A Phase 2, Multicentre, Randomized, Double-blind, Placebo-controlled Study in Patients With New-onset Type 1 Diabetes
Condition: Diabetes Mellitus, Insulin-Dependent
MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 1
Study type: Interventional
Phase: Phase 2

Summary: 
      The objective of this clinical trial is to investigate whether ladarixin has sufficient
      activity (preservation of β-cell function and slow-down of the progression of T1D) to warrant
      its further development (proof of concept trial). The safety of ladarixin in the specific
      clinical setting will be also evaluated.

      The study is a phase 2, multicentre, double-blind study. 72 patients with new-onset type 1
      diabetes (T1D) were planned to be involved, 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).

      Recruitment was competitive among the study sites, until the planned number of patients was
      enrolled. A total of 76 patients were actually recruited.
    

Detailed description: 
      T1D is an organ-specific autoimmune disease in which the immune system attacks the
      insulin-producing β-cells. The onset of the disease typically occurs before adulthood and
      seriously affects a person's quality of life.

      T1D is treated with life-long daily exogenous insulin injections and monitoring of blood
      glucose levels. However, even optimization of glucose control through the most recent
      technologies cannot adequately substitute for the finely tuned normal balance of the glucose
      levels. Therefore, despite marked improvements in diabetes care in recent years,
      insulin-dependent diabetes results in secondary long-term complications and is one of the
      leading causes of end-stage renal disease, blindness and amputation. Additionally,
      hypoglycaemia unawareness is a serious consequence of recurrent hypoglycaemia often requiring
      emergency care.

      Maintenance of residual β-cell function (as measured by C-peptide response) was demonstrated
      to be associated with reduced rate of microvascular complications and hypoglycaemia, improved
      quality of life, and overall reduction in morbidity and associated management costs.
      Therefore, pharmacological approaches aimed at controlling the autoimmune response and
      restoring self-tolerance to pancreatic β-cells had attracted the clinical/scientific
      interest.

      Among these, rituximab, CD3-specific monoclonal antibodies, GAD65, DiaPep277 have progressed
      to phase III clinical trials. Other agents, including cytokines modulators such as anti-TNF
      or anti-IL1, are under clinical evaluation. Unfortunately, even if safe preservation of
      β-cell function and improvement of glycaemic control have been evidenced for some of the
      pharmacological approaches evaluated so far, none has been definitely approved for the
      "treatment" of diabetes onset. New strategies are being evaluated which combine agents
      targeting sequential arms of the immune and inflammatory response involved in β-cell
      disruption. In this regard, IL-8 appears to be an important mediator in the progression of
      type 1 diabetes. Production and secretion of pro-inflammatory IL-8 has been demonstrated from
      human pancreatic islets upon enterovirus infections, and LPS-induced production of IL-8 by
      neutrophils is increased in type 1 pre-diabetic and diabetic patients. In parallel,
      circulating levels of IL-8 were elevated in children with T1D compared to non-diabetic
      controls. Specifically, levels of IL-8 correlate with glycaemic control, higher level being
      associated to poorer or unfavorable glucose control.

      As a result of these findings, the modulation or inhibition of IL8 activity is considered a
      valid target for the development of innovative treatments aimed to control the progression of
      T1D.

      Results obtained with ladarixin in mouse models of T1D, and particularly reversal of
      "diabetes" in the NOD mice, clearly showed the ability of this CXCR1/2 inhibitor to protect
      β-cells and either prevent or delay the progression of hyperglycaemia. The positive effects
      of ladarixin, coupled with the safety shown in phase 1 studies, provided a sound rationale
      for a clinical study aimed at evaluating the effect of ladarixin in patients with new onset
      diabetes and supported the conduct of the present study.
    

Intervention name(s): Ladarixin; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): Ladarixin oral capsule; Placebo oral capsule
Other intervention name(s): Active treatment; Placebo treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment
Keywords: Diabetes mellitus Type 1; Beta cells function