DFMO in Children With Type 1 Diabetes

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. .

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