scholarly journals Study protocol: Minimum effective low dose: anti-human thymocyte globulin (MELD-ATG): phase II, dose ranging, efficacy study of antithymocyte globulin (ATG) within 6 weeks of diagnosis of type 1 diabetes

BMJ Open ◽  
2021 ◽  
Vol 11 (12) ◽  
pp. e053669
Author(s):  
Charlotte S Wilhelm-Benartzi ◽  
Sarah E Miller ◽  
Sylvaine Bruggraber ◽  
Diane Picton ◽  
Mark Wilson ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Antithymocyte Globulin ◽  
Low Dose ◽  
Insulin Dose ◽  
Double Blind ◽  
C Peptide ◽  
Link Type ◽  
Significant Difference ◽  
Allocation Ratio

IntroductionType 1 diabetes (T1D) is a chronic autoimmune disease, characterised by progressive destruction of the insulin-producing β cells of the pancreas. One immunosuppressive agent that has recently shown promise in the treatment of new-onset T1D subjects aged 12–45 years is antithymocyte globulin (ATG), Thymoglobuline, encouraging further exploration in lower age groups.Methods and analysisMinimal effective low dose (MELD)-ATG is a phase 2, multicentre, randomised, double-blind, placebo-controlled, multiarm parallel-group trial in participants 5–25 years diagnosed with T1D within 3–9 weeks of planned treatment day 1. A total of 114 participants will be recruited sequentially into seven different cohorts with the first cohort of 30 participants being randomised to placebo, 2.5 mg/kg, 1.5 mg/kg, 0.5 mg/kg and 0.1 mg/kg ATG total dose in a 1:1:1:1:1 allocation ratio. The next six cohorts of 12–15 participants will be randomised to placebo, 2.5 mg/kg, and one or two selected middle ATG total doses in a 1:1:1:1 or 1:1:1 allocation ratio, as dependent on the number of middle doses, given intravenously over two consecutive days. The primary objective will be to determine the changes in stimulated C-peptide response over the first 2 hours of a mixed meal tolerance test at 12 months for 2.5 mg/kg ATG arm vs the placebo. Conditional on finding a significant difference at 2.5 mg/kg, a minimally effective dose will be sought. Secondary objectives include the determination of the effects of a particular ATG treatment dose on (1) stimulated C-peptide, (2) glycated haemoglobin, (3) daily insulin dose, (4) time in range by intermittent continuous glucose monitoring measures, (5) fasting and stimulated dry blood spot (DBS) C-peptide measurements.Ethics and disseminationMELD-ATG received first regulatory and ethical approvals in Belgium in September 2020 and from the German and UK regulators as of February 2021. The publication policy is set in the INNODIA (An innovative approach towards understanding and arresting Type 1 diabetes consortium) grant agreement (www.innodia.eu).Trial registration numberNCT03936634; Pre-results.

Partial remission in children and adolescents with type 1 diabetes: an analysis based on the insulin dose-adjusted hemoglobin A1c

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Emine Ayça Cimbek ◽  
Aydın Bozkır ◽  
Deniz Usta ◽  
Nazım Ercüment Beyhun ◽  
Ayşenur Ökten ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Partial Remission ◽  
Hemoglobin A1c ◽  
Insulin Dose ◽  
Age At Onset ◽  
Insulin Requirement ◽  
C Peptide ◽  
Factors Associated ◽  
Daily Insulin

Abstract Objectives Most patients with type 1 diabetes (T1D) experience a transient phase of partial remission (PR). This study aimed to identify the demographic and clinical factors associated with PR. Methods This was a longitudinal retrospective cohort study of 133 children and adolescents with T1D. PR was defined by the gold standard insulin dose-adjusted hemoglobin A1c (HbA1c) (IDAA1c) of ≤9. Results Remission was observed in 77 (57.9%) patients. At diagnosis, remitters had significantly higher pH (7.3 ± 0.12 vs. 7.23 ± 0.15, p=0.003), higher C-peptide levels (0.45 ± 0.31 ng/mL vs. 0.3 ± 0.22, p=0.003), and they were significantly older (9.3 ± 3.6 years vs. 7.3 ± 4.2, p=0.008) compared with non-remitters. PR developed more frequently in patients without diabetic ketoacidosis (DKA) (p=0.026) and with disease onset after age 5 (p=0.001). Patients using multiple daily insulin regimen were more likely to experience PR than those treated with a twice daily regimen (63.9 vs. 32%, p=0.004). Only age at onset was an independent predictor of PR (OR: 1.12, 95% CI: 1-1.25; p=0.044). Remitters had lower HbA1c levels and daily insulin requirement from diagnosis until one year after diagnosis (p<0.001). PR recurred in 7 (9%) patients. The daily insulin requirement at three months was lower in remitters with PR recurrence compared to those without (0.23 ± 0.14 vs. 0.4 ± 0.17 U/kg/day, p=0.014). Conclusions Addressing factors associated with the occurrence of PR could provide a better comprehension of metabolic control in T1D. The lack of DKA and higher C-peptide levels may influence PR, but the main factor associated with PR presence was older age at onset. PR may recur in a small proportion of patients.

scholarly journals Insulin-Like Growth Factor-1 at Diagnosis and during Subsequent Years in Adolescents with Type 1 Diabetes

2018 ◽  
Vol 2018 ◽  
pp. 1-6 ◽  
Author(s):  
Simona I. Chisalita ◽  
J. Ludvigsson
Keyword(s):  
Type 1 Diabetes ◽  
Insulin Secretion ◽  
Insulin Treatment ◽  
Insulin Dose ◽  
Newly Diagnosed ◽  
Blood Samples ◽  
C Peptide ◽  
Endogenous Insulin ◽  
High Hba1c

Background. Type 1 diabetes (T1D) in adolescents is associated with alterations in the insulin-like factor system probably caused both by a deranged metabolism and insulinopenia in the portal vein. Objective. To study how the circulating IGF-1 is affected at diagnosis and during subsequent years in adolescents with T1D. Methods. Ten girls and ten boys with type 1 diabetes (T1D), aged 13.0 ± 1.4 (mean ± SD) years at diagnosis, took part in the study. Blood samples were drawn at diagnosis and after 3, 9, 18, and 48 months. HbA1c, total IGF-1, and C-peptide were measured. Results. At diagnosis, the patients had high HbA1c, low IGF-1, and measurable C-peptide. After the start of insulin treatment, maximal improvement in glycemic control and IGF-1 occurred within 3 months and then both tended to deteriorate, that is, HbA1c to increase and IGF-1 to decrease. C-peptide decreased with time, and after 4 years, half of the patients were C-peptide negative. At diagnosis, C-peptide correlated positively to IGF-1 (r=0.50; p<0.03). C-peptide correlated negatively with insulin dose (U/kg) after 18 and 48 months from diagnosis (r=−0.48; p<0.03 and r=−0.72; p<0.001, resp.). Conclusions. In conclusion, our results show that in newly diagnosed adolescents with type 1 diabetes and deranged metabolism, the IGF-1 level is low and rapidly improves with insulin treatment but later tends to decrease concomitantly with declining endogenous insulin secretion.

scholarly journals Low-dose ATG/GCSF in Established Type 1 Diabetes: A Five-Year Follow-up Report

2021 ◽  
Author(s):  
Andrea Lin ◽  
Jasmine A. Mack ◽  
Brittany Bruggeman ◽  
Laura M. Jacobsen ◽  
Amanda L. Posgai ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Low Dose ◽  
Area Under The Curve ◽  
Tolerance Test ◽  
Modeling Framework ◽  
C Peptide ◽  
Recent Onset

Previously, we demonstrated low-dose anti-thymocyte globulin (ATG) and granulocyte colony stimulating factor (GCSF) immunotherapy preserved C-peptide for two years in a pilot study of subjects with established type 1 diabetes (n=25). Herein, we evaluated the long-term outcomes of ATG/GCSF in study participants with five years of available follow-up data (n=15). The primary endpoint was area under the curve (AUC) C-peptide during a two-hour mixed-meal tolerance test (MMTT). After five years, there were no statistically significant differences in AUC C-peptide when comparing subjects who received ATG/GCSF versus placebo (p = 0.41). A modeling framework based on mean trajectories in C-peptide AUC over five years, accounting for differing trends between groups, was applied to re-categorize responders (n=9) and non-responders (n=7). ATG/GCSF reponders demonstrated nearly unchanged HbA1c over five years [mean (95% CI) adjusted change = 0.29% (-0.69%, 1.27%)], but the study was not powered for comparisons against non-responders 1.75% (-0.57%, 4.06%) and placebo 1.44% (0.21%, 2.66%). These data underscore the importance of long-term follow up in previous and ongoing phase 2 trials of low-dose ATG in recent-onset type 1 diabetes.

scholarly journals Specific features of pregnancy in patients with type 1 diabetes in the prepubertal period. Results of a 15-year long clinical observation

2009 ◽  
Vol 12 (4) ◽  
pp. 28-31
Author(s):  
Lyubov' Leonidovna Bolotskaya ◽  
Natalya Vladimirovna Efremova ◽  
Yury Ivanovich Suntsov
Keyword(s):  
Type 1 Diabetes ◽  
Diabetic Complications ◽  
Insulin Dose ◽  
Research Centre ◽  
Nocturnal Hypoglycemia ◽  
Significant Difference ◽  
Before And After ◽  
Pregnancy And Delivery ◽  
The Difference

Aim. To evaluate effect of different factors on pregnancy course in patients with type 1 diabetes mellitus developing in the prepubertal period. Materials and methods. The study based at Endocrinological Research Centre included 77 women with prepubertal diabetes 18 of whom developedpregnancy that ended in delivery. Results. As per 2009, the age of the patients is 26,6?4,6 years. They became pregnant at 23,2?3,3 years and had had diabetes since the age of9,6?4,8 years. Their HbA1c level before and after pregnancy was 8,6?1,4 and 6,8?1,6% respectively, the difference being insignificant (p=0,3).Significant difference was documented between these HbA1c levels and that during pregnancy (p=0,0004 and 0.003 respectively). Nine (56,2%) patientsused ultrashort-acting insulin analogs and the remaining 7 (43,7%) recombinant human insulins. The mean insulin dose was 43,7?11 U/din the 1st trimester, 51,8?13,7 U/d in the 2bd trimester, and 45,3?10,8 U/d after delivery. 16 (88%) of the patients reported frequent hypoglycemia,five (27,8%) of them had episodes of severe daytime and nocturnal hypoglycemia. 11 (61%) developed microvascular diabetic complications beforepregnancy, with 9 (50%) having DR and 4 (22,2%) DN (microalbuminuria). The delivery occurred on weeks 36-37 in 7 (38,9%) women. Naturaland cesarean section deliveries took place in one and 17 (94,4%) patients respectively. Conclusion. Long-term follow-up of patients wit DM1 in accordance with algorithms of specialized medical aid to DM1 patients in Russia at a multidisciplinaryendocrinological centre decreases the risk of pregnancy and delivery complications and that of microvascular diabetic complications

scholarly journals A Pilot Study of Flat and Circadian Insulin Infusion Rates in Continuous Subcutaneous Insulin Infusion (CSII) in Adults with Type 1 Diabetes (FIRST1D)

2020 ◽  
pp. 193229682090619
Author(s):  
Siân Rilstone ◽  
Monika Reddy ◽  
Nick Oliver
Keyword(s):  
Type 1 Diabetes ◽  
Pilot Study ◽  
Insulin Infusion ◽  
Insulin Dose ◽  
Total Daily Dose ◽  
Subcutaneous Insulin ◽  
Basal Rate ◽  
Absolute Change ◽  
Significant Difference

Background: Initiation of continuous subcutaneous insulin therapy (CSII) in type 1 diabetes requires conversion of a basal insulin dose into a continuous infusion regimen. There are limited data to guide the optimal insulin profile to rapidly achieve target glucose and minimize healthcare professional input. The aim of this pilot study was to compare circadian and flat insulin infusion rates in CSII naïve adults with type 1 diabetes. Methods: Adults with type 1 diabetes commencing CSII were recruited. Participants were randomized to circadian or flat basal profile calculated from the total daily dose. Basal rate testing was undertaken on days 7, 14 and 28 and basal rates were adjusted. The primary outcome was the between-group difference in absolute change in insulin basal rate over 24 hours following three rounds of basal testing. Secondary outcomes included the number of basal rate changes and the time blocks. Results: Seventeen participants (mean age 33.3 (SD 8.6) years) were recruited. There was no significant difference in absolute change in insulin basal rates between groups ( P = .85). The circadian group experienced significant variation in the number of changes made with the most changes in the morning and evening ( P = .005). The circadian group received a greater reduction in total insulin (−14.1 (interquartile range (IQR) −22.5-12.95) units) than the flat group (−7.48 (IQR −11.90-1.23) units) ( P = .021). Conclusion: The initial insulin profile does not impact on the magnitude of basal rate changes during optimization. The circadian profile requires changes at specific time points. Further development of the circadian profile may be the optimal strategy.

Low-dose interleukin 2 in patients with type 1 diabetes: a phase 1/2 randomised, double-blind, placebo-controlled trial

2013 ◽  
Vol 1 (4) ◽  
pp. 295-305 ◽  
Author(s):  
Agnès Hartemann ◽  
Gilbert Bensimon ◽  
Christine A Payan ◽  
Sophie Jacqueminet ◽  
Olivier Bourron ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Low Dose ◽  
Controlled Trial ◽  
Phase 1 ◽  
Interleukin 2 ◽  
Double Blind ◽  
Double Blind Placebo

scholarly journals Phase II multicentre, double-blind, randomised trial of ustekinumab in adolescents with new-onset type 1 diabetes (USTEK1D): trial protocol

BMJ Open ◽  
2021 ◽  
Vol 11 (10) ◽  
pp. e049595
Author(s):  
John W Gregory ◽  
Kymberley Carter ◽  
Wai Yee Cheung ◽  
Gail Holland ◽  
Jane Bowen-Morris ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Beta Cell ◽  
Research Ethics ◽  
Beta Cells ◽  
Beta Cell Function ◽  
Cell Function ◽  
Double Blind ◽  
C Peptide ◽  
New Onset

IntroductionMost individuals newly diagnosed with type 1 diabetes (T1D) have 10%–20% of beta-cell function remaining at the time of diagnosis. Preservation of residual beta-cell function at diagnosis may improve glycaemic control and reduce longer-term complications.Immunotherapy has the potential to preserve endogenous beta-cell function and thereby improve metabolic control even in poorly compliant individuals. We propose to test ustekinumab (STELARA), a targeted and well-tolerated therapy that may halt T-cell and cytokine-mediated destruction of beta-cells in the pancreas at the time of diagnosis.Methods and analysisThis is a double-blind phase II study to assess the safety and efficacy of ustekinumab in 72 children and adolescents aged 12–18 with new-onset T1D.Participants should have evidence of residual functioning beta-cells (serum C-peptide level >0.2nmol/L in the mixed-meal tolerance test (MMTT) and be positive for at least one islet autoantibody (GAD, IA-2, ZnT8) to be eligible.Participants will be given ustekinumab/placebo subcutaneously at weeks 0, 4 and 12, 20, 28, 36 and 44 in a dose depending on the body weight and will be followed for 12 months after dose 1.MMTTs will be used to measure the efficacy of ustekinumab for preserving C-peptide area under the curve at week 52 compared with placebo. Secondary objectives include further investigations into the efficacy and safety of ustekinumab, patient and parent questionnaires, alternative methods for measuring insulin production and exploratory mechanistic work.Ethics and disseminationThis trial received research ethics approval from the Wales Research Ethics Committee 3 in September 2018 and began recruiting in December 2018.The results will be disseminated using highly accessed, peer-reviewed medical journals and presented at conferences.Trial registration numberISRCTN14274380.

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