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Clinical Trial Details — Status: Active, not recruiting

Administrative data

NCT number NCT03696797
Other study ID # IRB00044393
Secondary ID 1R01DK119913-01
Status Active, not recruiting
Phase N/A
First received
Last updated
Start date May 1, 2019
Est. completion date February 1, 2025

Study information

Verified date August 2023
Source Wake Forest University Health Sciences
Contact n/a
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial Summary

This is a treatment study to determine if reducing the body's iron stores by blood donation will improve diabetes control and other problems associated with diabetes such as fatty liver disease.


Description:

Investigators propose that high iron triggers a number of events in different tissues, some of which will predispose to diabetes. Investigators will therefore study normal individuals who have higher than average iron levels in tissues, test your glucose control through standard blood tests like the hemoglobin A1c and by placing a continuous glucose monitor before and after participants have donated blood to determine if decreasing iron levels had any effect. In addition, iron may also play a role in the progression of fatty liver to scarring and cirrhosis. Since 75% of people with diabetes have some degree of fatty liver, investigators would also like to study how the liver reacts to the lowering of iron. There will be two optional sub studies conducted only at Wake Forest University Health Sciences they are: 1) Liver substudy that will look at liver complication of diabetes and the role it plays in the progression of fatty liver to scarring and cirrhosis. Investigators will look at how liver reacts to the lowering of iron. 2)Glucose Tolerance Mechanism substudy that will look at the mechanism the body uses to regulate blood sugar levels by insulin, this will require the frequently sample intravenous glucose tolerance test (FSIVGTT).


Recruitment information / eligibility

Status Active, not recruiting
Enrollment 68
Est. completion date February 1, 2025
Est. primary completion date February 1, 2025
Accepts healthy volunteers No
Gender All
Age group 40 Years to 75 Years
Eligibility Inclusion Criteria: - Ages 40-75 - At least 3 months since diagnosis of prediabetes or diabetes - HgbA1C value within three months or at screening of 5.7-6.4% for those with prediabetes and 7- 8.5% for those with diabetes (the upper limit of the latter to reduce the likelihood of major changes in glycemic intervention during the trial period, and the lower limit to allow some room for improvement) - Undiagnosed on no medication HgA1C 6.5-6.9 - C-reactive protein levels up to 11.0 - Aim 2-serum ALT> 1.5 times the upper limit of normal, or; liver stiffness of > 12.5 kPa by Fibroscan transient elastography - Serum ferritin levels within 1 year or at the time of screening in the upper half of the normal range (>50 ng/mL for women; >100ng/mL for men) Exclusion Criteria: - Documented anemia - Hemoglobin levels within 0.5 g/dL of the lower limit of normal (<12.5 g/dL for women; 13.5 g/dL for men) - Recent blood loss - Bleeding diatheses (coagulation abnormalities or treatment with anticoagulants) - Serious chronic infections or chronic inflammatory conditions that could elevate ferritin as an "acute phase reactant - C-reactive protein greater than the upper limit of normal to further validate the lack of significant chronic inflammation - Active cancer diagnosis (excluding skin cell cancers other than melanoma) - Renal insufficiency (eGFR<60 ml/min) - History of orthostatic hypotension - Heavy alcohol use (NIH criteria for men, greater than 4 drinks on any day or 14/week) - Pregnancy or premenopausal women of childbearing age, unless unable to become pregnant because of oral contraceptive use or surgical loss of ovaries or uterus - Aim 2 - individuals meeting the additional inclusion criteria for aim 2 will be tested for anti-HAV IgM, HBs Ag, anti-HBc. IgM, anti HCV IgM and IgG. Subjects who prove positive for any of these viral serologies, except for HCV IgG will be excluded. The latter will be tested for HCV RNA by PRC, and if negative they will be eligible for enrollment

Study Design


Related Conditions & MeSH terms


Intervention

Procedure:
Blood Donation
Participants in the TREATMENT GROUP will have a Unit of blood (two cups, the same amount you would donate at the Red Cross) drawn. This involves having a needle inserted into a vein in your arm. Prior to taking the blood, staff will measure blood count to be sure participants are not anemic, and blood pressure to be sure there is no dehydration. During or after donation, participants will be given a sports drink to replace the fluid loss. Participants in the CONTROL GROUP will not donate blood, but will have a needle inserted into a vein in your arm. Neither group will not know to which they have been assigned, all will have a sleep mask (like a blindfold, covering the eyes, held on with an elastic band) placed so they will not know whether blood was actually removed.
Sham Blood Donation
Participants will have a needle inserted their arm, however, no blood will be drawn.

Locations

Country Name City State
United States University of North Carolina at Chapel Hill (UNC) Chapel Hill North Carolina
United States Wake Forest University Health Sciences Winston-Salem North Carolina

Sponsors (3)

Lead Sponsor Collaborator
Wake Forest University Health Sciences National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), University of North Carolina, Chapel Hill

Country where clinical trial is conducted

United States, 

References & Publications (40)

Abraham D, Rogers J, Gault P, Kushner JP, McClain DA. Increased insulin secretory capacity but decreased insulin sensitivity after correction of iron overload by phlebotomy in hereditary haemochromatosis. Diabetologia. 2006 Nov;49(11):2546-51. doi: 10.1007/s00125-006-0445-7. Epub 2006 Sep 22. — View Citation

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Afkhami-Ardekani M, Rashidi M. Iron status in women with and without gestational diabetes mellitus. J Diabetes Complications. 2009 May-Jun;23(3):194-8. doi: 10.1016/j.jdiacomp.2007.11.006. Epub 2008 Apr 16. — View Citation

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Andrews Guzman M, Arredondo Olguin M. Association between ferritin, high sensitivity C-reactive protein (hsCRP) and relative abundance of Hepcidin mRNA with the risk of type 2 diabetes in obese subjects. Nutr Hosp. 2014 Sep 1;30(3):577-84. doi: 10.3305/nh.2014.30.3.7647. — View Citation

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Beaton MD, Chakrabarti S, Adams PC. Inflammation is not the cause of an elevated serum ferritin in non-alcoholic fatty liver disease. Ann Hepatol. 2014 May-Jun;13(3):353-6. — View Citation

Beutler E, Felitti V, Ho NJ, Gelbart T. Relationship of body iron stores to levels of serum ferritin, serum iron, unsaturated iron binding capacity and transferrin saturation in patients with iron storage disease. Acta Haematol. 2002;107(3):145-9. doi: 10.1159/000057632. — View Citation

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Cheng HL, Bryant C, Cook R, O'Connor H, Rooney K, Steinbeck K. The relationship between obesity and hypoferraemia in adults: a systematic review. Obes Rev. 2012 Feb;13(2):150-61. doi: 10.1111/j.1467-789X.2011.00938.x. Epub 2011 Oct 10. — View Citation

Cooksey RC, Jones D, Gabrielsen S, Huang J, Simcox JA, Luo B, Soesanto Y, Rienhoff H, Abel ED, McClain DA. Dietary iron restriction or iron chelation protects from diabetes and loss of beta-cell function in the obese (ob/ob lep-/-) mouse. Am J Physiol Endocrinol Metab. 2010 Jun;298(6):E1236-43. doi: 10.1152/ajpendo.00022.2010. Epub 2010 Mar 30. — View Citation

Dmochowski K, Finegood DT, Francombe W, Tyler B, Zinman B. Factors determining glucose tolerance in patients with thalassemia major. J Clin Endocrinol Metab. 1993 Aug;77(2):478-83. doi: 10.1210/jcem.77.2.8345055. — View Citation

Dongiovanni P, Fracanzani AL, Fargion S, Valenti L. Iron in fatty liver and in the metabolic syndrome: a promising therapeutic target. J Hepatol. 2011 Oct;55(4):920-32. doi: 10.1016/j.jhep.2011.05.008. Epub 2011 Jun 28. — View Citation

Duvnjak M, Barsic N, Tomasic V, Lerotic I. Genetic polymorphisms in non-alcoholic fatty liver disease: clues to pathogenesis and disease progression. World J Gastroenterol. 2009 Dec 28;15(48):6023-7. doi: 10.3748/wjg.15.6023. — View Citation

Fargion S, Mattioli M, Fracanzani AL, Sampietro M, Tavazzi D, Fociani P, Taioli E, Valenti L, Fiorelli G. Hyperferritinemia, iron overload, and multiple metabolic alterations identify patients at risk for nonalcoholic steatohepatitis. Am J Gastroenterol. 2001 Aug;96(8):2448-55. doi: 10.1111/j.1572-0241.2001.04052.x. — View Citation

Fargnoli JL, Fung TT, Olenczuk DM, Chamberland JP, Hu FB, Mantzoros CS. Adherence to healthy eating patterns is associated with higher circulating total and high-molecular-weight adiponectin and lower resistin concentrations in women from the Nurses' Health Study. Am J Clin Nutr. 2008 Nov;88(5):1213-24. doi: 10.3945/ajcn.2008.26480. — View Citation

Fernandez-Real JM, Penarroja G, Castro A, Garcia-Bragado F, Hernandez-Aguado I, Ricart W. Blood letting in high-ferritin type 2 diabetes: effects on insulin sensitivity and beta-cell function. Diabetes. 2002 Apr;51(4):1000-4. doi: 10.2337/diabetes.51.4.1000. — View Citation

Fleming DJ, Tucker KL, Jacques PF, Dallal GE, Wilson PW, Wood RJ. Dietary factors associated with the risk of high iron stores in the elderly Framingham Heart Study cohort. Am J Clin Nutr. 2002 Dec;76(6):1375-84. doi: 10.1093/ajcn/76.6.1375. — View Citation

Ford ES, Cogswell ME. Diabetes and serum ferritin concentration among U.S. adults. Diabetes Care. 1999 Dec;22(12):1978-83. doi: 10.2337/diacare.22.12.1978. — View Citation

Forouhi NG, Harding AH, Allison M, Sandhu MS, Welch A, Luben R, Bingham S, Khaw KT, Wareham NJ. Elevated serum ferritin levels predict new-onset type 2 diabetes: results from the EPIC-Norfolk prospective study. Diabetologia. 2007 May;50(5):949-56. doi: 10.1007/s00125-007-0604-5. Epub 2007 Mar 2. — View Citation

Gabrielsen JS, Gao Y, Simcox JA, Huang J, Thorup D, Jones D, Cooksey RC, Gabrielsen D, Adams TD, Hunt SC, Hopkins PN, Cefalu WT, McClain DA. Adipocyte iron regulates adiponectin and insulin sensitivity. J Clin Invest. 2012 Oct;122(10):3529-40. doi: 10.1172/JCI44421. Epub 2012 Sep 10. — View Citation

Gao Y, Li Z, Gabrielsen JS, Simcox JA, Lee SH, Jones D, Cooksey B, Stoddard G, Cefalu WT, McClain DA. Adipocyte iron regulates leptin and food intake. J Clin Invest. 2015 Sep;125(9):3681-91. doi: 10.1172/JCI81860. Epub 2015 Aug 24. — View Citation

Houschyar KS, Ludtke R, Dobos GJ, Kalus U, Broecker-Preuss M, Rampp T, Brinkhaus B, Michalsen A. Effects of phlebotomy-induced reduction of body iron stores on metabolic syndrome: results from a randomized clinical trial. BMC Med. 2012 May 30;10:54. doi: 10.1186/1741-7015-10-54. — View Citation

Jehn M, Clark JM, Guallar E. Serum ferritin and risk of the metabolic syndrome in U.S. adults. Diabetes Care. 2004 Oct;27(10):2422-8. doi: 10.2337/diacare.27.10.2422. — View Citation

Jiang R, Manson JE, Meigs JB, Ma J, Rifai N, Hu FB. Body iron stores in relation to risk of type 2 diabetes in apparently healthy women. JAMA. 2004 Feb 11;291(6):711-7. doi: 10.1001/jama.291.6.711. — View Citation

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Kowdley KV, Belt P, Wilson LA, Yeh MM, Neuschwander-Tetri BA, Chalasani N, Sanyal AJ, Nelson JE; NASH Clinical Research Network. Serum ferritin is an independent predictor of histologic severity and advanced fibrosis in patients with nonalcoholic fatty liver disease. Hepatology. 2012 Jan;55(1):77-85. doi: 10.1002/hep.24706. Epub 2011 Dec 6. — View Citation

Koziol JA, Ho NJ, Felitti VJ, Beutler E. Reference centiles for serum ferritin and percentage of transferrin saturation, with application to mutations of the HFE gene. Clin Chem. 2001 Oct;47(10):1804-10. — View Citation

Kusminski CM, Holland WL, Sun K, Park J, Spurgin SB, Lin Y, Askew GR, Simcox JA, McClain DA, Li C, Scherer PE. MitoNEET-driven alterations in adipocyte mitochondrial activity reveal a crucial adaptive process that preserves insulin sensitivity in obesity. Nat Med. 2012 Oct;18(10):1539-49. doi: 10.1038/nm.2899. Epub 2012 Sep 9. — View Citation

Lorenzo C, Wagenknecht LE, Rewers MJ, Karter AJ, Bergman RN, Hanley AJ, Haffner SM. Disposition index, glucose effectiveness, and conversion to type 2 diabetes: the Insulin Resistance Atherosclerosis Study (IRAS). Diabetes Care. 2010 Sep;33(9):2098-103. doi: 10.2337/dc10-0165. — View Citation

Murali AR, Gupta A, Brown K. Systematic review and meta-analysis to determine the impact of iron depletion in dysmetabolic iron overload syndrome and non-alcoholic fatty liver disease. Hepatol Res. 2018 Feb;48(3):E30-E41. doi: 10.1111/hepr.12921. Epub 2017 Jul 20. — View Citation

Qiu C, Zhang C, Gelaye B, Enquobahrie DA, Frederick IO, Williams MA. Gestational diabetes mellitus in relation to maternal dietary heme iron and nonheme iron intake. Diabetes Care. 2011 Jul;34(7):1564-9. doi: 10.2337/dc11-0135. — View Citation

Sharifi F, Nasab NM, Zadeh HJ. Elevated serum ferritin concentrations in prediabetic subjects. Diab Vasc Dis Res. 2008 Mar;5(1):15-8. doi: 10.3132/dvdr.2008.003. — View Citation

Toyokuni S. Role of iron in carcinogenesis: cancer as a ferrotoxic disease. Cancer Sci. 2009 Jan;100(1):9-16. doi: 10.1111/j.1349-7006.2008.01001.x. Epub 2008 Oct 23. — View Citation

Valenti L, Fracanzani AL, Bugianesi E, Dongiovanni P, Galmozzi E, Vanni E, Canavesi E, Lattuada E, Roviaro G, Marchesini G, Fargion S. HFE genotype, parenchymal iron accumulation, and liver fibrosis in patients with nonalcoholic fatty liver disease. Gastroenterology. 2010 Mar;138(3):905-12. doi: 10.1053/j.gastro.2009.11.013. Epub 2009 Nov 18. — View Citation

Valenti L, Fracanzani AL, Dongiovanni P, Rovida S, Rametta R, Fatta E, Pulixi EA, Maggioni M, Fargion S. A randomized trial of iron depletion in patients with nonalcoholic fatty liver disease and hyperferritinemia. World J Gastroenterol. 2014 Mar 21;20(11):3002-10. doi: 10.3748/wjg.v20.i11.3002. — View Citation

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Zhang W, Iso H, Ohira T, Date OC, Tanabe N, Kikuchi S, Tamakoshi A. Associations of dietary iron intake with mortality from cardiovascular disease: the JACC study. J Epidemiol. 2012;22(6):484-93. doi: 10.2188/jea.je20120006. Epub 2012 Sep 15. — View Citation

* Note: There are 40 references in allClick here to view all references

Outcome

Type Measure Description Time frame Safety issue
Primary Change in HgbA1C Change in glycemia as measured byHgbA1C. Values from baseline and month 6 will be reported. Baseline, Month 6
Primary Change in ALT ALT values from baseline and month 12 will be reported. Baseline, Month 12
Primary Change in FSIGTT DI (Frequently sampled intravenous glucose tolerance test) FSIGTT DI Values from baseline and month 6 will be reported. Baseline, Month 6
Secondary HgbA1C at Month 12 HgbA1C values will be reported. Month 12
Secondary Change in fasting glucose Fasting glucose measured on glucose machine (Abbott Freestyle Libre Pro system). Values of month 6 and month 12 will be reported. Month 6, Month 12
Secondary Change in HOMA-IR (Homeostatic Model Assessment-Insulin Resistance) Insulin sensitivity measured by HOMA-IR (Homeostatic Model Assessment-Insulin Resistance) calculated from fasting glucose and insulin. Values will be reported for Baseline and 12 months. Baseline, 12 months
Secondary Number of participants that Discontinued of oral antihyperglycemic agent The numbers of participants that discontinued of oral antihyperglycemic agents Month 12
Secondary Change in Weight The change in weight from baseline to month 12 will be reported Baseline, Month 12
Secondary Change in Blood Pressure The change in Blood pressure from baseline to month 12 will be reported Baseline, Month 12
Secondary Number of participants that converted from pre-diabetes to Diabetes Number of participants that converted from pre-Diabetes to Diabetes based on the HbA1C criteria. Month 12
Secondary Number of participants that converted from pre-diabetes to normal glucose tolerance Number of participants that converted from pre-Diabetes to normal glucose tolerance based on the HbA1C criteria. Month 12
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