TArgeting Type 1 Diabetes Using POLyamines (TADPOL)

• Sponsor: Emily K. Sims (Other)
• Overall Status: Not yet recruiting
• CT.gov ID: NCT05594563
• Collaborator: Juvenile Diabetes Research Foundation (Other), Cancer Prevention Pharmaceuticals, Inc. (Industry)
• Enrollment: 70
• Locations: 6
• Arms: 2
• Anticipated Duration (Months): 60
• Patients Per Site: 11.7
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Type 1 Diabetes	Drug: DFMO; Drug: Placebo	Phase 2

Detailed Description

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.

Study Design

• Study Type: Interventional
• Anticipated Enrollment: 70 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Subject are randomized to either treatment or placebo arm.Subject are randomized to either treatment or placebo arm.
• Masking: Triple (Participant, Care Provider, Investigator)
• Masking Description: Participant, Care provider and Investigator blinded
• Primary Purpose: Treatment
• Official Title: 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
• Anticipated Study Start Date: Dec 1, 2022
• Anticipated Primary Completion Date: Dec 1, 2026
• Anticipated Study Completion Date: Dec 1, 2027

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Treatment Arm Difluoromethylornithine (DFMO) pill ,1000mg/m2/day, for 6 months	Drug: DFMO; DFMO orally twice a day; Other Names: Difluoromethylornithine
Placebo Comparator: Placebo Arm Placebo pill taken twice a day orally for 6 months	Drug: Placebo; Placebo orally twice a day

Outcome Measures

Primary Outcome Measures

1. Clinical efficacy of 1000 mg/m2/day of oral DFMO after 6 months of treatment [6 month]

   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

2. Number of participants with treatment-related adverse events as assessed by CTCAE v5 [through study completion, an average of one year]

   A summary of serious and non-serious adverse events (AEs) will be reported.

Secondary Outcome Measures

1. 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). [through study completion, an average of one year]

   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.

2. Decrease in urinary polyamides after 6 months of DFMO treatment. [up to 24 weeks after treatment]

   Decrease in urinary putrescine (in umol/g Cr) from baseline after 6 months of DFMO treatment, measured using high performance liquid chromatography.

3. Biomarkers of β cell stress at 3, 6, 9, and 12 months after treatment. [through study completion, an average of one year]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 6 Years to 40 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Males and females 6- ≥40 years of age with a clinical diagnosis of T1D

2. T1D clinical diagnosis with insulin start date no more than 100 days prior to the time of randomization

3. Random non-fasting C-peptide level of >0.2 pmol/mL (equivalent to >0.6ng/ml) at screening.

4. Positive for any one of the following diabetes-related autoantibodies (IAA, GAA, IA-2, or ZnT8)

5. Treatment naïve of any immunomodulatory agent

6. 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. Allergy to milk or soy (components of Boost® drink used for mixed meal tolerance testing)

10. 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)

11. 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Barbara Davis Center	Aurora	Colorado	United States	80045
2	University of Chicago	Chicago	Illinois	United States	60637
3	IU Health Riley Hospital for Children	Indianapolis	Indiana	United States	46202
4	Children's Mercy Hospital	Kansas City	Kansas	United States	64108
5	University of Michigan	Ann Arbor	Michigan	United States	48109
6	Medical College of Wisconsin	Milwaukee	Wisconsin	United States	53226

Sponsors and Collaborators

• Emily K. Sims
• Juvenile Diabetes Research Foundation
• Cancer Prevention Pharmaceuticals, Inc.

Investigators

• Study Chair: Emily K Sims, MD,MS, Indiana University School of Medicine

Study Documents (Full-Text)

None provided.

More Information

Publications

• Bardocz S, Duguid TJ, Brown DS, Grant G, Pusztai A, White A, Ralph A. The importance of dietary polyamines in cell regeneration and growth. Br J Nutr. 1995 Jun;73(6):819-28. doi: 10.1079/bjn19950087.
• Brooks WH. Autoimmune diseases and polyamines. Clin Rev Allergy Immunol. 2012 Feb;42(1):58-70. doi: 10.1007/s12016-011-8290-y.
• Jeter JM, Alberts DS. Difluoromethylornithine: the proof is in the polyamines. Cancer Prev Res (Phila). 2012 Dec;5(12):1341-4. doi: 10.1158/1940-6207.CAPR-12-0429.
• Maier B, Tersey SA, Mirmira RG. Hypusine: a new target for therapeutic intervention in diabetic inflammation. Discov Med. 2010 Jul;10(50):18-23.
• McCann PP, Pegg AE. Ornithine decarboxylase as an enzyme target for therapy. Pharmacol Ther. 1992;54(2):195-215. doi: 10.1016/0163-7258(92)90032-u.
• Renaudineau Y, Youinou P. Epigenetics and autoimmunity, with special emphasis on methylation. Keio J Med. 2011;60(1):10-6. doi: 10.2302/kjm.60.10.
• Seiler N. Catabolism of polyamines. Amino Acids. 2004 Jun;26(3):217-33. doi: 10.1007/s00726-004-0070-z. Epub 2004 Apr 20.

• Responsible Party: Emily K. Sims, Associate Professor of Pediatrics, Indiana University School of Medicine
• ClinicalTrials.gov Identifier: NCT05594563
• Other Study ID Numbers: 4-SRA-2022-1205-M-B
• First Posted: Oct 26, 2022
• Last Update Posted: Oct 26, 2022
• Last Verified: Oct 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 1; Eflornithine

Study Results

No Results Posted as of Oct 26, 2022