DFMO in Children With Type 1 Diabetes
Condition: Type 1 Diabetes
MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 1
Study type: Interventional
Phase: Phase 1

Summary: 
      This study is a multicenter, double-blind, placebo-controlled, 2:1 randomly assigned, phase 1
      clinical trial for individuals with type 1 diabetes. It is a blinded dose-ranging study
      enrolling patients with new onset type 1 diabetes with documented continued residual
      C-peptide production. After a 4 week screening and run-in period during which eligibility
      will be determined and glycemic control optimized, subjects will have a 3-month double-masked
      treatment period with either DFMO or placebo. After a 3 month wash-out period the durability
      of effect will be assessed. Subjects will be randomly assigned (6 to DFMO; 3 to placebo in
      each cohort) to 1 of 4 sequential dose cohorts.
    

Detailed description: 
      This study is repurposing alpha difluoromethylornithine (DFMO) in order to characterize its
      effects in persons with new onset type 1 diabetes. In preliminary studies in mice, inhibition
      of polyamine synthesis with DFMO preserved β-cell insulin production and delayed diabetes
      onset. Polyamine modulation has the potential to improve β cell health in persons with T1D.
      The investigators propose that decreasing polyamine synthesis in persons with new onset T1D
      will improve markers of ß cell health and function.

      This double-masked, placebo-controlled dose-finding randomized multiple ascending dose study
      will include a 1-month screening period; a 3-month double-masked treatment period; and a
      3-month follow-up period. Subjects will be randomly assigned to 1 of 4 sequential dose
      cohorts: DFMO at nominal (starting) doses of 125 mg/m2 per day, 250 mg/m2 per day, 500 mg/m2
      per day, and then 750 mg/m2 per day. Dose escalation will be done based upon whether any dose
      limiting toxicities are observed and whether any suggestion of effect on biomarkers of β-cell
      stress is observed. At a maximum dose, the cohort will be expanded in order to estimate
      biomarker activity. If there is no suggestion of effect and no dose-limiting toxicity 750
      mg/m2 per day, a 750 mg per day group will be enrolled. Regardless of the dose we expand, the
      investigators will evaluate efficacy of treatment on the primary and secondary outcomes. The
      primary outcome endpoint in this study will be the safety of the doses. In particular, the
      dose-limiting toxicities known to be potential side effects of DFMO (thrombocytopenia,
      neutropenia, anemia, audiometric impairment) will be reviewed and monitored by an internal
      safety review committee before each cohort is enrolled. Secondary outcomes will include
      biomarkers of beta cell stress, measures of insulin production/glycemia. Exploratory outcomes
      will include flow cytometry assessment of B- and T-cell subsets, quantification of polyamine
      intake and excretion, and pharmacokinetic DFMO concentrations. Completion of this study will
      facilitate future work in studies of DFMO or other inhibitors of pathways that influence
      intracellular polyamine levels, including non-steroidal inflammatory agents, and novel
      polyamine transport inhibitors. .
    

Intervention name(s): Difluoromethylornithine; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): Active Therapy with DFMO; Placebo Comparitor
Other intervention name(s): DFMO; Comparitor
Intervention MeSH terms: Eflornithine
Allocation: Randomized
Intervention model: Single Group Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Treatment