Desferal Administration to Improve the Impaired Reaction to Hypoxia in Diabetes

NCT03085771 | Unknown Phase 2

• 1 other identifier: 2016/1925-31
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

Brief Summary

The general aim of this study is to investigate the influence of systemic administration of Desferal (Deferoxamine \[DFO\]) on the response to hypoxic challenge in patients with diabetes mellitus (DM). The investigation will elucidate if DFO can restore:

• the impaired angiogenetic response to hypoxia in patients with type 1 DM.
• the disturbed respiratory and cardiovascular regulation in response to hypoxia in patients with DM type 1

Conditions

Diabetes Mellitus, Type 1

Outcome Measures

Primary Outcomes (1)

• Endothelial precursor cell account (EPC)

  The absolute amount of endothelial precursor cells in 10 ml of blood

  24 hours

Study Arms (2)

Desferal treatment

ACTIVE COMPARATOR

Patients will be randomized (by block randomization) to Desferal (DFO) treatment.

Drug: desferal

Isotonic saline treatment

PLACEBO COMPARATOR

Patients will be randomized (by block randomization) to isotonic saline treatment.

Drug: Isotonic saline

Interventions

desferal DRUG

It is a blinded randomized cross-over study that investigates the efficacy of DFO (50mg/kg) given i.v before intermittent hypoxia (IH) to improve the cardiorespiratory and angiogenetic response in patients with diabetes.

Also known as: deferoxamine

Desferal treatment

Isotonic saline DRUG

It is a blinded randomized cross-over study that investigates the efficacy of isotonic saline given i.v before intermittent hypoxia (IH) to improve the cardiorespiratory and angiogenetic response in patients with diabetes.

Also known as: Isotonic solution

Isotonic saline treatment

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Patients with type1 diabetes with a duration of the disease between 10-20 years (HbA1c ≥ 55 mmol/mol)
• Age 18-55
• Diabetes duration 5-40 years
• Contraception: Female subjects must be postmenopausal, surgically sterile, or if premenopausal (and not surgically sterile), be prepared to use more than 1 effective method of contraception during the study and for 30 days after the last visit. Effective methods of contraception are considered to be those listed below:
• Double barrier method, i.e. (a) condom (male or female) or (b) diaphragm, with spermicide; or
• Intrauterine device; or
• Vasectomy (partner); or
• Hormonal (e.g. contraceptive pill, patch, intramuscular implant or injection); or
• Abstinence, if in line with the preferred and usual lifestyle of the subject.
• Signed informed consent

You may not qualify if:

• Smoking
• Infections during the last month
• Major cardiovascular complications such as coronary heart disease, unstable or stable angina, myocardial infarction, ventricular arrhythmias, and atrial fibrillation in the last 3 months
• Decompensated congestive heart failure or functional class 3-4.
• therapy with beta-blockers
• severe hypertension (180 mmHg systolic or 110 mmHg diastolic blood pressure
• proliferative retinopathy.
• Sign for peripheral diabetic neuropathy (decreased/absent sensitivity to 10 g monofilament, vibration, plantar reflex)
• definite autonomic dysfunction
• HbA1c \> 100 mmol/l
• Any concomitant disease or condition that may interfere with the possibility for the patient to comply with or complete the study protocol
• Malignancy
• History of alcohol or drug abuse
• Participant in another ongoing pharmacological study
• If female: plans to become pregnant, known pregnancy or a positive urine pregnancy test (confirmed by a positive serum pregnancy test), or lactating

Sponsors & Collaborators

• Karolinska University Hospital: lead

Study Sites (1)

Karolinska University Hospital

Stockholm, 17176, Sweden

RECRUITING

Related Publications (26)

• Arden GB, Sivaprasad S. The pathogenesis of early retinal changes of diabetic retinopathy. Doc Ophthalmol. 2012 Feb;124(1):15-26. doi: 10.1007/s10633-011-9305-y.

  PMID: 22302291 BACKGROUND

• Schaper NC, Huijberts M, Pickwell K. Neurovascular control and neurogenic inflammation in diabetes. Diabetes Metab Res Rev. 2008 May-Jun;24 Suppl 1:S40-4. doi: 10.1002/dmrr.862.

  PMID: 18442183 BACKGROUND

• Flyvbjerg A. Diabetic angiopathy, the complement system and the tumor necrosis factor superfamily. Nat Rev Endocrinol. 2010 Feb;6(2):94-101. doi: 10.1038/nrendo.2009.266.

  PMID: 20098449 BACKGROUND

• Ruiter MS, van Golde JM, Schaper NC, Stehouwer CD, Huijberts MS. Diabetes impairs arteriogenesis in the peripheral circulation: review of molecular mechanisms. Clin Sci (Lond). 2010 Jun 8;119(6):225-38. doi: 10.1042/CS20100082.

  PMID: 20545627 BACKGROUND

• Friederich M, Fasching A, Hansell P, Nordquist L, Palm F. Diabetes-induced up-regulation of uncoupling protein-2 results in increased mitochondrial uncoupling in kidney proximal tubular cells. Biochim Biophys Acta. 2008 Jul-Aug;1777(7-8):935-40. doi: 10.1016/j.bbabio.2008.03.030. Epub 2008 Apr 7.

  PMID: 18439413 BACKGROUND

• Ivan M, Kondo K, Yang H, Kim W, Valiando J, Ohh M, Salic A, Asara JM, Lane WS, Kaelin WG Jr. HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Science. 2001 Apr 20;292(5516):464-8. doi: 10.1126/science.1059817. Epub 2001 Apr 5.

  PMID: 11292862 BACKGROUND

• Elson DA, Ryan HE, Snow JW, Johnson R, Arbeit JM. Coordinate up-regulation of hypoxia inducible factor (HIF)-1alpha and HIF-1 target genes during multi-stage epidermal carcinogenesis and wound healing. Cancer Res. 2000 Nov 1;60(21):6189-95.

  PMID: 11085544 BACKGROUND

• Ceradini DJ, Kulkarni AR, Callaghan MJ, Tepper OM, Bastidas N, Kleinman ME, Capla JM, Galiano RD, Levine JP, Gurtner GC. Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1. Nat Med. 2004 Aug;10(8):858-64. doi: 10.1038/nm1075. Epub 2004 Jul 4.

  PMID: 15235597 BACKGROUND

• Devlin C, Greco S, Martelli F, Ivan M. miR-210: More than a silent player in hypoxia. IUBMB Life. 2011 Feb;63(2):94-100. doi: 10.1002/iub.427. Epub 2011 Feb 24.

  PMID: 21360638 BACKGROUND

• Epstein AC, Gleadle JM, McNeill LA, Hewitson KS, O'Rourke J, Mole DR, Mukherji M, Metzen E, Wilson MI, Dhanda A, Tian YM, Masson N, Hamilton DL, Jaakkola P, Barstead R, Hodgkin J, Maxwell PH, Pugh CW, Schofield CJ, Ratcliffe PJ. C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation. Cell. 2001 Oct 5;107(1):43-54. doi: 10.1016/s0092-8674(01)00507-4.

  PMID: 11595184 BACKGROUND

• Mehrabani M, Najafi M, Kamarul T, Mansouri K, Iranpour M, Nematollahi MH, Ghazi-Khansari M, Sharifi AM. Deferoxamine preconditioning to restore impaired HIF-1alpha-mediated angiogenic mechanisms in adipose-derived stem cells from STZ-induced type 1 diabetic rats. Cell Prolif. 2015 Oct;48(5):532-49. doi: 10.1111/cpr.12209.

  PMID: 26332145 BACKGROUND

• Weng R, Li Q, Li H, Yang M, Sheng L. Mimic hypoxia improves angiogenesis in ischaemic random flaps. J Plast Reconstr Aesthet Surg. 2010 Dec;63(12):2152-9. doi: 10.1016/j.bjps.2010.02.001. Epub 2010 Mar 31.

  PMID: 20359971 BACKGROUND

• Botusan IR, Sunkari VG, Savu O, Catrina AI, Grunler J, Lindberg S, Pereira T, Yla-Herttuala S, Poellinger L, Brismar K, Catrina SB. Stabilization of HIF-1alpha is critical to improve wound healing in diabetic mice. Proc Natl Acad Sci U S A. 2008 Dec 9;105(49):19426-31. doi: 10.1073/pnas.0805230105. Epub 2008 Dec 4.

  PMID: 19057015 BACKGROUND

• Catrina SB. Impaired hypoxia-inducible factor (HIF) regulation by hyperglycemia. J Mol Med (Berl). 2014 Oct;92(10):1025-34. doi: 10.1007/s00109-014-1166-x. Epub 2014 Jun 12.

  PMID: 25027070 BACKGROUND

• Ram M, Singh V, Kumawat S, Kumar D, Lingaraju MC, Uttam Singh T, Rahal A, Kumar Tandan S, Kumar D. Deferoxamine modulates cytokines and growth factors to accelerate cutaneous wound healing in diabetic rats. Eur J Pharmacol. 2015 Oct 5;764:9-21. doi: 10.1016/j.ejphar.2015.06.029. Epub 2015 Jun 19.

  PMID: 26101070 BACKGROUND

• Wang C, Cai Y, Zhang Y, Xiong Z, Li G, Cui L. Local injection of deferoxamine improves neovascularization in ischemic diabetic random flap by increasing HIF-1alpha and VEGF expression. PLoS One. 2014 Jun 25;9(6):e100818. doi: 10.1371/journal.pone.0100818. eCollection 2014.

  PMID: 24963878 BACKGROUND

• Hou Z, Nie C, Si Z, Ma Y. Deferoxamine enhances neovascularization and accelerates wound healing in diabetic rats via the accumulation of hypoxia-inducible factor-1alpha. Diabetes Res Clin Pract. 2013 Jul;101(1):62-71. doi: 10.1016/j.diabres.2013.04.012. Epub 2013 May 28.

  PMID: 23726275 BACKGROUND

• Smith TG, Balanos GM, Croft QP, Talbot NP, Dorrington KL, Ratcliffe PJ, Robbins PA. The increase in pulmonary arterial pressure caused by hypoxia depends on iron status. J Physiol. 2008 Dec 15;586(24):5999-6005. doi: 10.1113/jphysiol.2008.160960. Epub 2008 Oct 27.

  PMID: 18955380 BACKGROUND

• Ren X, Dorrington KL, Maxwell PH, Robbins PA. Effects of desferrioxamine on serum erythropoietin and ventilatory sensitivity to hypoxia in humans. J Appl Physiol (1985). 2000 Aug;89(2):680-6. doi: 10.1152/jappl.2000.89.2.680.

  PMID: 10926654 BACKGROUND

• Balanos GM, Dorrington KL, Robbins PA. Desferrioxamine elevates pulmonary vascular resistance in humans: potential for involvement of HIF-1. J Appl Physiol (1985). 2002 Jun;92(6):2501-7. doi: 10.1152/japplphysiol.00965.2001.

  PMID: 12015365 BACKGROUND

• Duennwald T, Bernardi L, Gordin D, Sandelin A, Syreeni A, Fogarty C, Kyto JP, Gatterer H, Lehto M, Horkko S, Forsblom C, Burtscher M, Groop PH; FinnDiane Study Group. Effects of a single bout of interval hypoxia on cardiorespiratory control in patients with type 1 diabetes. Diabetes. 2013 Dec;62(12):4220-7. doi: 10.2337/db13-0167. Epub 2013 Jun 3.

  PMID: 23733200 BACKGROUND

• Duennwald T, Gatterer H, Groop PH, Burtscher M, Bernardi L. Effects of a single bout of interval hypoxia on cardiorespiratory control and blood glucose in patients with type 2 diabetes. Diabetes Care. 2013 Aug;36(8):2183-9. doi: 10.2337/dc12-2113. Epub 2013 Mar 27.

  PMID: 23536585 BACKGROUND

• Balczewska D, Ptaszynski P, Cygankiewicz I. [Baroreflex sensitivity: measurement and clinical aspects]. Przegl Lek. 2015;72(11):682-9. Polish.

  PMID: 27012131 BACKGROUND

• Svacinova J, Moudr J, Honzikova N. [Baroreflex sensitivity: diagnostic importance, methods of determination and a model of baroreflex blood-pressure regulation]. Cesk Fysiol. 2013;62(1):10-8. Czech.

  PMID: 23821958 BACKGROUND

• Collier DJ, Bernardi L, Angell-James JE, Caulfield MJ, Sleight P; Anglo-Scandinavian Cardiac Outcomes Trial. Baroreflex sensitivity and heart rate variability as predictors of cardiovascular outcome in hypertensive patients with multiple risk factors for coronary disease. J Hum Hypertens. 2001 Aug;15 Suppl 1:S57-60. doi: 10.1038/sj.jhh.1001077. No abstract available.

  PMID: 11685912 BACKGROUND

• La Rovere MT, Maestri R, Robbi E, Caporotondi A, Guazzotti G, Febo O, Pinna GD. Comparison of the prognostic values of invasive and noninvasive assessments of baroreflex sensitivity in heart failure. J Hypertens. 2011 Aug;29(8):1546-52. doi: 10.1097/HJH.0b013e3283487827.

  PMID: 21666492 BACKGROUND

MeSH Terms

Conditions

Diabetes Mellitus, Type 1

Interventions

Deferoxamine; Sodium Chloride; Isotonic Solutions

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Autoimmune Diseases; Immune System Diseases

Intervention Hierarchy (Ancestors)

Hydroxamic Acids; Hydroxylamines; Amines; Organic Chemicals; Hydroxy Acids; Carboxylic Acids; Chlorides; Hydrochloric Acid; Chlorine Compounds; Inorganic Chemicals; Sodium Compounds; Solutions; Pharmaceutical Preparations

Study Officials

• Sergiu Catrina, Ass. prof.

  Karolinska University Hospital

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Sergiu Catrina, Ass. prof.

CONTACT

+46-8-517 700 00; sergiu.catrina@ki.se

Neda Rajamand Ekberg, M.D./Ph.D.

CONTACT

+46-8-51772769; neda.ekberg@ki.se

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: This is a double-blind study.
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Senior consultant / associated professor

Model Details: This is a randomised, double-blind, placebo-controlled, cross-over, single center study of patients with diabetes mellitus type 1 without chronic complications.

Study Record Dates

• First Submitted: March 7, 2017
• First Posted: March 21, 2017
• Study Start: January 1, 2017
• Primary Completion: December 12, 2023
• Study Completion: December 12, 2024
• Last Updated: May 26, 2022

Record last verified: 2022-05

Data Sharing

• IPD Sharing: Will not share

Locations

SE (1)