. |
| Fat percentage | 68 weeks | For a subgroup consisting of the first 40 patients from two specified sites: The fat percentage is measured by DXA scan at randomisation and at end-of-treatment. |
| Lean mass | 68 weeks | For a subgroup consisting of the first 40 patients from two specified sites: Lean body mass is measured by DXA scan at randomisation and at end-of-treatment. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Patient reported outcome measures - Diabetes distress | 74 weeks | Questionnaires (PAID) will be analyzed to evaluate changes in diabetes treatment satisfaction before treatment, throughout the 68-week regimen, at its conclusion, and again six weeks post-treatment during follow-up. |
| Adverse events | 74 weeks | Tolerability will be assessed through standardized adverse event reporting (including episodes of hypoglycemia) throughout the 68-week regimen, at its conclusion, and again six weeks post-treatment during follow-up. |
| Patient reported outcome measures - Diabetes treatment satisfaction | 74 weeks | Questionnaires (DTSQ-s and DTSQ-c) will be analyzed to evaluate changes in diabetes treatment satisfaction before treatment, throughout the 68-week regimen, at its conclusion, and again six weeks post-treatment during follow-up. |
| Patient reported outcome measures - Dietary patterns | 74 weeks | Questionnaires (DNBCs FFQ) will be analyzed to evaluate changes in dietary patterns before treatment, throughout the 68-week regimen, at its conclusion, and again six weeks post-treatment during follow-up. |
Countries
Denmark
Contacts
Primary ContactThomas F Dejgaard, MD, ph.d., endocrinologist
Backup ContactHasan I Mirza, MD, ph.d.-student
Outcome results
None listed