14 CLINICAL STUDIES

Two clinical studies (Studies A and B) were conducted in adults and one clinical study was conducted in pediatric patients (Study C) to assess the efficacy and safety of sodium ferric gluconate complex in sucrose injection.

Study A

Study A was a three-center, randomized, open-label study of the safety and efficacy of two doses of sodium ferric gluconate complex in sucrose injection administered intravenously to iron-deficient hemodialysis patients. The study included both a dose-response concurrent control and an historical control. Enrolled patients received a test dose of sodium ferric gluconate complex in sucrose injection (25 mg of elemental iron) and were then randomly assigned to receive sodium ferric gluconate complex in sucrose injection at cumulative doses of either 500 mg (low dose) or 1000 mg (high dose) of elemental iron. Sodium ferric gluconate complex in sucrose injection was given to both dose groups in eight divided doses during sequential dialysis sessions (a period of 16 to 17 days). At each dialysis session, patients in the low-dose group received sodium ferric gluconate complex in sucrose injection 62.5 mg of elemental iron over 30 minutes, and those in the high-dose group received sodium ferric gluconate complex in sucrose injection 125 mg of elemental iron over 60 minutes. The primary endpoint was the change in hemoglobin from baseline to the last available observation through Day 40.

Eligibility for this study included chronic hemodialysis patients with a hemoglobin below 10 g/dL (or hematocrit at or below 32%) and either serum ferritin below 100 ng/mL or transferrin saturation below 18%. Exclusion criteria included significant underlying disease or inflammatory conditions or an epoetin requirement of greater than 10,000 units three times per week. Parenteral iron and red cell transfusion were not allowed for two months before the study. Oral iron and red cell transfusion were not allowed during the study for sodium ferric gluconate complex in sucrose injection-treated patients.

The historical control population consisted of 25 chronic hemodialysis patients who received only oral iron supplementation for 14 months and did not receive red cell transfusion. All patients had stable epoetin doses and hematocrit values for at least two months before initiation of oral iron therapy.

The evaluated population consisted of 39 patients in the low-dose sodium ferric gluconate complex in sucrose injection group (50% female, 50% male; 74% white, 18% black, 5% Hispanic, 3% Asian; mean age 54 years, range 22-83 years), 44 patients in the high-dose sodium ferric gluconate complex in sucrose injection group (50% female, 48% male, 2% unknown; 75% white, 11% black, 5% Hispanic, 7% other, 2% unknown; mean age 56 years, range 20-87 years), and 25 historical control patients (68% female, 32% male; 40% white, 32% black, 20% Hispanic, 4% Asian, 4% unknown; mean age 52 years, range 25-84 years).

The mean baseline hemoglobin and hematocrit were similar between treatment and historical control patients: 9.8 g/dL and 29% and 9.6 g/dL and 29% in low- and high-dose sodium ferric gluconate complex in sucrose injection-treated patients, respectively, and 9.4 g/dL and 29% in historical control patients. Baseline serum transferrin saturation was 20% in the low-dose group, 16% in the high-dose group, and 14% in the historical control. Baseline serum ferritin was 106 ng/mL in the low-dose group, 88 ng/mL in the high-dose group, and 606 ng/mL in the historical control.

Patients in the high-dose sodium ferric gluconate complex in sucrose injection group achieved significantly higher increases in hemoglobin and hematocrit than patients in the low-dose sodium ferric gluconate complex in sucrose injection group. See Table 1.

Table 1: Study A: Hemoglobin, Hematocrit, and Iron Studies

p<0.01 versus the 500 mg group.
	Mean Change from Baseline to Two Weeks after Cessation of Therapy
Sodium Ferric Gluconate Complex in Sucrose Injection 1000 mg IV (N=44)	Sodium Ferric Gluconate Complex in Sucrose Injection 500 mg IV (N=39)	Historical Control Oral Iron (N=25)
Hemoglobin (g/dL)	1.1*	0.3	0.4
Hematocrit (%)	3.6*	1.4	0.8
Transferrin Saturation (%)	8.5	2.8	6.1
Serum Ferritin (ng/mL)	199	132	NA

Study B

Study B was a single-center, non-randomized, open-label, historically controlled, study of the safety and efficacy of variable, cumulative doses of intravenous sodium ferric gluconate complex in sucrose injection in iron- deficient hemodialysis patients. Sodium ferric gluconate complex in sucrose injection administration was identical to Study A. The primary efficacy variable was the change in hemoglobin from baseline to the last available observation through Day 50.

Inclusion and exclusion criteria were identical to those of Study A as was the historical control population. Sixty-three patients were evaluated in this study: 38 in the sodium ferric gluconate complex in sucrose injection-treated group (37% female, 63% male; 95% white, 5% Asian; mean age 56 years, range 22-84 years) and 25 in the historical control group (68% female, 32% male; 40% white, 32% black, 20% Hispanic, 4% Asian, 4% unknown; mean age 52 years, range 25-84 years).

Sodium ferric gluconate complex in sucrose injection-treated patients were considered to have completed the study per protocol if they received at least eight sodium ferric gluconate complex in sucrose injection doses of either 62.5 mg or 125 mg of elemental iron. A total of 14 patients (37%) completed the study per protocol. Twelve (32%) sodium ferric gluconate complex in sucrose injection-treated patients received less than eight doses, and 12 (32%) patients had incomplete information on the sequence of dosing. Not all patients received sodium ferric gluconate complex in sucrose injection at consecutive dialysis sessions and many received oral iron during the study.

Cumulative Sodium Ferric Gluconate Complex in Sucrose Injection Dose (mg of elemental iron)	62.5	250	375	562.5	625	750	1000	1125	1187.5
Patients (#)	1	1	2	1	10	4	12	6	1

Baseline hemoglobin and hematocrit values were similar between the treatment and control groups, and were 9.1 g/dL and 27.3%, respectively, for sodium ferric gluconate complex in sucrose injection-treated patients. Serum iron studies were also similar between treatment and control groups, with the exception of serum ferritin, which was 606 ng/mL for historical control patients, compared to 77 ng/mL for sodium ferric gluconate complex in sucrose injection-treated patients.

In this patient population, only the sodium ferric gluconate complex in sucrose injection-treated group achieved increase in hemoglobin and hematocrit from baseline. See Table 2.

Table 2: Study B: Hemoglobin, Hematocrit, and Iron Studies

	Mean Change from Baseline to One Month after Treatment
Sodium Ferric Gluconate Complex in Sucrose Injection (N=38)	Oral Iron (N=25)
Change	Change
Hemoglobin (g/dL)	1.3	0.4
Hematocrit (%)	3.8	0.2
Transferrin Saturation (%)	6.7	1.7
Serum Ferritin (ng/mL)	73	-145

Study C

Study C was a multicenter, randomized, open-label study of the safety and efficacy of two sodium ferric gluconate complex in sucrose injection dose regimens (1.5 mg/kg or 3.0 mg/kg of elemental iron) administered intravenously to 66 iron-deficient (transferrin saturation <20% and/or serum ferritin <100 ng/mL) pediatric hemodialysis patients, 6 to 15 years of age, inclusive who were receiving a stable erythropoietin dosing regimen.

Sodium ferric gluconate complex in sucrose injection at a dose of 1.5 mg/kg or 3.0 mg/kg (up to a maximum dose of 125 mg of elemental iron) in 25 mL 0.9% sodium chloride was infused intravenously over 1 hour during each hemodialysis session for eight sequential dialysis sessions. Thirty-two patients received the 1.5 mg/kg dosing regimen (47% male, 53% female; 66% Caucasian, 25% Hispanic, and 3% Black, Asian, or Other; mean age 12.3 years). Thirty-four patients received the 3.0 mg/kg dosing regimen (56% male, 44% female; 77% Caucasian, 12% Hispanic, 9% Black, and 3% Other; mean age 12.0 years).

The primary endpoint was the change in hemoglobin concentration from baseline to 2 weeks after last sodium ferric gluconate complex in sucrose injection administration. There was no significant difference between the treatment groups. Improvements in hematocrit, transferrin saturation, serum ferritin, and reticulocyte hemoglobin concentrations compared to baseline values were observed 2 weeks after the last sodium ferric gluconate complex in sucrose injection infusion in both the 1.5 mg/kg and 3.0 mg/kg treatment groups (Table 3).

Table 3: Study C: Hemoglobin, Hematocrit, and Iron Status

	Mean Change from Baseline to Two Weeks after Cessation of Therapy in Patients Completing Treatment
1.5 mg/kg Sodium Ferric Gluconate Complex in Sucrose Injection (N=25)	3.0 mg/kg Sodium Ferric Gluconate Complex in Sucrose Injection (N=32)
Hemoglobin (g/dL)	0.8	0.9
Hematocrit (%)	2.6	3.0
Transferrin Saturation (%)	5.5	10.5
Serum Ferritin (ng/mL)	192	314
Reticulocyte Hemoglobin Content (pg)	1.3	1.2

The increased hemoglobin concentrations were maintained at 4 weeks after the last sodium ferric gluconate complex in sucrose injection infusion in both the 1.5 mg/kg and the 3.0 mg/kg sodium ferric gluconate complex in sucrose injection dose treatment groups.