TArgeting Type 1 Diabetes Using POLyamines (TADPOL)

Study Overview
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Brief Summary
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The goal of this clinical trial is to test a drug known as DFMO in people with Type 1 Diabetes (T1D). The main question[s] it aims to answer are: Does it reduce stress on the cells that make insulin? Does it preserve what is left of the body's insulin production? Participants will take either DFMO or a placebo (looks like DFMO but has no active ingredients) two times a day for about 6 months. Participants will have 6 in person visits and 1 phone visit over a period of 12 months. Visits will include blood draws urine collection and other tests.

Detailed Description
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This study will be a multicenter, double-blind, placebo-controlled, 2:1 random assigned, phase II clinical trial for individuals with recent onset type 1 diabetes. The investigators are conducting a double masked placebo-controlled intention to treat study enrolling persons with new onset T1D with documented continued residual C-peptide production. Within 45 days of screening and a run-in period during which eligibility will be determined and glycemic control optimized, subjects will have a 6-month double-masked treatment period with either DFMO or placebo. After a 6-month wash-out period the durability of effect will be assessed. Subjects will be randomly assigned either 1000mg/m2/day oral DFMO or placebo treatment at a 2:1 ratio.

Official Title
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TArgeting Type 1 Diabetes Using POLyamines (TADPOL): A Randomized, Double-Masked, Placebo-Controlled Phase 2 Study to Evaluate the Efficacy and Safety of Difluoromethylornithine (DFMO) to Preserve Insulin Production in Type 1 Diabetes

Conditions
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Type 1 Diabetes

Intervention / Treatment
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* Drug: DFMO
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males and females 6- ≥40 years of age with a clinical diagnosis of T1D T1D clinical diagnosis with insulin start date no more than 100 days prior to the time of randomization Random non-fasting C-peptide level of >0.2 pmol/mL (equivalent to >0.6ng/ml) at screening. Positive for any one of the following diabetes-related autoantibodies (IAA, GAA, IA-2, or ZnT8) Treatment naïve of any immunomodulatory agent 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: 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. Diabetes other than T1D 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) Inability to swallow pills Psychiatric impairment or current use of anti-psychotic medication Any condition that, in the investigator's opinion, may compromise study participation or may confound the interpretation of the study results. Hematologic abnormalities at screening (anemia, leukopenia (particularly neutropenia), or thrombocytopenia) Impaired renal function (assessed by history and BUN/Creatinine, DFMO is renally excreted) Allergy to milk or soy (components of Boost® drink used for mixed meal tolerance testing) Female participants of child-bearing age with reproductive potential, must not be pregnant and agree to use 2 effective forms of birth control or be abstinent during the study period (see below) Active seizure disorder, defined as requiring chronic medication at the time of study or having had a seizure within the past 12 months at the time of screening

Ages Eligible for Study
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Minimum Age: 6 Years
Maximum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Subject are randomized to either treatment or placebo arm.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Treatment Arm<br>Difluoromethylornithine (DFMO) pill ,1000mg/m2/day, for 6 months | Drug: DFMO<br>* DFMO orally twice a day<br>* Other names: Difluoromethylornithine;|
| Placebo Comparator: Placebo Arm<br>Placebo pill taken twice a day orally for 6 months | Drug: Placebo<br>* Placebo orally twice a day<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical efficacy of 1000 mg/m2/day of oral DFMO after 6 months of treatment | Primary endpoint defining clinical efficacy will be based on mixed-meal stimulated C-peptide area under the curve (AUC; in arbitrary units) in the treatment group compared to placebo after 6 months of DFMO treatment | 6 month | 
| Number of participants with treatment-related adverse events as assessed by CTCAE v5 | A summary of serious and non-serious adverse events (AEs) will be reported. | through study completion, an average of one year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical efficacy of 1000 mg/m2/day of oral DFMO after 3 months of treatment, 9 months after treatment (or 3 months after treatment end), and 12 months after treatment (or 6 months after treatment end). | Secondary endpoints will be based on mixed meal stimulated C-peptide AUC (arbitrary units) at 3 months after treatment, 9 months after treatment, and 12 months after treatment. | through study completion, an average of one year | 
| Decrease in urinary polyamides after 6 months of DFMO treatment. | Decrease in urinary putrescine (in umol/g Cr) from baseline after 6 months of DFMO treatment, measured using high performance liquid chromatography. | up to 24 weeks after treatment | 
| Biomarkers of β cell stress at 3, 6, 9, and 12 months after treatment. | Fasting and stimulated proinsulin/c-peptide ratios (%) will be measured using immunoassays and reported at baseline, 3 months after treatment, 6 months after treatment, 9 months after treatment, and 12 months after treatment. | through study completion, an average of one year |