Clinical Trial Results:
A phase III, randomized, comparative, open-label study of intravenous iron isomaltoside 1000 (Monofer®) administered by infusions or repeated bolus injections in comparison with oral iron sulphate in subjects with non-dialysis dependent chronic kidney disease and with renal-related anaemia
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Summary
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EudraCT number |
2009-016728-29 |
Trial protocol |
SE DK GB IE DE PL AT |
Global end of trial date |
25 Apr 2014
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Results information
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Results version number |
v2(current) |
This version publication date |
30 Mar 2016
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First version publication date |
16 Jul 2015
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Other versions |
v1 |
Version creation reason |
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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-02
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01102413 | ||
WHO universal trial number (UTN) |
- | ||
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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, +45 59485935, trial@pharmacosmos.com
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Scientific contact |
Clinical trial disclosure desk, Pharmacosmos A/S, +45 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 |
25 Apr 2014
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
25 Apr 2014
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Global end of trial reached? |
Yes
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Global end of trial date |
25 Apr 2014
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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 |
To demonstrate that intravenous Iron Isomaltoside 1000 (Monofer®) is non-inferior to oral iron sulphate in reducing renal-related anaemia in NDD-CKD subjects, determined as ability to increase haemoglobin (Hb).
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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 |
30 Jun 2010
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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 |
India: 202
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Country: Number of subjects enrolled |
Russian Federation: 17
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Country: Number of subjects enrolled |
United States: 21
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Country: Number of subjects enrolled |
Sweden: 1
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Country: Number of subjects enrolled |
United Kingdom: 31
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Country: Number of subjects enrolled |
Austria: 21
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Country: Number of subjects enrolled |
Denmark: 19
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Country: Number of subjects enrolled |
Germany: 31
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Country: Number of subjects enrolled |
Poland: 8
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Worldwide total number of subjects |
351
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EEA total number of subjects |
111
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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) |
244
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From 65 to 84 years |
93
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85 years and over |
14
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Recruitment
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Recruitment details |
Subjects were screened in the period 30 June 2010 to 24 February 2014. The trial took place at 67 sites (hospitals or private dialysis clinics) in 3 continents: 17 in India, 10 in Germany, 7 in United Kingdom, 7 in Austria, 7 in Russia, 5 in Poland, 4 in Denmark, 3 in Romania, 3 in USA, 2 in Sweden, and 2 in Ireland. | |||||||||||||||||||||||||||||||||||||||||||||
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Pre-assignment
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Screening details |
Patients who were ≥18 years of age with estimated glomerular filtration rate (eGFR) between 15-59 mL/min/1.73 m2, Hb <11.0 g/dL, either or both of serum-ferritin <200 μg/L and TSAT < 20%, and had not received ESA treatment within 8 weeks prior to screening, were eligible to participate. | |||||||||||||||||||||||||||||||||||||||||||||
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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 | |||||||||||||||||||||||||||||||||||||||||||||
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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 |
The total IV iron needed for each subject in group A was calculated according to an adapted Ganzoni formula (target Hb was 13 g/dL (8.1 mmol/L) as the subjects were ESA naive): Cumulative iron dose (mg) = [body weight (kg) x (target Hb - actual Hb (g/dL)] x 2.4 + depot iron (set at 500 mg). Subjects treated with iron isomaltoside 1000 either received an IV infusion (group A1) of maximum 1000 mg iron isomaltoside 1000 as single doses over 15 minutes (full iron replacement was achieved by 1 or up to 2 doses at a weekly interval) or IV bolus injections (group A2) of 500 mg iron isomaltoside 1000 administered over 2 minutes once weekly until full replacement dose was achieved. | |||||||||||||||||||||||||||||||||||||||||||||
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 |
The total IV iron needed for each subject in group A was calculated according to an adapted Ganzoni formula (target Hb was 13 g/dL (8.1 mmol/L) as the subjects were ESA naive): Cumulative iron dose (mg) = [body weight (kg) x (target Hb - actual Hb (g/dL)] x 2.4 + depot iron (set at 500 mg). Subjects treated with iron isomaltoside 1000 either received an IV infusion (group A1) of maximum 1000 mg iron isomaltoside 1000 as single doses over 15 minutes (full iron replacement was achieved by 1 or up to 2 doses at a weekly interval) or IV bolus injections (group A2) of 500 mg iron isomaltoside 1000 administered over 2 minutes once weekly until full replacement dose was achieved.
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 sulphate | |||||||||||||||||||||||||||||||||||||||||||||
Arm description |
Subjects receiving with oral iron sulphate were treated daily for 8 weeks with 200 mg given as 100 mg twice a day. | |||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Active comparator | |||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Iron sulphate
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Investigational medicinal product code |
ATC code: B03AA07
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Other name |
Ferro Duretter
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Subjects receiving oral iron sulphate were treated daily for 8 weeks with 200 mg given as 100 mg twice a day.
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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 |
The total IV iron needed for each subject in group A was calculated according to an adapted Ganzoni formula (target Hb was 13 g/dL (8.1 mmol/L) as the subjects were ESA naive): Cumulative iron dose (mg) = [body weight (kg) x (target Hb - actual Hb (g/dL)] x 2.4 + depot iron (set at 500 mg). Subjects treated with iron isomaltoside 1000 either received an IV infusion (group A1) of maximum 1000 mg iron isomaltoside 1000 as single doses over 15 minutes (full iron replacement was achieved by 1 or up to 2 doses at a weekly interval) or IV bolus injections (group A2) of 500 mg iron isomaltoside 1000 administered over 2 minutes once weekly until full replacement dose was achieved. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Group B, iron sulphate
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Reporting group description |
Subjects receiving with oral iron sulphate were treated daily for 8 weeks with 200 mg given as 100 mg twice a day. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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=345) included all subjects who were randomised and received at least one dose of the trial drug.
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Subject analysis set title |
Full analysis set
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Subject analysis set type |
Full analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
The full analysis set (FAS) population (N=340) included all subjects who were randomised 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
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Subject analysis set type |
Per protocol | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
The per protocol (PP) population (N=327) included all patients 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 |
The total IV iron needed for each subject in group A was calculated according to an adapted Ganzoni formula (target Hb was 13 g/dL (8.1 mmol/L) as the subjects were ESA naive): Cumulative iron dose (mg) = [body weight (kg) x (target Hb - actual Hb (g/dL)] x 2.4 + depot iron (set at 500 mg). Subjects treated with iron isomaltoside 1000 either received an IV infusion (group A1) of maximum 1000 mg iron isomaltoside 1000 as single doses over 15 minutes (full iron replacement was achieved by 1 or up to 2 doses at a weekly interval) or IV bolus injections (group A2) of 500 mg iron isomaltoside 1000 administered over 2 minutes once weekly until full replacement dose was achieved. | ||
Reporting group title |
Group B, iron sulphate
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Reporting group description |
Subjects receiving with oral iron sulphate were treated daily for 8 weeks with 200 mg given as 100 mg twice a day. | ||
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=345) included all subjects who were randomised and received at least one dose of the trial drug.
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Subject analysis set title |
Full analysis set
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
The full analysis set (FAS) population (N=340) included all subjects who were randomised 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
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Subject analysis set type |
Per protocol | ||
Subject analysis set description |
The per protocol (PP) population (N=327) included all patients in the FAS who did not have any major protocol deviation of clinical or statistical relevance.
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End point title |
Change in Hb concentration from baseline to week 4, FAS | ||||||||||||
End point description |
Change in Hb concentration from baseline to week 4.
Analysis performed on the FAS.
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End point type |
Primary
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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 non-inferiority, MMRM | ||||||||||||
Statistical analysis description |
A mixed model for repeated measures (MMRM) was used to compare the average change in Hb concentration from baseline to week 4.
The number of subjects may differ from the analysis population if data is missing.
With a 2:1 randomisation, a two-sided significance level of 5%, and a non-inferiority margin of -0.5 g/dL, there was 80% power to demonstrate non-inferiority with 214 patients in group A and 107 patients in group B.
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Comparison groups |
Group B, iron sulphate v Group A, iron isomaltoside 1000
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Number of subjects included in analysis |
317
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Analysis specification |
Pre-specified
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Analysis type |
non-inferiority [1] | ||||||||||||
P-value |
< 0.0001 [2] | ||||||||||||
Method |
MMRM | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
0.2216
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
0.012 | ||||||||||||
upper limit |
0.431 | ||||||||||||
Variability estimate |
Standard error of the mean
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Dispersion value |
0.1064
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| Notes [1] - A mixed model for repeated measures (MMRM) was used to compare the average change in Hb concentration from baseline to week 4 with the inclusion of treatment, visit, treatment*visit interactions, country, and stratum (past treatment with parenteral iron (Yes/No) and current eGFR between 15-45 mL/min/1.73 m2 or between 46-59 mL/min/1.73 m2) as factors and baseline Hb as covariate. The treatment difference at week 4 was derived from the interaction between treatment and visit. [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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Statistical analysis title |
Test for superiority, MMRM | ||||||||||||
Statistical analysis description |
In case the 95 % CI lay entirely above 0, this was evidence of superiority in terms of statistical significance at the 5 % level. In that case, the p-value associated with a test of superiority was calculated and evaluated whether this was sufficiently small to reject the hypothesis of no difference.
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Comparison groups |
Group A, iron isomaltoside 1000 v Group B, iron sulphate
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Number of subjects included in analysis |
317
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.0385 | ||||||||||||
Method |
MMRM | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
0.2216
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
0.012 | ||||||||||||
upper limit |
0.431 | ||||||||||||
Variability estimate |
Standard error of the mean
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Dispersion value |
0.1064
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End point title |
Change in Hb concentration from baseline to week 4, PP | ||||||||||||
End point description |
Change in Hb concentration from baseline to week 4.
The analysis is performed on the PP analysis set.
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End point type |
Primary
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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 non-inferiority, MMRM | ||||||||||||
Statistical analysis description |
A mixed model for repeated measures (MMRM) was used to compare the average change in Hb
concentration from baseline to week 4.
The number of subjects may differ from the analysis population if data is missing.
With a 2:1 randomisation, a two-sided significance level of 5%, and a non-inferiority margin of -0.5
g/dL, there was 80% power to demonstrate non-inferiority with 214 patients in group A and 107
patients in group B.
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Comparison groups |
Group B, iron sulphate v Group A, iron isomaltoside 1000
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Number of subjects included in analysis |
310
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Analysis specification |
Pre-specified
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Analysis type |
non-inferiority [3] | ||||||||||||
P-value |
< 0.0001 [4] | ||||||||||||
Method |
MMRM | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
0.2176
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
0.003 | ||||||||||||
upper limit |
0.432 | ||||||||||||
Variability estimate |
Standard error of the mean
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Dispersion value |
0.109
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| Notes [3] - A mixed model for repeated measures (MMRM) was used to compare the average change in Hb concentration from baseline to week 4 with the inclusion of treatment, visit, treatment*visit interactions, country, and stratum (past treatment with parenteral iron (Yes/No) and current eGFR between 15-45 mL/min/1.73 m2 or between 46-59 mL/min/1.73 m2) as factors and baseline Hb as covariate. The treatment difference at week 4 was derived from the interaction between treatment and visit. [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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Statistical analysis title |
Test for superiority, MMRM | ||||||||||||
Statistical analysis description |
In case the 95 % CI lay entirely above 0, this was evidence of superiority in terms of statistical significance at the 5 % level. In that case, the p-value associated with a test of superiority was calculated and evaluated whether this was sufficiently small to reject the hypothesis of no difference.
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Comparison groups |
Group A, iron isomaltoside 1000 v Group B, iron sulphate
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Number of subjects included in analysis |
310
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Analysis specification |
Pre-specified
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Analysis type |
superiority [5] | ||||||||||||
P-value |
= 0.0471 [6] | ||||||||||||
Method |
MMRM | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
0.2176
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
0.003 | ||||||||||||
upper limit |
0.432 | ||||||||||||
Variability estimate |
Standard error of the mean
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Dispersion value |
0.109
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| Notes [5] - A mixed model for repeated measures (MMRM) was used to compare the average change in Hb concentration from baseline to week 4 with the inclusion of treatment, visit, treatment*visit interactions, country, and stratum (past treatment with parenteral iron (Yes/No) and current eGFR between 15-45 mL/min/1.73 m2 or between 46-59 mL/min/1.73 m2) as factors and baseline Hb as covariate. The treatment difference at week 4 was derived from the interaction between treatment and visit. [6] - 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 |
Number of subjects who had a change in Hb concentration ≥ 1.0 g/dL from baseline to week 2, 4, or 8 | |||||||||||||||
End point description |
The subjects had to have an increase in Hb ≥ 1.0 g/dL at either week 2,4, or week 8 in order to be a responder.
The analysis was performed on the FAS.
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End point type |
Secondary
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End point timeframe |
Number of subjects who had a change in Hb concentration ≥ 1.0 g/dL from baseline to week 2, 4, or 8.
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Statistical analysis title |
Superiority test, logistic regression | |||||||||||||||
Statistical analysis description |
The p-values is calculated with logistic regression with treatment and stratum as factors and baseline values as covariates.
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Comparison groups |
Group A, iron isomaltoside 1000 v Group B, iron sulphate
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Number of subjects included in analysis |
338
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Analysis specification |
Pre-specified
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Analysis type |
superiority | |||||||||||||||
P-value |
= 0.1464 | |||||||||||||||
Method |
Regression, Logistic | |||||||||||||||
Confidence interval |
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End point title |
Number of subjects who had a change in Hb concentration ≥ 2.0 g/dL from baseline to week 2, 4, or 8 | |||||||||||||||
End point description |
Number of subjects who had a change in Hb concentration ≥ 2.0 g/dL from baseline to week 2, 4, or 8.
The analysis was performed on FAS.
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End point type |
Secondary
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|||||||||||||||
End point timeframe |
Number of subjects who had a change in Hb concentration ≥ 2.0 g/dL from baseline to week 2, 4, or 8.
|
|||||||||||||||
|
||||||||||||||||
Statistical analysis title |
Superiority test, logistic regression | |||||||||||||||
Comparison groups |
Group A, iron isomaltoside 1000 v Group B, iron sulphate
|
|||||||||||||||
Number of subjects included in analysis |
338
|
|||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||
Analysis type |
superiority [7] | |||||||||||||||
P-value |
= 0.1792 | |||||||||||||||
Method |
Regression, Logistic | |||||||||||||||
Confidence interval |
||||||||||||||||
| Notes [7] - The p-value was calculated by Logistic Regression with treatment and stratum as factors and baseline values as covariates. |
||||||||||||||||
|
||||||||||||||||
End point title |
Number of subjects who had Hb > 11 g/dL (6.80 mmol/L), serum (s)-ferritin (200-800 µg/L) and had achieved transferrin saturation (TSAT) (20-50 %) at week 2, 4, or 8 | |||||||||||||||
End point description |
Number of subjects who had Hb > 11 g/dL (6.80 mmol/L), serum (s)-ferritin (200-800 µg/L) and had achieved transferrin saturation (TSAT) (20-50 %) at week 2, 4, or 8.
The analysis was performed on the FAS.
|
|||||||||||||||
End point type |
Secondary
|
|||||||||||||||
End point timeframe |
Number of subjects who had Hb > 11 g/dL (6.80 mmol/L), serum (s)-ferritin (200-800 µg/L) and had achieved transferrin saturation (TSAT) (20-50 %) at week 2, 4, or 8.
|
|||||||||||||||
|
||||||||||||||||
Statistical analysis title |
Superiority test, logistic regression | |||||||||||||||
Statistical analysis description |
The p-value was calculated by logistic regression with treatment and stratum as factors and baseline values as covariates.
|
|||||||||||||||
Comparison groups |
Group A, iron isomaltoside 1000 v Group B, iron sulphate
|
|||||||||||||||
Number of subjects included in analysis |
338
|
|||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||
Analysis type |
superiority | |||||||||||||||
P-value |
= 0.0019 | |||||||||||||||
Method |
Regression, Logistic | |||||||||||||||
Confidence interval |
||||||||||||||||
|
|||||||||||||
End point title |
Change in Hb from baseline to week 2 | ||||||||||||
End point description |
Change in Hb from baseline to week 2.
The analysis was performed on the FAS.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Change in Hb from baseline to week 2.
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Superiority tested by MMRM | ||||||||||||
Statistical analysis description |
The MMRM included treatment, country and stratum (past treatment with parenteral iron (Yes/No) and current eGFR between 15-45 ml/min or between 46-59 ml/min) as factors and baseline value as covariates.
|
||||||||||||
Comparison groups |
Group A, iron isomaltoside 1000 v Group B, iron sulphate
|
||||||||||||
Number of subjects included in analysis |
320
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.4902 | ||||||||||||
Method |
MMRM | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
0.0594
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-0.11 | ||||||||||||
upper limit |
0.229 | ||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||
Dispersion value |
0.0859
|
||||||||||||
|
|||||||||||||
End point title |
Change in Hb from baseline to week 8 | ||||||||||||
End point description |
Change in Hb from baseline to week 8.
The analysis was performed on the FAS.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Change in Hb from baseline to week 8.
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Superiority tested by MMRM | ||||||||||||
Statistical analysis description |
The MMRM included treatment, country and stratum (past treatment with parenteral iron (Yes/No) and current eGFR between 15-45 ml/min or between 46-59 ml/min) as factors and baseline value as covariates.
|
||||||||||||
Comparison groups |
Group A, iron isomaltoside 1000 v Group B, iron sulphate
|
||||||||||||
Number of subjects included in analysis |
322
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.0004 | ||||||||||||
Method |
MMRM | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
0.445
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
0.199 | ||||||||||||
upper limit |
0.691 | ||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||
Dispersion value |
0.1248
|
||||||||||||
|
|||||||||||||
End point title |
Change in s-iron from baseline to week 1 | ||||||||||||
End point description |
Change in s-iron from baseline to week 1.
The analysis was performed on the FAS.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Change in s-iron from baseline to week 1.
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Superiority tested by MMRM | ||||||||||||
Statistical analysis description |
The MMRM included treatment, country and stratum (past treatment with parenteral iron (Yes/No) and current eGFR between 15-45 ml/min or between 46-59 ml/min) as factors and baseline value as covariates.
|
||||||||||||
Comparison groups |
Group A, iron isomaltoside 1000 v Group B, iron sulphate
|
||||||||||||
Number of subjects included in analysis |
326
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
< 0.0001 | ||||||||||||
Method |
MMRM | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
3.5545
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
1.801 | ||||||||||||
upper limit |
5.308 | ||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||
Dispersion value |
0.8896
|
||||||||||||
|
|||||||||||||
End point title |
Change in s-iron from baseline to week 2 | ||||||||||||
End point description |
Change in s-iron from baseline to week 2.
The analysis was performed on the FAS.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Change in s-iron from baseline to week 2.
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Superiority tested by MMRM | ||||||||||||
Statistical analysis description |
The MMRM included treatment, country and stratum (past treatment with parenteral iron (Yes/No) and
current eGFR between 15-45 ml/min or between 46-59 ml/min) as factors and baseline value as
covariates.
|
||||||||||||
Comparison groups |
Group A, iron isomaltoside 1000 v Group B, iron sulphate
|
||||||||||||
Number of subjects included in analysis |
319
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.0026 | ||||||||||||
Method |
MMRM | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
2.0305
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
0.716 | ||||||||||||
upper limit |
3.344 | ||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||
Dispersion value |
0.6666
|
||||||||||||
|
|||||||||||||
End point title |
Change in s-iron from baseline to week 4 | ||||||||||||
End point description |
Change in s-iron from baseline to week 4.
The analysis was performed on the FAS.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Change in s-iron from baseline to week 4.
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Superiority tested by MMRM | ||||||||||||
Statistical analysis description |
The MMRM included treatment, country and stratum (past treatment with parenteral iron (Yes/No) and
current eGFR between 15-45 ml/min or between 46-59 ml/min) as factors and baseline value as
covariates.
|
||||||||||||
Comparison groups |
Group A, iron isomaltoside 1000 v Group B, iron sulphate
|
||||||||||||
Number of subjects included in analysis |
316
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.1439 | ||||||||||||
Method |
MMRM | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
0.8978
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-0.309 | ||||||||||||
upper limit |
2.104 | ||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||
Dispersion value |
0.6119
|
||||||||||||
|
|||||||||||||
End point title |
Change in s-iron from baseline to week 8 | ||||||||||||
End point description |
Change in s-iron from baseline to week 8.
The analysis was performed on the FAS.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Change in s-iron from baseline to week 8.
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Superiority tested by MMRM | ||||||||||||
Statistical analysis description |
The MMRM included treatment, country and stratum (past treatment with parenteral iron (Yes/No) and
current eGFR between 15-45 ml/min or between 46-59 ml/min) as factors and baseline value as
covariates.
|
||||||||||||
Comparison groups |
Group A, iron isomaltoside 1000 v Group B, iron sulphate
|
||||||||||||
Number of subjects included in analysis |
321
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.0914 | ||||||||||||
Method |
MMRM | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
0.9513
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-0.155 | ||||||||||||
upper limit |
2.057 | ||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||
Dispersion value |
0.561
|
||||||||||||
|
|||||||||||||
End point title |
Change in s-ferritin from baseline to week 1 | ||||||||||||
End point description |
Change in s-ferritin from baseline to week 1.
The analysis was performed on the FAS.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Change in s-ferritin from baseline to week 1.
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Superiority tested by MMRM | ||||||||||||
Statistical analysis description |
The MMRM included treatment, country and stratum (past treatment with parenteral iron (Yes/No) and
current eGFR between 15-45 ml/min or between 46-59 ml/min) as factors and baseline value as
covariates.
|
||||||||||||
Comparison groups |
Group A, iron isomaltoside 1000 v Group B, iron sulphate
|
||||||||||||
Number of subjects included in analysis |
326
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
< 0.0001 | ||||||||||||
Method |
MMRM | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
321.4931
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
270.348 | ||||||||||||
upper limit |
372.639 | ||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||
Dispersion value |
25.4367
|
||||||||||||
|
|||||||||||||
End point title |
Change in s-ferritin from baseline to week 2 | ||||||||||||
End point description |
Change in s-ferritin from baseline to week 2.
The analysis was performed on the FAS.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Change in s-ferritin from baseline to week 2.
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Superiority tested by MMRM | ||||||||||||
Statistical analysis description |
The MMRM included treatment, country and stratum (past treatment with parenteral iron (Yes/No) and
current eGFR between 15-45 ml/min or between 46-59 ml/min) as factors and baseline value as
covariates.
|
||||||||||||
Comparison groups |
Group A, iron isomaltoside 1000 v Group B, iron sulphate
|
||||||||||||
Number of subjects included in analysis |
319
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
< 0.0001 | ||||||||||||
Method |
MMRM | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
334.9454
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
251.812 | ||||||||||||
upper limit |
418.079 | ||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||
Dispersion value |
42.0643
|
||||||||||||
|
|||||||||||||
End point title |
Change in s-ferritin from baseline to week 4 | ||||||||||||
End point description |
Change in s-ferritin from baseline to week 4.
The analysis was performed on the FAS.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Change in s-ferritin from baseline to week 4.
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Superiority tested by MMRM | ||||||||||||
Statistical analysis description |
The MMRM included treatment, country and stratum (past treatment with parenteral iron (Yes/No) and
current eGFR between 15-45 ml/min or between 46-59 ml/min) as factors and baseline value as
covariates.
|
||||||||||||
Comparison groups |
Group B, iron sulphate v Group A, iron isomaltoside 1000
|
||||||||||||
Number of subjects included in analysis |
316
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
< 0.0001 | ||||||||||||
Method |
MMRM | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
235.2231
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
169.697 | ||||||||||||
upper limit |
300.749 | ||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||
Dispersion value |
33.1761
|
||||||||||||
|
|||||||||||||
End point title |
Change in s-ferritin from baseline to week 8 | ||||||||||||
End point description |
Change in s-ferritin from baseline to week 8.
The analysis was performed on the FAS.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Change in s-ferritin from baseline to week 8.
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Superiority tested by MMRM | ||||||||||||
Statistical analysis description |
The MMRM included treatment, country and stratum (past treatment with parenteral iron (Yes/No) and current eGFR between 15-45 ml/min or between 46-59 ml/min) as factors and baseline value as covariates.
|
||||||||||||
Comparison groups |
Group A, iron isomaltoside 1000 v Group B, iron sulphate
|
||||||||||||
Number of subjects included in analysis |
321
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
< 0.0001 | ||||||||||||
Method |
MMRM | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
155.6132
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
104.764 | ||||||||||||
upper limit |
206.463 | ||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||
Dispersion value |
25.7608
|
||||||||||||
|
|||||||||||||
End point title |
Change in transferrin saturation (TSAT) from baseline to week 1 | ||||||||||||
End point description |
Change in transferrin saturation (TSAT) from baseline to week 1.
The analysis was performed on the FAS.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Change in transferrin saturation (TSAT) from baseline to week 1.
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Superiority tested by MMRM | ||||||||||||
Statistical analysis description |
The MMRM included treatment, country and stratum (past treatment with parenteral iron (Yes/No) and current eGFR between 15-45 ml/min or between 46-59 ml/min) as factors and baseline value as covariates.
|
||||||||||||
Comparison groups |
Group A, iron isomaltoside 1000 v Group B, iron sulphate
|
||||||||||||
Number of subjects included in analysis |
326
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
< 0.0001 | ||||||||||||
Method |
MMRM | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
8.3699
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
5.172 | ||||||||||||
upper limit |
11.568 | ||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||
Dispersion value |
1.6246
|
||||||||||||
|
|||||||||||||
End point title |
Change in transferrin saturation (TSAT) from baseline to week 2 | ||||||||||||
End point description |
Change in transferrin saturation (TSAT) from baseline to week 2.
The analysis was performed on the FAS.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Change in transferrin saturation (TSAT) from baseline to week 2.
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Superiority tested by MMRM | ||||||||||||
Statistical analysis description |
The MMRM included treatment, country and stratum (past treatment with parenteral iron (Yes/No) and current eGFR between 15-45 ml/min or between 46-59 ml/min) as factors and baseline value as covariates.
|
||||||||||||
Comparison groups |
Group A, iron isomaltoside 1000 v Group B, iron sulphate
|
||||||||||||
Number of subjects included in analysis |
319
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
< 0.0001 | ||||||||||||
Method |
MMRM | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
6.2022
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
3.862 | ||||||||||||
upper limit |
8.542 | ||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||
Dispersion value |
1.1885
|
||||||||||||
|
|||||||||||||
End point title |
Change in transferrin saturation (TSAT) from baseline to week 4 | ||||||||||||
End point description |
Change in transferrin saturation (TSAT) from baseline to week 4.
The analysis was performed on the FAS.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Change in transferrin saturation (TSAT) from baseline to week 4.
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Superiority tested by MMRM | ||||||||||||
Statistical analysis description |
The MMRM included treatment, country and stratum (past treatment with parenteral iron (Yes/No) and current eGFR between 15-45 ml/min or between 46-59 ml/min) as factors and baseline value as covariates.
|
||||||||||||
Comparison groups |
Group A, iron isomaltoside 1000 v Group B, iron sulphate
|
||||||||||||
Number of subjects included in analysis |
316
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
< 0.0001 | ||||||||||||
Method |
MMRM | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
4.7666
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
2.452 | ||||||||||||
upper limit |
7.082 | ||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||
Dispersion value |
1.1759
|
||||||||||||
|
|||||||||||||
End point title |
Change in transferrin saturation (TSAT) from baseline to week 8 | ||||||||||||
End point description |
Change in transferrin saturation (TSAT) from baseline to week 8.
The analysis was performed on the FAS.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Change in transferrin saturation (TSAT) from baseline to week 8.
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Superiority tested by MMRM | ||||||||||||
Statistical analysis description |
The MMRM included treatment, country and stratum (past treatment with parenteral iron (Yes/No) and current eGFR between 15-45 ml/min or between 46-59 ml/min) as factors and baseline value as covariates.
|
||||||||||||
Comparison groups |
Group A, iron isomaltoside 1000 v Group B, iron sulphate
|
||||||||||||
Number of subjects included in analysis |
321
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.0035 | ||||||||||||
Method |
MMRM | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
3.1969
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
1.063 | ||||||||||||
upper limit |
5.331 | ||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||
Dispersion value |
1.0829
|
||||||||||||
|
|||||||||||||
End point title |
Change in total iron binding capacity (TIBC) from baseline to week 1 | ||||||||||||
End point description |
Change in total iron binding capacity (TIBC) from baseline to week 1.
The analysis was performed on the FAS.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Change in total iron binding capacity (TIBC) from baseline to week 1.
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Superiority tested by MMRM | ||||||||||||
Statistical analysis description |
The MMRM included treatment, country and stratum (past treatment with parenteral iron (Yes/No) and
current eGFR between 15-45 ml/min or between 46-59 ml/min) as factors and baseline value as
covariates.
|
||||||||||||
Comparison groups |
Group A, iron isomaltoside 1000 v Group B, iron sulphate
|
||||||||||||
Number of subjects included in analysis |
326
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
< 0.0001 | ||||||||||||
Method |
MMRM | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
-3.9216
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-5.43 | ||||||||||||
upper limit |
-2.413 | ||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||
Dispersion value |
0.7652
|
||||||||||||
|
|||||||||||||
End point title |
Change in total iron binding capacity (TIBC) from baseline to week 2 | ||||||||||||
End point description |
Change in total iron binding capacity (TIBC) from baseline to week 2.
The analysis was performed on the FAS.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Change in total iron binding capacity (TIBC) from baseline to week 2.
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Superiority tested by MMRM | ||||||||||||
Statistical analysis description |
The MMRM included treatment, country and stratum (past treatment with parenteral iron (Yes/No) and current eGFR between 15-45 ml/min or between 46-59 ml/min) as factors and baseline value as covariates.
|
||||||||||||
Comparison groups |
Group A, iron isomaltoside 1000 v Group B, iron sulphate
|
||||||||||||
Number of subjects included in analysis |
319
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
< 0.0001 | ||||||||||||
Method |
MMRM | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
-5.1839
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-7.011 | ||||||||||||
upper limit |
-3.357 | ||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||
Dispersion value |
0.9249
|
||||||||||||
|
|||||||||||||
End point title |
Change in total iron binding capacity (TIBC) from baseline to week 4 | ||||||||||||
End point description |
Change in total iron binding capacity (TIBC) from baseline to week 4.
The analysis was performed on the FAS.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Change in total iron binding capacity (TIBC) from baseline to week 4.
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Superiority tested by MMRM | ||||||||||||
Statistical analysis description |
The MMRM included treatment, country and stratum (past treatment with parenteral iron (Yes/No) and current eGFR between 15-45 ml/min or between 46-59 ml/min) as factors and baseline value as covariates.
|
||||||||||||
Comparison groups |
Group A, iron isomaltoside 1000 v Group B, iron sulphate
|
||||||||||||
Number of subjects included in analysis |
316
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
< 0.0001 | ||||||||||||
Method |
MMRM | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
-7.1556
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-8.987 | ||||||||||||
upper limit |
-5.324 | ||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||
Dispersion value |
0.9303
|
||||||||||||
|
|||||||||||||
End point title |
Change in total iron binding capacity (TIBC) from baseline to week 8 | ||||||||||||
End point description |
Change in total iron binding capacity (TIBC) from baseline to week 8.
The analysis was performed on the FAS.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Change in total iron binding capacity (TIBC) from baseline to week 8.
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Superiority tested by MMRM | ||||||||||||
Statistical analysis description |
The MMRM included treatment, country and stratum (past treatment with parenteral iron (Yes/No) and current eGFR between 15-45 ml/min or between 46-59 ml/min) as factors and baseline value as covariates.
|
||||||||||||
Comparison groups |
Group A, iron isomaltoside 1000 v Group B, iron sulphate
|
||||||||||||
Number of subjects included in analysis |
321
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
< 0.0001 | ||||||||||||
Method |
MMRM | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
-4.7777
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-6.354 | ||||||||||||
upper limit |
-3.202 | ||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||
Dispersion value |
0.7998
|
||||||||||||
|
||||||||||||||||
End point title |
Number of subjects who discontinued the study because of lack of response, need for blood transfusion, or intolerance of investigational drugs | |||||||||||||||
End point description |
Number of subjects in each randomisation group who discontinued study because of lack of response, need for blood transfusion, or intolerance of investigational drugs.
The analysis was performed on the safety population.
|
|||||||||||||||
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 sulphate
|
|||||||||||||||
Number of subjects included in analysis |
345
|
|||||||||||||||
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 MMRM will include treatment, visit, treatment*visit interactions, country, stratum (past treatment with parenteral iron (Yes/No) and current eGFR between 15-45 ml/min or between 46-59 ml/min) as factors and baseline values as covariates.
|
||||||||||||
Comparison groups |
Group A, iron isomaltoside 1000 v Group B, iron sulphate
|
||||||||||||
Number of subjects included in analysis |
297
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.6754 | ||||||||||||
Method |
MMRM | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
0.8106
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-3 | ||||||||||||
upper limit |
4.62 | ||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||
Dispersion value |
1.9327
|
||||||||||||
|
|||||||||||||
End point title |
Change in total quality of life (QoL) score (LASA: Energy level) from baseline to week 8. | ||||||||||||
End point description |
Change in total quality of life (QoL) score (LASA: Energy level) from baseline to week 8.
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 8.
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Superiority tested by MMRM | ||||||||||||
Statistical analysis description |
The MMRM included treatment, country and stratum (past treatment with parenteral iron (Yes/No) and current eGFR between 15-45 ml/min or between 46-59 ml/min) as factors and baseline value as covariates.
|
||||||||||||
Comparison groups |
Group B, iron sulphate v Group A, iron isomaltoside 1000
|
||||||||||||
Number of subjects included in analysis |
312
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.9625 | ||||||||||||
Method |
MMRM | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
0.09616
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-3.93 | ||||||||||||
upper limit |
4.12 | ||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||
Dispersion value |
2.0424
|
||||||||||||
|
|||||||||||||
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 |
Superiority tested by MMRM | ||||||||||||
Statistical analysis description |
The MMRM included treatment, country and stratum (past treatment with parenteral iron (Yes/No) and
current eGFR between 15-45 ml/min or between 46-59 ml/min) as factors and baseline value as
covariates.
|
||||||||||||
Comparison groups |
Group A, iron isomaltoside 1000 v Group B, iron sulphate
|
||||||||||||
Number of subjects included in analysis |
297
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.2788 | ||||||||||||
Method |
MMRM | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
2.0436
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-1.67 | ||||||||||||
upper limit |
5.75 | ||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||
Dispersion value |
1.8823
|
||||||||||||
|
|||||||||||||
End point title |
Change in total quality of life (QoL) score (LASA: Ability to do daily activities) from baseline to week 8 | ||||||||||||
End point description |
Change in total quality of life (QoL) score (LASA: Ability to do daily activities) from baseline to week 8.
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 8.
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Superiority tested by MMRM | ||||||||||||
Statistical analysis description |
The MMRM included treatment, country and stratum (past treatment with parenteral iron (Yes/No) and current eGFR between 15-45 ml/min or between 46-59 ml/min) as factors and baseline value as covariates.
|
||||||||||||
Comparison groups |
Group A, iron isomaltoside 1000 v Group B, iron sulphate
|
||||||||||||
Number of subjects included in analysis |
312
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.3303 | ||||||||||||
Method |
MMRM | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
2.0155
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-2.06 | ||||||||||||
upper limit |
6.09 | ||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||
Dispersion value |
2.0649
|
||||||||||||
|
|||||||||||||
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 |
Superiority tested by MMRM | ||||||||||||
Statistical analysis description |
The MMRM included treatment, country and stratum (past treatment with parenteral iron (Yes/No) and current eGFR between 15-45 ml/min or between 46-59 ml/min) as factors and baseline value as covariates.
|
||||||||||||
Comparison groups |
Group A, iron isomaltoside 1000 v Group B, iron sulphate
|
||||||||||||
Number of subjects included in analysis |
297
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.3905 | ||||||||||||
Method |
MMRM | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
1.5796
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-2.04 | ||||||||||||
upper limit |
5.2 | ||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||
Dispersion value |
1.8359
|
||||||||||||
|
|||||||||||||
End point title |
Change in total quality of life (QoL) score (LASA: Overall quality of life) from baseline to week 8 | ||||||||||||
End point description |
Change in total quality of life (QoL) score (LASA: Overall quality of life) from baseline to week 8.
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 8.
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Superiority tested by MMRM | ||||||||||||
Statistical analysis description |
The MMRM included treatment, country and stratum (past treatment with parenteral iron (Yes/No) and current eGFR between 15-45 ml/min or between 46-59 ml/min) as factors and baseline value as covariates.
|
||||||||||||
Comparison groups |
Group A, iron isomaltoside 1000 v Group B, iron sulphate
|
||||||||||||
Number of subjects included in analysis |
312
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.4723 | ||||||||||||
Method |
MMRM | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
1.4573
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-2.53 | ||||||||||||
upper limit |
5.45 | ||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||
Dispersion value |
2.0236
|
||||||||||||
|
|||||||||||||
End point title |
Change in estimated glomerular filtration rate (eGFR) from baseline to week 8 | ||||||||||||
End point description |
Change in estimated glomerular filtration rate (eGFR) from baseline to week 8.
The analysis was performed on the FAS.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Change in estimated glomerular filtration rate (eGFR) from baseline to week 8.
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Superiority tested by ANCOVA | ||||||||||||
Statistical analysis description |
The ANCOVA model included treatment and stratum (past treatment with parenteral iron (Yes/No) and current eGFR between 15-45 ml/min or between 46-59 ml/min) as factors and baseline values as covariates.
|
||||||||||||
Comparison groups |
Group A, iron isomaltoside 1000 v Group B, iron sulphate
|
||||||||||||
Number of subjects included in analysis |
321
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.4493 | ||||||||||||
Method |
ANCOVA | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
0.6548
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-1.05 | ||||||||||||
upper limit |
2.36 | ||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||
Dispersion value |
0.8645
|
||||||||||||
|
|||||||||||||
End point title |
Change in restless legs syndrome (RLS) symptoms (Cambridge-Hopkins RLS questionnaire (CH-RLSq) score) from baseline to week 8 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 8 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 8 in subjects with RLS symptoms at baseline.
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Superiority tested by ANCOVA | ||||||||||||
Statistical analysis description |
The ANCOVA mixed model will include treatment and stratum as factors and baseline value as covariates.
|
||||||||||||
Comparison groups |
Group A, iron isomaltoside 1000 v Group B, iron sulphate
|
||||||||||||
Number of subjects included in analysis |
6
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.5957 | ||||||||||||
Method |
ANCOVA | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
1.4739
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-23.936 | ||||||||||||
upper limit |
26.884 | ||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||
Dispersion value |
1.9998
|
||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Adverse events information
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Timeframe for reporting adverse events |
From the time a subject had signed the ICF and until he/she had completed the trial, all AEs/SAEs were collected in the CRF.
|
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Adverse event reporting additional description |
All AEs classified as serious and/or related to the study drug were followed by the principle investigator (PI) until the subject had recovered, recovered with sequelae, or died, and until all queries related to the AEs had been resolved. All other AEs were followed by the PI until the subject had recovered or until EOS whichever came first.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
17.0
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Reporting groups
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Reporting group title |
Group A, iron isomaltoside 1000
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Reporting group description |
The total IV iron needed for each subject in group A was calculated according to an adapted Ganzoni formula (target Hb was 13 g/dL (8.1 mmol/L) as the subjects were ESA naive): Cumulative iron dose (mg) = [body weight (kg) x (target Hb - actual Hb (g/dL)] x 2.4 + depot iron (set at 500 mg). Subjects treated with iron isomaltoside 1000 either received an IV infusion (group A1) of maximum 1000 mg iron isomaltoside 1000 as single doses over 15 minutes (full iron replacement was achieved by 1 or up to 2 doses at a weekly interval) or IV bolus injections (group A2) of 500 mg iron isomaltoside 1000 administered over 2 minutes once weekly until full replacement dose was achieved. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Group B, oral iron sulphate
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Reporting group description |
Subjects receiving with oral iron sulphate were treated daily for 8 weeks with 200 mg given as 100 mg twice a day. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 2% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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15 Feb 2010 |
• The replacement dose was modified to 750 mg iron isomaltoside 1000 for subjects with body weight between 35-45 kg and 500 mg iron isomaltoside 1000 for < 35 kg body weight
• Laboratory assessment of s-calcium was added to obtain a complete serum chemistry
• It was clarified that the UPT will be done only at screening
• Packaging of iron isomaltoside 1000 was changed from 10 mL (1000 mg iron) am-poules to 5 mL (500 mg iron) vials
• Analysis of phosphate as part of safety lab after 25, 50, and 100 subjects had been ex-posed to iron isomaltoside 1000 was added to monitor changes in phosphate levels
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28 Sep 2011 |
• Subjects with body weight < 30 kg were excluded from the study for safety reasons
• In the secondary endpoints, target limits for Hb, s-ferritin, and TSAT were removed on request from investigators, as these limits were too high
• Text regarding the number of study centres was revised from “4 countries (UK, Denmark, Sweden, and India)” to “several countries in the European Union and India”
• Levels of s-ferritin in the inclusion criteria were modified from s-ferritin < 100 µg/L to s-ferritin < 200 µg/L
• Text describing non-serious AEs, ADRs, and SUSARs were added for clarity
• Text regarding “3 months follow-up for pregnancy and study drug related SAEs” after EOS was removed
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18 Mar 2013 |
• Primary endpoint of change in Hb concentration from baseline was changed from week 8 to week 4.
• In the secondary endpoints, it was clarified that the responder can fulfil the criteria at any time point instead of all time points
• A secondary endpoint of the number of subjects with a change in Hb ≥ 2.0 g/dL at different time points was added, in alignment with previous studies
• The number of AEs of special interest (i.e. hypersensitivity reactions or hypotension at pre-specified time points in relation to administration of study drug) was added as a secondary endpoint
• Secondary endpoint of change in Hb concentration was changed from week 4 to week 8 in order to align with the change in primary endpoint
• Exclusion criteria 5 was modified to clarify that if the subject did not have an impaired liver function then there was no need to exclude the subject from the study.
• Exclusion criteria no. 6 and 20 were removed as there was no increased risk for subjects infected with human immunodeficiency virus or hepatitis virus in participating in the study and it is not a contraindication in the SmPC of the study drug
• To allow addition of new centres in countries other than Europe and India, the text describing the participating countries was generalised
• Window periods for recording vital signs were increased from 0-5 to 0-10 min, and approximate time points were added for 5 min and 30 min after injection to allow a more flexible procedure
• The word “approximately” was added to the administration time in order to make the drug administration more flexible for the centre personal
• The provision for re-screening was added
• The pregnancy reporting procedure was updated as there is no safety issue for women of which the spouse has been enrolled in the study
• Appendix 2 related to CH-RLSq was updated
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
