FER-CARS-05

Vifor Pharma

Flughofstrasse 61, Glattbrugg, Switzerland, CH-8152

Medical Information, Vifor (International) Inc., +41 58851 8222, medinfo@viforpharma.com

Medical Information, Vifor (International) Inc., +41 58851 8222, medinfo@viforpharma.com

No

No

No

Final

25 Nov 2014

No

Yes

13 Feb 2014

No

The primary objective of this study was to determine, relative to placebo, the effect of iron repletion therapy using IV ferric carboxymaltose (FCM) on functional capacity, as assessed by the 6-minute walk test (6MWT), at 24 weeks after initiation of therapy in subjects with chronic heart failure (CHF) and iron deficiency ID.

The study was conducted in accordance with the principles of the Declaration of Helsinki including amendments in force up to and including the time the study was conducted. The study was conducted in compliance with the International Conference on Harmonisation (ICH) E6 Guideline for Good Clinical Practice (GCP) [2], Committee for Proprietary Medicinal Products Guideline (CPMP/ICH/135/95), and compliant with the EU Clinical Trial Directive (Directive 2001/20/EC) and/or the Code of Federal Regulations (CFR) for informed consent and protection of patient rights (21 CFR, Parts 50 and 56). Before each subject was admitted to the study, a signed and dated informed consent was obtained from the subject (or his/her legally authorised representative) according to the regulatory and legal requirements of the participating country. This consent form was retained by the Investigator as part of the study records. A copy of the document was provided to the subject. No investigations specifically required for the study were conducted until valid consent was obtained. The Investigator explained the aims, methods, reasonably anticipated benefits and potential hazards of the study and any potential discomforts. Subjects were informed that their participation in the study was entirely voluntary and would have no effect on clinical care otherwise available and that they could withdraw consent to participate at any time without penalty or loss of further medical treatment. Subjects were told that competent authorities and authorised persons could examine their records but that personal information would be treated as strictly confidential and would not be publicly available.

24 Sep 2011

No

Yes

Russian Federation: 161

Ukraine: 50

Poland: 50

Portugal: 2

Spain: 17

Sweden: 8

United Kingdom: 6

Austria: 8

Italy: 2

304

93

0

0

0

0

0

0

85

212

7

Overall trial (overall period)

Randomised - controlled

Because FCM is a dark brown solution which is easily distinguishable from placebo (i.e., saline solution), each site was required to have blinded and unblinded site personnel. The Investigator, the subject, and the Sponsor were blinded. Unblinded site personnel (including at least 1 physician) were responsible for the preparation and administration of the study treatment. The unblinded personnel were not involved or did not perform any study assessments.

Yes

Ferric carboxymaltose

FCM, Ferinject®, iron

Solution for injection/infusion

Intravenous use

Intravenous bolus dose of either 500 or 1,000 mg of FCM depending upon screening Hb and body weight. Potential additional doses on Week 6 depending upon screening Hb and body weight. Potential additional doses on Weeks 12, 24 and 36 depending upon body weight and whether serum ferritin <100 ng/mL or serum ferritin 100-300 ng/mL with transferrin saturation <20%.

Normal saline

NaCl solution

Solution for infusion

Intravenous use

Intravenous bolus dose of saline in a volume to match the doses of FCM depending upon screening Hb and body weight. Potential additional doses on Week 6 depending upon screening Hb and body weight. Potential additional doses on Weeks 12, 24 and 36 depending upon body weight and whether serum ferritin <100 ng/mL or serum ferritin 100-300 ng/mL with transferrin saturation <20%.

Ferric carboxymaltose

Placebo

Ferric carboxymaltose

Placebo

Full analysis set (FAS) - FCM

The full analysis set was defined as all randomised subjects who received at least 1 dose of study drug and had 1 post-baseline assessment.

Full analysis set (FAS) - Placebo

The full analysis set was defined as all randomised subjects who received at least 1 dose of study drug and had 1 post-baseline assessment.

The 6MWT was performed in an area equipped for cardiopulmonary resuscitation and was administered by qualified and experienced personnel blinded to a subject’s treatment allocation. Subjects were instructed to walk at their own pace while attempting to cover as much ground as possible in 6 minutes. Subjects were allowed to rest during the test, but were encouraged to resume walking as soon as they felt physically capable to do so. The distance walked in 6 minutes, to the nearest metre, was recorded. Baseline is the last non-missing assessment prior to the first dose of treatment. If a subject was hospitalized and unable to exercise, the worst non-null value across the study for all subjects was used. If a subject died prior to the visit, value was set to zero. If a subject was alive and not hospitalized, no imputation was done for missing values. Positive change values indicate greater distance walked at week 24 and therefore improved functional capacity.

Primary

Day 1 (baseline), Week 24

The primary efficacy analyses of the change in 6MWT from Baseline to Week 24 were conducted using an analysis of covariance (ANCOVA), with adjustment for baseline 6MWT distance, Hb level at screening (<12 g/dL, ≥12 g/dL) and pooled country (Russia, Ukraine, Poland, and Pooled C (other European countries: Austria, Italy, Portugal, Spain, Sweden, and United Kingdom)).

Full analysis set (FAS) - FCM v Full analysis set (FAS) - Placebo

261

Pre-specified

33.2

2-sided

Standard error of the mean

10.52

The change in 6MWT from baseline over time (i.e., to weeks 6, 12, 24, 36 and 52) was analysed with the imputation for death and hospitalisation assessment using an ANCOVA with repeated measures for the FAS. Baseline is the last non-missing assessment prior to the first dose of treatment. If a subject was hospitalized and unable to exercise, the worst non-null value across the study for all subjects was used. If a subject died prior to the visit, value was set to zero. If a subject was alive and not hospitalized, no imputation was done for missing values. Positive change values indicate greater distance walked at week 24 and therefore improved functional capacity.

Secondary

Day 1 (baseline), Weeks 6, 12, 24, 36, 52

The change in 6MWT from baseline over time (i.e., to weeks 6, 12, 24, 36 and 52) was analysed with the imputation for death and hospitalisation assessment using an ANCOVA with repeated measures for the FAS. Treatment, visit, gender, age, pooled country, baseline score, and Hb level at screening (<12 g/dL or ≥12 g/dL) were included as covariates in the repeated measures model; a term of interaction between visit and treatment was also included. Subjects in this analysis is 291.

Full analysis set (FAS) - FCM v Full analysis set (FAS) - Placebo

301

Pre-specified

13.6

2-sided

Standard error of the mean

9.63

The change in 6MWT from baseline over time (i.e., to weeks 6, 12, 24, 36 and 52) was analysed with the imputation for death and hospitalisation assessment using an ANCOVA with repeated measures for the FAS. Treatment, visit, gender, age, pooled country, baseline score, and Hb level at screening (<12 g/dL or ≥12 g/dL) were included as covariates in the repeated measures model; a term of interaction between visit and treatment was also included. Subjects in this analysis is 283.

Full analysis set (FAS) - FCM v Full analysis set (FAS) - Placebo

301

Pre-specified

15.9

2-sided

Standard error of the mean

9.77

The change in 6MWT from baseline over time (i.e., to weeks 6, 12, 24, 36 and 52) was analysed with the imputation for death and hospitalisation assessment using an ANCOVA with repeated measures for the FAS. Treatment, visit, gender, age, pooled country, baseline score, and Hb level at screening (<12 g/dL or ≥12 g/dL) were included as covariates in the repeated measures model; a term of interaction between visit and treatment was also included. Subjects in this analysis is 261.

Full analysis set (FAS) - FCM v Full analysis set (FAS) - Placebo

301

Pre-specified

32.9

2-sided

Standard error of the mean

10.17

The change in 6MWT from baseline over time (i.e., to weeks 6, 12, 24, 36 and 52) was analysed with the imputation for death and hospitalisation assessment using an ANCOVA with repeated measures for the FAS. Treatment, visit, gender, age, pooled country, baseline score, and Hb level at screening (<12 g/dL or ≥12 g/dL) were included as covariates in the repeated measures model; a term of interaction between visit and treatment was also included. Subjects in this analysis is 245.

Full analysis set (FAS) - FCM v Full analysis set (FAS) - Placebo

301

Pre-specified

41.8

2-sided

Standard error of the mean

10.5

The change in 6MWT from baseline over time (i.e., to weeks 6, 12, 24, 36 and 52) was analysed with the imputation for death and hospitalisation assessment using an ANCOVA with repeated measures for the FAS. Treatment, visit, gender, age, pooled country, baseline score, and Hb level at screening (<12 g/dL or ≥12 g/dL) were included as covariates in the repeated measures model; a term of interaction between visit and treatment was also included. Subjects in this analysis is 246.

Full analysis set (FAS) - FCM v Full analysis set (FAS) - Placebo

301

Pre-specified

36.1

2-sided

Standard error of the mean

10.47

The PGA, which was translated in the local language, asked subjects to rate the change in their medical condition since the start of the study as follows: “has much improved”, “has (moderately) improved”, “has a little improved”, “is unchanged”, “is a little worse”, “is (moderately) worse” or “is much worse”. Questionnaires were completed before any other procedures at each visit. Missing PGA values due to death were imputed as “died” and missing PGA values due to hospitalisation were imputed as “much worse.”

Secondary

Week 6

Results at each time point are from a repeated measures polytomous model including treatment, visit, gender, age, pooled country, haemoglobin level at screening (<12 g/dL, ≥12 g/dL), as well as interaction between visit and treatment. Wald 95% CI are offered below.

Full analysis set (FAS) - FCM v Full analysis set (FAS) - Placebo

291

Pre-specified

0.81

2-sided

The PGA, which was translated in the local language, asked subjects to rate the change in their medical condition since the start of the study as follows: “has much improved”, “has (moderately) improved”, “has a little improved”, “is unchanged”, “is a little worse”, “is (moderately) worse” or “is much worse”. Questionnaires were completed before any other procedures at each visit. Missing PGA values due to death were imputed as “died” and missing PGA values due to hospitalisation were imputed as “much worse.”

Secondary

Week 12

Results at each time point are from a repeated measures polytomous model including treatment, visit, gender, age, pooled country, haemoglobin level at screening (<12 g/dL, ≥12 g/dL), as well as interaction between visit and treatment. Wald 95% CI are offered below.

Full analysis set (FAS) - FCM v Full analysis set (FAS) - Placebo

285

Pre-specified

0.65

2-sided

The PGA, which was translated in the local language, asked subjects to rate the change in their medical condition since the start of the study as follows: “has much improved”, “has (moderately) improved”, “has a little improved”, “is unchanged”, “is a little worse”, “is (moderately) worse” or “is much worse”. Questionnaires were completed before any other procedures at each visit. Missing PGA values due to death were imputed as “died” and missing PGA values due to hospitalisation were imputed as “much worse.”

Secondary

Week 24

Results at each time point are from a repeated measures polytomous model including treatment, visit, gender, age, pooled country, haemoglobin level at screening (<12 g/dL, ≥12 g/dL), as well as interaction between visit and treatment. Wald 95% CI are offered below.

Full analysis set (FAS) - FCM v Full analysis set (FAS) - Placebo

261

Pre-specified

0.63

2-sided

The PGA, which was translated in the local language, asked subjects to rate the change in their medical condition since the start of the study as follows: “has much improved”, “has (moderately) improved”, “has a little improved”, “is unchanged”, “is a little worse”, “is (moderately) worse” or “is much worse”. Questionnaires were completed before any other procedures at each visit. Missing PGA values due to death were imputed as “died” and missing PGA values due to hospitalisation were imputed as “much worse.”

Secondary

Week 36

Results at each time point are from a repeated measures polytomous model including treatment, visit, gender, age, pooled country, haemoglobin level at screening (<12 g/dL, ≥12 g/dL), as well as interaction between visit and treatment. Wald 95% CI are offered below.

Full analysis set (FAS) - FCM v Full analysis set (FAS) - Placebo

247

Pre-specified

0.44

2-sided

The PGA, which was translated in the local language, asked subjects to rate the change in their medical condition since the start of the study as follows: “has much improved”, “has (moderately) improved”, “has a little improved”, “is unchanged”, “is a little worse”, “is (moderately) worse” or “is much worse”. Questionnaires were completed before any other procedures at each visit. Missing PGA values due to death were imputed as “died” and missing PGA values due to hospitalisation were imputed as “much worse.”

Secondary

Week 52

Results at each time point are from a repeated measures polytomous model including treatment, visit, gender, age, pooled country, haemoglobin level at screening (<12 g/dL, ≥12 g/dL), as well as interaction between visit and treatment. Wald 95% CI are offered below.

Full analysis set (FAS) - FCM v Full analysis set (FAS) - Placebo

246

Pre-specified

0.44

2-sided

The PGA, which was translated in the local language, asked subjects to rate the change in their medical condition since the start of the study as follows: “has much improved”, “has (moderately) improved”, “has a little improved”, “is unchanged”, “is a little worse”, “is (moderately) worse” or “is much worse”. Questionnaires were completed before any other procedures at each visit. Missing PGA values due to death were imputed as “died” and missing PGA values due to hospitalisation were imputed as “much worse.” The Week 52 Endpoint value used last-observation-carried-forward (LOCF).

Secondary

Last available PGA value, up to Week 52

Results for the Week 52 Endpoint analysis are from logistic regression including treatment, gender, age, pooled country, haemoglobin level at screening (<12 g/dL, ≥12 g/dL), as well as interaction between visit and treatment. Wald 95% CI are offered below.

Full analysis set (FAS) - FCM v Full analysis set (FAS) - Placebo

301

Pre-specified

0.53

2-sided

Assessments of NYHA functional class were completed by a cardiologist. - Class I Patients have cardiac disease but without the resulting limitations of physical activity. - Class II Patients have slight limitation of physical activity. They are comfortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnoea, or angina pain. - Class III Patients marked limitation of physical activity. They are comfortable at rest. Less than ordinary physical activity causes fatigue, palpitation, dyspnoea, or anginal pain. - Class IV Patients an inability to carry on any physical activity without discomfort. Symptoms may be present even at rest. If any physical activity is undertaken, discomfort is increased. - Class V Patient died Subjects who were hospitalised at the time of assessment were imputed as “Class IV” and those who had died were imputed as “Class V.” Negative change from baseline values indicate improvement in functional class.

Secondary

Baseline (Day 1), Weeks 6, 12, 24, 36, 52

The change in NYHA classification at each time point was analysed using repeated measures polytomous regression model including treatment, visit, gender, age, pooled country, baseline score and Hb level at screening (<12 g/dL or ≥12 g/dL) as covariates in the model; a term of interaction between visit and treatment was also included. Wald 95% CI are offered below. Subjects in this analysis is 292.

Full analysis set (FAS) - FCM v Full analysis set (FAS) - Placebo

301

Pre-specified

0.68

2-sided

The change in NYHA classification at each time point was analysed using repeated measures polytomous regression model including treatment, visit, gender, age, pooled country, baseline score and Hb level at screening (<12 g/dL or ≥12 g/dL) as covariates in the model; a term of interaction between visit and treatment was also included. Wald 95% CI are offered below. Subjects in this analysis is 285.

Full analysis set (FAS) - FCM v Full analysis set (FAS) - Placebo

301

Pre-specified

0.6

2-sided

The change in NYHA classification at each time point was analysed using repeated measures polytomous regression model including treatment, visit, gender, age, pooled country, baseline score and Hb level at screening (<12 g/dL or ≥12 g/dL) as covariates in the model; a term of interaction between visit and treatment was also included. Wald 95% CI are offered below. Subjects in this analysis is 264.

Full analysis set (FAS) - FCM v Full analysis set (FAS) - Placebo

301

Pre-specified

0.36

2-sided

The change in NYHA classification at each time point was analysed using repeated measures polytomous regression model including treatment, visit, gender, age, pooled country, baseline score and Hb level at screening (<12 g/dL or ≥12 g/dL) as covariates in the model; a term of interaction between visit and treatment was also included. Wald 95% CI are offered below. Subjects in this analysis is 248.

Full analysis set (FAS) - FCM v Full analysis set (FAS) - Placebo

301

Pre-specified

0.23

2-sided

The change in NYHA classification at each time point was analysed using repeated measures polytomous regression model including treatment, visit, gender, age, pooled country, baseline score and Hb level at screening (<12 g/dL or ≥12 g/dL) as covariates in the model; a term of interaction between visit and treatment was also included. Wald 95% CI are offered below. Subjects in this analysis is 248.

Full analysis set (FAS) - FCM v Full analysis set (FAS) - Placebo

301

Pre-specified

0.21

2-sided

Prior to performing the 6MWT, and after vital signs were recorded, subjects completed the fatigue score self-assessment which was determined using a 10-point visual analogue fatigue scale (Version 1.1 dated 2 November 2011), ranging from 1 for no fatigue to 10 for very severe fatigue. The Week 52 Endpoint value used last-observation-carried-forward (LOCF). Negative change scores indicate an improvement in severity of fatigue. Least-Squares-Means are from an ANCOVA with repeated measures model with treatment, visit, gender, age, pooled country, baseline value, haemoglobin level at screening (<12g/dL, >=12g/dL). Also interaction between visit and treatment. “Pooled country” is defined as Poland, Russia, Ukraine considered separately all remaining countries are pooled together.

Secondary

Baseline (Day 1), Weeks 6, 12, 24, 36, 52

Least-Squares-Means are from an ANCOVA with repeated measures model with treatment, visit, gender, age, pooled country, baseline value, haemoglobin level at screening (<12g/dL, >=12g/dL). Also interaction between visit and treatment. Subjects in this analysis is 280.

Full analysis set (FAS) - FCM v Full analysis set (FAS) - Placebo

301

Pre-specified

-0.2

2-sided

Standard error of the mean

0.18

Least-Squares-Means are from an ANCOVA with repeated measures model with treatment, visit, gender, age, pooled country, baseline value, haemoglobin level at screening (<12g/dL, >=12g/dL). Also interaction between visit and treatment. Subjects in this analysis is 266.

Full analysis set (FAS) - FCM v Full analysis set (FAS) - Placebo

301

Pre-specified

-0.5

2-sided

Standard error of the mean

0.19

Least-Squares-Means are from an ANCOVA with repeated measures model with treatment, visit, gender, age, pooled country, baseline value, haemoglobin level at screening (<12g/dL, >=12g/dL). Also interaction between visit and treatment. Subjects in this analysis is 241.

Full analysis set (FAS) - FCM v Full analysis set (FAS) - Placebo

301

Pre-specified

-0.6

2-sided

Standard error of the mean

0.2

Least-Squares-Means are from an ANCOVA with repeated measures model with treatment, visit, gender, age, pooled country, baseline value, haemoglobin level at screening (<12g/dL, >=12g/dL). Also interaction between visit and treatment. Subjects in this analysis is 222.

Full analysis set (FAS) - FCM v Full analysis set (FAS) - Placebo

301

Pre-specified

-0.8

2-sided

Standard error of the mean

0.21

Least-Squares-Means are from an ANCOVA with repeated measures model with treatment, visit, gender, age, pooled country, baseline value, haemoglobin level at screening (<12g/dL, >=12g/dL). Also interaction between visit and treatment. Subjects in this analysis is 213.

Full analysis set (FAS) - FCM v Full analysis set (FAS) - Placebo

301

Pre-specified

-0.7

2-sided

Standard error of the mean

0.21

Least-Squares-Means are from an ANCOVA with repeated measures model with treatment, visit, gender, age, pooled country, baseline value, haemoglobin level at screening (<12g/dL, >=12g/dL). Also interaction between visit and treatment. Subjects in this analysis is 293.

Full analysis set (FAS) - FCM v Full analysis set (FAS) - Placebo

301

Pre-specified

-0.5

2-sided

Standard error of the mean

0.19

The KCCQ is a 23-item, self-administered questionnaire that quantifies physical limitation, symptoms (stability, frequency, and burden), self-efficacy, social function, and quality of life (QoL). Scores are transformed to a range of 0 to 100, in which higher scores reflect better health status. The Overall Summary Score is the mean of the scores for physical limitation, total symptom, QoL, and social limitation. The KCCQ was translated in the local language (validated, official versions) of each of the participating countries, and were completed by the subjects before any other procedures at each visit. The Week 52 Endpoint value used last-observation-carried-forward (LOCF). Positive change from baseline scores indicate improving health status.

Secondary

Baseline (Day 1), Weeks 6, 12, 24, 36, 52

Least-Squares-Means are from an ANCOVA with repeated measures model with treatment, visit, gender, age, pooled country, baseline value, haemoglobin level at screening (<12g/dL, >=12g/dL). Also interaction between visit and treatment. Subjects in this analysis is 289.

Full analysis set (FAS) - FCM v Full analysis set (FAS) - Placebo

301

Pre-specified

1.8

2-sided

Standard error of the mean

1.52

Least-Squares-Means are from an ANCOVA with repeated measures model with treatment, visit, gender, age, pooled country, baseline value, haemoglobin level at screening (<12g/dL, >=12g/dL). Also interaction between visit and treatment. Subjects in this analysis is 274.

Full analysis set (FAS) - FCM v Full analysis set (FAS) - Placebo

301

Pre-specified

3.3

2-sided

Standard error of the mean

1.57

Least-Squares-Means are from an ANCOVA with repeated measures model with treatment, visit, gender, age, pooled country, baseline value, haemoglobin level at screening (<12g/dL, >=12g/dL). Also interaction between visit and treatment. Subjects in this analysis is 249.

Full analysis set (FAS) - FCM v Full analysis set (FAS) - Placebo

301

Pre-specified

1.3

2-sided

Standard error of the mean

1.64

Least-Squares-Means are from an ANCOVA with repeated measures model with treatment, visit, gender, age, pooled country, baseline value, haemoglobin level at screening (<12g/dL, >=12g/dL). Also interaction between visit and treatment. Subjects in this analysis is 227.

Full analysis set (FAS) - FCM v Full analysis set (FAS) - Placebo

301

Pre-specified

5

2-sided

Standard error of the mean

1.72

Least-Squares-Means are from an ANCOVA with repeated measures model with treatment, visit, gender, age, pooled country, baseline value, haemoglobin level at screening (<12g/dL, >=12g/dL). Also interaction between visit and treatment. Subjects in this analysis is 220.

Full analysis set (FAS) - FCM v Full analysis set (FAS) - Placebo

301

Pre-specified

4.5

2-sided

Standard error of the mean

1.75

Least-Squares-Means are from an ANCOVA with repeated measures model with treatment, visit, gender, age, pooled country, baseline value, haemoglobin level at screening (<12g/dL, >=12g/dL). Also interaction between visit and treatment. Subjects in this analysis is 299.

Full analysis set (FAS) - FCM v Full analysis set (FAS) - Placebo

301

Pre-specified

4.5

2-sided

Standard error of the mean

1.76

The KCCQ is a 23-item, self-administered questionnaire that quantifies physical limitation, symptoms (stability, frequency, and burden), self-efficacy, social function, and quality of life (QoL). Scores are transformed to a range of 0 to 100, in which higher scores reflect better health status. Only the symptom frequency score is reported in this outcome. The KCCQ was translated in the local language (validated, official versions) of each of the participating countries, and were completed by the subjects before any other procedures at each visit. The Week 52 Endpoint value used last-observation-carried-forward (LOCF). Positive change from baseline scores indicate improving health status.

Secondary

Baseline (Day 1), Weeks 6, 12, 24, 36, 52

Least-Squares-Means are from an ANCOVA with repeated measures model with treatment, visit, gender, age, pooled country, baseline value, haemoglobin level at screening (<12g/dL, >=12g/dL). Also interaction between visit and treatment. Subjects in this analysis is 287.

Full analysis set (FAS) - FCM v Full analysis set (FAS) - Placebo

301

Pre-specified

2.4

2-sided

Standard error of the mean

2.04

Least-Squares-Means are from an ANCOVA with repeated measures model with treatment, visit, gender, age, pooled country, baseline value, haemoglobin level at screening (<12g/dL, >=12g/dL). Also interaction between visit and treatment. Subjects in this analysis is 272.

Full analysis set (FAS) - FCM v Full analysis set (FAS) - Placebo

301

Pre-specified

1.6

2-sided

Standard error of the mean

2.1

Least-Squares-Means are from an ANCOVA with repeated measures model with treatment, visit, gender, age, pooled country, baseline value, haemoglobin level at screening (<12g/dL, >=12g/dL). Also interaction between visit and treatment. Subjects in this analysis is 247.

Full analysis set (FAS) - FCM v Full analysis set (FAS) - Placebo

301

Pre-specified

2.7

2-sided

Standard error of the mean

2.2

Least-Squares-Means are from an ANCOVA with repeated measures model with treatment, visit, gender, age, pooled country, baseline value, haemoglobin level at screening (<12g/dL, >=12g/dL). Also interaction between visit and treatment. Subjects in this analysis is 226.

Full analysis set (FAS) - FCM v Full analysis set (FAS) - Placebo

301

Pre-specified

3.5

2-sided

Standard error of the mean

2.3

Least-Squares-Means are from an ANCOVA with repeated measures model with treatment, visit, gender, age, pooled country, baseline value, haemoglobin level at screening (<12g/dL, >=12g/dL). Also interaction between visit and treatment. Subjects in this analysis is 220.

Full analysis set (FAS) - FCM v Full analysis set (FAS) - Placebo

301

Pre-specified

5.5

2-sided

Standard error of the mean

2.34

Least-Squares-Means are from an ANCOVA with repeated measures model with treatment, visit, gender, age, pooled country, baseline value, haemoglobin level at screening (<12g/dL, >=12g/dL). Also interaction between visit and treatment. Subjects in this analysis is 297.

Full analysis set (FAS) - FCM v Full analysis set (FAS) - Placebo

301

Pre-specified

4.3

2-sided

Standard error of the mean

2.35

The EQ-5D is a descriptive system of health-related QoL consisting of 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. For each dimension, subjects gave 1 of 3 responses for severity (1=no problems; 2=some or moderate problems; and 3=extreme problems/not able to do). A EQ-5D index score was calculated using the algorithm from the UK scoring methodology currently advised for a European based trial. Full health receives a score of 1; scores of 2 or 3 for any of the five dimensions plus combinations of scores result in subtractions from the 'full health' index score of 1. The Week 52 Endpoint value used last-observation-carried-forward (LOCF).

Secondary

Baseline (Day 1), Weeks 6, 12, 24, 36, 52

Least-Squares-Means are from an ANCOVA with repeated measures model with treatment, visit, gender, age, pooled country, baseline value, haemoglobin level at screening (<12g/dL, >=12g/dL). Also interaction between visit and treatment. “Pooled country” is defined as Poland, Russia, Ukraine considered separately all remaining countries are pooled together. Subjects in this analysis is 289.

Full analysis set (FAS) - FCM v Full analysis set (FAS) - Placebo

301

Pre-specified

0.0026

2-sided

Standard error of the mean

0.02021

Least-Squares-Means are from an ANCOVA with repeated measures model with treatment, visit, gender, age, pooled country, baseline value, haemoglobin level at screening (<12g/dL, >=12g/dL). Also interaction between visit and treatment. “Pooled country” is defined as Poland, Russia, Ukraine considered separately all remaining countries are pooled together. Subjects in this analysis is 272.

Full analysis set (FAS) - FCM v Full analysis set (FAS) - Placebo

301

Pre-specified

-0.0088

2-sided

Standard error of the mean

0.02084

Least-Squares-Means are from an ANCOVA with repeated measures model with treatment, visit, gender, age, pooled country, baseline value, haemoglobin level at screening (<12g/dL, >=12g/dL). Also interaction between visit and treatment. “Pooled country” is defined as Poland, Russia, Ukraine considered separately all remaining countries are pooled together. Subjects in this analysis is 249.

Full analysis set (FAS) - FCM v Full analysis set (FAS) - Placebo

301

Pre-specified

-0.0046

2-sided

Standard error of the mean

0.02177

Least-Squares-Means are from an ANCOVA with repeated measures model with treatment, visit, gender, age, pooled country, baseline value, haemoglobin level at screening (<12g/dL, >=12g/dL). Also interaction between visit and treatment. “Pooled country” is defined as Poland, Russia, Ukraine considered separately all remaining countries are pooled together. Subjects in this analysis is 227.

Full analysis set (FAS) - FCM v Full analysis set (FAS) - Placebo

301

Pre-specified

0.0534

2-sided

Standard error of the mean

0.0228

Least-Squares-Means are from an ANCOVA with repeated measures model with treatment, visit, gender, age, pooled country, baseline value, haemoglobin level at screening (<12g/dL, >=12g/dL). Also interaction between visit and treatment. “Pooled country” is defined as Poland, Russia, Ukraine considered separately all remaining countries are pooled together. Subjects in this analysis is 220.

Full analysis set (FAS) - FCM v Full analysis set (FAS) - Placebo

301

Pre-specified

-0.0058

2-sided

Standard error of the mean

0.02318

Least-Squares-Means are from an ANCOVA with repeated measures model with treatment, visit, gender, age, pooled country, baseline value, haemoglobin level at screening (<12g/dL, >=12g/dL). Also interaction between visit and treatment. “Pooled country” is defined as Poland, Russia, Ukraine considered separately all remaining countries are pooled together. Subjects in this analysis is 299.

Full analysis set (FAS) - FCM v Full analysis set (FAS) - Placebo

301

Pre-specified

0.0046

2-sided

Standard error of the mean

0.02206

Time-to-event was calculated as (date of event – date of first study medication administration) + 1. Endpoint is defined as any time post baseline and on/before completion or withdrawal. Subjects are censored at completion or withdrawal. Values of 999 indicates the time could not be calculated due to insufficient events.

Secondary

Day 1 up to day 418

The hazard ratio and associated 95% CI comes from the proportional hazards modeling.

Full analysis set (FAS) - Placebo v Full analysis set (FAS) - FCM

301

Pre-specified

0.7

2-sided

Time-to-event was calculated as (date of event – date of first study medication administration) + 1. Endpoint is defined as any time post baseline and on/before completion or withdrawal. Subjects are censored at completion or withdrawal. Values of 999 indicates the time could not be calculated due to insufficient events.

Secondary

Day 1 up to Day 418

The hazard ratio and associated 95% CI comes from the proportional hazards modeling.

Full analysis set (FAS) - FCM v Full analysis set (FAS) - Placebo

301

Pre-specified

0.9

2-sided

An adverse event (AE) is any unfavorable and unintended sign (including an abnormal laboratory finding), symptom or disease temporally associated with the administration, at any dose, of a medicinal or therapeutic product whether or not considered related to that product. Relation to study drug was assessed by the investigator. Severity was rated by the investigator on a scale of 1 (mild) to 3 (severe - defined as incapacitating and the subject is unable to work or complete usual activity). Serious AEs include death (death due to progressive disease were not reported as an SAE), a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, or an important medical event that jeopardized the patient and required medical intervention to prevent the previously listed serious outcomes.

Secondary

Day 1 up to Week 52

“Any cardiac failure event” includes the following preferred terms: cardiac failure, cardiac failure chronic, cardiac failure acute, acute left ventricular failure, cardiogenic shock, and left ventricular failure.

Secondary

Day 1 to Week 52

Only treatment-emergent adverse events leading to hospitalisation were adjudicated for this analysis. Adjudication was performed by the independent and blinded Clinical Adjudication Committee. Where multiple events led to the same hospitalisation, then only the primary reason for hospitalisation was adjudicated. Incidence of hospitalisation was computed as the number of subjects who experienced adverse events leading to hospitalisation divided by the number of subjects in that treatment group. CHF - chronic heart failure CV - cardiovascular

Secondary

Day 1 to Week 52

The MDRD6 formula is: eGFR=161.5 * (standardised serum creatinine * 0.0113)^-0.999 * (age)^-0.176 * (BUN mmol/L * 2.801)^-0.17 * (albumin g/L * 0.1)^0.318 * 1.18 (if African American) * 0.762 (if female). Given that the reliability of the MDRD6 formula is limited for results >60 mL/min/1.73 m^2, all results for MDRD6 which were reported by the laboratory as >60 mL/min/1.73 m^2 were rounded up to 61, therefore limiting the interpretation of summary statistics for this data. The Week 52 Endpoint value used last-observation-carried-forward (LOCF).

Secondary

Baseline (Day 1), Weeks 6, 12, 24, 36, 52

EPI-CKD uses a formula that takes into account race, gender and serum creatinine value. The Week 52 Endpoint value used last-observation-carried-forward (LOCF).

Secondary

Baseline (Day 1), Weeks 6, 12, 24, 36, 52

Day 0 (post treatment) up to Week 52

16.0

Placebo

Ferric carboxymaltose