New onset Type 1 diabetes in adults Nutritional, Metabolic, Endocrine
Conditions
Interventions
Verapamil. Oral. Once daily. V0 (Day 0) 120 mg daily. V1 (week 4) 240 mg daily. V2 (Week 8) 360 mg daily – continues until V6 (month 12)
ATG (Thymoglobuline). Infusion. Given at V0 (Day 0 or within
Sponsors
Cardiff University
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Have given written informed consent 2. Age =18 and <45 years at consent 3. Must have had a clinical diagnosis of stage 3 T1D within 6 weeks of screening (from date of the first insulin injection) – defined as hyperglycaemia satisfying ADA criteria for diabetes and a clinical decision to commence insulin treatment 4. Must have at least one or more of the following diabetes-related autoantibodies present at screening: GADA, IA-2A and/or ZnT8A 5. Must have fasting serum C-peptide levels =100 pmol/L measured at screening 6. Be willing to comply with intensive diabetes management.
Exclusion criteria
Exclusion criteria: 1. Be immunodeficient or have clinically significant chronic lymphopenia 2. Have active signs or symptoms of acute infection at the time of randomisation 3. Be currently pregnant or lactating, or anticipate getting pregnant during the 12-month trial period 4. Require use of immunosuppressive agents, including chronic use of systemic steroids 5. Evidence of current or past human immunodeficiency virus (HIV), Hepatitis B or C infection and be serologically tested for these 6. Any complicating medical issues or abnormal clinical laboratory results that interfere with trial conduct, or cause increased risk to include pre-existing cardiac disease, chronic obstructive pulmonary disease (COPD), sickle cell disease, neurological, or blood count abnormalities 7. Have a persistent history of malignancies (including lymphoma) other than skin 8. History of liver insufficiency or laboratory evidence of liver dysfunction with aspartate aminotransferase (AST) or alanine transaminase (ALT) greater than 3 times the upper limits of normal 9. History of renal insufficiency or evidence of renal dysfunction with creatinine greater than 1.5 times the upper limit of normal 10. Current or ongoing use of non-insulin pharmaceuticals that affect glycaemic control within 7 days prior to screening 11. Use of other investigational drug in the previous 30 days and/or intent to use any investigational drug that does not form part of T1D Plus trial for the duration of the trial 12. Current use of Verapamil SR or other calcium channel blockers 13. Known hypersensitivity to Verapamil SR or any of its excipients 14. Current use of Ivabradine 15. Known allergies, severe reaction, intolerance, hypersensitivity, or anaphylaxis to human, humanized, or murine monoclonal antibodies, or any of its components or excipients 16. Any autoimmune disease other than T1D (eg, rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, multiple sclerosis, systemic lupus erythematosus), with the exception of stable thyroid or celiac disease 17. Active infection and/or fever =38.5°C (101.3°F) within the 48 hours prior to randomisation, prone to infections, or chronic, recurrent or opportunistic infectious disease, including but not limited to renal, respiratory or skin infections, Pneumocystis carinii, aspergillosis, latent or active granulomatous infection, histoplasmosis, or coccidioidomycosis 18. History of or serologic evidence at screening of current or past infection with HIV, hepatitis B or C virus 19. Symptoms of Epstein-Barr virus, Cytomegalovirus or TB (Tuberculosis) – test for Interferon-gamma release assay (IGRA) 20. A history of significant cardiovascular disease, including heart failure 21. Current or prior (within 30 days before screening) treatment known to cause a significant, ongoing change in the course of T1D or immunologic status, including high-dose inhaled, extensive topical, or systemic glucocorticoids 22. Current or prior (within 30 days before screening) use of drugs other than insulin to treat hyperglycemia (eg, metformin, sulfonylureas, glinides, thiazolidinediones, exenatide, liraglutide, dipeptidyl peptidase-4 [DPP-IV], sodium-glucose cotransporter 2 [SGLT2] inhibitors or amylin 23. Current or prior (within 30 days before screening) use of medication known to significantly influence glucose tolerance (eg, atypical antipsychotics, diphenylhydantoin, niacin) 24. Recent or planned vaccinations as follows: 2
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| The area under the stimulated C-peptide response curve over the first two hours of a mixed meal tolerance test (MMTT) after 12 months therapy between the Verapamil SR only arm and the Verapamil SR plus immunotherapy arm. | — |
Secondary
| Measure | Time frame |
|---|---|
| 1. The area under the stimulated C-peptide response curve over the first two hours of a mixed meal tolerance test (MMTT) at baseline, 3, 6, 9 and 24 months 2. Estimated C-peptide AUC at baseline, 3, 6, 9, 12 and 24 months. 3. Fasting C-peptide after 12 months therapy compared between intervention and control arms. 4. Change in HbA1c baseline to 12 months. 5. Number of treatment emergent severe hypoglycaemic episodes (Level 3). Severe hypoglycaemia denotes severe cognitive impairment requiring external assistance for recovery according to the American Diabetes Association (ADA) 6. Number of treatment emergent significant hypoglycaemic episodes (Level 2). Significant hypoglycaemia denotes events with capillary blood glucose < 3.0mmol/L (54mg/dl) according to the American Diabetes Association (ADA) 7. Number of treatment emergent episodes of diabetic ketoacidosis (DKA) 8. Change in insulin requirements, baseline to 12 months as the daily total dose (three days average) in units per kg body weight (BW) 9. Change in T1D associated autoantibodies (GADA, IA-2A and ZnT8A) from baseline to 12 months. 10. The area under the stimulated C-peptide response curve over the first two hours of a mixed meal tolerance test (MMTT) at 24 months 11. CGM metrics (Time in range, time below range, variability, other derived parameters) at baseline, 3, 6, 9, 12 and 24 months. | — |
Countries
Australia, Austria, Belgium, France, Germany, Italy, United Kingdom
Contacts
Public ContactColin Dayan
Outcome results
None listed