FER-CARS-04

Vifor (International) Inc.

Rechenstrasse 37, St. Gallen, Switzerland, CH-9001

Medical Information, Vifor (International) Inc., 41 588518222, medinfo@viforpharma.com

Medical Information, Vifor (International) Inc., 41 588518222, medinfo@viforpharma.com

No

No

No

Final

27 Mar 2017

No

Yes

18 May 2016

No

Primary objective of the trial is to evaluate the effect of intravenous (IV) ferric carboxymaltose (FCM) compared to standard of care (SoC) on exercise capacity as assessed by weight-adjusted peak oxygen uptake (VO2).

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), 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 authorized persons could examine their records but that personal information would be treated as strictly confidential and would not be publicly available.

08 Sep 2011

No

Yes

Netherlands: 22

Poland: 36

Spain: 10

Belgium: 8

France: 10

Germany: 24

Italy: 18

Russian Federation: 42

Australia: 4

174

128

0

0

0

0

0

0

90

82

2

Overall trial (overall period)

Randomised - controlled

This study was conducted as an open-label study. To minimise bias, the readings for the primary endpoint (peak VO2) were completed by an independent consultant unaware of subject treatment. All peak VO2 assessments were recalculated by the centralised CORELAB which was blinded to all subject and visit identifiers. Echocardiography (ECHO) assessments were conducted in a blinded manner by the ECHOLAB, and New York Heart Association (NYHA) assessments were performed by a blinded physician.

Yes

Ferric carboxymaltose

FCM, Ferinject

Solution for injection/infusion

Intravenous use, Intravenous bolus use

FCM solution containing 5% w/v iron; doses of 500 mg iron (10 mL) or 1,000 mg iron (20 mL). FCM was administered as either an undiluted bolus IV injection or by IV infusion by designated staff at each site. For bolus injection, FCM was to be administered over at least 1 minute. For IV infusion, FCM was diluted in sterile 0.9% sodium chloride (saline): i.e., 500 mg (10 mL) diluted into approximately 100 mL saline and administered over at least 6 minutes; or 1,000 mg (20 mL) diluted into approximately 250 mL saline and administered over at least 15 minutes. All administrations, including duration of injection/infusion and if the injection/infusion was interrupted/stopped, and any related information, were documented in the site source data and in the Case Report Form (CRF).

No investigational medicinal product assigned in this arm

Ferric carboxymaltose (FCM)

Standard of Care (SoC)

Ferric carboxymaltose (FCM)

Standard of Care (SoC)

Full analysis set (FAS) - FCM

Full analysis set (FAS) consisted of all subjects randomised to FCM group, received at least 1 dose of randomised study treatment and attended at least 1 post-Baseline (BL) visit with valid efficacy data measurements. Note: One subject was randomised to SoC but received FCM. This subject is counted in the SoC group for the FAS. One subject was randomized to FCM, but did not receive treatment with the study drug and therefore, was excluded from the Full Analysisi Set (FAS).

Full analysis set (FAS) - SoC

Full analysis set (FAS) consisted of all subjects randomised to SoC group and attended at least 1 post-baseline visit with non-missing efficacy data measurement. Note: The subject randomised to SoC who received FCM treatment is counted in the SoC group for the FAS.

Safety Set (SS) - FCM

Safety population consists of all randomised subjects who have received at least 1 dose of study medication.

Safety Set (SS) - SoC

Sefety set consists of all randomised subjects for SoC group. NOTE: One subject was randomised to SoC but received FCM and is therefore, not counted in the SoC arm for the SS, but in the FCM arm. Another subject was randomized to FCM, but did not receive treatment with the study drug and therefore, was excluded from the Safety Set (SS).

The primary efficacy endpoint of the study was the change in weight-adjusted peak VO2 (mL/kg/min) from Baseline (BL) to Week 24 (LOCF). Results are presented for the absolute values at BL and Week 24 (LOCF) and change value from BL to Week 24 (LOCF). Imputation for death is equivalent to 0.

Primary

From Baseline to Week 24 (LOCF)

For analysis of the primary endpoint (with Last Observation Carried Forward (LOCF) and imputation for deaths), a comparison between treatment groups was assessed using an ANCOVA model with adjustment for BL peak VO2,Hb level at screening (<12 g/dl, ≥12 g/dl), and pooled country. A second ANCOVA (sensitivity analysis) was conducted to examine the terms of interaction between pooled country and treatment group and between Hb level at screening and treatment group. Subjects in the analysis are 161.

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

161

Pre-specified

1.04

2-sided

Standard error of the mean

0.442

The change in peak VO2 from BL over time (i.e., to Weeks 12 and 24) was analysed on observed cases (without any imputation) using an ANCOVA with repeated measures for the FAS with treatment, visit gender, age, BL score, pooled country and Hb level at screening (<12 g/dl or ≥12 g/dl) (FAS). Also interaction between visit and treatment.

Secondary

Week 12, Week 24

Peak VO2 from BL over time at Week 12 was analysed on observed cases (without any imputation) using an ANCOVA with repeated measures with treatment, gender, age, BL score, pooled country, visit and Hb level at screening (<12 g/dl or ≥12 g/dl). Also interaction between visit and treatment. Subjects in this analysis are 135.

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

135

Pre-specified

0.45

2-sided

Standard error of the mean

0.379

Peak VO2 from BL over time at Week 24 was analysed on observed cases (without any imputation) using an ANCOVA with repeated measures, treatment, gender, age, BL score, pooled country, visit and Hb level at screening (<12 g/dl or ≥12 g/dl). Also interaction between visit and treatment. Subjects in this analysis are 134.

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

135

Pre-specified

0.35

2-sided

Standard error of the mean

0.38

Chronic Heart Failure (CHF) severity was determined by blinded study physicians using the NYHA functional classification system which relates symptoms to everyday activities and the subject’s Quality of life (QoL). Whenever possible, assessment of NYHA was performed by the same site physician at each visit and for all subjects at the site. Values missing due to subjects who died were imputed using the worst possible assessment of Class V, and subjects hospitalised during the planned assessment were attributed a value of Class IV. If a subject was alive and not hospitalised, no imputation was done for missing values. The analysis of change in NYHA scores over time is a single analysis that includes together the analysis from BL to week 6, 12, 24. As it is not possible to represent it in EudraCT as an unique end point (single analysis model), it has been populated separately for every time point (week).

Secondary

From Baseline to Week 6

The change in NYHA classification at each time point was analysed using repeated measures polytomous regression as described for non-continuous variables. Treatment, visit, gender, age, pooled country, BL score, and Hb level at screening (<12 g/dl or ≥12 g/dl) were included as covariates in the model; a term of interaction between visit and treatment was also included.

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

156

Pre-specified

2.49

2-sided

Chronic Heart Failure (CHF) severity was determined by blinded study physicians using the NYHA functional classification system which relates symptoms to everyday activities and the subject’s Quality of life (QoL). Whenever possible, assessment of NYHA was performed by the same site physician at each visit and for all subjects at the site. Values missing due to subjects who died were imputed using the worst possible assessment of Class V, and subjects hospitalised during the planned assessment were attributed a value of Class IV. If a subject was alive and not hospitalised, no imputation was done for missing values. The analysis of change in NYHA scores over time is a single analysis that includes together the analysis from BL to week 6, 12, 24. As it is not possible to represent it in EudraCT as an unique end point (single analysis model), it has been populated separately for every time point (week).

Secondary

From Baseline to Week 12

The change in NYHA classification at each time point was analysed using repeated measures polytomous regression as described for non-continuous variables. Treatment, visit, gender, age, pooled country, BL score, and Hb level at screening (<12 g/dl or ≥12 g/dl) were included as covariates in the model; a term of interaction between visit and treatment was also included.

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

152

Pre-specified

2.45

2-sided

Chronic Heart Failure (CHF) severity was determined by blinded study physicians using the NYHA functional classification system which relates symptoms to everyday activities and the subject’s Quality of life (QoL). Whenever possible, assessment of NYHA was performed by the same site physician at each visit and for all subjects at the site. Values missing due to subjects who died were imputed using the worst possible assessment of Class V, and subjects hospitalised during the planned assessment were attributed a value of Class IV. If a subject was alive and not hospitalised, no imputation was done for missing values. The analysis of change in NYHA scores over time is a single analysis that includes together the analysis from BL to week 6, 12, 24. As it is not possible to represent it in EudraCT as an unique end point (single analysis model), it has been populated separately for every time point (week).

Secondary

From Baseline to Week 24

The change in NYHA classification at each time point was analysed using repeated measures polytomous regression as described for non-continuous variables. Treatment, visit, gender, age, pooled country, BL score, and Hb level at screening (<12 g/dl or ≥12 g/dl) were included as covariates in the model; a term of interaction between visit and treatment was also included.

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

153

Pre-specified

3.84

2-sided

Chronic Heart Failure (CHF) severity was determined by blinded study physicians using the NYHA functional classification system which relates symptoms to everyday activities and the subject’s Quality of life (QoL). Whenever possible, assessment of NYHA was performed by the same site physician at each visit and for all subjects at the site. Values missing due to subjects who died were imputed using the worst possible assessment of Class V, and subjects hospitalised during the planned assessment were attributed a value of Class IV. If a subject was alive and not hospitalised, no imputation was done for missing values.

Secondary

From Baseline to Week 24 (LOCF) is the last non-missing post-baseline value on or before Week 24.

The change in NYHA classification at Week 24 (LOCF) point was analysed using logistic regression as described for non-continuous variables. Treatment, gender, age, pooled country, BL score, and Hb level at screening (<12 g/dl or ≥12 g/dl) were included as covariates in the model.

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

172

Pre-specified

2.18

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 analysis of PGA over time is a single analysis that includes together the analysis at week 6, 12, 24 and 24(LOCF). As it is not possible to represent it in EudraCT as an unique end point (single analysis model), it has been populated separately for every time point (week).

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) - SoC

152

Pre-specified

1.3

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 analysis of PGA over time is a single analysis that includes together the analysis at week 6, 12, 24 and 24(LOCF). As it is not possible to represent it in EudraCT as an unique end point (single analysis model), it has been populated separately for every time point (week).

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) - SoC

151

Pre-specified

2.3

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 analysis of PGA over time is a single analysis that includes together the analysis at week 6, 12, 24 and 24 (LOCF). As it is not possible to represent it in EudraCT as an unique end point (single analysis model), it has been populated separately for every time point (week).

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) - SoC

153

Pre-specified

2.9

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.” Week 24 (LOCF) is the last non-missing post baseline value on or before week 24. The analysis of PGA over time is a single analysis that includes together the analysis at week 6, 12, 24 and 24 (LOCF). As it is not possible to represent it in EudraCT as an unique end point (single analysis model), it has been populated separately for every time point (week).

Secondary

Week 24 (LOCF)

At Week 24 (LOCF), PGA was analysed with a logistic regression including the same covariates as described for non-continuous variables. Treatment, gender, age, pooled country, and Hb level at screening (<12 g/dl or ≥12 g/dl) were included as covariates in the model.

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

172

Pre-specified

2.3

2-sided

Hospitalisation rate is computed as number of patients experiencing adverse events leading to hospitalisation divided by the number of patients in that treatment group.

Secondary

From Baseline until Week 24

Death rate is computed as number of patients experiencing adverse events leading to death divided by the number of patients in that treatment group.

Secondary

From Baseline until Week 24

Time-to-event analyses for hospitalisation and for death (as well as incidence of hospitalisations and deaths) were based on adjudicated events and were analysed for the SS. Qualification of events as “worsening of CHF” event was determined by an independent and blinded committee that reviewed all deaths and unplanned hospitalisations. For each reason, the incidence rate ratios of the number of recurrent events between treatment groups and its relative 95% confidence interval (CI) and p-values were calculated using a negative binomial regression including total study duration (calculated from BL to Week 24 (LOCF)) as covariate. Number of subjects with at least one event is 11 (12.5%) for the FCM group and 6 (7.1%) for the SoC group.

Secondary

Before Week 6, Week 12, Week 18, Week 24

Safety Set (SS) - FCM v Safety Set (SS) - SoC

173

Pre-specified

1.76

2-sided

Secondary

Before Week 6, Week 12, Week 18, Week 24, Maximum time

Time to First Hospitalisation or Death for Worsening of CHF or Other Cardiovascular Related (CV) Events. 95% CI (confidence interval) for the estimated probability are derived using Greenwood formula. The hazard ratio and associated 95% CI (confidence interval) are calculated from the proportional hazards model.

Safety Set (SS) - FCM v Safety Set (SS) - SoC

173

Pre-specified

2.07

2-sided

From the time the subjects signed the Informed Consent Form. The Adverse Event (AE) reporting ended on the last study visit (Week 24). AEs spontaneously reported within 30 days after the last study visit were included in the safety analyses.

Only Treatment Emergent Adverse Event are reported.

19.0

Ferric carboxymaltose

Standard of Care