DFMO in Children With Type 1 Diabetes

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.

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. .

Eligibility Criteria:
Inclusion Criteria:

1. Males and females 12-40 years of age with a clinical diagnosis of T1D within 2 - 8 months after diagnosis at the time of visit 2.
2. Random non-fasting C-peptide level of \>0.2 pmol/mL at visit 1.
3. Positive for any one of the following diabetes-related autoantibodies (mIAA, GADA, IA-2A, or ZnT8A)
4. Treatment naïve of any immunomodulatory agent
5. Normal hearing at screening, defined as acceptable results of pure-tone audiometry (\<20 decibel \[dB\] baseline thresholds for frequencies 250, 500, 1000, and 2000 Hz

Exclusion Criteria:

1. Presence of severe, active disease that interferes with dietary intake or requires the use of chronic medication, with the exception of well-controlled hypothyroidism and mild asthma not requiring oral steroids. Presence of any psychiatric disorder that will affect ability to participate in study.
2. Diabetes other than T1D
3. Chronic illness known to affect glucose metabolism (e.g. Cushing syndrome, polycystic ovarian disorder, cystic fibrosis) or taking medications that affect glucose metabolism (e.g. steroids, metformin)
4. Inability to swallow pills
5. Psychiatric impairment or current use of anti-psychotic medication
6. Any condition that, in the investigator's opinion, may compromise study participation or may confound the interpretation of the study results.
7. Hematologic abnormalities at screening (anemia, leukopenia (particularly neutropenia), or thrombocytopenia)
8. Impaired renal function (assessed by history and BUN/Creatinine, DFMO is renally excreted)
9. Female participants of child-bearing age must not be pregnant and agree to use an effective form of birth control or be abstinent during the study period.
10. BMI \>95% for age and sex