Clinical Trial Results:
A randomized comparative, open-label study of intravenous iron isomaltoside 1000 (Monofer®) administered by high single dose infusions or red blood cell transfusion in women with severe postpartum iron deficiency anaemia
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Summary
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EudraCT number |
2012-005783-10 |
Trial protocol |
DK |
Global end of trial date |
04 Jul 2015
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Results information
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Results version number |
v1(current) |
This version publication date |
17 Apr 2016
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First version publication date |
17 Apr 2016
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Other versions |
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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-PP-02
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01895205 | ||
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, Pharmacosmos A/S, +45 59485935, trial@pharmacosmos.com
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Scientific contact |
Clinical trial disclosure desk, Pharmacosmos A/S, 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 |
04 Jul 2015
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
04 Jul 2015
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Global end of trial reached? |
Yes
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Global end of trial date |
04 Jul 2015
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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 objective of this study is to get explorative information about IV high single dose infusion of iron isomaltoside 1000 compared to RBC transfusion in the treatment of severe PP-IDA evaluated as physical fatigue.
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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 |
06 Aug 2013
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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 |
Denmark: 13
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Worldwide total number of subjects |
13
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EEA total number of subjects |
13
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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) |
13
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
Subjects were screened in the period 06 August 2013 to 12 April 2015. The trial took place at one site in Denmark. | |||||||||
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Pre-assignment
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Screening details |
Women who were ≥18 years of age with PPH > 1000 mL and Hb ≥ 5.5 and ≤ 8.0 g/dL (≥ 3.5 and ≤ 5.0 mmol/L) were able 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 |
1500 mg iron isomaltoside 1000 (or 1000 mg in women with a pre-pregnancy weight below 45 kg) was administered over approximately 15 min as a single IV infusion. | |||||||||
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 |
1500 mg iron isomaltoside 1000 (or 1000 mg in women with a pre-pregnancy weight below 45 kg) was administered over approximately 15 min as a single IV infusion. 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, RBC transfusion | |||||||||
Arm description |
Subjects received 1 or 2 units of red blood cells (RBC) administered at the baseline visit according to the hospital’s standard operating procedure. | |||||||||
Arm type |
RBC transfusion | |||||||||
Investigational medicinal product name |
No investigational medicinal product assigned in this arm
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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 |
1500 mg iron isomaltoside 1000 (or 1000 mg in women with a pre-pregnancy weight below 45 kg) was administered over approximately 15 min as a single IV infusion. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Group B, RBC transfusion
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Reporting group description |
Subjects received 1 or 2 units of red blood cells (RBC) administered at the baseline visit according to the hospital’s standard operating procedure. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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 analysis set included all subjects who were randomised and received 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 FAS consisted of all randomised subjects, who received the trial drug and had at least 1 post-baseline physical fatigue score.
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Subject analysis set title |
Per protocol analysis set
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Subject analysis set type |
Per protocol | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
The PP population included all subjects in the FAS who did not have any major PDs (i.e. did not receive ‘rescue’ allogenic RBC transfusion, did not receive less than 80 % or more than 120 % of planned dose, and did not receive prohibited concomitant medication during the trial).
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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 |
1500 mg iron isomaltoside 1000 (or 1000 mg in women with a pre-pregnancy weight below 45 kg) was administered over approximately 15 min as a single IV infusion. | ||
Reporting group title |
Group B, RBC transfusion
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Reporting group description |
Subjects received 1 or 2 units of red blood cells (RBC) administered at the baseline visit according to the hospital’s standard operating procedure. | ||
Subject analysis set title |
Safety analysis set
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
The safety analysis set included all subjects who were randomised and received 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 FAS consisted of all randomised subjects, who received the trial drug and had at least 1 post-baseline physical fatigue score.
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Subject analysis set title |
Per protocol analysis set
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Subject analysis set type |
Per protocol | ||
Subject analysis set description |
The PP population included all subjects in the FAS who did not have any major PDs (i.e. did not receive ‘rescue’ allogenic RBC transfusion, did not receive less than 80 % or more than 120 % of planned dose, and did not receive prohibited concomitant medication during the trial).
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End point title |
Aggregated change in physical fatigue score from baseline to week 12 (area under the curve (AUC)) in the 2 treatment arms measured by the Multidimensional Fatigue Inventory (MFI) | ||||||||||||
End point description |
Aggregated change in physical fatigue score from baseline to week 12 (area under the curve (AUC)) in the 2 treatment arms measured by the Multidimensional Fatigue Inventory (MFI).
Analysis performed on the FAS.
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End point type |
Primary
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End point timeframe |
Aggregated change in physical fatigue score from baseline to week 12 (area under the curve (AUC)) in the 2 treatment arms.
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Statistical analysis title |
Analysis of covariance (ANCOVA) model | ||||||||||||
Statistical analysis description |
The primary endpoint was analysed using an analysis of covariance (ANCOVA) model, with treatment as factor and baseline MFI physical fatigue score as covariate. The estimated treat-ment differences (iron isomaltoside 1000 - RBC transfusion) expressed as contrasts of the adjusted means were presented with corresponding 95 % CI and the p-value for test of no treatment difference.
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Comparison groups |
Group A, iron isomaltoside 1000 v Group B, RBC transfusion
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Number of subjects included in analysis |
13
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.6051 | ||||||||||||
Method |
ANCOVA | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
-0.63
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-3.28 | ||||||||||||
upper limit |
2.02 | ||||||||||||
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End point title |
Aggregated change in physical fatigue score from baseline to week 12 (area under the curve (AUC)) in the 2 treatment arms measured by the Multidimensional Fatigue Inventory (MFI), PP | ||||||||||||
End point description |
Aggregated change in physical fatigue score from baseline to week 12 (area under the curve (AUC)) in the 2 treatment arms measured by the Multidimensional Fatigue Inventory (MFI).
Analysis performed on the PP analysis set.
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End point type |
Primary
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End point timeframe |
Aggregated change in physical fatigue score from baseline to week 12 (area under the curve (AUC)) in the 2 treatment arms.
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Statistical analysis title |
Analysis of covariance (ANCOVA) model | ||||||||||||
Statistical analysis description |
The primary endpoint was analysed using an analysis of covariance (ANCOVA) model, with treatment as factor and baseline MFI physical fatigue score as covariate. The estimated treat-ment differences (iron isomaltoside 1000 - RBC transfusion) expressed as contrasts of the adjusted means were presented with corresponding 95 % CI and the p-value for test of no treatment difference.
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Comparison groups |
Group A, iron isomaltoside 1000 v Group B, RBC transfusion
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Number of subjects included in analysis |
10
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.8475 | ||||||||||||
Method |
ANCOVA | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
0.3
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-3.26 | ||||||||||||
upper limit |
3.86 | ||||||||||||
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End point title |
Change in haemoglobin from baseline to day 1 | ||||||||||||
End point description |
Change in haemoglobin from baseline to day 1.
Analysis performed on FAS.
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End point type |
Secondary
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End point timeframe |
Change in haemoglobin from baseline to day 1.
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Statistical analysis title |
Test for superiority, MMRM | ||||||||||||
Statistical analysis description |
A mixed model for repeated measurements (MMRM) with treatment-by-visit as factor, baseline value as covariate, and subject as random effect was used.
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Comparison groups |
Group A, iron isomaltoside 1000 v Group B, RBC transfusion
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Number of subjects included in analysis |
12
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.0411 | ||||||||||||
Method |
MMRM | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
-1.02
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-2 | ||||||||||||
upper limit |
-0.04 | ||||||||||||
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End point title |
Change in haemoglobin from baseline to day 2 | ||||||||||||
End point description |
Change in haemoglobin from baseline to day 2.
Analysis performed on FAS.
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End point type |
Secondary
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End point timeframe |
Change in haemoglobin from baseline to day 2.
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Statistical analysis title |
Test for superiority, MMRM | ||||||||||||
Statistical analysis description |
A mixed model for repeated measurements (MMRM) with treatment-by-visit as factor, baseline value as covariate, and subject as random effect was used.
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Comparison groups |
Group A, iron isomaltoside 1000 v Group B, RBC transfusion
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Number of subjects included in analysis |
13
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.0805 | ||||||||||||
Method |
MMRM | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
-0.85
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-1.81 | ||||||||||||
upper limit |
0.11 | ||||||||||||
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End point title |
Change in haemoglobin from baseline to day 3 | ||||||||||||
End point description |
Change in haemoglobin from baseline to day 3.
Analysis performed on FAS.
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End point type |
Secondary
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End point timeframe |
Change in haemoglobin from baseline to day 3.
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Statistical analysis title |
Test for superiority, MMRM | ||||||||||||
Statistical analysis description |
A mixed model for repeated measurements (MMRM) with treatment-by-visit as factor, baseline value as covariate, and subject as random effect was used.
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Comparison groups |
Group A, iron isomaltoside 1000 v Group B, RBC transfusion
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Number of subjects included in analysis |
13
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.5134 | ||||||||||||
Method |
MMRM | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
-0.31
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-1.27 | ||||||||||||
upper limit |
0.65 | ||||||||||||
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End point title |
Change in haemoglobin from baseline to day 4 | ||||||||||||
End point description |
Change in haemoglobin from baseline to day 4.
Analysis performed on FAS.
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End point type |
Secondary
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End point timeframe |
Change in haemoglobin from baseline to day 4.
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Statistical analysis title |
Test for superiority, MMRM | ||||||||||||
Statistical analysis description |
A mixed model for repeated measurements (MMRM) with treatment-by-visit as factor, baseline value as covariate, and subject as random effect was used.
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Comparison groups |
Group A, iron isomaltoside 1000 v Group B, RBC transfusion
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Number of subjects included in analysis |
13
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.6753 | ||||||||||||
Method |
MMRM | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
-0.2
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-1.16 | ||||||||||||
upper limit |
0.76 | ||||||||||||
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End point title |
Change in haemoglobin from baseline to day 5 | ||||||||||||
End point description |
Change in haemoglobin from baseline to day 5.
Analysis performed on FAS.
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End point type |
Secondary
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End point timeframe |
Change in haemoglobin from baseline to day 5.
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Statistical analysis title |
Test for superiority, MMRM | ||||||||||||
Statistical analysis description |
A mixed model for repeated measurements (MMRM) with treatment-by-visit as factor, baseline value as covariate, and subject as random effect was used.
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Comparison groups |
Group A, iron isomaltoside 1000 v Group B, RBC transfusion
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Number of subjects included in analysis |
12
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.5633 | ||||||||||||
Method |
MMRM | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
-0.28
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-1.26 | ||||||||||||
upper limit |
0.7 | ||||||||||||
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End point title |
Change in haemoglobin from baseline to day 6 | ||||||||||||
End point description |
Change in haemoglobin from baseline to day 6.
Analysis performed on FAS.
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End point type |
Secondary
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End point timeframe |
Change in haemoglobin from baseline to day 6.
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Statistical analysis title |
Test for superiority, MMRM | ||||||||||||
Statistical analysis description |
A mixed model for repeated measurements (MMRM) with treatment-by-visit as factor, baseline value as covariate, and subject as random effect was used.
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Comparison groups |
Group A, iron isomaltoside 1000 v Group B, RBC transfusion
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Number of subjects included in analysis |
12
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.8183 | ||||||||||||
Method |
MMRM | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
-0.11
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-1.09 | ||||||||||||
upper limit |
0.86 | ||||||||||||
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End point title |
Change in haemoglobin from baseline to day 7 | ||||||||||||
End point description |
Change in haemoglobin from baseline to day 7.
Analysis performed on FAS.
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End point type |
Secondary
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End point timeframe |
Change in haemoglobin from baseline to day 7.
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Statistical analysis title |
Test for superiority, MMRM | ||||||||||||
Statistical analysis description |
A mixed model for repeated measurements (MMRM) with treatment-by-visit as factor, baseline value as covariate, and subject as random effect was used.
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Comparison groups |
Group A, iron isomaltoside 1000 v Group B, RBC transfusion
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Number of subjects included in analysis |
11
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.07 | ||||||||||||
Method |
MMRM | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
-0.92
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-1.92 | ||||||||||||
upper limit |
0.08 | ||||||||||||
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End point title |
Change in haemoglobin from baseline to week 3 | ||||||||||||
End point description |
Change in haemoglobin from baseline to week 3.
Analysis performed on FAS.
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End point type |
Secondary
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End point timeframe |
Change in haemoglobin from baseline to week 3.
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Statistical analysis title |
Test for superiority, MMRM | ||||||||||||
Statistical analysis description |
A mixed model for repeated measurements (MMRM) with treatment-by-visit as factor, baseline value as covariate, and subject as random effect was used.
|
||||||||||||
Comparison groups |
Group A, iron isomaltoside 1000 v Group B, RBC transfusion
|
||||||||||||
Number of subjects included in analysis |
12
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.0295 | ||||||||||||
Method |
MMRM | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
1.09
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
0.12 | ||||||||||||
upper limit |
2.07 | ||||||||||||
|
|||||||||||||
End point title |
Change in haemoglobin from baseline to week 8 | ||||||||||||
End point description |
Change in haemoglobin from baseline to week 8.
Analysis performed on FAS.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Change in haemoglobin from baseline to week 8.
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Test for superiority, MMRM | ||||||||||||
Statistical analysis description |
A mixed model for repeated measurements (MMRM) with treatment-by-visit as factor, baseline value as covariate, and subject as random effect was used.
|
||||||||||||
Comparison groups |
Group A, iron isomaltoside 1000 v Group B, RBC transfusion
|
||||||||||||
Number of subjects included in analysis |
13
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.0122 | ||||||||||||
Method |
MMRM | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
1.25
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
0.29 | ||||||||||||
upper limit |
2.21 | ||||||||||||
|
|||||||||||||
End point title |
Change in haemoglobin from baseline to week 12 | ||||||||||||
End point description |
Change in haemoglobin from baseline to week 12.
Analysis performed on FAS.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Change in haemoglobin from baseline to week 12.
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Test for superiority, MMRM | ||||||||||||
Statistical analysis description |
A mixed model for repeated measurements (MMRM) with treatment-by-visit as factor, baseline value as covariate, and subject as random effect was used.
|
||||||||||||
Comparison groups |
Group A, iron isomaltoside 1000 v Group B, RBC transfusion
|
||||||||||||
Number of subjects included in analysis |
13
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.0115 | ||||||||||||
Method |
MMRM | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
1.26
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
0.3 | ||||||||||||
upper limit |
2.22 | ||||||||||||
|
|||||||||||||
End point title |
Change in s-ferritin from baseline to day 1 | ||||||||||||
End point description |
Change in s-ferritin from baseline to day 1.
Analysis performed on FAS
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Change in s-ferritin from baseline to day 1.
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Test for superiority, MMRM | ||||||||||||
Statistical analysis description |
A mixed model for repeated measurements (MMRM) with treatment-by-visit as factor, baseline value as covariate, and subject as random effect was used.
|
||||||||||||
Comparison groups |
Group A, iron isomaltoside 1000 v Group B, RBC transfusion
|
||||||||||||
Number of subjects included in analysis |
11
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.0156 | ||||||||||||
Method |
MMRM | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
399.2
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
84.4 | ||||||||||||
upper limit |
714.1 | ||||||||||||
|
|||||||||||||
End point title |
Change in s-ferritin from baseline to day 2 | ||||||||||||
End point description |
Change in s-ferritin from baseline to day 2.
Analysis performed on FAS.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Change in s-ferritin from baseline to day 2.
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Test for superiority, MMRM | ||||||||||||
Statistical analysis description |
A mixed model for repeated measurements (MMRM) with treatment-by-visit as factor, baseline value as covariate, and subject as random effect was used.
|
||||||||||||
Comparison groups |
Group A, iron isomaltoside 1000 v Group B, RBC transfusion
|
||||||||||||
Number of subjects included in analysis |
13
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
< 0.0001 | ||||||||||||
Method |
MMRM | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
745.2
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
436.9 | ||||||||||||
upper limit |
1053.5 | ||||||||||||
|
|||||||||||||
End point title |
Change in s-ferritin from baseline to day 3 | ||||||||||||
End point description |
Change in s-ferritin from baseline to day 3.
Analysis performed on FAS.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Change in s-ferritin from baseline to day 3.
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Test for superiority, MMRM | ||||||||||||
Statistical analysis description |
A mixed model for repeated measurements (MMRM) with treatment-by-visit as factor, baseline value as covariate, and subject as random effect was used.
|
||||||||||||
Comparison groups |
Group A, iron isomaltoside 1000 v Group B, RBC transfusion
|
||||||||||||
Number of subjects included in analysis |
12
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
< 0.0001 | ||||||||||||
Method |
MMRM | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
1087.3
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
776.1 | ||||||||||||
upper limit |
1398.6 | ||||||||||||
|
|||||||||||||
End point title |
Change in s-ferritin from baseline to day 4 | ||||||||||||
End point description |
Change in s-ferritin from baseline to day 4.
Analysis performed on FAS.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Change in s-ferritin from baseline to day 4.
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Test for superiority, MMRM | ||||||||||||
Statistical analysis description |
A mixed model for repeated measurements (MMRM) with treatment-by-visit as factor, baseline value as covariate, and subject as random effect was used.
|
||||||||||||
Comparison groups |
Group A, iron isomaltoside 1000 v Group B, RBC transfusion
|
||||||||||||
Number of subjects included in analysis |
13
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
< 0.0001 | ||||||||||||
Method |
MMRM | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
1217.5
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
909.2 | ||||||||||||
upper limit |
1525.8 | ||||||||||||
|
|||||||||||||
End point title |
Change in s-ferritin from baseline to day 5 | ||||||||||||
End point description |
Change in s-ferritin from baseline to day 5.
Analysis performed on FAS.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Change in s-ferritin from baseline to day 5.
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Test for superiority, MMRM | ||||||||||||
Statistical analysis description |
A mixed model for repeated measurements (MMRM) with treatment-by-visit as factor, baseline value as covariate, and subject as random effect was used.
|
||||||||||||
Comparison groups |
Group A, iron isomaltoside 1000 v Group B, RBC transfusion
|
||||||||||||
Number of subjects included in analysis |
12
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
< 0.0001 | ||||||||||||
Method |
MMRM | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
1228.7
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
917.8 | ||||||||||||
upper limit |
1539.6 | ||||||||||||
|
|||||||||||||
End point title |
Change in s-ferritin from baseline to day 6 | ||||||||||||
End point description |
Change in s-ferritin from baseline to day 6.
Analysis performed on FAS.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Change in s-ferritin from baseline to day 6.
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Test for superiority, MMRM | ||||||||||||
Statistical analysis description |
A mixed model for repeated measurements (MMRM) with treatment-by-visit as factor, baseline value as covariate, and subject as random effect was used.
|
||||||||||||
Comparison groups |
Group A, iron isomaltoside 1000 v Group B, RBC transfusion
|
||||||||||||
Number of subjects included in analysis |
11
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
< 0.0001 | ||||||||||||
Method |
MMRM | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
1165.7
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
850.9 | ||||||||||||
upper limit |
1480.4 | ||||||||||||
|
|||||||||||||
End point title |
Change in s-ferritin from baseline to day 7 | ||||||||||||
End point description |
Change in s-ferritin from baseline to day 7.
Analysis performed on FAS.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Change in s-ferritin from baseline to day 7.
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Test for superiority, MMRM | ||||||||||||
Statistical analysis description |
A mixed model for repeated measurements (MMRM) with treatment-by-visit as factor, baseline value as covariate, and subject as random effect was used.
|
||||||||||||
Comparison groups |
Group A, iron isomaltoside 1000 v Group B, RBC transfusion
|
||||||||||||
Number of subjects included in analysis |
11
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
< 0.0001 | ||||||||||||
Method |
MMRM | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
1046.4
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
731.7 | ||||||||||||
upper limit |
1361.1 | ||||||||||||
|
|||||||||||||
End point title |
Change in s-ferritin from baseline to week 3 | ||||||||||||
End point description |
Change in s-ferritin from baseline to week 3.
Analysis performed on FAS.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Change in s-ferritin from baseline to week 3.
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Test for superiority, MMRM | ||||||||||||
Statistical analysis description |
A mixed model for repeated measurements (MMRM) with treatment-by-visit as factor, baseline value as covariate, and subject as random effect was used.
|
||||||||||||
Comparison groups |
Group A, iron isomaltoside 1000 v Group B, RBC transfusion
|
||||||||||||
Number of subjects included in analysis |
11
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.0727 | ||||||||||||
Method |
MMRM | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
286.1
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-29 | ||||||||||||
upper limit |
601.1 | ||||||||||||
|
|||||||||||||
End point title |
Change in s-ferritin from baseline to week 8 | ||||||||||||
End point description |
Change in s-ferritin from baseline to week 8.
Analysis performed on FAS.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Change in s-ferritin from baseline to week 8.
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Test for superiority, MMRM | ||||||||||||
Statistical analysis description |
A mixed model for repeated measurements (MMRM) with treatment-by-visit as factor, baseline value as covariate, and subject as random effect was used.
|
||||||||||||
Comparison groups |
Group A, iron isomaltoside 1000 v Group B, RBC transfusion
|
||||||||||||
Number of subjects included in analysis |
13
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.3015 | ||||||||||||
Method |
MMRM | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
156
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-152.3 | ||||||||||||
upper limit |
464.3 | ||||||||||||
|
|||||||||||||
End point title |
Change in s-ferritin from baseline to week 12 | ||||||||||||
End point description |
Change in s-ferritin from baseline to week 12.
Analysis performed on FAS.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Change in s-ferritin from baseline to week 12.
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Test for superiority, MMRM | ||||||||||||
Statistical analysis description |
A mixed model for repeated measurements (MMRM) with treatment-by-visit as factor, baseline value as covariate, and subject as random effect was used.
|
||||||||||||
Comparison groups |
Group A, iron isomaltoside 1000 v Group B, RBC transfusion
|
||||||||||||
Number of subjects included in analysis |
13
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.3614 | ||||||||||||
Method |
MMRM | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
137.3
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-171 | ||||||||||||
upper limit |
445.6 | ||||||||||||
|
|||||||||||||
End point title |
Change in transferrin saturation from baseline to day 1 | ||||||||||||
End point description |
Change in transferrin saturation from baseline to day 1.
Analysis performed on FAS.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Change in transferrin saturation from baseline to day 1.
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Change in transferrin saturation from baseline to day 2 | ||||||||||||
End point description |
Change in transferrin saturation from baseline to day 2.
Analysis performed on FAS.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Change in transferrin saturation from baseline to day 2.
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Change in transferrin saturation from baseline to day 3 | ||||||||||||
End point description |
Change in transferrin saturation from baseline to day 3.
Analysis performed on FAS.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Change in transferrin saturation from baseline to day 3.
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Change in transferrin saturation from baseline to day 4 | ||||||||||||
End point description |
Change in transferrin saturation from baseline to day 4.
Analysis performed on FAS.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Change in transferrin saturation from baseline to day 4.
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Change in transferrin saturation from baseline to day 5 | ||||||||||||
End point description |
Change in transferrin saturation from baseline to day 5.
Analysis performed on FAS.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Change in transferrin saturation from baseline to day 5.
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Change in transferrin saturation from baseline to day 6 | ||||||||||||
End point description |
Change in transferrin saturation from baseline to day 6.
Analysis performed on FAS.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Change in transferrin saturation from baseline to day 6.
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Change in transferrin saturation from baseline to day 7 | ||||||||||||
End point description |
Change in transferrin saturation from baseline to day 7.
Analysis performed on FAS.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Change in transferrin saturation from baseline to day 7.
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Change in transferrin saturation from baseline to week 3 | ||||||||||||
End point description |
Change in transferrin saturation from baseline to week 3.
Analysis performed on FAS.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Change in transferrin saturation from baseline to week 3.
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Change in transferrin saturation from baseline to week 8 | ||||||||||||
End point description |
Change in transferrin saturation from baseline to week 8.
Analysis performed on FAS.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Change in transferrin saturation from baseline to week 8.
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Change in transferrin saturation from baseline to week 12 | ||||||||||||
End point description |
Change in transferrin saturation from baseline to week 12.
Analysis performed on FAS.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Change in transferrin saturation from baseline to week 12.
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Adverse events information
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Timeframe for reporting adverse events |
From the time a subject had signed the informed consent form and until she had completed the trial, all AEs/SAEs were reported in the electronic case report form.
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse event reporting additional description |
An AE was described in the following manner: The nature of the event will be described in precise, standard medical terminology (i.e. not necessarily the exact words used by the subject). If known, a specific diagnosis was stated. Furthermore the Investigator described an AE regarding seriousness,
severity, relatedness, and outcome.
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Assessment type |
Systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Dictionary used for adverse event reporting
|
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Dictionary name |
MedDRA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
16.0
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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 |
1500 mg iron isomaltoside 1000 (or 1000 mg in women with a pre-pregnancy weight below 45 kg) was administered over approximately 15 min as a single IV infusion. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Group B, RBC transfusion
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Reporting group description |
Subjects received 1 or 2 units of red blood cells (RBC) administered at the baseline visit according to the hospital’s standard operating procedure. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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20 Aug 2013 |
• The endpoint ‘Change in other MFI fatigue symptoms’ should be calculated from day 1 to day 2, 3, 4, 5, 6, and 7, week 3, 8, and 12.
• It was specified that maternal milk iron level was to be assessed only in subjects ran-domised to iron isomaltoside 1000.
• It was specified that assessment of anaemia and gastrointestinal symptoms should be performed at day 1, 3, and 7, week 3, 8, and 12.
• It was specified that anaemia and gastrointestinal symptoms should be assessed by asking the subject if she had experienced any of the following symptoms: Palpitation, tinnitus, headache, dizziness, dyspnoea, nausea, vomiting, epigastric pain, thin feces, constipation, painful defecation, and symptomatic haemorrhoids.
• Exclusion criteria number 7 was changed from ‘Known decompensated liver cirrhosis and active hepatitis’ to ‘Known decompensated liver cirrhosis or active hepatitis’ to correct a previous error.
• Exclusion criteria number 10 was split into 2 different criteria.
• To avoid selection bias, the geographical constraint on eligible subjects was changed from subjects living in the catchment area of Copenhagen University Hospital, Rigshospitalet to subjects living within a radius of 30 kilometres from the hospital.
• It was added that in case the infusion of iron isomaltoside 1000 was interrupted, it would be allowed to restart the infusion after clinical assessment by the Principal In-vestigator or a sub investigator.
• Table 2 of the protocol, summarising adverse events with IV iron, was updated ac-cording to the Monofer® SmPC.
• It was specified that admission to the maternity hotel was not considered to meet the regulatory definition for a SAE due to hospitalisation, and that admission of the new-born to the neonatal intensive care unit was to be evaluated case by case for serious-ness.
• The visit window for visit 2-8 (day 1-7) was enlarged from 18 hours to 1 day to ensure full follow-up of as many subjects as possible.
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13 Feb 2014 |
• Timing of maternal milk sample collection was changed from baseline, day 1, 2, and 3 to day 3 and week 1, and should be done in all subjects when possible. At the time of implementing this amendment, collection of milk samples from baseline and onwards had not been possible in any subjects.
• It was specified that a ‘current smoker’ was defined as smoking within the last 6 months.
• The reference document for SARs was changed from the Monofer® SmPC to the IB for iron isomaltoside 1000, as the trial investigated a new indication for iron isomaltoside 1000. The implication of this change was negligible as the list of ex-pected side effects for iron isomaltoside 1000 was similar in the 2 documents.
• It was specified that the data collection tool was an eCRF.
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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 | |||
