Chronic Inflammation, Insulin Sensitivity, Type 1 Diabetes
Conditions
Brief summary
The aim for this clinical trial is to evaluate if colchicine in addition to standard of care improves insulin sensitivity in individuals with type 1 diabetes, systemic low-grade inflammaiton and reduced insulin sensitivity. The insulin sensitivity will be evaluated by a hyperinsulinemic, euglycemic clamp.
Interventions
DRUGColchicin 0.5 mg once daily for two weeks, then twice daily for two weeks
Colchicine treatment in the first period
DRUGPlacebo once daily for two weeks, then twice daily for two weeks
Placebo treatment in the first period
DRUGColchicine tablet 0.5 mg once-daily for two weeks, then twice daily for two weeks
Colchicine treatment in the second period
Sponsors
University of Copenhagen
Asger Lund, MD
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Intervention model description
Being a cross-over trial, participants will undergo 2 treatment periods: 4 weeks of treatment with daily colchicine and 4 weeks of treatment with placebo. The order of the treatment periods is randomized 1:1. Each treatment period will be interposed by 8 weeks of wash-out period. In the end of each treatment period the insulin sensitivity will be evaluated by a hyperinsulinemic, euglycemic clamp.
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Type 1 diabetes for more than five years according to World Health Organization criteria and c-peptid \<200 pmol/L * Age 18-80 years * User of a continuous glucose monitor (CGM) system * Glycated hemoglobin A1c (HbA1c) 42-75 mmol/mol * Stable insulin therapy (defined as no change in insulin brand and no newly initiated Continuous subcutaneous insulin infusion (CSII) or Multiple dose injection (MDI) therapy) and, if applicable, stable usage of glucose monitoring technology (e.g., continuous glucose monitor or intermittently scanned continuous glucose monitor) ≥ 3 months with either multiple daily injections or continuous subcutaneous insulin infusion * Estimated glomerular filtration rate ≥ 60 mL/min/L/1.73 m² * Estimated glucose disposal rate (eGDR)\* \< 8 mg/kg/min OR insulin usage of ≥1 IU/kg pr day * C-reactive protein (CRP) hsCRP ≥ 2 mg/L, (measured by high-sensitivity assay)\*\*
Exclusion criteria
* Hypoglycaemia unawareness (inability to register low blood glucose) ad modum Pedersen-Bjergaard, 24 unless the individual uses a continuous glucose monitor with alarm function * Liver disease with elevated plasma alanine aminotransferase (ALT) \> three times the upper limit of normal (measured at screening visit with the possibility of one repeat analysis within seven days, and the last measured value as being conclusive) * History of cirrhosis, chronic active hepatitis, or severe hepatic disease * Inflammatory bowel disease or chronic diarrhoea * Pre-existing progressive neuromuscular disease or individuals with creatinine kinase levels \> three times the upper limit of normal (measured at screening visit with the possibility of one repeat analysis within a week, and the last measured value as being conclusive) * Cancer or lymphoproliferative disease unless in complete remission for \> 5 years * Blood dyscrasias (e.g., myelodysplastic syndromes or related haematological disorders) * Leukocyte cell count \< 3.0 X 109/L * Thrombocyte count \< 110 X 109/L * Immunosuppressive therapy or state of chronic immunodeficiency, including infection with human immunodeficiency virus (HIV) * Treatment with anti-inflammatory drugs (e.g., non-steroidal anti-inflammatory drugs (NSAID), acetylsalicylic acid (ASA), prednisone) or whole-body topical steroid during the study or within four weeks before study start. Inhaled steroids are allowed. Short term oral NSAID treatment (≤ 3 days) within four weeks before study start or during the study period is allowed. Treatment of ASA is allowed for up to 1000 mg daily. * Treatment with colchicine within 60 days of screening visit * Known or suspected hypersensitivity to colchicine * Treatment with glucose lowering drugs other than insulin (e.g., Glucagon Like Peptide 1 (GLP-1) receptor agonists, metformin, selective sodium glucose cotransporter-2 (SGLT2)-inhibitors) during the study period or within four weeks before study start * Haemodialysis or peritoneal dialysis therapy (since colchicine cannot be removed by dialysis or exchange transfusion) * Treatment with a P-glycoprotein inhibitor (e.g., azithromycin and verapamil) or a strong CYP3A4 inhibitor (e.g., clarithromycin and ritonavir) * Intake of grapefruit juice * Other concomitant disease or treatment that according to the investigator's assessment makes the individual unsuitable for study participation * Alcohol/drug abuse (assessed by the investigator) * Regarding fertile women: * A woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. * Sterilised or postmenopausal women (no menses for 12 months without an alternative medical cause) can be included without the human chorionic gonadotrophin (hCG)-testing during the trial period * Women who are pregnant, intend to become pregnant, or are breastfeeding will not be included in the study * Female of childbearing potential: must use highly effective contraceptives during the trial and three months after the trial. To exclude pregnancy, urine hCG tests are performed in relation to all visits (V1-V5) and to the phone call in the washout period (P2) and there will be instructions to ensure monthly testing three months after the end of the trial. * The following contraceptive methods are considered highly effective and thus adequate for study enrolment for females if maintained throughout the study duration and three months after the trial: Combined hormonal contraception associated with inhibition of ovulation (containing estrogen and progestogen administered oral, intravaginal or transdermal). Progestogen-only hormonal contraception associated with inhibition of ovulation (admninistered oral, injectable or implantable). Intrauterine device (IUD). Intrauterine hormone-releasing system. Bilateral tubal occlusion. Vasectomised partner. Sexual abstinence (sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the subject). * Male participants with partners of childbearing potential: must either use a condom or ensure that their partner uses a highly effective contraceptive method during the trial and six months after the trial. * Pregnant or nursing women * Participants unable to speak or understand Danish * Receipt of any investigational drug within 30 days prior to visit 1 * Simultaneous participation in any other clinical intervention trial
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean difference in M-value | Four weeks of treatment comparing colchicine to placebo. | Mean difference in insulin sensitivity is measured by the M-value (glucose infusion rate mg/kg/min) during the last 30 minutes of a 180 minutes hyperinsulinemic euglycemic clamp procedure using insulin infusion rate of 60 mU/m²/min |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean difference in M-value | After four weeks of placebo/colchicine | Measured in mg/m²/min. Adjusted to body surface area (BSA) |
| Mean difference in M-value (adjusted to fat free mass (FFM)) | After four weeks of placebo/colchicine | Measured in mg/kg FFM/min |
| Mean difference in Insulin Sensitivity Index (ISI) | After four weeks of placebo/colchicine | Glucose infusion rate / Plasma insulin in steady state |
| Mean difference in average daily insulin dosage | During four weeks of placebo/colchicine | Units/day. Total daily dose, short acting, long acting |
| Fold difference in fasting serum/plasma concentrations of C-reactive protein (CRP) measured by a high-sensitivity assay (hsCRP) (mg/L) | After four weeks of placebo/colchicine | Ratio |
| Fold difference in in fasting serum/plasma concentrations iInterleukin 6 (IL-6) (pg/mL) | After four weeks of placebo/colchicine | Ratio |
| Fold difference in in fasting serum/plasma concentrations of tumour necrosis factor alpha (TNF alpha) | After four weeks of placebo/colchicine | Ratio |
| Fold difference in Insulin sensitivity by estimated glucose disposal rate (eGDR) | After four weeks of placebo/colchicine | Ratio. It is calculated using clinical variables such as waist circumference, hypertension status, and HbA1c. Higher eGDR values indicate better insulin sensitivity |
Other
| Measure | Time frame | Description |
|---|---|---|
| Time spent in hypoglycemia level 2 (< 3.0 mmol/L)evaluated by a continous glucose monitor (CGM) | The last 7 days of each treatment period. | Measured in % of 24 hours. |
| Change in glycaemic variability assessed as coefficient of variance (CV) | The last 7 days of each treatment period. | %-point |
| Change in standard deviation evaluated by a continous glucose monitor (mmol/L) | The last 7 days of each treatment period. | %-point |
| Mean difference in Body mass index (BMI) | After four weeks of placebo/colchicine | kg/m² |
| Fold difference in waist-hip ratio | ratio | After four weeks of placebo/colchicine |
| Mean difference in respiratory exchange ratio between basal state and during clamp | After four weeks of placebo/colchicine | Ratio |
| Adipocyte tissue biopsies | After four weeks of placebo/colchicine | Ratio. Fold difference in Adipocyte size, Inflammation, Glucose metabolism, Extracellular matrix, Oxygen consumption, Transcriptomics, Proteomics |
| Time spent in target blood glucose range (3.9 - 10 mmol/L) evaluated by a continous glucose monitor (CGM) | The last 7 days of each treatment period. | Measured in % of 24 hours. |
| Time spent in tight range (3.9 - 7.8 mmol/L) evaluated by a continous glucose monitor (CGM) | The last 7 days of each treatment period. | Measured in % of 24 hours. |
| Time spent in hyperglycemia level 1 (10-13.9 mmol/L) evaluated by a continous glucose monitor (CGM) | The last 7 days of each treatment period. | Measured in % of 24 hours. |
| Time spent in hyperglycemia level 2 (> 13.9 mmol/L) evaluated by a continous glucose monitor (CGM) | The last 7 days of each treatment period. | Measured in % of 24 hours. |
| Time spent in hypoglycemia level 1 (3.0-3.8 mmol/L) evaluated by a continous glucose monitor (CGM) | The last 7 days of each treatment period. | Measured in % of 24 hours. |
| Fold difference in body composition (fat-free mass, total fat mass, visceral fat mass rating and bone mass) as measured by bioimpedance | After four weeks of placebo/colchicine | Ratio |
| Fold difference in fasting serum/plasma concentrations of inflammatory biomarkers | After four weeks of placebo/colchicine | Ratio. Interleukines and other cytokines |
| Fold difference in fasting serum/plasma concentrations of total leukocyte count, including neutrophil, lymphocyte, basophil and eosinophil counts (10^9/L) | After four weeks of placebo/colchicine | Ratio. |
| Fold difference in fasting serum/plasma concentrations of very low-density lipoprotein (VLDL) cholesterol (mmol/L) | After four weeks of placebo/colchicine | Ratio. |
| Fold difference in fasting serum/plasma concentrations of hemoglobin A1c (mmol/mol) | After four weeks of placebo/colchicine | Ratio |
| Fold difference in fasting serum/plasma concentrations of insulin (pmol/L) | After four weeks of placebo/colchicine | Ratio |
| Fold difference fasting serum/plasma concentrations of C-peptide (pmol/L) | After four weeks of placebo/colchicine | Ratio |
| Fold difference in fasting serum/plasma concentrations of glucagon (pmol/L) | After four weeks of placebo/colchicine | Ratio |
| Mean difference in resting energy expenditure ratio between basal state and during clamp | After four weeks of placebo/colchicine | Ratio. Participants undergo indirect calorimetry in the basal state and during the clamp (from 120-150 minutes) |
| Fold difference in FibroScan®-assessed liver steatosis (dB/m) | After four weeks of placebo/colchicine | Ratio. Measured before- and after each treatment period. |
| Fold difference in Fatty Liver Index (FLI, range 0-100; higher scores indicate greater likelihood of fatty liver) | After four weeks of placebo/colchicine Ratio | Ratio |
| Fold difference in Fibrosis-4 (FIB-4) score | After four weeks of placebo/colchicine | Ratio. The Fibrosis-4 score is a non-invasive index used to estimate liver fibrosis. It is calculated using age, aspartate aminotransferase, alanine aminotransferase, and platelet count. Scale range: Typically from 0 to greater than 3.25 |
| Fold difference in fasting coagulability as measured by thromboelastography (TEG) | After four weeks of placebo/colchicine | Ratio. Measured before and after each treatment period. |
| Fold difference in fasting serum/plasma concentrations of hormones during the HIE clamp | After four weeks of placebo/colchicine | Ratio. Insulin, C-peptide and other counter-regulatory hormones |
| Difference in rate of treatment-emergent AEs | From signed consent form to last clamp day (week 16-18) | Rate ratio |
| Difference in rate of serious AEs (SAEs) | From signed consent form to last clamp day (week 16-18) | Rate ratio |
| Mean difference in waist circumference | After four weeks of placebo/colchicine | Cm |
| Difference in rate of diabetic ketoacidosis | From signed consent form to last clamp day (week 16-18) | Rate ratio |
| Change in diabetes treatment satisfactory questionnaire, status version (DTSQs) (From 0 (min) to 6 (max), higher scores indicate a better outcome ) | At Visit 2 (week 0), Visit 3 (week 4), Visit 4 (week 12) and Visit 5 (week 16) | %-point |
| Change in diabetes treatment satisfactory questionnaire, change version (DTSQc) (From -3 (min) to 3 (max), higher scores indicate a better outcome | At Visit 3 (week 4) and Visit 5 (week 16) | %-point |
| Change in fasting serum/plasma concentrations of hemoglobin (mmol/L) | After four weeks of placebo/colchicine | %-point |
| Change in fasting serum/plasma concentrations of thrombocytes (10^9/L) | After four weeks of placebo/colchicine | %-point |
| Change in fasting serum/plasma concentrations of albumin (g/L) | After four weeks of placebo/colchicine | %-point |
| Change in fasting serum/plasma concentrations of potassium (mmol/L) | After four weeks of placebo/colchicine | %-point |
| Change in fasting serum/plasma concentrations of sodium (mmol/L) | After four weeks of placebo/colchicine | %-point |
| Change in fasting serum/plasma concentrations of creatinine (umol/L) | After four weeks of placebo/colchicine | %-point |
| Change in fasting serum/plasma concentrations of creatine kinase (U/L) | After four weeks of placebo/colchicine | %-point |
| Change in fasting serum/plasma concentrations of estimated glomerular filtration rate (eGFR) (mL/min/1.73 m2) | After four weeks of placebo/colchicine | %-point |
| Change in fasting serum/plasma concentrations of alanine aminotransferase (U/L) | After four weeks of placebo/colchicine | %-point |
| Change in fasting serum/plasma concentrations of aspartate aminotransferase (U/L) | After four weeks of placebo/colchicine | %-point |
| Change in fasting serum/plasma concentrations of bilirubin (umol/L) | After four weeks of placebo/colchicine | %-point |
| Difference in rate of severe hypoglycaemia (defined as hypoglycaemia with need of external assistance) | From signed consent form to last clamp day (week 16-18) | Rate ratio |
| Mean difference in systolic blood pressure | After four weeks of placebo/colchicine | mmHg |
| Mean difference in diastolic blood pressure | After four weeks of placebo/colchicine | mmHg |
| Mean difference in heart rate | After four weeks of placebo/colchicine | beats per minute |
| Change in fasting serum/plasma concentrations of amylase (units/L) | After four weeks of placebo/colchicine | %-point |
| Fold difference in fasting serum/plasma concentrations of high-density lipoprotein (HDL) cholesterol (mmol/L) | After four weeks of placebo/colchicine | Ratio. |
| Fold difference in fasting serum/plasma concentrations of total cholesterol (mmol/L) | After four weeks of placebo/colchicine | Ratio. |
| Fold difference in fasting serum/plasma concentrations of triglycerides (mmol/L) | After four weeks of placebo/colchicine | Ratio. |
| in fasting serum/plasma concentrations of lipoprotein (a) (mg/L) | After four weeks of placebo/colchicine | Ratio. |
Countries
Denmark
Contacts
Primary ContactAskee N. Høck, MD
Outcome results
None listed