ORIGINAL ARTICLE
`
`JN
`EPHROL
`
`2011;
`
`24
`
`(
`
`:05) 589-596
`
`Iron isomaltoside 1000: a new intravenous iron
`for treating iron deficiency in chronic kidney
`disease
`
`Björn Wikström 1, Sunil Bhandari 2, Peter Barany 3,
`Philip A. Kalra 4, Søren Ladefoged 5, Jan Wilske 6,
`Lars L. Thomsen 7
`
`AbstrAct
`
`Background: Patients with chronic kidney disease
`(CKD) often suffer from iron deficiency anemia neces-
`sitating treatment with intravenous iron. This study
`was designed to assess the safety of iron isomalto-
`side 1000 (Monofer) in CKD patients. The secondary
`objective was to assess its effect on iron deficiency
`anemia.
`Methods: This open-label, noncomparative, multi-
`center trial assigned 182 patients with CKD (n=161
`in dialysis and n=21 in predialysis) to iron isomalto-
`side 1000 either as 4 intravenous bolus injections
`of 100-200 mg iron per dose or as a fast high-dose
`infusion at baseline. Patients were generally under-
`going erythropoiesis-stimulating agent (ESA) treat-
`ment (82%), and the dosage was to be kept constant
`during the trial. They were either switched from an
`existing parenteral maintenance therapy (n=144)
`or were not currently being treated with parenteral
`iron (n=38). Frequency of adverse events (AEs) and
`changes in markers of iron deficiency anemia were
`measured during 8 weeks from baseline.
`Results: Nineteen treatment-related AEs occurred in
`13 patients (7.1%) and after 584 treatments (3.3%).
`No anaphylactic or delayed allergic reactions were
`observed. There were no clinically significant chang-
`
`1 Department of Renal Medicine, Uppsala University, Upp-
`sala - Sweden
`2 Department of Renal Medicine, Hull and East Yorkshire
`Hospitals NHS Trust, and Hull York Medical School, East
`Yorkshire - UK
`3 Department of Renal Medicine, CLINTEC, Karolinska
`Institutet, Stockholm - Sweden
`4 Department of Renal Medicine, Salford Royal Hospital,
`Salford - UK
`5 Department of Nephrology, University Hospital of Copen-
`hagen, Copenhagen - Denmark
`6 Department of Renal medicine, Värnamo Hospital, Vär-
`namo - Sweden
`7 Pharmacosmos A/S, Holbaek - Denmark
`
`es in routine clinical laboratory tests or vital signs.
`Hemoglobin increased from 99.2 g/L (SD=9.0) at
`baseline to 111.2 g/L (SD=14.7) at week 8 in patients
`not currently treated with parenteral iron (p<0.001)
`and increased slightly or stabilized in patients in
`maintenance therapy. S-Ferritin, s-iron and transfer-
`rin saturation increased significantly at all visits.
`Conclusions: Iron isomaltoside 1000 was clinically well
`tolerated, safe and effective. This new intravenous
`iron may offer a further valuable choice in treating the
`anemia of CKD.
`
`Key-words: Anemia, Chronic kidney disease, Intrave-
`nous iron treatment, Iron deficiency
`
`IntroductIon
`
`Anemia is common in chronic kidney disease (CKD) (1)
`and is associated with an increased morbidity and mor-
`tality (2-4). Diagnosing both absolute and functional iron
`deficiency in these patients is crucial for correct ane-
`mia management (5). Use of erythropoiesis-stimulating
`agents (ESAs) and intravenous (i.v.) iron repletion has
`played central roles in the optimal correction of this ane-
`
`589
`
`DOI:10.5301/JN.2010.6248
`
`© 2011 Società Italiana di Nefrologia - ISSN 1121-8428
`
`PGR2020-00009
`Pharmacosmos A/S v. American Regent, Inc.
`Petitioner Ex. 1101 - Page 1
`
`

`

`mia (6-10). Some studies even suggest that i.v. iron will
`often cause an increase in hemoglobin even without ESA
`(11). Although different i.v. iron compounds are available
`(12), there is still a need for improved compounds.
`The new i.v. iron with the name iron isomaltoside 1000 is a
`chemical modification of isomalto-oligosaccharides with
`a mean molecular weight of 1,000 Da and consists pre-
`dominantly of 3-5 glucose units with a low immunologi-
`cal potential. Iron isomaltoside 1000 has strongly bound
`iron within the iron-isomaltoside matrix, which enables a
`controlled, slow release of bioavailable iron to the iron-
`binding proteins, with little risk of free iron toxicity. This
`report describes the first clinical phase III trial assessing
`the use of iron isomaltoside 1000 administered without
`a test dose by either repeated bolus injections or rapid
`high single iron repletion infusions (defined as total dose
`infusion [TDI] in the protocol) to CKD patients.
`
`subjects And methods
`
`This open-label noncomparative safety trial was conducted
`at 15 centers in 3 countries (6 in Denmark, 7 in Sweden and
`2 in the UK). The eligibility criteria were based on the Nation-
`al Institute for Health and Clinical Excellence (NICE) clinical
`guidelines (6). CKD patients in predialysis or undergoing
`dialysis who were not currently treated with parenteral iron
`and had a hemoglobin (Hb) level ≤110 g/L at baseline (crite-
`ria A) or who were willing to switch their current parenteral
`iron maintenance therapy to iron isomaltoside1000 and had
`an Hb ≤130 g/L at baseline (criteria B) were included if they
`were at least 18 years of age, had s-ferritin <800 µg/L and
`a life expectancy greater than 12 months and were willing
`to participate after written informed consent.
`Excluded were patients with other predominant causes
`of anemia, hemochromatosis, hemosiderosis, previous
`hypersensitivity to iron dextran or mono-disaccharide
`complex, history of multiple allergies, liver cirrhosis or
`hepatitis, ongoing infections or rheumatoid arthritis,
`or who were pregnant or currently nursing, had active
`bleeding, planned surgery during the study or were par-
`ticipating in any other clinical study within 3 months prior
`to screening.
`Patients attended 6 visits during the 8-week study period.
`At the investigator’s discretion, iron isomaltoside 1000
`(Monofer) was administered either as 4 repeated i.v. bolus
`injections with 100-200 mg iron/dose at baseline and at
`week 1, 2 and 4 (the last treatment could consist of the to-
`tal remaining dose, if the total calculated iron requirement
`exceeded 800 mg) or as a high single full iron repletion
`dose at baseline. The total calculated iron requirement
`
`590
`
`Fig. 1 - Trial flow chart.
`
`and administered cumulative dose in each patient were
`calculated according to the Ganzoni formula (13). If given
`as an infusion, the iron isomaltoside 1000 was diluted in
`100-500 mL of 0.9% saline and infused over 30-60 min-
`utes (0-10 mg iron/kg over 30 minutes, 11-20 mg iron/kg
`over 60 minutes) at baseline. The i.v. bolus injections of
`100-200 mg iron were given undiluted or diluted in 10-20
`mL of 0.9% saline and administered slowly (max 50 mg
`iron/min).
`The primary end points of the study were adverse events
`(AEs), serious adverse events (SAEs), treatment-related
`AEs, physical examination findings, vital signs (blood
`pressure, pulse, weight), ECG, hematological (Hb and
`full blood count with differentials and platelets) and bio-
`chemical (sodium, potassium, creatinine, albumin, urea,
`bilirubin and alanine aminotransferase [ALT]) and alka-
`line phosphatase) parameters assessed at baseline and
`at weeks 1, 2, 4 and 8. The secondary end points were
`values of Hb, transferrin saturation (TSAT) and s-ferritin
`concentration at 1, 2, 4 and 8 weeks and the change
`from baseline for each of these parameters.
`The trial adhered to the Declaration of Helsinki, was ap-
`proved by the appropriate ethics committees and followed
`the International Conference for Harmonization (ICH) Good
`Clinical Practice guidelines (14).
`
`Wikström et al: Iron isomaltoside 1000 in CKD
`
`© 2011 Società Italiana di Nefrologia - ISSN 1121-8428
`
`PGR2020-00009
`Pharmacosmos A/S v. American Regent, Inc.
`Petitioner Ex. 1101 - Page 2
`
`

`

`JN
`EPHROL
`
`2011;
`
`24
`
`(
`
`:05) 589-596
`
`Statistical methods
`
`and baseline values as covariates. Each on-treatment value
`was compared with the baseline value by a t-test.
`
`Vital signs, physical examination and ECGs were present-
`ed by descriptive statistics. Frequencies of AEs and SAEs
`were presented as number and percentage of patients and
`events, respectively, and tabulated by Medical Dictionary for
`Regulatory Activities (MedDRA) preferred term (15). Groups
`were compared by Fisher’s exact test. Laboratory data
`were tabulated and presented as absolute values and as
`change from baseline. Between groups, a mixed model re-
`peated measures ANCOVA was used to compare the aver-
`age change in efficacy parameters (Hb, TSAT and s-ferritin)
`from baseline to the end of the study visits, with the use
`of treatment, visit and treatment*visit interaction as factors,
`
`results
`
`Patients who entered the trial (n=182) received at least 1
`dose of iron isomaltoside 1000 (38 patients not currently
`treated with parenteral iron [criteria A] and 144 patients
`switched from an existing parenteral iron treatment [criteria
`B]). Figure 1 shows the trial flow chart. The mean baseline
`Hb, ferritin and TSAT according to criteria A and B are shown
`in Table I. Other baseline and demographic clinical charac-
`teristics of the study population are depicted in Table II. The
`mean single dose per treatment and the mean cumulative
`administered dose per patient during the trial according to
`
`TABLE I
`MEAN Hb, S-FERRITIN AND TSAT VALUES AT BASELINE, WEEK 8 AND TIME OF MAXIMAL CHANGES FROM BASE-
`LINE FOR PATIENTS INCLUDED ACCORDING TO CRITERIA A AND B
`
`Criteria A
`(not currently treated with i.v.
`iron at inclusion)
`
`p Value
`
`Criteria B
`(switched from a i.v. iron
`maintenance regimen)
`
`p Value
`
`38 (19 predialysis, 19 dialysis, 24
`on ESA treatment)
`
`144 (2 predialysis, 142 dialysis, 126
`on ESA treatment)
`
`99.2 (9.0)
`
`111.2 (14.7)
`
`p<0.001
`
`114.9 (10.3)
`
`117.5 (11.7)
`
`p=0.0504
`
`112.0 (14.4)
`
`p<0.001
`
`121.6 (11.1)
`
`p<0.001
`
`Number
`
`Hb in g/L (SD)
`
` At baseline
`
` At week 8
`
` At time of
`maximal change from
`baseline
`
`s-Ferritin in µg/L (SD)
`
` At baseline
`
` At week 8
`
` At time of maximal
`change from baseline
`
`TSAT in % (SD)
`
` At baseline
`
` At week 8
`
` At time of maximal
`change from baseline
`
`231.0 (154.0)
`
`407.1 (301.5)
`
`722.5 (360.1)
`
`18.9 (11.3)
`
`23.4 (12.2)
`
`34.2 (22.3)
`
`p<0.001
`
`p<0.001
`
`p=0.084
`
`p<0.001
`
`380.4 (194.7)
`
`408.0 (234.3)
`
`501.2 (270.7)
`
`21.7 (9.6)
`
`23.0 (10.8)
`
`28.6 (11.1)
`
`ESA = erythropoiesis-stimulating agent; Hb = hemoglobin; TSAT = transferrin saturation.
`
`p=0.006
`
`p<0.001
`
`p=0.089
`
`p<0.001
`
`591
`
`© 2011 Società Italiana di Nefrologia - ISSN 1121-8428
`
`PGR2020-00009
`Pharmacosmos A/S v. American Regent, Inc.
`Petitioner Ex. 1101 - Page 3
`
`

`

`TABLE II
`DEMOGRAPHICS AND BASELINE CHARACTERISTICS
`
`Participants, no. (%)
`
`Sex, no. (%)
` Male
` Female
`
`Ethnic origin, no. (%)
` White
` Black
` Asian
` Other
`
`Age, weight and height
` Mean age, years (SD) (range)
` Mean weight, kg (SD) (range)
` Mean BMI - (SD) (range)
`
`Dialysis, creatinine, albumin status
` No. of patients on dialysis
` No. of patients in predialysis
`
`S-Creatinine, µmol/L, mean (SD)
` All patients
` Dialysis patients
` Predialysis patients
`
`S-Albumin, µmol/L, mean (SD)
` All patients
` Dialysis patients
` Predialysis patients
`
`ESA treatment (dosage kept constant during trial)
` No. of patients on ESAs
` Mean duration of previous ESA treatment, months
`
`Iron treatment
` No. of patients switched from an existing iron treatment
` Mean duration of previous iron treatment, months
`
`Common concomitant illness
` Ischemic heart disease, no. (%)
` Arterial hypertension, no. (%)
` Diabetes mellitus, no. (%)
`
`BMI = body mass index; ESA = erythropoiesis-stimulating agent.
`
`592
`
`182 (100)
`
`128 (70.3)
`54 (29.7)
`
`181 (99.5)
`0 ( 0.0)
`0 ( 0.0)
`1 ( 0.5)
`
`63.3 (13.8) (21-90.7)
`79.4 (17.4) (42.6-142.7)
`27.0 (5.5) (16.9-45.5)
`
`161
`21
`
`658 (241)
`706.(216.)
`325 (131)
`
`585.5 (51.28)
`586.17 (51.42)
`573.42 (64.64)
`
`150 (82%)
`23.1
`
`144
`16.8
`
`44 (24.2)
`142 (78)
`62 (34.0)
`
`Wikström et al: Iron isomaltoside 1000 in CKD
`
`© 2011 Società Italiana di Nefrologia - ISSN 1121-8428
`
`PGR2020-00009
`Pharmacosmos A/S v. American Regent, Inc.
`Petitioner Ex. 1101 - Page 4
`
`

`

`JN
`EPHROL
`
`2011;
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`24
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`(
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`:05) 589-596
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`dialysis status, dosing regimen and inclusion criteria A or B
`are detailed in Table III.
`AEs, no matter whether judged as related or not related to
`the study drug, were reported in 62% of the patients. The
`observed AEs were either mild or moderate in intensity.
`No difference in the AE frequencies were seen between
`bolus doses (60% of patients) and TDI (68% of patients)
`(p=0.46; Fisher’s exact test). Nineteen of the reported
`AEs were classified as possibly or probably related to the
`study drug (Tab. IV) and are referred to as “related AEs.”
`The number of related AEs which occurred after first, sec-
`ond, third and fourth administration of iron isomaltoside
`1000 were 8, 2, 3 and 5, respectively, and for 1 event the
`number of prior doses could not be determined. Three
`subjects (1.6%) reported >1 treatment-related AEs: 1 pa-
`tient had 2 events of nausea; another patient had diarrhea,
`influenza, hyperhidrosis, low s-ferritin and arthralgia; and
`a third patient had a hemorrhagic cyst in the right kidney
`and pruritus. Two of the AEs which were determined by
`the attending physician to be possibly treatment-related
`fulfilled criteria for SAEs (sepsis with Staphylococcus au-
`reus and unstable angina).
`Two deaths, both considered unrelated to the study drug
`(one reported as due to unknown cause and the other pneu-
`monia) occurred. No acute anaphylactic/anaphylactoid or
`delayed allergic reactions were reported. There were no
`clinically significant changes in routine clinical laboratory
`tests or vital signs.
`
`The mean maximal increase in Hb in the overall mixed CKD
`population was 7.9 g/L (SD=9.9; p<0.001). Hb increased
`from 99.2 g/L (SD=9.0) at baseline to 111.2 g/L (SD=14.7) at
`week 8 in patients not currently treated with parenteral iron
`(p<0.001) and stabilized in patients in maintenance therapy
`(114.9 g/L at baseline, 117.5 g/L at week 8; p=0.05; Tab. I).
`Figure 2 shows the changes in these parameters in bolus-
`treated and TDI-treated patients. The mean maximal in-
`crease from baseline for Hb was 7.9 g/L (SD=10.1; p<0.001)
`in the patients on dialysis and 8.5 g/L (SD=8.8; p<0.001) in
`the patients on predialysis.
`
`dIscussIon
`
`Patients were exposed to different dosage forms without
`a test dose. In approximately 20% of the patients, the
`full iron repletion dose was given as a single rapid infu-
`sion at baseline. Other studies suggest that this single
`dose method of complete iron repletion is likely to have
`pharmacoeconomic advantages associated with reduced
`number of ambulatory contacts necessary for each non-
`hospitalized patient (16, 17).
`The frequency of patients who had treatment-related AEs
`was 7.1%. The type of related AEs observed is in line with
`what has been reported to have been observed with other
`parenteral iron compounds in the literature (7, 18). The fre-
`quency per administered treatment was only 3.3%, with
`no difference between bolus and TDI. There was no trend
`
`TABLE III
`MEAN SINGLE DOSE PER TREATMENT AND MEAN CUMULATIVE DOSE PER PATIENT DURING THE TRIAL (OVERALL,
`BY DOSE REGIMEN, INCLUSION CRITERIA A OR B AND BY DIALYSIS STATUS)
`
`Bolus
`
`TDI
`
`Crit. A
`
`Crit. B
`
`Dialysis
`
`Predialysis
`
`All
`
`Mean single dose per patient
`Number
`Mean
`SD
`
`Total cumulative dose per patient
`Number
`Mean
`SD
`
`142
`104.7
`24.2
`
`142
`398.8
`107.9
`
`40
`975.3*
`238.0
`
`40
`992.5†
`219.9
`
`38
`948.7
`305.9
`
`38
`1,008.6
`229.2
`
`144
`122.0
`111.1
`
`144
`402.8
`104.2
`
`161
`208.7
`300.8
`
`161
`470.9
`237.4
`
`21
`953.5
`222.5
`
`21
`976.7
`195.2
`
`182
`294.6
`377.4
`
`182
`529.3
`283.3
`
`TDI = total dose infusion.
`* Mean TDI dose at baseline, time: <10 mg iron/kg: 30 minutes; and 10-20 mg iron/kg: 60 minutes.
`† If the iron requirement exceeded 20 mg iron/kg, this TDI was divided into 2 doses given with 1-week interval, therefore 2 patients
`received additional infusions of 463 mg and 225 mg, respectively.
`
`593
`
`© 2011 Società Italiana di Nefrologia - ISSN 1121-8428
`
`PGR2020-00009
`Pharmacosmos A/S v. American Regent, Inc.
`Petitioner Ex. 1101 - Page 5
`
`

`

`Fig. 2 - Change in efficacy parameters from baseline to week
`8 (repeated measurement method) by dose regimen: bolus,
`total dose infusion (TDI) and all patients. Changes in s-hemo-
`globin (Hb) (A), s-ferritin (B) and transferrin saturation (TSAT)
`(C). There was a significant difference in mean change from
`baseline to week 8 in Hb and s-ferritin between bolus- and
`TDI-treated patients. The mean change from baseline for Hb
`was 2.0 g/L (SD=10.9; p=0.042) in the bolus-treated patients
`and 9.8 g/L (SD=14.5; p<0.001) in the TDI-treated patients
`(p=0.015, for difference between bolus and TDI). The vertical
`bars represent means ± SE.
`
`between an accumulated iron isomaltoside1000 dose and
`the related event frequency. In 3 cases, an AE was classi-
`fied by the investigator as possibly related to the treatment
`for unclear reason. This reflects wide interpretation of re-
`latedness which may not always imply causality but simply
`suggest a temporal relationship. In another bolus-treated
`patient, an increase in s-ferritin from 750 µg/L at baseline
`to a maximum of 1,100 µg/L was reported as a related AE
`by the investigator because the iron-dosing regime was re-
`duced accordingly. In 2 cases an AE was considered as
`serious and possibly related to the study drug. One was
`unstable angina and the other was septicemia with Staphy-
`lococcus aureus. Both recovered with treatment. Angina
`has previously been reported in trials with iron sucrose (19).
`However, in the context of this patient’s prior medical histo-
`ry and the time interval between study drug administration
`and the event, any causal relationship can be questioned.
`Also in the case of septicemia, the causality may be ques-
`tioned, and the literature data supporting the role of i.v. iron
`in enhancing risk of infection are controversial (20). While
`such an effect at present cannot be excluded, it should be
`noted that CKD (21) and dialysis (22, 23) are in themselves
`
`associated with significant major infectious complications.
`A statistically significant mean increase in all efficacy param-
`eters (Hb, TSAT and s-ferritin) was observed over time in the
`overall mixed CKD/dialysis population who also received
`ESA treatment at a constant dosage. The most pronounced
`changes were found in TDI-treated patients who received
`higher cumulative doses compared with bolus-treated pa-
`tients. All of these parameters were within the recommended
`treatment targets according to the current NICE guidelines (6).
`Seventy-nine percent of patients were switched from a cur-
`rent parenteral iron maintenance therapy to iron isomaltoside.
`The aim in this group of patients was Hb stabilization.
`The trial is limited by having an open-label uncontrolled
`design in a mixed CKD population with broad entry cri-
`teria where the treatment schedule was left up to the
`investigator. Hence safety and efficacy findings were
`not evaluated in relation to a comparator drug or pla-
`cebo. However, the primary goal of testing the safety of
`isomaltoside 1000 in a naturalistic clinical setting in CKD
`patients both on dialysis and predialysis and with differ-
`ent clinically relevant dosing regimes has been accom-
`plished.
`
`594
`
`Wikström et al: Iron isomaltoside 1000 in CKD
`
`© 2011 Società Italiana di Nefrologia - ISSN 1121-8428
`
`PGR2020-00009
`Pharmacosmos A/S v. American Regent, Inc.
`Petitioner Ex. 1101 - Page 6
`
`

`

`JN
`EPHROL
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`24
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`(
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`:05) 589-596
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`TABLE IV
`ADVERSE EVENTS CLASSIFIED AS PROBABLY OR POSSIBLY RELATED TO IRON ISOMALTOSIDE BY INVESTIGATOR
`
`Adverse event
`
`Subject
`
`Event*
`
`Treatment
`regimen
`
`Relatedness to iron
`isomaltoside
`
`2 serious
`
`17 nonserious
`
`1
`
`2
`
`3
`
`4
`
`5
`
`6
`
`7
`
`8
`
`9
`
`10
`
`11
`
`12
`
`13
`
`Unstable angina
`
`TDI: 1,400 mg
`
`Possible
`
`Sepsis with Staphylococcus aureus
`
`Bolus: 100 mg
`
`Nausea
`
`Nausea
`High s-ferritin†
`
`Constipation
`
`Gastroenteritis
`
`Low s-ferritin†
`
`Diarrhea
`
`Influenza
`
`Hyperhidrosis
`
`Low s-ferritin†
`
`Arthralgia
`
`Hemorrhagic cyst
`
`Headache
`
`Nausea
`
`Dysphonia
`
`Abdominal pain
`
`Bolus: 100 mg
`
`Bolus: 100 mg
`
`Bolus: 100 mg
`
`Bolus: 100 mg
`
`Bolus: 100 mg
`
`Bolus: 100 mg
`
`Bolus: 100 mg
`
`Bolus: 100 mg
`
`Bolus: 100 mg
`
`Bolus: 100 mg
`
`Bolus: 100 mg
`
`Possible
`
`Possible
`
`Possible
`Probable
`
`Possible
`
`Possible
`
`Possible
`
`Possible
`
`Possible
`
`Possible
`
`Possible
`
`Possible
`
`Possible
`
`Possible
`
`Probable
`
`Probable
`
`Possible
`
`TDI = total dose infusion.
`* Preferred term according to MedDRA classification.
`† The 2 cases of low s-ferritin classified as related AEs by investigator concerned a temporary drop in ferritin level from baseline
`which can be considered as part of the underlying iron deficiency. In another bolus-treated patient an increase in ferritin from
`750 µg/L at baseline to a maximum of 1,100 µg/L was rated as a related AE by investigator because the iron-dosing regime was
`reduced accordingly (according to protocol, laboratory values leading to adjustment in therapy had to be reported as AE).
`
`In conclusion, iron isomaltoside 1000 administered to CKD
`patients as repeated bolus injections or a rapid full iron re-
`pletion infusion without a test dose, was safe and well toler-
`ated and resulted in improved markers of iron status and
`anemia, without safety concerns.
`
`Informed consent: Ethics committee approval was obtained for
`the study, and the study adhered to the Declaration of Helsinki.
`
`Financial support: The study was sponsored by Pharmacosmos A/S.
`
`Conflict of interest statement: L.L.T. is employed by Pharmacosmos
`A/S.
`
`Address for correspondence:
`Björn Wikström
`Department of Renal Medicine
`Uppsala University Hospital
`SE-75185 Uppsala , Sweden
`bjornwik@yahoo.com
`
`595
`
`© 2011 Società Italiana di Nefrologia - ISSN 1121-8428
`
`PGR2020-00009
`Pharmacosmos A/S v. American Regent, Inc.
`Petitioner Ex. 1101 - Page 7
`
`

`

`references
`
`1. Hsu CY, McCulloch CE, Curhan GC. Iron status and hemo-
`globin level in chronic renal insufficiency. J Am Soc Nephrol.
`2002;13:2783-2786.
`2. Ma JZ, Ebben J, Xia H, Collins AJ. Hematocrit level and asso-
`ciated mortality in hemodialysis patients. J Am Soc Nephrol.
`1999;10:610-619.
`3. Collins AJ, Li S, St Peter W, et al. Death, hospitalization, and
`economic associations among incident hemodialysis pa-
`tients with hematocrit values of 36 to 39%. J Am Soc Neph-
`rol. 2001;12:2465-2473.
`4. Ofsthun N, Labrecque J, Lacson E, Keen M, Lazarus JM. The
`effects of higher hemoglobin levels on mortality and hospitaliza-
`tion in hemodialysis patients. Kidney Int. 2003;63:1908-1914.
`5. Fusaro M, Munaretto G, Spinello M, et al. Soluble transfer-
`rin receptors and reticulocyte hemoglobin concentration in
`the assessment of iron deficiency in hemodialysis patients. J
`Nephrol. 2005;18:72-79.
`6. National Collaborating Centre for Chronic Conditions. Ane-
`mia management in chronic kidney disease: national clinical
`guideline for management in adults and children. London:
`Royal College of Physicians; 2006. Available at: http://guid-
`ance.nice.org.uk/cg39. Accessed November 24, 2010.
`7. Fishbane S, Maesaka JK. Iron management in end stage re-
`nal disease. Am J Kidney Dis. 1997;29:319-333.
`8. Pfeffer MA, Burdmann EA, Chen CY, et al; TREAT Investiga-
`tors. A trial of darbepoetin alfa in type 2 diabetes and chronic
`kidney disease. N Engl J Med. 2009;361:2019-2032.
`9. Drüeke TB, Locatelli F, Clyne N, et al; CREATE Inves-
`tigators. Normalization of hemoglobin level in patients
`with chronic kidney disease and anemia. N Engl J Med.
`2006;355:2071-2084.
`10. Singh AK, Szczech L, Tang KL, et al; CHOIR Investigators.
`Correction of anemia with epoetin alfa in chronic kidney dis-
`ease. N Engl J Med. 2006;355:2085-2098.
`11. Gotloib L, Silverberg D, Fudin R, Shostak A. Iron deficien-
`cy is a common cause of anemia in chronic kidney disease
`and can often be corrected with intravenous iron. J Nephrol.
`2006;19(2):161-167.
`12. Macdougall IC. Evolution of iv iron compounds over the last
`century. J Ren Care. 2009;35(Suppl 2):8-13.
`
`13. Ganzoni AM. [Intravenous iron-dextran: therapeutic and ex-
`perimental possibilities] [article in German]. Schweiz Med
`Wochenschr. 1970;100:301-303.
`14. European Medicines Agency. ICH topic E 6 (R1) guide-
`line for good clinical practice: note for guidance on good
`clinical practice. (CPMP/ICH/135/95). 2002. Available at:
`http://www.ema.europa.eu/pdfs/human/ich/013595en.
`pdf. Accessed November 24, 2010.
`15. Medical Dictionary for Regulatory Activities. Chantilly, VA,
`USA: Maintenance and Support Services Organization. Avail-
`able at: http://www.meddramsso.com/. Accessed November
`24, 2010.
`16. Peebles G. Clinical management: where medicine meets man-
`agement – pumping iron. Health Serv J. 2004;114:28-29.
`17. Bhandari S, Naudeer S. Improving efficiency and value in
`health care: intravenous iron management for anemia associ-
`ated with chronic kidney disease: linking treatment to an out-
`patient clinic, optimizing service provision and patient choice.
`J Eval Clin Pract. 2008;14:996-1001.
`18. Chertow GM, Mason PD, Vaage-Nilsen O, Ahlmen J. Up-
`date on adverse drug events associated with parenteral iron.
`Nephrol Dial Transplant. 2006;21:378-382.
`19. Critchley U, Dundar Y. Adverse events associated with intra-
`venous iron infusion (low-molecular-weight iron dextran and
`iron sucrose): a systematic review. Transfusion Alternatives in
`Transfusion Medicine. 2007;9:8-36.
`20. Maynor L, Brophy DF. Risk of infection with intravenous iron
`therapy. Ann Pharmacother. 2007;41:1476-1480.
`21. Naqvi SB, Collins AJ. Infectious complications in chronic kid-
`ney disease. Adv Chronic Kidney Dis. 2006;13:199-204.
`22. Laupland KB, Ross T, Gregson DB. Staphylococcus aureus
`bloodstream infections: risk factors, outcomes, and the influ-
`ence of methicillin resistance in Calgary, Canada, 2000-2006.
`J Infect Dis. 2008;198:336-343.
`23. Parkins MD, Gregson DB, Pitout JD, Ross T, Laupland KB.
`Population-based study of the epidemiology and the risk fac-
`tors for Pseudomonas aeruginosa bloodstream infection. In-
`fection. 2010;38:25-32.
`
`Accepted: August 25, 2010
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`596
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`Wikström et al: Iron isomaltoside 1000 in CKD
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`© 2011 Società Italiana di Nefrologia - ISSN 1121-8428
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`PGR2020-00009
`Pharmacosmos A/S v. American Regent, Inc.
`Petitioner Ex. 1101 - Page 8
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