VIT-RLS-2012-013

Vifor (International) Inc.

Rechenstrasse 37, St. Gallen, Switzerland, 9001

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

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

No

No

No

Final

22 Apr 2016

Yes

01 Sep 2015

Yes

01 Sep 2015

No

To demonstrate the efficacy of ferric carboxymaltose (FCM) versus placebo in the improvement of symptom severity of restless legs syndrome (RLS) as measured by the International Restless Legs Scale (IRLS) rating after 4 weeks.

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 E6 Guideline for Good Clinical Practice, 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 for informed consent and protection of subject rights (21 CFR, Parts 50 and 56). At the screening visit, subjects were informed about the clinical study. Informed Consent Forms (ICFs) were obtained from the subject according to the regulatory and legal requirements of the participating country, and were retained by the Investigator as part of the study records. Copies of the documents were provided to the subjects. No study specific investigations were conducted until the appropriate valid consent had been obtained. The content of the ICFs was in accordance with the current revision of the Declaration of Helsinki, current International Conference on Harmonisation and Good Clinical Practice guidelines, and Vifor Pharma-Vifor International Inc. policy. 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.

08 Apr 2014

No

No

Finland: 36

Germany: 70

Switzerland: 4

110

106

0

0

0

0

0

0

76

34

0

Overall trial (overall period)

Randomised - controlled

Subjects were blinded for the study drug administration. 2 Assessors were assigned to administer the subject assessment surveys (RLS-DI and CGI surveys/IRLS, RLS-6, PGI-I, Medical Outcomes Study (MOS) sleep scales and QoL-RLS surveys). Assessors were not allowed to randomise, treat subjects, have access to the treatment information, or be present during the administration. A staff member was appointed to randomise, prepare and administer the study drug (not disclosing such information).

Yes

Ferric carboxymaltose

Ferinject®, FCM

Solution for injection

Intravenous use

Fixed single dose of iron as FCM. The 20 mL solution of FCM solution was to be diluted in 250 mL sterile 0.9% NaCl solution and administered by IV drip infusion up to a maximum single dose of 20 mL of FCM (1,000 mg of iron) over 15 (±2) minutes.

Placebo

NaCl

Solution for injection

Intravenous use

Fixed single dose of 250 mL 0.9% NaCl on Day 1 by drip infusion over 15 (±2) minutes.

Ferric carboxymaltose

Placebo

Full Analysis Set (FAS)

All subjects who were randomised to treatment, received at least 1 dose of study medication, and had at least 1 baseline and 1 post-baseline assessment within an analysis visit window for an efficacy parameter before the start of a standard of care treatment if any. There were 110 subjects in the FAS (FCM: 59 subjects, placebo: 51 subjects).

Safety Set (SS)

All randomised subjects who received at least 1 dose of study medication. The subjects in the SS were analysed based on the treatment that they received. In the SS, 58 subjects received FCM and 52 subjects received placebo. One subject was given placebo instead of FCM due to a procedural error. The subject that received placebo instead of FCM was analysed in the placebo treatment group.

Per-Protocol Set (PPS)

All subjects in the FAS who had no major protocol deviations. There were 94 subjects in the PPS (FCM: 52 subjects, placebo: 42 subjects).

Ferric carboxymaltose

Placebo

Full Analysis Set (FAS)

All subjects who were randomised to treatment, received at least 1 dose of study medication, and had at least 1 baseline and 1 post-baseline assessment within an analysis visit window for an efficacy parameter before the start of a standard of care treatment if any. There were 110 subjects in the FAS (FCM: 59 subjects, placebo: 51 subjects).

Safety Set (SS)

All randomised subjects who received at least 1 dose of study medication. The subjects in the SS were analysed based on the treatment that they received. In the SS, 58 subjects received FCM and 52 subjects received placebo. One subject was given placebo instead of FCM due to a procedural error. The subject that received placebo instead of FCM was analysed in the placebo treatment group.

Per-Protocol Set (PPS)

All subjects in the FAS who had no major protocol deviations. There were 94 subjects in the PPS (FCM: 52 subjects, placebo: 42 subjects).

The 2 treatment groups (FCM and placebo) were compared with respect to the change in the IRLS total score (gold standard for efficacy evaluation in RLS) between baseline and Week 4 (Day 29). Only IRLS score values collected prior to the use of standard of care therapy were used in the analysis. The FAS was used as the primary analysis set and, for sensitivity analysis, the PPS was used as a secondary analysis set. For the purpose of the primary efficacy analysis, if a subject discontinued the study before Week 4 (Day 29) or was using a concomitant RLS standard of care at Week 4 (Day 29), the last observation carried forward (LOCF) was used.

Primary

Baseline (Day 1); Week 4 (Day 29).

A mixed model with IRLS measure as fixed effects and site as random effect and subsequent contrast tests (t-tests on least squares means) was applied to analyse the IRLS total score at Week 4 (Day 29) (last observation carried forward (LOCF) in dropouts), using the FAS population.

Placebo v Ferric carboxymaltose

110

Pre-specified

-2.46

2-sided

Standard error of the mean

1.75

A mixed model with IRLS measure as fixed effects and site as random effect and subsequent contrast tests (t-tests on least squares means) was applied to analyse the IRLS total score at Week 4 (Day 29) (last observation carried forward (LOCF) in dropouts), using the PPS population.

Ferric carboxymaltose v Placebo

110

Pre-specified

-2.21

2-sided

Standard error of the mean

1.852

The analysis of change from baseline in IRLS scores over time is a single analysis that includes together the analysis from baseline to week 1, 4, 8 and 12. 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). For Week 1, the 2 treatment groups (FCM and placebo) were compared with respect to the change in the IRLS total score (gold standard for efficacy evaluation in RLS) between baseline (Day 1) and Week 1 (Day 8). Only IRLS score values collected prior to the use of standard of care therapy were used in the analysis. The FAS was used for the secondary efficacy analyses.

Secondary

Baseline (Day 1); Week 1 (Day 8).

The analysis of change from baseline in IRLS scores over time including the analysis from baseline to week 1, 4, 8 and 12 has been populated separately for every time point (week). The analysis was performed using a repeated measures mixed model that includes: score at baseline and serum ferritin level at baseline as fixed effects, visits as repeated measures and centre as a random effect. Treatment groups were compared at each visit through t-test between least squares means within the visit.

Ferric carboxymaltose v Placebo

110

Pre-specified

-0.93

2-sided

Standard error of the mean

1.491

The analysis of change from baseline in IRLS scores over time is a single analysis that includes together the analysis from baseline to week 1, 4, 8 and 12. 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). For Week 4, the 2 treatment groups (FCM and placebo) were compared with respect to the change in the IRLS total score (gold standard for efficacy evaluation in RLS) between baseline (Day 1) and Week 4 (Day 29). Only IRLS score values collected prior to the use of standard of care therapy were used in the analysis. The FAS was used for the secondary efficacy analyses.

Secondary

Baseline (Day 1); Week 4 (Day 29).

The analysis of change from baseline in IRLS scores over time including the analysis from baseline to week 1, 4, 8 and 12 has been populated separately for every time point (week). The analysis was performed using a repeated measures mixed model that includes: score at baseline and serum ferritin level at baseline as fixed effects, visits as repeated measures and centre as a random effect. Treatment groups were compared at each visit through t-test between least squares means within the visit.

Ferric carboxymaltose v Placebo

110

Pre-specified

-2.89

2-sided

Standard error of the mean

1.752

The analysis of change from baseline in IRLS scores over time is a single analysis that includes together the analysis from baseline to week 1, 4, 8 and 12. 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). For Week 8, the 2 treatment groups (FCM and placebo) were compared with respect to the change in the IRLS total score (gold standard for efficacy evaluation in RLS) between baseline (Day 1) and Week 8 (Day 57). Only IRLS score values collected prior to the use of standard of care therapy were used in the analysis. The FAS was used for the secondary efficacy analyses.

Secondary

Baseline (Day 1); Week 8 (Day 57).

The analysis of change from baseline in IRLS scores over time including the analysis from baseline to week 1, 4, 8 and 12 has been populated separately for every time point (week). The analysis was performed using a repeated measures mixed model that includes: score at baseline and serum ferritin level at baseline as fixed effects, visits as repeated measures and centre as a random effect. Treatment groups were compared at each visit through t-test between least squares means within the visit.

Ferric carboxymaltose v Placebo

110

Pre-specified

-3.72

2-sided

Standard error of the mean

1.982

The analysis of change from baseline in IRLS scores over time is a single analysis that includes together the analysis from baseline to week 1, 4, 8 and 12. 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). For Week 12, the 2 treatment groups (FCM and placebo) were compared with respect to the change in the IRLS total score (gold standard for efficacy evaluation in RLS) between baseline (Day 1) and Week 12 (Day 85). Only IRLS score values collected prior to the use of standard of care therapy were used in the analysis. The FAS was used for the secondary efficacy analyses.

Secondary

Baseline (Day 1); Week 12 (Day 85).

The analysis of change from baseline in IRLS scores over time including the analysis from baseline to week 1, 4, 8 and 12 has been populated separately for every time point (week). The analysis was performed using a repeated measures mixed model that includes: score at baseline and serum ferritin level at baseline as fixed effects, visits as repeated measures and centre as a random effect. Treatment groups were compared at each visit through t-test between least squares means within the visit.

Ferric carboxymaltose v Placebo

110

Pre-specified

-4.66

2-sided

Standard error of the mean

1.974

Proportion of subjects with an improvement by at least 6 points in the IRLS from baseline at any time during the treatment period. FAS population.

Secondary

Baseline (Day 1); any time during the treatment period.

The analysis was performed using a logistic regression model with treatment as a factor and baseline IRLS total score as a covariate. Treatment groups have been compared by the Odds ratio Wald Chi-square test.

Ferric carboxymaltose v Placebo

110

Pre-specified

3.1

2-sided

Adverse Events (AEs) were collected from the time of informed consent for the duration of the trial.

Subjects were to be observed for AEs for at least 30 min. following the infusion. AEs and SAEs that were ongoing after a subject’s last scheduled visit/last contact were followed up until resolution or stabilisation, or the patient was lost to follow-up and could not be contacted.

16.1

Ferric carboxymaltose

Placebo