Iron Reduction for the Treatment of Diabetes and Nonalcoholic Fatty Liver Disease

Study Overview
=================
Brief 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.

Detailed 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).

Official Title
-----------------
Iron Reduction by Phlebotomy for the Treatment of Diabetes and Nonalcoholic Fatty Liver Disease

Conditions
-----------------
Iron, Diabetes, Nonalcoholic Fatty Liver

Intervention / Treatment
-----------------
* Procedure: Blood Donation
* Procedure: Sham Blood Donation


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Minimum Age: 40 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Treatment Group<br>Will have a Unit of blood (two cups, the same amount donated 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 your blood count to be sure you are not anemic, and blood pressure to be sure no dehydration. During or after donation, a sports drink is provided to replace the fluid loss. Phlebotomy | Procedure: Blood Donation<br>* 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.<br>|
| Sham Comparator: Control Group<br>Will not donate blood, but will have a needle inserted into a vein in your arm. Both groups will not know which group assignment they have been randomized. Sham Phlebotomy | Procedure: Sham Blood Donation<br>* Participants will have a needle inserted their arm, however, no blood will be drawn.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in HgbA1C | Change in glycemia as measured byHgbA1C. Values from baseline and month 6 will be reported. | Baseline, Month 6 | 
| Change in ALT | ALT values from baseline and month 12 will be reported. | Baseline, Month 12 | 
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| HgbA1C at Month 12 | HgbA1C values will be reported. | Month 12 | 
| 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 | 
| 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 | 
| Number of participants that Discontinued of oral antihyperglycemic agent | The numbers of participants that discontinued of oral antihyperglycemic agents | Month 12 | 
| Change in Weight | The change in weight from baseline to month 12 will be reported | Baseline, Month 12 | 
| Change in Blood Pressure | The change in Blood pressure from baseline to month 12 will be reported | Baseline, Month 12 | 
| 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 | 
| 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 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Iron Reduction, Phlebotomy