`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
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`APPLICATION NUMBER:
`203565Orig1s000
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`STATISTICAL REVIEW(S)
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`U.S. Department of Health and Human Services
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Translational Sciences
`Office of Biostatistics
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`S TAT I S T I C A L R E V I E W A N D E VA L U AT I O N
`CLINICAL STUDIES
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`NDA 203565/0
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`NDA/BLA Serial
`Number:
`Drug Name:
`Indication(s):
`Applicant:
`Date(s):
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`Review Priority:
`
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`Medical Division:
`Clinical Team:
`
`Ferric Carboxymaltose
`Iron Deficiency Anemia
`Luitpold Pharmaceuticals, Inc.
`Stamp Date: 10/3/2011
`PUDFA Date: August 3, 2012
`Standard
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`Biometrics Division:
`Division of Biometrics V
`Statistical Reviewer:
`Kyung Yul Lee, Ph.D., Statistical Reviewer
`Concurring Reviewers: Mark Rothmann, Ph.D., Lead Mathematical Statistician
`Tomas Gwise, Ph.D., Division Deputy Director
`
`Division of Hematology Products
`Dr. Min Lu, Clinical Reviewer
`Dr. Kathy Robie Suh, Clinical Team Leader
`Ms. Baird
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`Project Manager:
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`Keywords:
`Iron deficiency anemia, impaired renal function, hemoglobin, noninferiority test, ANCOVA,
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`Reference ID: 3151928
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`

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`Table of Contents
`LIST OF TABLES.......................................................................................................................................................3
`LIST OF FIGURES.....................................................................................................................................................4
`1. EXECUTIVE SUMMARY .................................................................................................................................5
`2.
`INTRODUCTION ...............................................................................................................................................6
`2.1
`OVERVIEW......................................................................................................................................................6
`2.2
`DATA SOURCES ..............................................................................................................................................8
`3. STATISTICAL EVALUATION ........................................................................................................................8
`3.1
`DATA AND ANALYSIS QUALITY .....................................................................................................................8
`3.2
`EVALUATION OF EFFICACY ............................................................................................................................8
`3.2.1 1VIT9030 ......................................................................................................................................................8
`3.2.2 1VIT9031 ....................................................................................................................................................17
`3.3 EVALUATION OF SAFETY ....................................................................................................................................29
`4.
` FINDINGS IN SPECIAL/SUBGROUP POPULATIONS ............................................................................32
`4.1
`GENDER, RACE, AGE, AND GEOGRAPHIC REGION ........................................................................................32
`4.2
`OTHER SPECIAL/SUBGROUP POPULATIONS ..................................................................................................34
`5. SUMMARY AND CONCLUSIONS ................................................................................................................36
`5.1
`STATISTICAL ISSUES AND COLLECTIVE EVIDENCE .......................................................................................36
`5.2
`CONCLUSIONS AND RECOMMENDATIONS .....................................................................................................37
`SIGNATURES/DISTRIBUTION LIST...................................................................................................................38
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`Reference ID: 3151928
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`LIST OF TABLES
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`Table 1 : List of all studies included in analysis...........................................................................................7
`Table 2 : Patient Disposition: Treated Population (Study 1VIT9030)........................................................10
`Table 3 : Number of subjects in Treated and mITT Populations (Stusy 1VIT9030)..................................12
`Table 4 : Demographic Characteristics: Treated Population (Study 1VIT9030)........................................12
`Table 5 : Baseline Characteristics: Treated Population (Study 1VIT9030)................................................13
`Table 6 : Mean Change in Hemoglobin from Baseline to the Highest Value between Baseline and Day 56
`(or time of intervention): mITT Population (Study 1VIT9030)..................................................................14
`Table 7 : Percent of Subjects With an Increase in Hemoglobin ≥ 1.0 g/dL Anytime Between Baseline and
`Day 56 (or time of intervention): mITT population (Study 1VIT9030) .....................................................16
`Table 8 : Mean Change in Ferritin, TSAT, Serum Iron, TIBC, Unsaturated IBC from Baseline to the
`Highest Value between Baseline and Day 56 ((or time of intervention)): mITT Population (Study
`1VIT9030) ..................................................................................................................................................16
`Table 9: Patient Disposition (Study 1VIT9031): Treated Population.........................................................20
`Table 10: Demographic Characteristics (Study 1VIT9031): Treated Population.......................................21
`Table 11: Baseline Characteristics (Study 1VIT9031): Treated Population...............................................22
`Table 12: Mean Change in Hemoglobin from Baseline to the Highest Value between Baseline and Day 35
`(or time of intervention) (mITT) (Cohort 1 in Study 1VIT9031) ...............................................................24
`Table 13: Mean Change in Hemoglobin from Baseline to the Highest Value between Baseline and Day 35
`(or time of intervention) (mITT) (Cohort 2 in Study 1VIT9031) ...............................................................24
`Table 14: Proportion of Subjects Achieving a Hemoglobin >12.0 g/dL Anytime between Baseline and
`Day 35 (or time of intervention): mITT population (Study 1VIT9031) .....................................................25
`Table 15: Mean Change in Ferritin from Baseline to the Highest Value between Baseline and Day 35 (or
`time of intervention): mITT Population (Cohort 1 in Study 1VIT9031) ....................................................25
`Table 16: Proportion of Subjects with Hemoglobin >12.0 g/dL and an Increase in Ferritin......................26
`Table 17: Proportion of Subjects with a Clinically Meaningful Increase in Hemoglobin..........................27
`Table 18: Mean Change in Hemoglobin and Other Iron Indices from Baseline to Day 35 (or time of
`intervention): mITT Population (Cohort 1 in Study 1VIT9031) ................................................................28
`Table 19: Mean Change in Hemoglobin and Other Iron Indices from Baseline to Day 35 (or time of
`intervention): mITT Population (Cohort 2 in Study 1VIT9031) ................................................................28
`Table 20: Primary Composite Safety Endpoint: Safety Population (Study 1VIT9030) .............................30
`Table 21: Summary Results for Primary Composite Safety Endpoint Analyses (Study 1VIT9030) .........30
`Table 22: Cox Proportional Hazard Analyses Results for Primary Composite Safety Endpoint (Study
`1VIT9030) ..................................................................................................................................................31
`Table 23: Primary Composite Safety Endpoint: Safety Population (Study 1VIT9031) .............................32
`Table 24: Study 1VIT9030 Subgroup Analyses for Mean Change in Hemoglobin from Baseline to the
`Highest Value between Baseline and Day 56 (or time of intervention): Age, Gender and Race: mITT
`Population ...................................................................................................................................................33
`Table 25: Study 1VIT9031 Subgroup Analyses for Mean Change in Hemoglobin from Baseline to the
`Highest Value between Baseline and Day 35 (or time of intervention): Age, Gender and Race: mITT
`Population ...................................................................................................................................................34
`Table 26 : Mean Change in Hemoglobin from Baseline to the Highest Value between Baseline and Day
`56 ((or time of intervention)) by Baseline Hemoglobin: mITT Population (Study 1VIT9030) .................35
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`Reference ID: 3151928
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`3
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`LIST OF FIGURES
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`Figure 1: Mean Hemoglobin Change from Baseline (Study 1VIT9030) ..................................... 15
`Figure 2: Mean Hemoglobin Change from Baseline (Study 1VIT9031) ..................................... 29
`Figure 3: Kaplan Meier Curves for the Primary Composite Safety Endpoint (Study 1VIT9030) 31
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`Reference ID: 3151928
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`EXECUTIVE SUMMARY
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`1.
`
`This submission consists of the results of two studies, 1VIT9030 and 1VIT9031. Study
`1VIT9030 was a multicenter, randomized, active-controlled, open-label study that compared the
`safety and efficacy of intravenous (IV) Ferric carboxymaltose (FCM) versus IV Venofer in
`subjects who had iron deficiency anemia (IDA) and impaired renal function. Study 1VIT9031
`was a multicenter, randomized, active-controlled study to compare the efficacy and safety of
`FCM in subjects who had IDA in two cohorts. Cohort 1 included oral iron subjects who had an
`unsatisfactory response to a 14-day oral iron run-in and Cohort 2 included subjects who were
`poorly tolerant or otherwise inappropriate for oral iron. The dose and schedule for these phase
`III trials was FCM 15 mg/kg to a maximum of 750 mg per dose on Days 0 and 7 for a total
`maximum dose of 1500 mg. These two studies were conducted in the United States.
`
`The observed mean changes in hemoglobin from baseline to the highest values during the study
`period demonstrated clinical benefit in subjects who had iron deficiency anemia impaired renal
`function with non-dialysis dependent chronic kidney disease (CKD) (1VIT9030) and oral iron
`subjects who had an unsatisfactory response to a 14-day oral iron run-in (1VIT9031).
`
`The key statistical issues and findings are as follows:
`
`
`• For Study 1VIT9030, the estimated mean difference between FCM and Venofer was 0.21
`g/dL with 95% CI of (0.13, 0.28). FCM was noninferior to Venofer in mean change in
`hemoglobin with the lower limit (0.13) of the 95% CI above the noninferiority margin of
`-0.2 g/dL. FCM was even statistically superior to Venofer on the mean change in
`hemoglobin from baseline to the highest value during the study period.
`
`• The primary composite safety endpoint in the Study 1VIT9030 was the proportion of
`subjects experiencing the primary composite safety endpoint of death, nonfatal
`myocardial infarction, nonfatal stroke, unstable angina requiring hospitalization,
`congestive heart failure, arrhythmias, protocol-defined hypertensive and hypotensive
`events. A total of 175 subjects (13.7%) in FCM and 156 subjects (12.2%) in Venofer had
`one or more composite safety events with 95 % CI of (-1.1, 4.3). The most common
`event among the primary composite safety endpoint was protocol-defined hypertensive
`events, 7.5% subjects in FCM and 4.4% subjects in Venofer, respectively. After
`excluding protocol-defined hypertensive and hypotensive events, 5.5% subjects in FCM
`and 5.4% subjects in Venofer had events. Death, nonfatal myocardial infarction or
`nonfatal stroke events were observed 1.9% subjects in FCM and 2.7% subjects in
`Venofer.
`
`• For the proportion of subjects with an increase in hemoglobin ≥ 1.0 g/dL from baseline to
`the end of study period, subjects in FCM not only demonstrated noninferiority with lower
`bound of 3.6 % above noninferiority margin of -7.5%, but also demonstrated superiority
`with 95% CI of (3.6, 11.5) compared to that of Venofer in study 1VIT9030.
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`5
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`Reference ID: 3151928
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`• For Study 1VIT9030, the mean increases in ferritin, total transferring saturation (TSAT),
`and serum iron and mean decreases in total iron building capacity (TIBC) and
`unsaturated iron building capacity (IBC) from baseline to the highest value from baseline
`to the end of study period were statistically significantly greater in the FCM subjects than
`in the Venofer subjects.
`
`• For study 1VIT9031, subjects in FCM demonstrated superiority to Oral Iron in Cohort 1
`which included oral iron subjects who had an unsatisfactory response to a 14-day oral
`iron run-in with an estimated difference between FCM and oral iron of 0.76 g/dL and
`95% CI of (0.59, 0.93) (P<0.0001) with respect to the mean change in hemoglobin from
`baseline to the highest value between baseline and Day 35 (or time of intervention) after
`adjusting for etiology.
`• For study 1VIT9031, all supportive efficacy endpoints for Cohort 1 and Cohort 2 were
`superior for subjects in the FCM arm compared to subjects in the oral Iron arm in Cohort
`1. Similar finding applied to the IV SC arm in Cohort 2.
`
`INTRODUCTION
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`2.
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`2.1 Overview
`
`
`Ferric carboxymaltose (FCM) is a Type I polynuclear iron (III)-hydroxide carbohydrate complex
`being developed as a parenteral iron replacement therapy for the treatment of iron-deficiency
`anemia (IDA).
`
`In the Drug Safety and Risk Management advisory meeting held February 01, 2008 for the
`previously submitted New Drug Application (NDA), FDA advisory committee members advised
`to reduce the maximum individual dose of FCM for the original NDA that was the maximum of
`1,000 mg per infusion with a total maximum cumulative dose of 2,500 mg over 3 infusions.
`
`Luitpold Pharmaceuticals, Inc. designed and conducted these two additional phase 3, open-label,
`randomized, multicenter, active controlled studies to assess the safety and efficacy collaborated
`with the
`. The FCM was administered with a maximum
`individual dose of 750 mg each with a total maximum cumulative dose of 1,500 mg over 2
`infusions in these two studies (1VIT09031 and 1VIT09030). At the May 18, 2009 meeting, it
`was discussed that two large studies of 1VIT9030 and 1VIT9031 would be the main studies and
`the results of these two trials would be taken in the context of the totality of the data available for
`evaluating the safety and efficacy of FCM. Both studies included the composite cardiovascular
`safety endpoint that was independently adjudicated by the Clinical Events Classification (CEC)
`committee of
`.
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`The primary objective of Study 1VIT9030 was to estimate the cardiovascular safety and efficacy
`of an investigational IV FCM compared to IV Venofer in subjects who had IDA and impaired
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`6
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`Reference ID: 3151928
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`(b) (4)
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`(b) (4)
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`renal function with non-dialysis dependent chronic kidney disease (CKD) at elevated risk of
`cardiovascular disease. A total of 2584 subjects were randomized (187 sites in the U.S); 1290
`subjects into FCM and 1294 subjects into Venofer. Subjects were administered FCM 15 mg/kg
`to a maximum of 750 mg per dose on Days 0 and 7 for a total maximum dose of 1500 mg or
`Venofer 200 mg on Days 0, 7, and 14 with 2 additional doses between Days 0 and 7 and between
`Days 7 and 14 for a total of 5 doses (1000 mg). The primary efficacy endpoint was the mean
`change from baseline to the highest observed hemoglobin (Hgb) any time from baseline to Day
`56 (or time of intervention). The composite safety endpoint included death due to any cause,
`nonfatal myocardial infarction, nonfatal stroke, unstable angina requiring hospitalization,
`congestive heart failure requiring hospitalization or medical intervention, arrhythmias,
`hypertension, or hypotension.
`
`The primary objective of Study 1VIT9031 was to demonstrate the efficacy and safety of an
`investigational IV FCM for subjects with IDA due to a variety of etiologies (unsatisfactory
`response, intolerability or side effects) to fail a 14-day run-in course of oral iron before
`randomization to FCM or continuation of oral iron and subjects who did not tolerate oral iron or
`who were deemed unsuitable by the Investigator for the oral iron lead-in. Cohort 1 included oral
`iron subjects who had an unsatisfactory response to a 14-day oral iron run-in. Subjects were
`randomized in a 1:1 ratio to receive either IV FCM 15 mg/kg to a maximum dose of 750 mg per
`dose on Days 0 and 7 for a total maximum dose of 1500 mg (Group A) or continuation of oral
`iron ferrouts sulfate 325 mg PO, TID for an additional 14 days (Group B). Cohort 2 included
`subjects who were poorly tolerant or otherwise inappropriate for oral iron. Subjects were
`randomized in a 1:1 ratio to receive either IV FCM (same dose with Group A) or IV standard
`care (SC) (other IV iron) as determined by the study site physician. A total of 997 subjects were
`randomized (84 sites in the U.S.); 246 subjects in Group A (FCM), 253 subjects in Group B (oral
`iron) in Cohort 1 and 253 subjects in Group C and 245 subjects in Group D in Cohort 2. The
`primary endpoint is the mean change from baseline to the highest observed hemoglobin any time
`between baseline and Day 35 (or time of intervention) in Cohort 1. The composite endpoint was
`the same with Study 1VIT9030.
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`Table 1 : List of all studies included in analysis
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`
` # of Subjects
`per Arm
`Randomized
`FCM:1290
`Venofer: 1294
`Randomized
`Cohort 1
`FCM: 246
`Oral Iron: 253
`Cohort 2
`FCM: 253
`IV SC: 245
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`Study Population
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`Iron deficiency
`anemia
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`unsatisfactory
`response to a 14-day
`oral iron run-in
`(Cohort 1)
`intolerant or
`unsuitable of oral
`iron (by investigator)
`during the run-in
`(Cohort 2)
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`7
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`Treatment
`Period
`Up to Day 56
`(additional up
`to 3 months)
`Up to Day 35
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`Follow-up
`Period
`1 month
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`1 month
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`Study
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`1VIT9030
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`Phase and
`Design
`Phase 3
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`1VIT9031
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`Phase 3
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`Reference ID: 3151928
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`2.2 Data Sources
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`STATISTICAL EVALUATION
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`
`Data and study reports were provided electronically, the location/names of data sets are as
`follows;
`Study reports:
`\\Cdsesub1\evsprod\NDA203565\0000\m5\53-clin-stud-rep\535-rep-effic-safety-stud\iron-def-
`anemia\5351-stud-rep-contr\1vit09030
`\\Cdsesub1\evsprod\NDA203565\0000\m5\53-clin-stud-rep\535-rep-effic-safety-stud\iron-def-
`anemia\5351-stud-rep-contr\1vit09031
`
`Data sets
`\\Cdsesub1\evsprod\NDA203565\0000\m5\datasets\1vit09030
`\\Cdsesub1\evsprod\NDA203565\0000\m5\datasets\1vit09031
`
`The “raw” and derived datasets were submitted, and the SAS programs were submitted.
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`3.
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`3.1 Data and Analysis Quality
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`Review the quality and integrity of the submitted data.
`•
`It was possible to reproduce the primary analysis dataset from tabulation or “raw”
`datasets.
`It was possible to trace how the primary endpoint was derived from the original data
`source (e.g., case report form).
`
`•
`
`3.2 Evaluation of Efficacy
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`3.2.1 1VIT9030
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`Study Design and Endpoints
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`Study Design
`Study 1VIT9030 was multicenter, randomized, active-controlled, open-label study that compared
`the safety and efficacy of IV FCM versus IV Venofer in subjects who had IDA and impaired
`renal function. Subjects must have had a hemoglobin ≤11.5 g/dL (based on the mean of 2 values
`determined by central laboratories drawn within 7 days; the two values being within 0.7 mg/dL
`of each other) and chronically impaired renal function as defined by either of the following:
`1. Glomerular filtration rate (GFR) <60 ml/min/1.73 m² on two measurements during the
`screening period (using the Modification of Diet in Renal Disease [MDRD] calculation), or
`2. GFR <90 ml/min/1.73 m² on two measurements during the screening period and either one or
`both of the following:
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`Reference ID: 3151928
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`8
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`• Kidney damage as indicated by abnormalities in composition of urine (as documented
`in the subject’s medical history)
`• Elevated risk of cardiovascular disease (Category 2 or 3) based on the Framingham
`Model
`The stratification factors were baseline hemoglobin (≤9, 9.1 to 10.0, >10.1 g/dL), baseline
`cardiovascular risk (history of myocardial infarction, stroke, or congestive heart failure [yes/no]),
`erythropoietin use (yes/no), and CKD stage as per K/DOQI stage of CKD (2, 3-4, or 5).
`During the Treatment Phase, the FCM Group received two doses of FCM at 15 mg/kg to a
`maximum of 750 mg per dose for a maximum total dose of 1,500 mg. The Venofer Group
`received 5 doses of Venofer, 200 mg for a total dose of 1,000 mg.
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`Endpoints
`The primary efficacy endpoint was the mean change from baseline to the highest observed
`hemoglobin any time between baseline and end of treatment period (Day 56) (or time of
`intervention).
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`Other supportive efficacy endpoints were as follows;
`• Proportion of subjects achieving an increase in hemoglobin of ≥1 g/dL any time between
`baseline and end of treatment period (Day 56) (or time of intervention)
`• Mean change from baseline to the highest observed ferritin any time between baseline
`and treatment period (Day 56) (or time of intervention)
`• Mean change from baseline to the highest observed TSAT any time between baseline and
`treatment period (Day 56) (or time of intervention)
`• Mean change from baseline to the pre-dosing value on Day 7 for hemoglobin, ferritin,
`and TSAT
`The hematologic parameters were to be measured on screening phase (days -14 and -1), days 7,
`14, 28 and 56 on treatment phase and days between 57 and 90 on the extra dose visit.
`
`The primary safety endpoint was the proportion of subjects experiencing at least one
`treatment-emergent adverse event included in the primary composite safety endpoint.
`Treatment-emergent events included events that start on or after the first dose of randomized
`treatment. The composite safety endpoints which were adjudicated by the Clinical Events
` include:
`Classification (CES) committee of
`• Death due to any cause
`• Nonfatal myocardial infarction
`• Nonfatal stroke
`• Unstable angina requiring hospitalization
`• Congestive heart failure requiring hospitalization or medical intervention
`• Arrhythmias
`• Hypertension
`• Hypotension
`
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`Patient Disposition, Demographic and Baseline Characteristics
`Sample size determination: This study enrolled a population with a high risk of cardiovascular
`events. Based on a comparison to the CHOIR database (data on file at
`) as well as the
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`9
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`Reference ID: 3151928
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`(b) (4)
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`(b) (4)
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`Applicant’s Phase 3 database for FCM, approximately 4% of subjects were expected to
`experience one or more of the events comprising the primary composite endpoint. The difference
`between FCM and Venofer in the proportion of subjects experiencing the primary composite endpoint
`was assessed with a 95% 2-sided CI constructed with the normal approximation to the binomial with
`continuity correction.
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`The planned sample size of 1250 per group was calculated providing evidence of equivalent
`cardiovascular risk for FCM and Venofer if the 95% CI included zero. This sample size
`provided >95% power to demonstrate noninferiority with a noninferiority margin of 0.2g/dL
`using 95% 2-sided CI for the difference between FCM and Venofer in the mean increase from
`baseline to the highest observed hemoglobin any time between baseline and end of study (or time
`of intervention).
`
`In Study 1VIT04004, the observed mean difference between FCM and oral iron for the mean
`increase from baseline to the highest hemoglobin between baseline and Day 56 was 0.5 g/dL. In
`Study 1VEN03027, Venofer 1,000 mg IV in divided doses over a 14-day period was compared
`to oral iron. The observed mean difference for the increase from baseline to Day 56 was 0.4 g/dL.
`A patient-level standard deviation of 1.0 g/dL was estimated from these two studies.
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`Assuming that the difference between Venofer and placebo exceeded the difference of 0.4 g/dL
`for IV iron versus oral iron, a non-inferiority margin of 0.2 g/dL was chosen as the difference
`from placebo.
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`Of a total of 2584 subjects, 1290 subjects and 1294 subjects were randomized to FCM or
`Venofer, respectively, from 187 centers in the United States. Among 2584 subjects, 14 FCM and
`9 Venofer randomized subjects were discontinued from the study prior to dosing due to subject’s
`request or selection criteria/study compliance reasons. A total of 1276 subjects were treated in
`the FCM group and 1285 subjects were treated in the Venofer group. The patient disposition is
`summarized for the treated population in Table 2.
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`Table 2 : Patient Disposition: Treated Population (Study 1VIT9030)
`
`
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`Subjects Treated FCM Venofer Total
` (N=1276) (N=1285) (N=2584)
`Completed Treatment Phase
`(Screening – Day 56) 1048 (82.1%) 1042 (81.1%) 2090 (81.6%)
`Not Complete Treatment Phase
`(Screening – Day 56) 228 (17.9%) 243 (18.9%) 471 (18.4%)
` Adverse event 20 (1.6%) 22 (1.7%) 42 (1.6%)
` Selection criteria/compliance 181 (14.2%) 188 (14.6%) 369 (14.4%)
` Lost to follow-up 11 (0.9%) 10 (0.8%) 21 (0.8%)
` Subject request 9 (0.7%) 17 (1.3%) 26 (1.0%)
` Physician decision 3 (0.2%) 2 (0.2%) 5 (0.2%)
` Other 4 (0.3%) 4 (0.3%) 8 (0.3%)
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`Reference ID: 3151928
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`Completed Study Period
`(Screening – Day 120) 1059 (83.0%) 1073 (83.5%) 2132 (83.2%)
`Not Complete Study Period
`(Screening – Day 120) 217 (17.0%) 212 (16.5%) 429 (16.8%)
` Adverse event 35 (2.7%) 30 (2.3%) 65 (2.5%)
` Selection criteria/compliance 138 (10.8%) 131 (10.2%) 269 (10.5%)
` Lost to follow-up 23 (1.8%) 23 (1.8%) 46 (1.8%)
` Subject request 17 (1.3%) 22 (1.7%) 39 (1.5%)
` Physician decision 2 (0.2%) 1 (0.1%) 3 (0.1%)
` Other 2 (0.2%) 5 (0.4%) 7 (0.3%)
`
` A
`
` total of 1048 subjects (82.1%) in FCM and 1042 subjects (81.1%) in Venofer completed the
`Treatment Phase as scheduled (Screening –Day 56). Among 228 subjects who did not complete
`the Treatment Phase in FCM; 181 discontinued due to selection criteria/compliance, 20
`discontinued due to adverse events, 11 were lost to follow-up, 9 discontinued due to subject’s
`request, 4 discontinued for “other” reasons, and 3 discontinued due to physician decision.
`Among 243 subjects who did not complete the Treatment Phase as scheduled in Venofer; 188
`discontinued due to selection criteria/compliance, 22 discontinued due to adverse events, 17
`discontinued due to subject’s request, 10 were lost to follow-up, 4 discontinued for “other”
`reasons, and 2 discontinued due to physician decision.
`
` A
`
` total of 1059 (83.0%) subjects in FCM and 1073 subjects (83.5%) in Venofer completed the
`study as scheduled (Screening – Day 120). Among 217 subjects who did not complete the study
`as scheduled in FCM; 138 discontinued due to compliance, 35 discontinued due to adverse
`events, 23 were lost to follow-up, 17 discontinued due to subject’s request, 2 discontinued for
`“other” reasons, and 2 discontinued due to physician decision. Among 212 subjects who did not
`complete the study as scheduled in Venofer; 131 discontinued due to selection
`criteria/compliance, 30 discontinued due to adverse events, 23 were lost to follow-up, 22
`discontinued due to subject request, 5 discontinued for “other” reasons, and 1 discontinued due
`to physician decision.
`
`The total number of subjects who completed the study period was greater than the total number
`of subjects who completed the treatment period because of two different completion criteria. A
`subject completed the treatment phase had to have received a dose of FCM or Venofer and
`completed the Day 56 Visit. A subject completed the study period needed to have at least one
`dose of FCM or Venofer and a safety follow-up on Days 120-125.
`
`The efficacy evaluation population was modified intent-to-treat (ITT) population who received at
`least one dose of randomized study medication, had at least one post-baseline hemoglobin
`assessment, and had a stable (± 20%) erythropoiesis stimulating agent (ESA) for four weeks,
`which may include a dose of zero, before randomization.
`
`The number of subjects in the safety and mITT populations is summarized in Table 3.
`
`
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`11
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`Reference ID: 3151928
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`

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`Table 3 : Number of subjects in Treated and mITT Populations (Study 1VIT9030)
`
`
` FCM Venofer Total
`Randomized subjects 1290 1294 2584
` No treatment 14 9 23
`Treated population 1276 1285 2561
` No post-baseline 23 33 56
` No stable ESA 6 8 14
`mITT population 1249* 1244 2493
`* Two subjects had no post baseline and no stable ESA.
`
`There were 2493 subjects in the mITT population, 1249 subjects on FCM and 1244 subjects on
`Venofer.
`
`Demographic characteristics are summarized for the treated population in Table 4.
`
`Table 4 : Demographic Characteristics: Treated Population (Study 1VIT9030)
`
`
` FCM Venofer Total
` (N=1276) (N=1285) (N=2561)
` n (%) n (%) n (%)
`Age (years)
` Mean (SD) 67.5 (13.0) 67.2 (13.0) 67.3 (13.0)
` ≤ 65 500 (39.2) 536 (41.7) 1036 (40.5)
` 66-75 395 (31.0) 394 (30.7) 789 (30.8)
` ≥ 76 381 (29.9) 355 (27.6) 736 (28.7)
`Sex
` Female 810 (63.5) 818 (63.7) 1628 (63.6)
` Male 466 (36.5) 467 (36.3) 933 (36.4)
`Race
` African American 334 (26.2) 325 (25.3) 659 (25.7)
` Asian 20 (1.6) 21 (1.6) 41 (1.6)
` Caucasian 676 (53.0) 693 (53.9) 1369 (53.5)
` Hispanic 2