Intravenous Ferric Carboxymaltose (Ferinject®) With or Without Erythropoietin in Patients Undergoing Orthopaedic Surgery
Intravenous Ferric Carboxymaltose (Ferinject®) With or Without Erythropoietin in Patients Undergoing Orthopaedic Surgery
Study Design: Single-centre, block randomised, blinded, controlled, phase IIIb, parallel
 group pilot study.

 Primary Objective:

 • To evaluate the effect of the administration of ferric carboxymaltose (Ferinject®) with or
 without erythropoietin vs. no treatment (standard therapy) on the preoperative anaemia status
 in patients undergoing orthopaedic surgery

 Secondary Objective:

 -  To gain informations for the design of a possible follow-up study

 -  To evaluate the effect of the administration of ferric carboxymaltose (Ferinject®) with
 or without erythropoietin vs. no treatment (standard therapy) on pre- and postoperative
 Hb levels, iron status, transfusion rate, days until discharge.

 -  To evaluate the tolerability and safety of Ferinject®

 Study Centres:

 This is a single centre study

 Patients:

 A total of 75 completed patients (50 patients in the intravenous iron treatment groups and 25
 patients in the no treatment group will be recruited.
TREATMENT:

 Patients will be randomised 1:1:1 to one of the following groups:

 Group I - Ferinject ® and EPO treatment group 25 patients will be randomised to the Ferinject
 and EPO treatment group.

 For each patient, the cumulative total iron requirement will be calculated using the formula
 of Ganzoni [Ganzoni et al, 1970]:

 Iron deficit [mg] = b.w. [kg]† x (target Hb - actual Hb) [g/L] x 0.24†† + depot iron [mg]

 † In patients with a body mass index (BMI = weight [kg] / (height [m] x height [m])) >25, a
 normalised weight will be used to calculate the iron deficit. Normalised weight [kg] = 25 x
 height [m] x height [m].

 †† Factor 0.24 = 0.0034 (iron content Hb = 0.34%) * 0.07 (blood volume = 7% of b.w.) * 1000
 (conversion g to mg) Target Hb: 150 g/L Actual Hb: Value obtained at screening visit Depot
 iron: 500 mg

 Patients will receive a first dose of 1000 mg iron as Ferinject® 21 days prior to the
 scheduled surgery. Patients will receive Ferinject® once weekly for up to two occasions (Day
 -21 and Day -14) until the calculated cumulative dose is reached for that individual. The Day
 -14 infusion may not be necessary, depending on the calculated total iron requirement for
 each patient. Patients in treatment group 1 will get additionally a single 10000 IU dose of
 EPO together on treatment day -14.

 Group II - Ferinject ® treatment group 25 patients will be randomised to the Ferinject
 without EPO.

 For each patient, the cumulative total iron requirement will be calculated using the formula
 of Ganzoni [Ganzoni et al, 1970]:

 Iron deficit [mg] = b.w. [kg]† x (target Hb - actual Hb) [g/L] x 0.24†† + depot iron [mg]

 † In patients with a body mass index (BMI = weight [kg] / (height [m] x height [m])) >25, a
 normalised weight will be used to calculate the iron deficit. Normalised weight [kg] = 25 x
 height [m] x height [m].

 †† Factor 0.24 = 0.0034 (iron content Hb = 0.34%) * 0.07 (blood volume = 7% of b.w.) *1000
 (conversion g to mg) Target Hb: 150 g/L Actual Hb: Value obtained at screening visit Depot
 iron: 500 mg

 Patients will receive a first dose of 1000 mg iron as Ferinject 21 days prior to the
 scheduled surgery. Patients will receive Ferinject® once weekly for up to two occasions (Day
 -21 and Day -14) until the calculated cumulative dose is reached for that individual. The Day
 -14 infusion may not be necessary, depending on the calculated total iron requirement for
 each patient.

 Group III - Control group 25 patients will receive the standard treatment for this patient
 population (no anaemia treatment).

 Primary Efficacy Endpoints

 • Hb increase from baseline till day of surgery

 Secondary Efficacy Endpoints

 -  Percentage of patients reaching an Hb of > 12 g/dl (women) or of > 13 g/dl (men) at any
 point in time during the study

 -  Change in Hb level from baseline to highest Hb level during the study

 -  Change in Ferritin value from baseline to highest ferritin value during the study

 -  Change in Tsat value from baseline to highest Tsat value during the study

 -  Transfusion rate

 -  Infection rate

 -  Days until discharge from hospital

 -  Days until rehabilitation therapy

 Secondary Safety Endpoints:

 -  Adverse events: type, nature, incidence and outcome

 -  Vital signs (temperature, blood pressure and heart rate)

 -  Clinical laboratory panels (haematology/coagulation, clinical chemistry, except Hb and
 iron status, which are considered to be efficacy endpoints)

 Laboratory parameters:

 Hematology/coagulation parameters to be analysed are Hb, haematocrit (Hct), red blood cell
 count (RBC), white blood cell count (WBC) with differential and platelet count, mean
 corpuscular volume (MCV), mean corpuscular haemoglobin (MCH), mean corpuscular haemoglobin
 concentration (MCHC).

 Clinical chemistry parameters to be analysed are alkaline phosphatase (AP), gamma-glutamyl
 transpeptidase (GGT), aspartate aminotransferase (AST), alanine aminotransferase (ALT),
 C-reactive protein (CRP), endogenous erythropoietin.

 Iron status parameters include serum iron, serum ferritin, serum transferrin and TSAT.

 Additional parameters - folic acid, vitamin B12 and beta-HCG will be analysed at baseline
 only, creatinin, soluble transferrin receptor and total bilirubin will be analysed at all
 visits.

 Statistical Methods:

 Summary statistics will be provided for safety and efficacy parameters as well as for the
 patients' demographic characteristics. Data will be presented per visit, if appropriate. The
 test for the primary endpoint is confirmative. Statistical tests of secondary endpoints will
 be employed for exploratory purposes to highlight interesting comparisons (e.g., baseline
 versus end of study) that may warrant further consideration. Unless otherwise specified, the
 significance level of all statistical tests will be 5% with a two-sided alternative. If
 appropriate, corresponding 95%-confidence intervals will be calculated. The sample size
 estimation is based on t-test calculation.

 Continuous variables will be summarized as mean +/- SD and median with range where
 appropriate. Continuous variables will be compared using the Kruskal-Wallis test followed by
 pairwise Mann-Whitney tests with Bonferroni-correction. Nominal variables will be compared
 using the chi-square test or Fisher's exact test where appropriate. Changes within groups of
 nominal variables will be analyzed using McNemar test.

 Changes within groups of continuous variables will be analyzed using the Friedman test
 followed by pairwise post hoc comparisons using the Wilcoxon signed rank test with Bonferroni
 correction. Prevalence of anaemia will be presented with exact confidence interval (CI).
 Continuous variables will be transformed to normal distribution, and CIs for the mean will be
 computed. The limits of these CIs then will be retransformed to the original units and
 interpreted as CIs for the median.
Inclusion Criteria:

 -  > 18 years of age and signed written informed consent

 -  Patients scheduled to undergo major orthopaedic surgery (hip or knee arthroplasty or
 back surgery)

 -  10 g/dl < Hb < 13.0 g/dl for men and 10 g/dl < Hb < 12.0 g/dl for women, at screening
 ( 3 weeks prior to surgery)

 -  Ferritin < 100 μg/l or 100-300 with TSat < 20%

 Exclusion Criteria:

 -  Suspicion of iron overload (Ferritin >300 μg/l or/and TSAT>50%)

 -  Active severe infection/inflammation (defined as serum CRP > 20 mg/l) or diagnosed
 malignancy

 -  Folate-and/or Vitamin B12 deficiency (according to local lab reference range)

 -  Known history of hepatitis B/C or HIV-positive

 -  Liver values 3 times higher than normal

 -  Immunosuppressive or myelosuppressive therapy

 -  A concurrent medical condition(s) that, in the view of the investigator, would prevent
 compliance or participation or jeopardize the health of the patients.

 -  Pregnancy or lactation

 -  Transfusion within 1 month prior to study inclusion, EPO treatment with in the last 4
 weeks, any iron treatment within 4 weeks prior to the inclusion in the trail

 -  Participation in any other therapeutic trial within the previous month

 -  History of thromboembolic events in the family or the patient

 -  Severe peripheral, coronary or carotid artery disease

 -  Bodyweight < 50 kg

 -  Patients not able to understand the German language