Clinical Trial Results:
A phase III, randomised, comparative, open-label study of intravenous iron isomaltoside 1000 (Monofer®) administered as maintenance therapy by single or repeated bolus injections in comparison with intravenous iron sucrose in subjects with stage 5 chronic kidney disease on dialysis therapy (CKD-5D)
Summary
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EudraCT number |
2010-023471-26 |
Trial protocol |
GB SE DK PL |
Global end of trial date |
28 Oct 2013
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Results information
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Results version number |
v1 |
This version publication date |
16 Mar 2016
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First version publication date |
15 Jul 2015
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Other versions |
v2 |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
P-Monofer-CKD-03
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01222884 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Pharmacosmos A/S
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Sponsor organisation address |
Roervangsvej 30, Holbaek, Denmark, Dk-4300
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Public contact |
Clinical trial disclosure desk, Pharmacosmos A/S, 045 59485935, trial@pharmacosmos.com
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Scientific contact |
Clinical trial disclosure desk, Pharmacosmos A/S, 045 59485935, trial@pharmacosmos.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
28 Oct 2013
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
28 Oct 2013
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Global end of trial reached? |
Yes
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Global end of trial date |
28 Oct 2013
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
The primary efficacy objective of the study was to demonstrate that IV iron isomaltoside 1000 is non-inferior to IV iron sucrose determined as ability to maintain haemoglobin (Hb) between 9.5 and 12.5 g/dL in subjects with CKD-5D who were on maintenance iron therapy.
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Protection of trial subjects |
The protocol and amendments were approved by local ethics committees/Institutional Review Boards and competent authorities. The trial was conducted in accordance with good clinical practice and the Declaration of Helsinki. Informed consent was obtained in writing prior to any trial-related activities.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
14 Jun 2011
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Poland: 13
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Country: Number of subjects enrolled |
Sweden: 10
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Country: Number of subjects enrolled |
United Kingdom: 187
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Country: Number of subjects enrolled |
Denmark: 11
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Country: Number of subjects enrolled |
India: 72
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Country: Number of subjects enrolled |
Romania: 26
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Country: Number of subjects enrolled |
Russian Federation: 9
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Country: Number of subjects enrolled |
Switzerland: 19
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Country: Number of subjects enrolled |
United States: 4
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Worldwide total number of subjects |
351
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EEA total number of subjects |
247
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
195
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From 65 to 84 years |
146
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85 years and over |
10
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Recruitment
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Recruitment details |
Subjects were screened in the period 14 June 2011 to 10 September 2013. The trial took place at 48 sites (hospitals or private dialysis clinics); 16 centres in India, 14 centres in the UK, 4 in Russia, 4 in Poland, 3 in Sweden, 3 in Switzerland, 2 in Romania, 1 in Denmark, and 1 in the USA. | |||||||||||||||||||||||||||||||||||||||
Pre-assignment
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Screening details |
Subjects ≥ 18 years of age with a diagnosis of CKD and on haemodialysis therapy for at least 90 days, Hb between 9.5 and 12.5 g/dL (inclusive both values) both at screening visit 1a and screening visit 1b, serum-ferritin < 800 ng/mL, TSAT < 35%, and receiving ESA treatment with stable dose for the previous 4 weeks prior to screening were enrolled. | |||||||||||||||||||||||||||||||||||||||
Period 1
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Period 1 title |
Overall trial (overall period)
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Is this the baseline period? |
Yes | |||||||||||||||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Not blinded | |||||||||||||||||||||||||||||||||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Group A, iron isomaltoside 1000 | |||||||||||||||||||||||||||||||||||||||
Arm description |
All subjects received a cumulative dose of 500 mg iron isomaltoside 1000. Subjects in subgroup A1 were administered iron isomaltoside 1000 as a single undiluted IV bolus injection of 500 mg over approximately 2 min at baseline, subjects in subgroup A2 were administered undiluted iron isomaltoside 1000 in split doses of 100 mg at baseline and 200 mg each at week 2 and 4 as IV bolus injections over approximately 2 min. | |||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Iron isomaltoside 1000
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Investigational medicinal product code |
ATC code: B03AC
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Other name |
Monofer, Monover, Monofar, Monoferro
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Pharmaceutical forms |
Solution for injection/infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
All subjects received a cumulative dose of 500 mg iron isomaltoside 1000. Subjects in subgroup A1 were administered iron isomaltoside 1000 as a single undiluted IV bolus injection of 500 mg over approximately 2 min at baseline, subjects in subgroup A2 were administered undiluted iron isomaltoside 1000 in split doses of 100 mg at baseline and 200 mg each at week 2 and 4 as IV bolus injections over approximately 2 min.
Iron isomaltoside 1000 is available as a dark brown, non-transparent aqueous solution for
injection/infusion containing 100 mg iron/mL with pH between 5.0 and 7.0.
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Arm title
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Group B, iron sucrose | |||||||||||||||||||||||||||||||||||||||
Arm description |
All subjects received a cumulative dose of 500 mg iron sucrose. Subjects in group B were administered undiluted iron sucrose in split doses of 100 mg at baseline and 200 mg each at week 2 and 4. | |||||||||||||||||||||||||||||||||||||||
Arm type |
Active comparator | |||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Iron sucrose
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Investigational medicinal product code |
ATC code: B03AB02,B03AC02
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Other name |
Venofer
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Pharmaceutical forms |
Concentrate for solution for infusion, Solution for injection
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Routes of administration |
Intravenous use
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Dosage and administration details |
Subjects in group B were administered undiluted iron sucrose in split doses of 100 mg at baseline and 200 mg each at week 2 and 4. The doses of iron sucrose were administered as per local summary product of characteristics or package insert and/or local hospital guidelines, as applicable. All dosages were administered during dialysis, at least 30 min after the start and at least 1 h before the end of dialysis.
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Baseline characteristics reporting groups
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Reporting group title |
Group A, iron isomaltoside 1000
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Reporting group description |
All subjects received a cumulative dose of 500 mg iron isomaltoside 1000. Subjects in subgroup A1 were administered iron isomaltoside 1000 as a single undiluted IV bolus injection of 500 mg over approximately 2 min at baseline, subjects in subgroup A2 were administered undiluted iron isomaltoside 1000 in split doses of 100 mg at baseline and 200 mg each at week 2 and 4 as IV bolus injections over approximately 2 min. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Group B, iron sucrose
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Reporting group description |
All subjects received a cumulative dose of 500 mg iron sucrose. Subjects in group B were administered undiluted iron sucrose in split doses of 100 mg at baseline and 200 mg each at week 2 and 4. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Subject analysis sets
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Subject analysis set title |
Safety analysis set
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Subject analysis set type |
Safety analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
The safety population (N=344) included all subjects who were randomized and received at least one dose of the trial drug.
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Subject analysis set title |
Full analysis set (FAS)
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Subject analysis set type |
Full analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
The full analysis set (FAS) population (N=341) included all subjects who were randomized into the trial, received at least one dose of the trial drug, and had at least one post-baseline Hb assessment.
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Subject analysis set title |
Per protocol (PP) analysis set
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Subject analysis set type |
Per protocol | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
The per protocol (PP) population (N=306) included all subjects in the FAS who did not have any major protocol deviation of clinical or statistical relevance.
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End points reporting groups
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Reporting group title |
Group A, iron isomaltoside 1000
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Reporting group description |
All subjects received a cumulative dose of 500 mg iron isomaltoside 1000. Subjects in subgroup A1 were administered iron isomaltoside 1000 as a single undiluted IV bolus injection of 500 mg over approximately 2 min at baseline, subjects in subgroup A2 were administered undiluted iron isomaltoside 1000 in split doses of 100 mg at baseline and 200 mg each at week 2 and 4 as IV bolus injections over approximately 2 min. | ||
Reporting group title |
Group B, iron sucrose
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Reporting group description |
All subjects received a cumulative dose of 500 mg iron sucrose. Subjects in group B were administered undiluted iron sucrose in split doses of 100 mg at baseline and 200 mg each at week 2 and 4. | ||
Subject analysis set title |
Safety analysis set
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
The safety population (N=344) included all subjects who were randomized and received at least one dose of the trial drug.
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Subject analysis set title |
Full analysis set (FAS)
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
The full analysis set (FAS) population (N=341) included all subjects who were randomized into the trial, received at least one dose of the trial drug, and had at least one post-baseline Hb assessment.
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Subject analysis set title |
Per protocol (PP) analysis set
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Subject analysis set type |
Per protocol | ||
Subject analysis set description |
The per protocol (PP) population (N=306) included all subjects in the FAS who did not have any major protocol deviation of clinical or statistical relevance.
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End point title |
Proportion of subjects who were able to maintain Hb between 9.5 and 12.5 g/dL (both values included) at week 6, FAS | |||||||||||||||
End point description |
Proportion of subjects who were able to maintain Hb between 9.5 and 12.5 g/dL (both values included) at week 6.
The analysis was performed on the FAS.
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End point type |
Primary
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End point timeframe |
Proportion of subjects who were able to maintain Hb between 9.5 and 12.5 g/dL (both values included) at week 6.
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Statistical analysis title |
Non-inferiority tested by risk difference | |||||||||||||||
Statistical analysis description |
A generalised linear model using the identity link function was used to compare the proportion of subjects with Hb concentration between 9.5 and 12.5 g/dL (both values included) at week 6 using the last observation carried forward approach.
The number of subjects may differ from the analysis population if data is missing.
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Comparison groups |
Group A, iron isomaltoside 1000 v Group B, iron sucrose
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Number of subjects included in analysis |
341
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Analysis specification |
Pre-specified
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Analysis type |
non-inferiority [1] | |||||||||||||||
P-value |
= 0.0106 [2] | |||||||||||||||
Method |
Risk differences | |||||||||||||||
Parameter type |
Risk difference (RD) | |||||||||||||||
Point estimate |
1
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Confidence interval |
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level |
95% | |||||||||||||||
sides |
2-sided
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lower limit |
-7.4 | |||||||||||||||
upper limit |
9.4 | |||||||||||||||
Notes [1] - Treatment and stratum (serum-ferritin (<100 versus ≥100 ng/mL) were used as factors and baseline value as a covariate. With a 2:1 randomisation, a two-sided significance level of 0.05, and a non-inferiority margin of 10 % points, there was approximately 80 % power to demonstrate non-inferiority with 214 subjects in group A and 107 subjects in group B. [2] - As the trial was designed to demonstrate non-inferiority, the analyses of FAS and PP population would lead to similar conclusions and therefore the analyses for both analysis sets needed to be powered properly. |
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End point title |
Proportion of subjects who were able to maintain Hb between 9.5 and 12.5 g/dL (both values included) at week 6, PP | |||||||||||||||
End point description |
Proportion of subjects who were able to maintain Hb between 9.5 and 12.5 g/dL (both values included) at week 6.
The analysis was performed on the PP analysis set.
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End point type |
Primary
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End point timeframe |
Proportion of subjects who were able to maintain Hb between 9.5 and 12.5 g/dL (both values included) at week 6.
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Statistical analysis title |
Non-inferiority tested by risk difference | |||||||||||||||
Statistical analysis description |
A generalised linear model using the identity link function was used to compare the proportion of subjects with Hb concentration between 9.5 and 12.5 g/dL (both values included) at week 6 using the last observation carried forward approach.
The number of subjects may differ from the analysis population if data is missing.
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Comparison groups |
Group B, iron sucrose v Group A, iron isomaltoside 1000
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Number of subjects included in analysis |
306
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Analysis specification |
Pre-specified
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Analysis type |
non-inferiority [3] | |||||||||||||||
P-value |
= 0.0057 [4] | |||||||||||||||
Method |
Risk difference | |||||||||||||||
Parameter type |
Risk difference (RD) | |||||||||||||||
Point estimate |
2.2
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Confidence interval |
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level |
95% | |||||||||||||||
sides |
2-sided
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lower limit |
-6.4 | |||||||||||||||
upper limit |
10.9 | |||||||||||||||
Notes [3] - Treatment and stratum (serum-ferritin (<100 versus ≥100 ng/mL) were used as factors and baseline value as a covariate. With a 2:1 randomisation, a two-sided significance level of 0.05, and a non-inferiority margin of 10 % points, there was approximately 80 % power to demonstrate non-inferiority with 214 subjects in group A and 107 subjects in group B. [4] - As the trial was designed to demonstrate non-inferiority, the analyses of FAS and PP population would lead to similar conclusions and therefore the analyses for both analysis sets needed to be powered properly. |
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End point title |
Change in Hb concentration from baseline to week 2 | ||||||||||||
End point description |
Change in Hb concentration from baseline to week 2.
Analysis performed on the FAS.
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End point type |
Secondary
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End point timeframe |
Change in Hb concentration from baseline to week 2.
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Statistical analysis title |
Test for superiority, MMRM | ||||||||||||
Statistical analysis description |
The mixed model for repeated measures includes treatment, visit, treatment*visit interactions and stratum (s-ferritin (<100 vs. >=100 ng/mL)) ,country as factors and baseline values as covariates.
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Comparison groups |
Group A, iron isomaltoside 1000 v Group B, iron sucrose
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Number of subjects included in analysis |
334
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.1239 | ||||||||||||
Method |
MMRM | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
0.1138
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-0.031 | ||||||||||||
upper limit |
0.259 | ||||||||||||
Variability estimate |
Standard error of the mean
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Dispersion value |
0.0737
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End point title |
Change in Hb concentration from baseline to week 4 | ||||||||||||
End point description |
Change in Hb concentration from baseline to week 4.
Analysis performed on the FAS.
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End point type |
Secondary
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End point timeframe |
Change in Hb concentration from baseline to week 4.
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Statistical analysis title |
Test for superiority, MMRM | ||||||||||||
Statistical analysis description |
The mixed model for repeated measures includes treatment, visit, treatment*visit interactions and stratum (s-ferritin (<100 vs. >=100 ng/mL)) ,country as factors and baseline values as covariates.
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Comparison groups |
Group A, iron isomaltoside 1000 v Group B, iron sucrose
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Number of subjects included in analysis |
327
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.5233 | ||||||||||||
Method |
MMRM | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
0.0546
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-0.113 | ||||||||||||
upper limit |
0.223 | ||||||||||||
Variability estimate |
Standard error of the mean
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Dispersion value |
0.0854
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End point title |
Change in Hb concentration from baseline to week 6. | ||||||||||||
End point description |
Change in Hb concentration from baseline to week 6.
Analysis performed on the FAS.
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End point type |
Secondary
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End point timeframe |
Change in Hb concentration from baseline to week 6.
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Statistical analysis title |
Test for superiority, MMRM | ||||||||||||
Statistical analysis description |
The mixed model for repeated measures includes treatment, visit, treatment*visit interactions and stratum (s-ferritin (<100 vs. >=100 ng/mL)) ,country as factors and baseline values as covariates.
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Comparison groups |
Group A, iron isomaltoside 1000 v Group B, iron sucrose
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Number of subjects included in analysis |
329
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.8557 | ||||||||||||
Method |
MMRM | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
-0.0069
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-0.204 | ||||||||||||
upper limit |
0.246 | ||||||||||||
Variability estimate |
Standard error of the mean
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Dispersion value |
0.1143
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End point title |
Change in s-iron concentration from baseline to week 1 | ||||||||||||
End point description |
Change in s-iron concentration from baseline to week 1.
Analysis performed on the FAS.
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End point type |
Secondary
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End point timeframe |
Change in s-iron concentration from baseline to week 1.
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Statistical analysis title |
Test for superiority, MMRM | ||||||||||||
Statistical analysis description |
The mixed model for repeated measures includes treatment, visit, treatment*visit interactions and stratum (s-ferritin (<100 vs. >=100 ng/mL)) ,country as factors and baseline values as covariates.
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Comparison groups |
Group A, iron isomaltoside 1000 v Group B, iron sucrose
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Number of subjects included in analysis |
333
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.1429 | ||||||||||||
Method |
MMRM | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
0.5793
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-0.197 | ||||||||||||
upper limit |
1.355 | ||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||
Dispersion value |
0.3942
|
|
|||||||||||||
End point title |
Change in s-iron concentration from baseline to week 2 | ||||||||||||
End point description |
Change in s-iron concentration from baseline to week 2.
Analysis performed on the FAS.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Change in s-iron concentration from baseline to week 2.
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Test for superiority, MMRM | ||||||||||||
Statistical analysis description |
The mixed model for repeated measures includes treatment, visit, treatment*visit interactions and stratum (s-ferritin (<100 vs. >=100 ng/mL)) ,country as factors and baseline values as covariates.
|
||||||||||||
Comparison groups |
Group A, iron isomaltoside 1000 v Group B, iron sucrose
|
||||||||||||
Number of subjects included in analysis |
335
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.5277 | ||||||||||||
Method |
MMRM | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
0.3761
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-0.797 | ||||||||||||
upper limit |
1.549 | ||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||
Dispersion value |
0.5943
|
|
|||||||||||||
End point title |
Change in s-iron concentration from baseline to week 4 | ||||||||||||
End point description |
Change in s-iron concentration from baseline to week 4.
Analysis performed on the FAS.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Change in s-iron concentration from baseline to week 4.
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Test for superiority, MMRM | ||||||||||||
Statistical analysis description |
The mixed model for repeated measures includes treatment, visit, treatment*visit interactions and stratum (s-ferritin (<100 vs. >=100 ng/mL)) ,country as factors and baseline values as covariates.
|
||||||||||||
Comparison groups |
Group A, iron isomaltoside 1000 v Group B, iron sucrose
|
||||||||||||
Number of subjects included in analysis |
326
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.438 | ||||||||||||
Method |
MMRM | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
-0.3576
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-1.265 | ||||||||||||
upper limit |
0.549 | ||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||
Dispersion value |
0.4603
|
|
|||||||||||||
End point title |
Change in s-iron concentration from baseline to week 6 | ||||||||||||
End point description |
Change in s-iron concentration from baseline to week 6.
Analysis performed on the FAS.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Change in s-iron concentration from baseline to week 6.
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Test for superiority, MMRM | ||||||||||||
Statistical analysis description |
The mixed model for repeated measures includes treatment, visit, treatment*visit interactions and stratum (s-ferritin (<100 vs. >=100 ng/mL)) ,country as factors and baseline values as covariates.
|
||||||||||||
Comparison groups |
Group A, iron isomaltoside 1000 v Group B, iron sucrose
|
||||||||||||
Number of subjects included in analysis |
329
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.9894 | ||||||||||||
Method |
MMRM | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
0.0066
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-0.965 | ||||||||||||
upper limit |
0.978 | ||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||
Dispersion value |
0.4932
|
|
|||||||||||||
End point title |
Change in transferrin saturation (TSAT) concentration from baseline to week 1 | ||||||||||||
End point description |
Change in transferrin saturation (TSAT) concentration from baseline to week 1.
Analysis performed on the FAS.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Change in transferrin saturation (TSAT) concentration from baseline to week 1.
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Test for superiority, MMRM | ||||||||||||
Statistical analysis description |
The mixed model for repeated measures includes treatment, visit, treatment*visit interactions and stratum (s-ferritin (<100 vs. >=100 ng/mL)) ,country as factors and baseline values as covariates.
|
||||||||||||
Comparison groups |
Group B, iron sucrose v Group A, iron isomaltoside 1000
|
||||||||||||
Number of subjects included in analysis |
332
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.386 | ||||||||||||
Method |
MMRM | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
-6.5236
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-21.376 | ||||||||||||
upper limit |
8.329 | ||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||
Dispersion value |
7.4956
|
|
|||||||||||||
End point title |
Change in transferrin saturation (TSAT) concentration from baseline to week 2 | ||||||||||||
End point description |
Change in transferrin saturation (TSAT) concentration from baseline to week 2.
Analysis performed on the FAS.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Change in transferrin saturation (TSAT) concentration from baseline to week 2.
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Test for superiority, MMRM | ||||||||||||
Statistical analysis description |
The mixed model for repeated measures includes treatment, visit, treatment*visit interactions and stratum (s-ferritin (<100 vs. >=100 ng/mL)) ,country as factors and baseline values as covariates.
|
||||||||||||
Comparison groups |
Group A, iron isomaltoside 1000 v Group B, iron sucrose
|
||||||||||||
Number of subjects included in analysis |
335
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.355 | ||||||||||||
Method |
MMRM | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
1.1992
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-1.35 | ||||||||||||
upper limit |
3.748 | ||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||
Dispersion value |
1.294
|
|
|||||||||||||
End point title |
Change in transferrin saturation (TSAT) concentration from baseline to week 4 | ||||||||||||
End point description |
Change in transferrin saturation (TSAT) concentration from baseline to week 4.
Analysis performed on the FAS.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Change in transferrin saturation (TSAT) concentration from baseline to week 4.
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Test for superiority, MMRM | ||||||||||||
Statistical analysis description |
The mixed model for repeated measures includes treatment, visit, treatment*visit interactions and stratum (s-ferritin (<100 vs. >=100 ng/mL)) ,country as factors and baseline values as covariates.
|
||||||||||||
Comparison groups |
Group A, iron isomaltoside 1000 v Group B, iron sucrose
|
||||||||||||
Number of subjects included in analysis |
326
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.3487 | ||||||||||||
Method |
MMRM | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
-0.9972
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-3.09 | ||||||||||||
upper limit |
1.095 | ||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||
Dispersion value |
1.0617
|
|
|||||||||||||
End point title |
Change in transferrin saturation (TSAT) concentration from baseline to week 6 | ||||||||||||
End point description |
Change in transferrin saturation (TSAT) concentration from baseline to week 6.
Analysis performed on the FAS.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Change in transferrin saturation (TSAT) concentration from baseline to week 6.
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Test for superiority, MMRM | ||||||||||||
Statistical analysis description |
The mixed model for repeated measures includes treatment, visit, treatment*visit interactions and stratum (s-ferritin (<100 vs. >=100 ng/mL)) ,country as factors and baseline values as covariates.
|
||||||||||||
Comparison groups |
Group A, iron isomaltoside 1000 v Group B, iron sucrose
|
||||||||||||
Number of subjects included in analysis |
329
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.9845 | ||||||||||||
Method |
MMRM | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
-0.0207
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-2.118 | ||||||||||||
upper limit |
2.077 | ||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||
Dispersion value |
1.0654
|
|
|||||||||||||
End point title |
Change in s-ferritin concentration from baseline to week 1 | ||||||||||||
End point description |
Change in s-ferritin concentration from baseline to week 1.
Analysis performed on the FAS.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Change in s-ferritin concentration from baseline to week 1.
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Test for superiority, MMRM | ||||||||||||
Statistical analysis description |
The mixed model for repeated measures includes treatment, visit, treatment*visit interactions and stratum (s-ferritin (<100 vs. >=100 ng/mL)) ,country as factors and baseline values as covariates.
|
||||||||||||
Comparison groups |
Group A, iron isomaltoside 1000 v Group B, iron sucrose
|
||||||||||||
Number of subjects included in analysis |
334
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
< 0.0001 | ||||||||||||
Method |
MMRM | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
107.8382
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
87.987 | ||||||||||||
upper limit |
127.689 | ||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||
Dispersion value |
10.0818
|
|
|||||||||||||
End point title |
Change in s-ferritin concentration from baseline to week 2 | ||||||||||||
End point description |
Change in s-ferritin concentration from baseline to week 2.
Analysis performed on the FAS.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Change in s-ferritin concentration from baseline to week 2.
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Test for superiority, MMRM | ||||||||||||
Statistical analysis description |
The mixed model for repeated measures includes treatment, visit, treatment*visit interactions and stratum (s-ferritin (<100 vs. >=100 ng/mL)) ,country as factors and baseline values as covariates.
|
||||||||||||
Comparison groups |
Group A, iron isomaltoside 1000 v Group B, iron sucrose
|
||||||||||||
Number of subjects included in analysis |
335
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
< 0.0001 | ||||||||||||
Method |
MMRM | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
123.36
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
96.449 | ||||||||||||
upper limit |
150.271 | ||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||
Dispersion value |
13.6719
|
|
|||||||||||||
End point title |
Change in s-ferritin concentration from baseline to week 4 | ||||||||||||
End point description |
Change in s-ferritin concentration from baseline to week 4.
Analysis performed on the FAS.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Change in s-ferritin concentration from baseline to week 4.
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Test for superiority, MMRM | ||||||||||||
Statistical analysis description |
The mixed model for repeated measures includes treatment, visit, treatment*visit interactions and stratum (s-ferritin (<100 vs. >=100 ng/mL)) ,country as factors and baseline values as covariates.
|
||||||||||||
Comparison groups |
Group A, iron isomaltoside 1000 v Group B, iron sucrose
|
||||||||||||
Number of subjects included in analysis |
326
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.002 | ||||||||||||
Method |
MMRM | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
49.3393
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
18.174 | ||||||||||||
upper limit |
80.505 | ||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||
Dispersion value |
15.8282
|
|
|||||||||||||
End point title |
Change in s-ferritin concentration from baseline to week 6 | ||||||||||||
End point description |
Change in s-ferritin concentration from baseline to week 6.
Analysis performed on the FAS.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Change in s-ferritin concentration from baseline to week 6.
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Test for superiority, MMRM | ||||||||||||
Statistical analysis description |
The mixed model for repeated measures includes treatment, visit, treatment*visit interactions and stratum (s-ferritin (<100 vs. >=100 ng/mL)) ,country as factors and baseline values as covariates.
|
||||||||||||
Comparison groups |
Group A, iron isomaltoside 1000 v Group B, iron sucrose
|
||||||||||||
Number of subjects included in analysis |
330
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.4489 | ||||||||||||
Method |
MMRM | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
-15.0585
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-54.196 | ||||||||||||
upper limit |
24.079 | ||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||
Dispersion value |
19.8434
|
|
|||||||||||||
End point title |
Change in reticulocyte count from baseline to week 1 | ||||||||||||
End point description |
Change in reticulocyte count from baseline to week 1.
Analysis performed on the FAS.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Change in reticulocyte count from baseline to week 1.
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Test for superiority, MMRM | ||||||||||||
Statistical analysis description |
The mixed model for repeated measures includes treatment, visit, treatment*visit interactions and stratum (s-ferritin (<100 vs. >=100 ng/mL)) ,country as factors and baseline values as covariates.
|
||||||||||||
Comparison groups |
Group A, iron isomaltoside 1000 v Group B, iron sucrose
|
||||||||||||
Number of subjects included in analysis |
320
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.0006 | ||||||||||||
Method |
MMRM | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
0.154
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
0.066 | ||||||||||||
upper limit |
0.242 | ||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||
Dispersion value |
0.0445
|
|
|||||||||||||
End point title |
Change in reticulocyte count from baseline to week 2 | ||||||||||||
End point description |
Change in reticulocyte count from baseline to week 2.
Analysis performed on the FAS.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Change in reticulocyte count from baseline to week 2.
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Test for superiority, MMRM | ||||||||||||
Statistical analysis description |
The mixed model for repeated measures includes treatment, visit, treatment*visit interactions and stratum (s-ferritin (<100 vs. >=100 ng/mL)) ,country as factors and baseline values as covariates.
|
||||||||||||
Comparison groups |
Group A, iron isomaltoside 1000 v Group B, iron sucrose
|
||||||||||||
Number of subjects included in analysis |
322
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.3448 | ||||||||||||
Method |
MMRM | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
0.0439
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-0.047 | ||||||||||||
upper limit |
0.135 | ||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||
Dispersion value |
0.0464
|
|
|||||||||||||
End point title |
Change in reticulocyte count from baseline to week 4 | ||||||||||||
End point description |
Change in reticulocyte count from baseline to week 4.
Analysis performed on the FAS.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Change in reticulocyte count from baseline to week 4.
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Test for superiority, MMRM | ||||||||||||
Statistical analysis description |
The mixed model for repeated measures includes treatment, visit, treatment*visit interactions and stratum (s-ferritin (<100 vs. >=100 ng/mL)) ,country as factors and baseline values as covariates.
|
||||||||||||
Comparison groups |
Group A, iron isomaltoside 1000 v Group B, iron sucrose
|
||||||||||||
Number of subjects included in analysis |
314
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.5171 | ||||||||||||
Method |
MMRM | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
0.0302
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-0.061 | ||||||||||||
upper limit |
0.122 | ||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||
Dispersion value |
0.0465
|
|
|||||||||||||
End point title |
Change in reticulocyte count from baseline to week 6 | ||||||||||||
End point description |
Change in reticulocyte count from baseline to week 6.
Analysis performed on the FAS.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Change in reticulocyte count from baseline to week 6.
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Test for superiority, MMRM | ||||||||||||
Statistical analysis description |
The mixed model for repeated measures includes treatment, visit, treatment*visit interactions and stratum (s-ferritin (<100 vs. >=100 ng/mL)) ,country as factors and baseline values as covariates.
|
||||||||||||
Comparison groups |
Group A, iron isomaltoside 1000 v Group B, iron sucrose
|
||||||||||||
Number of subjects included in analysis |
316
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.1564 | ||||||||||||
Method |
MMRM | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
0.0727
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-0.028 | ||||||||||||
upper limit |
0.173 | ||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||
Dispersion value |
0.0512
|
|
||||||||||||||||
End point title |
Number of subjects in each randomisation group who discontinued study because of lack of response or intolerance of investigational drugs | |||||||||||||||
End point description |
Number of subjects in each randomisation group who discontinued study because of lack of response or intolerance of investigational drugs.
The analysis was performed on the FAS.
|
|||||||||||||||
End point type |
Secondary
|
|||||||||||||||
End point timeframe |
The endpoint covers the complete trial period.
|
|||||||||||||||
|
||||||||||||||||
Statistical analysis title |
Superiority tested by Fisher Exact | |||||||||||||||
Comparison groups |
Group A, iron isomaltoside 1000 v Group B, iron sucrose
|
|||||||||||||||
Number of subjects included in analysis |
341
|
|||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||
Analysis type |
superiority | |||||||||||||||
P-value |
> 0.9999 | |||||||||||||||
Method |
Fisher exact | |||||||||||||||
Confidence interval |
|
|||||||||||||
End point title |
Change in total quality of life (QoL) score (LASA: Energy level) from baseline to week 4 | ||||||||||||
End point description |
Change in total quality of life (QoL) score (LASA: Energy level) from baseline to week 4.
The analysis was performed on the FAS.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Change in total quality of life (QoL) score (LASA: Energy level) from baseline to week 4.
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Superiority tested by MMRM | ||||||||||||
Statistical analysis description |
The mixed model for repeated measures includes treatment, visit, treatment*visit interactions and stratum (s-ferritin (<100 vs. >=100 ng/mL)) ,country as factors and baseline values as covariates.
|
||||||||||||
Comparison groups |
Group A, iron isomaltoside 1000 v Group B, iron sucrose
|
||||||||||||
Number of subjects included in analysis |
319
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.4653 | ||||||||||||
Method |
MMRM | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
1.4173
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-2.402 | ||||||||||||
upper limit |
5.237 | ||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||
Dispersion value |
1.9379
|
|
|||||||||||||
End point title |
Change in total quality of life (QoL) score (LASA: Energy level) from baseline to week 6 | ||||||||||||
End point description |
Change in total quality of life (QoL) score (LASA: Energy level) from baseline to week 6.
The analysis was performed on the FAS.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Change in total quality of life (QoL) score (LASA: Energy level) from baseline to week 6.
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Superiority tested by MMRM | ||||||||||||
Statistical analysis description |
The mixed model for repeated measures includes treatment, visit, treatment*visit interactions and stratum (s-ferritin (<100 vs. >=100 ng/mL)) ,country as factors and baseline values as covariates.
|
||||||||||||
Comparison groups |
Group A, iron isomaltoside 1000 v Group B, iron sucrose
|
||||||||||||
Number of subjects included in analysis |
317
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.9539 | ||||||||||||
Method |
MRMM | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
0.1111
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-3.667 | ||||||||||||
upper limit |
3.889 | ||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||
Dispersion value |
1.9182
|
|
|||||||||||||
End point title |
Change in total quality of life (QoL) score (LASA: Ability to do daily activities) from baseline to week 4 | ||||||||||||
End point description |
Change in total quality of life (QoL) score (LASA: Ability to do daily activities) from baseline to week 4.
The analysis was performed on the FAS.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Change in total quality of life (QoL) score (LASA: Ability to do daily activities) from baseline to week 4.
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Test for superiority, MMRM | ||||||||||||
Statistical analysis description |
The mixed model for repeated measures includes treatment, visit, treatment*visit interactions and stratum (s-ferritin (<100 vs. >=100 ng/mL)) ,country as factors and baseline values as covariates.
|
||||||||||||
Comparison groups |
Group A, iron isomaltoside 1000 v Group B, iron sucrose
|
||||||||||||
Number of subjects included in analysis |
319
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.4086 | ||||||||||||
Method |
MMRM | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
1.5719
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-2.168 | ||||||||||||
upper limit |
5.312 | ||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||
Dispersion value |
1.8991
|
|
|||||||||||||
End point title |
Change in total quality of life (QoL) score (LASA: Ability to do daily activities) from baseline to week 6 | ||||||||||||
End point description |
Change in total quality of life (QoL) score (LASA: Ability to do daily activities) from baseline to week 6.
The analysis was performed on the FAS.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Change in total quality of life (QoL) score (LASA: Ability to do daily activities) from baseline to week 6.
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Test for superiority, MMRM | ||||||||||||
Statistical analysis description |
The mixed model for repeated measures includes treatment, visit, treatment*visit interactions and stratum (s-ferritin (<100 vs. >=100 ng/mL)) ,country as factors and baseline values as covariates.
|
||||||||||||
Comparison groups |
Group A, iron isomaltoside 1000 v Group B, iron sucrose
|
||||||||||||
Number of subjects included in analysis |
317
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.6734 | ||||||||||||
Method |
MMRM | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
-0.8519
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-4.829 | ||||||||||||
upper limit |
3.125 | ||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||
Dispersion value |
2.0186
|
|
|||||||||||||
End point title |
Change in total quality of life (QoL) score (LASA: Overall quality of life) from baseline to week 4 | ||||||||||||
End point description |
Change in total quality of life (QoL) score (LASA: Overall quality of life) from baseline to week 4.
The analysis was performed on the FAS.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Change in total quality of life (QoL) score (LASA: Overall quality of life) from baseline to week 4.
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Test for superiority, MMRM | ||||||||||||
Statistical analysis description |
The mixed model for repeated measures includes treatment, visit, treatment*visit interactions and stratum (s-ferritin (<100 vs. >=100 ng/mL)) ,country as factors and baseline values as covariates.
|
||||||||||||
Comparison groups |
Group A, iron isomaltoside 1000 v Group B, iron sucrose
|
||||||||||||
Number of subjects included in analysis |
319
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.5711 | ||||||||||||
Method |
MMRM | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
1.0565
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-2.614 | ||||||||||||
upper limit |
4.727 | ||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||
Dispersion value |
1.8621
|
|
|||||||||||||
End point title |
Change in total quality of life (QoL) score (LASA: Overall quality of life) from baseline to week 6 | ||||||||||||
End point description |
Change in total quality of life (QoL) score (LASA: Overall quality of life) from baseline to week 6.
The analysis was performed on the FAS.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Change in total quality of life (QoL) score (LASA: Overall quality of life) from baseline to week 6.
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Test for superiority, MMRM | ||||||||||||
Statistical analysis description |
The mixed model for repeated measures includes treatment, visit, treatment*visit interactions and stratum (s-ferritin (<100 vs. >=100 ng/mL)) ,country as factors and baseline values as covariates.
|
||||||||||||
Comparison groups |
Group A, iron isomaltoside 1000 v Group B, iron sucrose
|
||||||||||||
Number of subjects included in analysis |
317
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.7964 | ||||||||||||
Method |
MMRM | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
0.4718
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-3.125 | ||||||||||||
upper limit |
4.069 | ||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||
Dispersion value |
1.8264
|
|
|||||||||||||
End point title |
Change in restless legs syndrome (RLS) symptoms (Cambridge Hopkins-RLS questionnaire (CH-RLSq) score) from baseline to week 6 in subjects with RLS symptoms at baseline | ||||||||||||
End point description |
Change in restless legs syndrome (RLS) symptoms (Cambridge Hopkins-RLS questionnaire (CH-RLSq) score) from baseline to week 6 in subjects with RLS symptoms at baseline.
The analysis was performed on the FAS.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Change in restless legs syndrome (RLS) symptoms (Cambridge Hopkins-RLS questionnaire (CH-RLSq) score) from baseline to week 6 in subjects with RLS symptoms at baseline.
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Superiority tested by ANCOVA | ||||||||||||
Statistical analysis description |
The ANCOVA mixed model includes treatment and stratum as factors and baseline value as covariates.
|
||||||||||||
Comparison groups |
Group A, iron isomaltoside 1000 v Group B, iron sucrose
|
||||||||||||
Number of subjects included in analysis |
108
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.7267 | ||||||||||||
Method |
ANCOVA | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
0.4033
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-1.88 | ||||||||||||
upper limit |
2.686 | ||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||
Dispersion value |
1.1507
|
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse events information
|
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Timeframe for reporting adverse events |
From the time a subject had signed the ICF and until he/she had completed the study, all AEs/SAEs were collected in the CRF. The SAEs occurring after study termination were re-ported if considered related to the study treatment.
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse event reporting additional description |
The principle investigator (PI) was responsible for ensuring that all AEs observed by PI or reported by the subject were properly collected and recorded in the subject’s medical record as well as on the AE form.
|
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Assessment type |
Systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
|
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Dictionary name |
MedDRA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
16.1
|
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Reporting groups
|
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Reporting group title |
Group A, iron isomaltoside 1000
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
All subjects received a cumulative dose of 500 mg iron isomaltoside 1000. Subjects in subgroup A1 were administered iron isomaltoside 1000 as a single undiluted IV bolus injection of 500 mg over approximately 2 min at baseline, subjects in subgroup A2 were administered undiluted iron isomaltoside 1000 in split doses of 100 mg at baseline and 200 mg each at week 2 and 4 as IV bolus injections over approximately 2 min. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Group B, iron sucrose
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
All subjects received a cumulative dose of 500 mg iron sucrose. Subjects in group B were administered undiluted iron sucrose in split doses of 100 mg at baseline and 200 mg each at week 2 and 4. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 2% | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||
Substantial protocol amendments (globally) |
|||
Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
||
11 Jan 2012 |
• Primary endpoint was changed from “change in Hb concentrations from baseline to week 6” to “proportion of subjects able to maintain Hb between 10 and 12.5 g/dl (both values included) at week 6”
• In the secondary endpoint “change in Hb concentration from baseline to week 2 and 4”, additional time point “week 6” was added
• Study design was revised in terms of number of treatment groups and extension of enrolment period to 18 months, and study centre at Norway was removed from the list of participating countries
• Text regarding iron isomaltoside 1000 was updated
• Inclusion criteria pertaining to Hb, ESA treatment, and subjects not on IV iron and exclusion criterion 3 were modified to bring more clarity to text
• Study flowchart was revised to clarify that height should be measured only at screening
• The option of performing blood pregnancy test instead of UPT was added
• Iron sucrose infusion time was changed to “according to SmPC”
• Iron sucrose test dose administration was changed to “according to SmPC or local guidelines”
• Statistical section was revised as per changes in the study endpoints (primary endpoint and first secondary endpoint)
• The possibility of re-screening the screen-failure subjects once 2 weeks after the screening visit was added
• Appendix 2 related to CH-RLSq was updated
|
||
10 Jul 2012 |
• Total study duration was increased to approximately 19 months, and study centres were rephrased as Europe, USA, and India
• In inclusion criterion # 5, the target Hb range between “10 and 12.5 g/dL” was revised to “9.5 and 12.5 g/dL”
• Additional text was included in sections: dosage and administration, prohibited medication, screen failure, and rescreening
• Re-screening was allowed “up to 3 times”
• The frequency of planned review by safety review committee was decreased from one meeting every 2 months to one meeting every 4 months for a feasible study conduct
|
||
Interruptions (globally) |
|||
Were there any global interruptions to the trial? No | |||
Limitations and caveats |
|||
Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
None reported |