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
Abstract: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, multi… Show more
“…age group, BMI). The criteria can also be adapted for each sub-trial if based on the IMP, individuals with specific concomitant or previous medical conditions, or taking certain medications need to be excluded [ 14 ].…”
Section: Methodsmentioning
confidence: 99%
“…An example of how the INNODIA backbone can be adapted for these additional studies is provided in Fig. 2 , where the INNODIA baseline visit is combined with the trial screening visit, and early visits incorporate collection of essential safety and potential pharmacokinetics/pharmacodynamics data, as needed based on the specific IMP tested in each trial [ 14 ]. Fig.…”
Background
The INNODIA consortium has established a pan-European infrastructure using validated centres to prospectively evaluate clinical data from individuals with newly diagnosed type 1 diabetes combined with centralised collection of clinical samples to determine rates of decline in beta-cell function and identify novel biomarkers, which could be used for future stratification of phase 2 clinical trials.
Methods
In this context, we have developed a Master Protocol, based on the “backbone” of the INNODIA natural history study, which we believe could improve the delivery of phase 2 studies exploring the use of single or combinations of Investigational Medicinal Products (IMPs), designed to prevent or reverse declines in beta-cell function in individuals with newly diagnosed type 1 diabetes. Although many IMPs have demonstrated potential efficacy in phase 2 studies, few subsequent phase 3 studies have confirmed these benefits. Currently, phase 2 drug development for this indication is limited by poor evaluation of drug dosage and lack of mechanistic data to understand variable responses to the IMPs. Identification of biomarkers which might permit more robust stratification of participants at baseline has been slow.
Discussion
The Master Protocol provides (1) standardised assessment of efficacy and safety, (2) comparable collection of mechanistic data, (3) the opportunity to include adaptive designs and the use of shared control groups in the evaluation of combination therapies, and (4) benefits of greater understanding of endpoint variation to ensure more robust sample size calculations and future baseline stratification using existing and novel biomarkers.
“…age group, BMI). The criteria can also be adapted for each sub-trial if based on the IMP, individuals with specific concomitant or previous medical conditions, or taking certain medications need to be excluded [ 14 ].…”
Section: Methodsmentioning
confidence: 99%
“…An example of how the INNODIA backbone can be adapted for these additional studies is provided in Fig. 2 , where the INNODIA baseline visit is combined with the trial screening visit, and early visits incorporate collection of essential safety and potential pharmacokinetics/pharmacodynamics data, as needed based on the specific IMP tested in each trial [ 14 ]. Fig.…”
Background
The INNODIA consortium has established a pan-European infrastructure using validated centres to prospectively evaluate clinical data from individuals with newly diagnosed type 1 diabetes combined with centralised collection of clinical samples to determine rates of decline in beta-cell function and identify novel biomarkers, which could be used for future stratification of phase 2 clinical trials.
Methods
In this context, we have developed a Master Protocol, based on the “backbone” of the INNODIA natural history study, which we believe could improve the delivery of phase 2 studies exploring the use of single or combinations of Investigational Medicinal Products (IMPs), designed to prevent or reverse declines in beta-cell function in individuals with newly diagnosed type 1 diabetes. Although many IMPs have demonstrated potential efficacy in phase 2 studies, few subsequent phase 3 studies have confirmed these benefits. Currently, phase 2 drug development for this indication is limited by poor evaluation of drug dosage and lack of mechanistic data to understand variable responses to the IMPs. Identification of biomarkers which might permit more robust stratification of participants at baseline has been slow.
Discussion
The Master Protocol provides (1) standardised assessment of efficacy and safety, (2) comparable collection of mechanistic data, (3) the opportunity to include adaptive designs and the use of shared control groups in the evaluation of combination therapies, and (4) benefits of greater understanding of endpoint variation to ensure more robust sample size calculations and future baseline stratification using existing and novel biomarkers.
“…Thirdly, it should also not forget that early diagnosis of stage 1 or stage 2 T1D could offer children and their families an opportunity to participate in clinical trials, with the aim of delay the clinical manifestations of the disease. There are several trials available in Europe, USA and elsewhere in the world and some drugs have shown promising results in postponing the progression to clinical T1D [ 30 ][ 31 ][ 32 ]. In individuals with a first-degree relative with T1D, one of these drugs (teplizumab, an anti-CD3 monoclonal antibodies) has shown to prolong a diabetes-free time of up to 6 years; this drug has been approved by the Food and Drug Administration (FDA) on November 2022 and it should be soon available in clinical practice.…”
In recent years screening of type 1 diabetes (T1D) in both at risk children and general population has been widely discussed with the aim of increasing awareness of the importance to early detect (and possibly treat) at-risk children in early stages of the chronic autoimmune progression to T1D.In fact, it is well known that first-degree relatives have the highest risk of T1D, but up to 90% of children who develop T1D do not have a family history and belong to the general population.The reasons for screening children well before the clinical onset of T1D include prevention of DKA (still up to 60% children are diagnosed with DKA) and related morbidities and mortality, reducing the need for hospitalisation, time to provide emotional support and education to ensure a smooth transition to insulin treatment, and opportunities for new treatments to prevent or delay progression.There are pros and cons of screening of T1D in children, but recent evidences suggest that it is now time to consider possible a screening for T1D in children.Recently, the European Society for Paediatric Endocrinology (ESPE) has endorsed a Position Statement, discussing the pros and cons of screening for T1D in the general population; ESPE supports national Societies for Paediatric Endocrinology to spread information on this important issue in various countries throughout Europe; the Italian Society for Paediatric Endocrinology and Diabetes (SIEDP-ISPED) and the Italian Society of Paediatrics (SIP) endorse this document with the specific aim of increasing awareness on screening for paediatric T1D in the general population.
“…Immunotherapies targeting T and B cells, using anti-CD3 (i.e., teplizumab and otelixizumab) ( 6 – 8 ) and anti-CD20 (i.e., rituximab) ( 9 ) monoclonal antibodies (mAbs), respectively, demonstrated acceptable safety and efficacy in maintaining functional β-cell mass, albeit temporarily, in patients with newly diagnosed type 1 diabetes. Hence, based on initial positive results, teplizumab ( 6 , 10 , 11 ), antithymocyte globulin (ATG) ( 12 – 14 ), rituximab ( 9 ), and abatacept (CTLA4-Ig fusion protein) ( 15 ) therapies are further explored in late-stage prediabetes and type 1 diabetes onset, but they still face variable therapeutic outcomes differences in treatment response on an individual basis ( 16 ). Furthermore, little information is available on their long-term potential to restore peripheral tolerance or on the type of patient who would benefit most from these therapies.…”
Immunomodulation combined with antigen therapy holds great promise to arrest autoimmune type 1 diabetes, but clinical translation is hampered by a lack of prognostic biomarkers. Lowdose anti-CD3 plus Lactococcus lactis (L. lactis) bacteria secreting proinsulin and IL-10 reversed new-onset disease in non-obese diabetic (NOD) mice, yet some mice were resistant to the therapy. Using microRNA (miRNA) profiling, six miRNAs (i.e., miR-34a-5p, miR-125a- 3p, miR-193b-3p, miR-328, miR-365-3p, and miR-671-3p) were identified as differentially expressed in plasma of responder versus non-responder mice before study entry. After validation and stratification in an independent cohort, plasma miR-193b-3p and miR-365-3p combined with age and glycemic status at study entry had the best power to predict with high sensitivity and specificity poor response to the therapy. These miRNAs were highly abundant in pancreas infiltrating neutrophils and basophils with a pro-inflammatory and activated phenotype. Here, a set of miRNAs and disease-associated parameters are presented as predictive signature for the L. lactis-based immunotherapy outcome in new-onset type 1 diabetes, hence allowing targeted recruitment of future trial participants and accelerated trial execution.
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