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aLD‐SCs/CB‐MSCs + G‐CSF Insulin requirement at 1 month NCT02354911 A Randomized, Double‐Blind, Placebo‐Controlled, Cross‐Over Study of the Safety and Efficacy of Autologous Immunoregulatory Dendritic Cells in Patients With Type 1 Diabetes Immunoregulatory Dendritic Cells MMTT C‐peptide at 12 and 24 months NCT02624804 A Pilot Study of the Therapeutic Potential of Stem Cell Educator Therapy in Type 1 Diabetes Stem Cell Educator Therapy Safety at 12 months NCT02846545 T1GER Golimumab MMTT C‐peptide at 12 months NCT03011021 Safety and Efficacy of Umbilical Cord Blood Regulatory T Cells Plus Liraglutide on Autoimmune Diabetes UCB ‐ Tregs + Liraglutide Safety at 24 months NCT02932826 Safety Study and Therapeutic Effects of Umbilical Cord Blood Treg Cells on Autoimmune Diabetes UCB ‐ Tregs Safety at 24 months NCT02384889 Targeting Polyamines Using DFMO in Persons with Type 1 Diabetes: A Randomized, Double‐Masked, Placebo‐Controlled Phase I Study to Evaluate the Safety, Tolerability, and Initial Pharmacodynamics of Multiple Ascending Doses Difluoromethylornithine Safety with dose escalation at 6 months NCT03046927 Vitamin D and Residual Beta‐Cell Function in Type 1 Diabetes Ergocalciferol MMTT C‐peptide at 12 months NCT01773707 CTLA4‐Ig (Abatacept)for Prevention of Abnormal Glucose Tolerance and Diabetes in Relatives At ‐Risk for Type 1 Abatacept Abnormal glucose tolerance NCT03298542 A Phase 1b Study to Evaluate SIMPONI (Golimumab) Therapy in Children, Adolescents and Young Adults With Pre‐Symptomatic Type 1 Diabetes Golimumab Safety at 26, 52, and 78 weeks NCT03182426 Autologous Hematopoietic Stem Cell Mobilization (Plerixafor) and Immunologic Reset in New Onset Type 1 Diabetes Mellitus Alemtuzumab + anakinra + etanercept + liraglutide + plerixafor Safety and MMTT C‐peptide at 3, 6, 9, 12, 18, and 24 months NCT02772679 TILT Tregs + IL‐2 Safety and Treg proportion at 3 years NCT02804165 Gene‐virus Interactions Implicated in Type 1 Diabetes Enterovirus vaccination T1D diagnosis NCT03243058 A Randomized, Double Blind, Phase I/II Trial of Low‐Dose Interlekin‐2 Immunotherapy in Established Type 1 Diabetes Proleukin (IL‐2) MMTT C‐peptide at 12 months NCT02081326 Repeat BCG Vaccinations for the Treatment of Established Type 1 Diabetes BCG HbA1C at 1,2,3,4 and 5 years EudraCT: 2014‐004319‐35 TregVac2.0 Tregs + anti‐CD20 antibody (Phase II Trial assessing expanded polytTregs in patients with recent onset Type 1 diabetes mellitus) EudraCT 2014‐004760‐37 Incretin‐based therapy in non‐symptomatic, early diagnosed Type 1 Diabetics Liraglutide MMTT C‐peptide at 3, 6, 9, and 12 months

      Pro‐inflammatory cytokine‐based treatments have proven to be safe and effective for treatment of various autoimmune diseases. Thus, inhibition of expression of those molecules can induce important changes in pancreatic β‐cells induce important changes in pancreatic β‐cells [51].

      The aim of using the Anti‐Interleukin‐1 in newly diagnosed T1D subjects is to test the feasibility, safety/tolerability and potential efficacy of anti‐IL‐1 therapy in maintaining or enhancing β‐cell function in people with new onset T1D. Anti‐IL‐1 administration for rheumatoid arthritis has been proven to be well tolerated in patients [52, 53]. IL‐1 is also involved in T1D progression by activating T‐helper cells and improving the number of circulating memory T‐cells [54]. The active substance is interleukin‐1 receptor antagonist, a blocker of an immune‐signal molecule named interleukin‐1. Two randomized placebo‐controlled trials aimed to assess whether canakinumab, a human monoclonal anti‐interleukin‐1 antibody, or anakinra, a human interleukin‐1 receptor antagonist, improved β‐cell function in recent‐onset T1D, but their effectiveness was not demonstrated [54, 55].

      More recently, the ongoing clinical trial EXTEND (Clinical trial NCT02293837; www.clinicaltrials.gov) is currently examining whether the blockade of IL‐6 signaling through tocilizumab, an anti‐IL‐6 receptor antibody, can induce a protection of β‐cell function in T1D patients (ages 6 to 17 years) (Table 2.3).

      Interleukin‐8 appears to be another important mediator in the progression of T1D. Circulating levels of IL‐8 are elevated in children with T1D compared to non‐diabetic controls. Furthermore, levels of IL‐8 correlate with glycemic control, higher level being associated to poorer glucose control. As a result, the modulation or inhibition of IL8 activity may be a valid target for the development of novel treatments aimed to control the progression of T1D.

      A multicenter, randomized, double‐blind, placebo‐controlled phase 2 trial of CXCR1/2 IL‐8 inhibitor (Ladarixin) has just presented its results at the American Diabetes Association's (ADA) 80th Scientific Sessions (Clinical trial NCT02814838; www.clinicaltrials.gov). The trial involved 76 patients with new‐onset T1D, randomly (2:1) assigned to receive either Ladarixin treatment (400 mg b.i.d. for 3 cycles of 14 days on/14 days off – treatment group) or placebo (control group). Although results indicated no statistically significant differences in stimulated C‐peptide at weeks 13 and 26, investigators noted 76.6% of patients receiving Ladarixin had an HbA1c below 7% and a daily insulin requirement of less than 0.50 IU/kg compared to just 45.8% of patients receiving placebo. Furthermore, in a prespecified subgroup analysis of patients with fasting C‐peptide below the median value of the trial population at baseline, MMTT AUC of C‐peptide trended at week 13 and reached statistical significance at week 26.

       Incretin‐based Therapies

      Recent knowledge regarding the heterogeneity in the extent of the β‐cell impairment and pancreatic lesions

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