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
Intervention: Ladarixin; Placebo
Intervention description: Ladarixin oral capsule; Placebo oral capsule
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 76.0
Sex: All
Minimum age: 18 Years
Maximum age: 45 Years
Healthy volunteers: No
Keywords: Diabetes mellitus Type 1; Beta cells function

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.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Male and female patients aged 18-45 years, inclusive;

          2. New-onset T1D (randomization within 100 days from 1st insulin administration);

          3. Positive for at least one diabetes-related auto-antibody (anti-GAD; IAA, if obtained
             within 10 days of the onset of insulin therapy; IA-2 antibody; ZnT8);

          4. Require, or has required at some time, insulin, with the exclusion of patients taking
             twice daily pre-mixed insulin or on insulin pump;

          5. Residual β-cell function as per peak stimulated (MMTT) C-peptide level >0.6ng/mL
             (0.2nmol/L); MMTT should not be performed within one week of resolution of a diabetic
             ketoacidosis event;

          6. Patient able to comply with all protocol procedures for the duration of the study,
             including scheduled follow-up visits and examinations;

          7. Patients who have given written informed consent prior of any study-related procedure
             not part of standard medical care.

        Exclusion Criteria:

          1. Patients taking twice daily pre-mixed insulin or on insulin pump;

          2. Any other chronic disease, including type 2 diabetes, apart from autoimmune
             hypothyroidism requiring thyroid hormone replacement only; patients with severe
             (myxedema) disease potentially requiring immunosuppressive therapy will be excluded;

          3. Moderate to severe renal impairment as per calculated creatinine clearance (CLcr) < 60
             mL/min according to the Cockcroft-Gault formula (Cockcroft-Gault, 1976);

          4. Hepatic dysfunction defined by increased ALT/AST > 3 x upper limit of normal (ULN) and
             increased total bilirubin > 3 mg/dL [>51.3 μmol/L];

          5. Hypoalbuminemia defined as serum albumin < 3 g/dL;

          6. QTcF > 470 msec;

          7. Complete Left Bundle Branch Block (LBBB), atrio-ventricular block (mobitz II 2nd
             degree or 2:1 atrio-ventricular block), complete heart block;

          8. Electronic pacemaker positioned or implanted defibrillator;

          9. History of significant cardiovascular disease;

         10. Known hypersensitivity to non-steroidal antiinflammatory drugs;

         11. Concomitant treatment with phenytoin, warfarin, sulphanylurea hypoglycemics (e.g.
             tolbutamide, glipizide, glibenclamide/glyburide, glimepiride, nateglinide) and high
             dose of amitriptyline (> 50 mg/day);

         12. Previous (within 2 weeks prior to randomization) and concomitant treatment with
             metformin, sulfonylureas, glinides, thiazolidinediones, exenatide, liraglutide, DPP-IV
             inhibitors or amylin, or any medications known to influence glucose tolerance (e.g.
             β-blockers, angiotensin-converting enzyme inhibitors, interferons, quinidine
             antimalarial drugs, lithium, niacin, etc.);

         13. Past (within 1 month prior to randomization) or current administration of any
             immunosuppressive medications (including oral, inhaled or systemically injected
             steroids) and use of any investigational agents, including any agents that impact the
             immune response or the cytokine system;

         14. Pregnant or breast feeding women. Unwillingness to use effective contraceptive
             measures up to 2 months after the end of study drug administration (females and
             males). Effective contraceptive measures include an hormonal birth control (e.g. oral
             pills, long term injections, vaginal ring, patch); the intrauterine device (IUD); a
             double barrier method (e.g. condom or diaphragm plus spermicide foam).