A Clinical Trial of Oral Versus IV Iron in Patients With Chronic Kidney Disease

Pathobiology of Kidney Disease: Role of Iron

The long-term goal is to assess the fall in kidney function measured by glomerular filtration rate (GFR) when patients with chronic kidney disease (CKD) are exposed to intravenous iron (IVIR). We hypothesize that in subjects with mild to moderate CKD, infusion of intravenous iron (IVIR), will generate oxidative stress and cause an inflammatory response that will be associated with a more rapid decline in glomerular filtration rate (GFR) compared to oral iron.

Study Overview

• Status: Terminated
• Conditions: Chronic Kidney Disease; Iron-deficiency Anemia
• Intervention / Treatment: Drug: IV Iron; Drug: Ferrous Sulfate

Detailed Description

Intravenous iron is commonly utilized and is likely a mechanism of renal injury in patients with CKD. This proposal will provide translational data on the role of intravenous iron to progression of kidney disease in patients with CKD. Comparison of IV iron with oral iron will allow testing the hypothesis that IVIR will generate an inflammatory response and albuminuria in the short-term, that will directly lead to a greater rate of fall in GFR, in the long-term, compared to oral iron. We hypothesize that after administration of one gram of IV iron over a course of 8 weeks, renal injury as documented by albuminuria (and fall in GFR) will be increased with IV iron sucrose therapy compared to those randomized to oral iron therapy. A randomized, parallel group, controlled trial will be performed. GFR will be measures every 6 months for two years in 200 participants by iothalamate clearances.

• Study Type: Interventional
• Enrollment (Actual): 136
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • VA Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age greater than 18 years
• Calculated GFR by MDRD formula < or = 60ml/min/1.73m2. We will use the MDRD formula that incorporates serum creatinine, age, race and sex, but not albumin, and blood urea nitrogen.
• Presence of anemia and iron deficiency. Anemia will be defined as blood hemoglobin concentration <12g/dL and iron deficiency will be defined using National Kidney Foundation/Kidney Disease Outcome Quality Initiative (NFK-K/DOQI) Guidelines as serum ferritin concentration of <100ng/mL or serum transferrin saturation of <25%.

Exclusion Criteria:

• Pregnant or breastfeeding women or women who are planning to become pregnant or those not using a reliable form of contraception (oral contraceptives, condoms, and diaphragms will be considered reliable).
• Known hypersensitivity to iron sucrose (Venofer), iothalamate meglumine (Conray 60, Mallinckrodt) or iodine.
• Anemia that requires RBD transfusion (Hgb <8g/dL) or may potentially need transfusion (active gastrointestinal bleeding). It would be unsafe to withdraw 150 mL blood over the study in such anemic patients.
• Presence of acute renal failure defined as an increase in the baseline serum creatinine concentration of 0.5 mg/dl over 48 hours. This would produce oxidative stress by itself, may give unreliable rate of decline in renal function and may confound results.
• History of IVIR use within 1 month of the study (may confound results of the study if the baseline oxidative stress is increased).
• Evidence of iron overload (serum ferritin >800ng/nl or transferrin saturation >50%)
• Anemia not caused by iron deficiency eg. sickle cell anemia.
• Surgery or systemic or urinary tract infection within 1 month.
• Organ transplant recipient or therapy with immunosuppressive agents. Nasal or inhaled corticosteroids will be permitted.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: IV Iron	Drug: IV Iron; IV iron sucrose 200 mg over 2 hours baseline visit, week 2, week 4, week 6 and week 8 for a total of 1000mg total dose. Further cycles of iv iron may be used based on periodic monitoring of iron stores.; Other Names: Venofer
Active Comparator: Oral Iron	Drug: Ferrous Sulfate; Oral ferrous sulfate 325mg three times daily over 8 weeks. Further cycles of oral iron may be used based on periodic monitoring of iron stores.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean Rate of Decline in mGFR in the Two Groups - Oral and IV Iron	Plasma clearance of iothalamate was measured by administering an IV bolus of 5 mL of iothalamate meglumine and sampling 2 mL of blood at 0, 5, 10, 20, 30, 45, 60, 90, 120, 150, 180, 240, and 300 min after injection. Iothalamate was measured by high-performance liquid chromatography. Plasma clearance was calculated using a two-pool model using validated pharmacokinetic software. The mean modeled iothalamate mGFR slope (e.g., change from baseline to 2 years) in each group (IV iron vs. oral iron) was then calculated after adjustment for baseline log urinary protein/creatinine ratio.	Baseline, 2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proteinuria	Proteinuria was estimated using measurements of urinary protein and creatinine before iron administration at baseline and at periodic intervals thereafter. Mean change from baseline log urinary protein/creatinine ratio (g/g) is reported at 2 years.	Baseline, 2 years

Collaborators and Investigators

• Sponsor: Indiana University
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Investigators: Principal Investigator: Rajiv Agarwal, MD FASN FAHA, Indiana University

Study record dates

Study Major Dates

• Study Start: August 1, 2008
• Primary Completion (Actual): November 1, 2014

Study Registration Dates

• First Submitted: January 26, 2009
• First Submitted That Met QC Criteria: January 26, 2009
• First Posted (Estimate): January 27, 2009

Study Record Updates

• Last Update Posted (Estimate): July 21, 2016
• Last Update Submitted That Met QC Criteria: June 9, 2016
• Last Verified: June 1, 2016

More Information

Terms related to this study

• Keywords: anemia; kidney disease; glomerular filtration rate; iron; progression
• Additional Relevant MeSH Terms: Metabolic Diseases; Urologic Diseases; Hematologic Diseases; Renal Insufficiency; Anemia, Hypochromic; Anemia; Iron Metabolism Disorders; Kidney Diseases; Renal Insufficiency, Chronic; Anemia, Iron-Deficiency
• Other Study ID Numbers: DK71633; U01DK071633 (U.S. NIH Grant/Contract); 5U01DK071633-02 (U.S. NIH Grant/Contract)