drugset / Trial / NCT05594563
TArgeting Type 1 Diabetes Using POLyamines (TADPOL)
Phase 2
Active not recruiting
81 enrolled
Emily K. Sims
Cancer Prevention Pharmaceuticals, Inc. · collabJuvenile Diabetes Research Foundation · collab
RandomizedParallel-groupTriple-blindTreatment
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.
Timeline
- Start
- 2023-03-14
- Primary completion
- 2027-12
- Completion
- 2028-05
Publications
- Background Brooks WH. Autoimmune diseases and polyamines. Clin Rev Allergy Immunol. 2012 Feb;42(1):58-70. doi: 10.1007/s12016-011-8290-y.
- Background Seiler N. Catabolism of polyamines. Amino Acids. 2004 Jun;26(3):217-33. doi: 10.1007/s00726-004-0070-z. Epub 2004 Apr 20.
- Background 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.
- Background Maier B, Tersey SA, Mirmira RG. Hypusine: a new target for therapeutic intervention in diabetic inflammation. Discov Med. 2010 Jul;10(50):18-23.
- Background 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.
- Background 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.
- Background 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.
- Results Hong SK, Chaturvedi R, Piazuelo MB, Coburn LA, Williams CS, Delgado AG, Casero RA Jr, Schwartz DA, Wilson KT. Increased expression and cellular localization of spermine oxidase in ulcerative colitis and relationship to disease activity. Inflamm Bowel Dis. 2010 Sep;16(9):1557-66. doi: 10.1002/ibd.21224.
- Results Maier B, Ogihara T, Trace AP, Tersey SA, Robbins RD, Chakrabarti SK, Nunemaker CS, Stull ND, Taylor CA, Thompson JE, Dondero RS, Lewis EC, Dinarello CA, Nadler JL, Mirmira RG. The unique hypusine modification of eIF5A promotes islet beta cell inflammation and dysfunction in mice. J Clin Invest. 2010 Jun;120(6):2156-70. doi: 10.1172/JCI38924. Epub 2010 May 24.
- Results Templin AT, Maier B, Nishiki Y, Tersey SA, Mirmira RG. Deoxyhypusine synthase haploinsufficiency attenuates acute cytokine signaling. Cell Cycle. 2011 Apr 1;10(7):1043-9. doi: 10.4161/cc.10.7.15206. Epub 2011 Apr 1.
- Results Bjelakovic G, Beninati S, Bjelakovic B, Sokolovic D, Jevtovic T, Stojanovic I, Rossi S, Tabolacci C, Kocic G, Pavlovic D, Saranac Lj, Zivic S. Does polyamine oxidase activity influence the oxidative metabolism of children who suffer of diabetes mellitus? Mol Cell Biochem. 2010 Aug;341(1-2):79-85. doi: 10.1007/s11010-010-0439-0. Epub 2010 Apr 20.
- Results Nishiki Y, Adewola A, Hatanaka M, Templin AT, Maier B, Mirmira RG. Translational control of inducible nitric oxide synthase by p38 MAPK in islet beta-cells. Mol Endocrinol. 2013 Feb;27(2):336-49. doi: 10.1210/me.2012-1230. Epub 2012 Dec 18.
- Results Higashi K, Yoshida M, Igarashi A, Ito K, Wada Y, Murakami S, Kobayashi D, Nakano M, Sohda M, Nakajima T, Narita I, Toida T, Kashiwagi K, Igarashi K. Intense correlation between protein-conjugated acrolein and primary Sjogren's syndrome. Clin Chim Acta. 2010 Mar;411(5-6):359-63. doi: 10.1016/j.cca.2009.11.032. Epub 2009 Dec 5.
- Results Furumitsu Y, Yukioka K, Kojima A, Yukioka M, Shichikawa K, Ochi T, Matsui-Yuasa I, Otani S, Nishizawa Y, Morii H. Levels of urinary polyamines in patients with rheumatoid arthritis. J Rheumatol. 1993 Oct;20(10):1661-5.
- Results Furumitsu Y, Yukioka K, Yukioka M, Ochi T, Morishima Y, Matsui-Yuasa I, Otani S, Inaba M, Nishizawa Y, Morii H. Interleukin-1beta induces elevation of spermidine/spermine N1-acetyltransferase activity and an increase in the amount of putrescine in synovial adherent cells from patients with rheumatoid arthritis. J Rheumatol. 2000 Jun;27(6):1352-7.
- Results Zoumas-Morse C, Rock CL, Quintana EL, Neuhouser ML, Gerner EW, Meyskens FL Jr. Development of a polyamine database for assessing dietary intake. J Am Diet Assoc. 2007 Jun;107(6):1024-7. doi: 10.1016/j.jada.2007.03.012.
- Results Milovic V. Polyamines in the gut lumen: bioavailability and biodistribution. Eur J Gastroenterol Hepatol. 2001 Sep;13(9):1021-5. doi: 10.1097/00042737-200109000-00004.
- Results Soda K, Kano Y, Sakuragi M, Takao K, Lefor A, Konishi F. Long-term oral polyamine intake increases blood polyamine concentrations. J Nutr Sci Vitaminol (Tokyo). 2009 Aug;55(4):361-6. doi: 10.3177/jnsv.55.361.
- Results Sjoholm A, Arkhammar P, Berggren PO, Andersson A. Polyamines in pancreatic islets of obese-hyperglycemic (ob/ob) mice of different ages. Am J Physiol Cell Physiol. 2001 Feb;280(2):C317-23. doi: 10.1152/ajpcell.2001.280.2.C317.
- Results Sjoholm A, Arkhammar P, Welsh N, Bokvist K, Rorsman P, Hallberg A, Nilsson T, Welsh M, Berggren PO. Enhanced stimulus-secretion coupling in polyamine-depleted rat insulinoma cells. An effect involving increased cytoplasmic Ca2+, inositol phosphate generation, and phorbol ester sensitivity. J Clin Invest. 1993 Oct;92(4):1910-7. doi: 10.1172/JCI116784.
- Results Roy UK, Rial NS, Kachel KL, Gerner EW. Activated K-RAS increases polyamine uptake in human colon cancer cells through modulation of caveolar endocytosis. Mol Carcinog. 2008 Jul;47(7):538-53. doi: 10.1002/mc.20414.
- Results Belting M, Mani K, Jonsson M, Cheng F, Sandgren S, Jonsson S, Ding K, Delcros JG, Fransson LA. Glypican-1 is a vehicle for polyamine uptake in mammalian cells: a pivital role for nitrosothiol-derived nitric oxide. J Biol Chem. 2003 Nov 21;278(47):47181-9. doi: 10.1074/jbc.M308325200. Epub 2003 Sep 11.
- Results Belting M, Persson S, Fransson LA. Proteoglycan involvement in polyamine uptake. Biochem J. 1999 Mar 1;338 ( Pt 2)(Pt 2):317-23.
- Results Welch JE, Bengtson P, Svensson K, Wittrup A, Jenniskens GJ, Ten Dam GB, Van Kuppevelt TH, Belting M. Single chain fragment anti-heparan sulfate antibody targets the polyamine transport system and attenuates polyamine-dependent cell proliferation. Int J Oncol. 2008 Apr;32(4):749-56.
- Results Nevins AK, Thurmond DC. Caveolin-1 functions as a novel Cdc42 guanine nucleotide dissociation inhibitor in pancreatic beta-cells. J Biol Chem. 2006 Jul 14;281(28):18961-72. doi: 10.1074/jbc.M603604200. Epub 2006 May 19.
- Results Park MH, Nishimura K, Zanelli CF, Valentini SR. Functional significance of eIF5A and its hypusine modification in eukaryotes. Amino Acids. 2010 Feb;38(2):491-500. doi: 10.1007/s00726-009-0408-7. Epub 2009 Dec 8.
- Results Robbins RD, Tersey SA, Ogihara T, Gupta D, Farb TB, Ficorilli J, Bokvist K, Maier B, Mirmira RG. Inhibition of deoxyhypusine synthase enhances islet beta cell function and survival in the setting of endoplasmic reticulum stress and type 2 diabetes. J Biol Chem. 2010 Dec 17;285(51):39943-52. doi: 10.1074/jbc.M110.170142. Epub 2010 Oct 18.
- Results Packham G, Cleveland JL. The role of ornithine decarboxylase in c-Myc-induced apoptosis. Curr Top Microbiol Immunol. 1995;194:283-90. doi: 10.1007/978-3-642-79275-5_33.
- Results Tersey SA, Nishiki Y, Templin AT, Cabrera SM, Stull ND, Colvin SC, Evans-Molina C, Rickus JL, Maier B, Mirmira RG. Islet beta-cell endoplasmic reticulum stress precedes the onset of type 1 diabetes in the nonobese diabetic mouse model. Diabetes. 2012 Apr;61(4):818-27. doi: 10.2337/db11-1293.
- Results Watkins RA, Evans-Molina C, Terrell JK, Day KH, Guindon L, Restrepo IA, Mirmira RG, Blum JS, DiMeglio LA. Proinsulin and heat shock protein 90 as biomarkers of beta-cell stress in the early period after onset of type 1 diabetes. Transl Res. 2016 Feb;168:96-106.e1. doi: 10.1016/j.trsl.2015.08.010. Epub 2015 Sep 4.
- Results Soda K, Kano Y, Nakamura T, Kasono K, Kawakami M, Konishi F. Spermine, a natural polyamine, suppresses LFA-1 expression on human lymphocyte. J Immunol. 2005 Jul 1;175(1):237-45. doi: 10.4049/jimmunol.175.1.237.
- Results Hsu HC, Thomas T, Sigal LH, Thomas TJ. Polyamine-fas interactions: inhibition of polyamine biosynthesis in MRL-lpr/lpr mice is associated with the up-regulation of fas mRNA in thymocytes. Autoimmunity. 1999;29(4):299-309. doi: 10.3109/08916939908994750.
- Results Abeloff MD, Slavik M, Luk GD, Griffin CA, Hermann J, Blanc O, Sjoerdsma A, Baylin SB. Phase I trial and pharmacokinetic studies of alpha-difluoromethylornithine--an inhibitor of polyamine biosynthesis. J Clin Oncol. 1984 Feb;2(2):124-30. doi: 10.1200/JCO.1984.2.2.124.
- Results Pepin J, Milord F, Guern C, Schechter PJ. Difluoromethylornithine for arseno-resistant Trypanosoma brucei gambiense sleeping sickness. Lancet. 1987 Dec 19;2(8573):1431-3. doi: 10.1016/s0140-6736(87)91131-7.
- Results Wolf JE Jr, Shander D, Huber F, Jackson J, Lin CS, Mathes BM, Schrode K; Eflornithine HCl Study Group. Randomized, double-blind clinical evaluation of the efficacy and safety of topical eflornithine HCl 13.9% cream in the treatment of women with facial hair. Int J Dermatol. 2007 Jan;46(1):94-8. doi: 10.1111/j.1365-4632.2006.03079.x. No abstract available.
- Results Gerner EW, Meyskens FL Jr. Combination chemoprevention for colon cancer targeting polyamine synthesis and inflammation. Clin Cancer Res. 2009 Feb 1;15(3):758-61. doi: 10.1158/1078-0432.CCR-08-2235.
- Results Lewis EC, Kraveka JM, Ferguson W, Eslin D, Brown VI, Bergendahl G, Roberts W, Wada RK, Oesterheld J, Mitchell D, Foley J, Zage P, Rawwas J, Rich M, Lorenzi E, Broglio K, Berry D, Saulnier Sholler GL. A subset analysis of a phase II trial evaluating the use of DFMO as maintenance therapy for high-risk neuroblastoma. Int J Cancer. 2020 Dec 1;147(11):3152-3159. doi: 10.1002/ijc.33044. Epub 2020 May 24.
- Results Bowlin TL, McKown BJ, Davis GF, Sunkara PS. Effect of polyamine depletion in vivo by DL-alpha-difluoromethylornithine on functionally distinct populations of tumoricidal effector cells in normal and tumor-bearing mice. Cancer Res. 1986 Nov;46(11):5494-8.
- Results Mari A, Tura A, Gastaldelli A, Ferrannini E. Assessing insulin secretion by modeling in multiple-meal tests: role of potentiation. Diabetes. 2002 Feb;51 Suppl 1:S221-6. doi: 10.2337/diabetes.51.2007.s221.
- Results Gitelman SE, Bundy BN, Ferrannini E, Lim N, Blanchfield JL, DiMeglio LA, Felner EI, Gaglia JL, Gottlieb PA, Long SA, Mari A, Mirmira RG, Raskin P, Sanda S, Tsalikian E, Wentworth JM, Willi SM, Krischer JP, Bluestone JA; Gleevec Trial Study Group. Imatinib therapy for patients with recent-onset type 1 diabetes: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Diabetes Endocrinol. 2021 Aug;9(8):502-514. doi: 10.1016/S2213-8587(21)00139-X. Epub 2021 Jun 29.
- Results Metcalf BW, Bey P, Danzin C, Jung MJ, Casara P, Vevert JP: Catalytic irreversible inhibition of mammalian ornithine decarboxylase (E.C.4.1.1.17) by substrate and product analogs. Journal of the American Chemical Society 1978;100:2551-2553
- Results Poulin R, Lu L, Ackermann B, Bey P, Pegg AE. Mechanism of the irreversible inactivation of mouse ornithine decarboxylase by alpha-difluoromethylornithine. Characterization of sequences at the inhibitor and coenzyme binding sites. J Biol Chem. 1992 Jan 5;267(1):150-8.
- Results Pegg AE, McGovern KA, Wiest L. Decarboxylation of alpha-difluoromethylornithine by ornithine decarboxylase. Biochem J. 1987 Jan 1;241(1):305-7. doi: 10.1042/bj2410305.
- Results Selamnia M, Mayeur C, Robert V, Blachier F. Alpha-difluoromethylornithine (DFMO) as a potent arginase activity inhibitor in human colon carcinoma cells. Biochem Pharmacol. 1998 Apr 15;55(8):1241-5. doi: 10.1016/s0006-2952(97)00572-8.
- Results Danzin C, Jung MJ, Grove J, Bey P. Effect of alpha-difluoromethylornithine, an enzyme-activated irreversible inhibitor of ornithine decarboxylase, on polyamine levels in rat tissues. Life Sci. 1979 Feb 5;24(6):519-24. doi: 10.1016/0024-3205(79)90173-5. No abstract available.
- Results Oredsson S, Anehus S, Heby O. Inhibition of cell proliferation by DL-alpha-difluoromethylornithine, a catalytic irreversible inhibitor of ornithine decarboxylase. Acta Chem Scand B. 1980;34(6):457-8. doi: 10.3891/acta.chem.scand.34b-0457. No abstract available.
- Results Pena A, Reddy CD, Wu S, Hickok NJ, Reddy EP, Yumet G, Soprano DR, Soprano KJ. Regulation of human ornithine decarboxylase expression by the c-Myc.Max protein complex. J Biol Chem. 1993 Dec 25;268(36):27277-85.
- Results Bello-Fernandez C, Packham G, Cleveland JL. The ornithine decarboxylase gene is a transcriptional target of c-Myc. Proc Natl Acad Sci U S A. 1993 Aug 15;90(16):7804-8. doi: 10.1073/pnas.90.16.7804.
- Results Celano P, Baylin SB, Giardiello FM, Nelkin BD, Casero RA Jr. Effect of polyamine depletion on c-myc expression in human colon carcinoma cells. J Biol Chem. 1988 Apr 25;263(12):5491-4.
- Results Tabib A, Bachrach U. Role of polyamines in mediating malignant transformation and oncogene expression. Int J Biochem Cell Biol. 1999 Nov;31(11):1289-95. doi: 10.1016/s1357-2725(99)00098-9.
- Results Liu R, Jia Y, Cheng W, Ling J, Liu L, Bi K, Li Q. Determination of polyamines in human urine by precolumn derivatization with benzoyl chloride and high-performance liquid chromatography coupled with Q-time-of-flight mass spectrometry. Talanta. 2011 Jan 15;83(3):751-6. doi: 10.1016/j.talanta.2010.10.039. Epub 2010 Nov 11.
- Results Ivanova A, Qaqish BF, Schell MJ. Continuous toxicity monitoring in phase II trials in oncology. Biometrics. 2005 Jun;61(2):540-5. doi: 10.1111/j.1541-0420.2005.00311.x.
Drugs
| Evaluation | Drug | Modality | Dose | Route |
|---|---|---|---|---|
| Comparator | alpha-difluoromethylornithine | Unknown | 1000 mg/m2 | Oral |