Conditions: Postoperative Anaemia
Keywords: postoperative anemia gynaecologic surgery
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 27
Healthy volunteers: yes

Brief summary:
The purpose of this study is to determine whether oral or intravenous iron is effective in the treatment of anaemia (iron-poor blood) after caesarean section.

Detailed description:
Anemia after caesarean section is often treated with iron therapy to ensure that the hemoglobin will return to normal more rapidly. Scientific evidence for this action is limited. Several studies, in which iron therapy was given after orthopaedic or cardiac surgery, show that after 6 to 10 weeks the hemoglobin was not significantly different between patients treated with oral preparations and patients treated with a placebo. These studies have not examined the hemoglobin level during the first few weeks after surgery including the quality of life analysis.

The purpose of this double blind randomized controlled trial therefore is to examine the effect of both oral iron therapy and intravenous iron therapy on hemoglobin level and on the quality of life during the first few weeks postcaesarean in patients with a moderate anemia.

Arms:
arm 1: Once an infusion of Ferinject 1000 mg, 1 day after surgery arm 2: 2 times a day 200 mg ferrous fumarate, starting 24-48 hours after surgery arm 3: Patient will get a once a placebo infusion (250 ml NaCl), one day after surgery, and 60 placebo tablets for 30 days (2 tablets a day), starting 24-48 hours after surgery

Interventions: intervention 1: Ferinject intervention 2: Ferrous fumarate intervention 3: Placebo for ferrous fumarate intervention 4: Placebo for ferinject
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None intervention 4: None

Protocol document:
Prot_SAP_000.pdf: 
 
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PROTOCOL 
  
  
The value of iron treatment for postoperative 
obstetric patients with anemia: a randomized 
double blind controlled trial  
  
  
  
  
  
                         
  
  
  
  
  
  
 
 


 
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Protocol ID  
41455.068.13  
Short title  
VITAPOP  
EudraCT number  
2012-003290-26  
Version  
7 
Date  
09APRIL2016 
Coordinating 
investigator  
Prof. Dr. RFPM Kruitwagen, Maastricht UMC  
Department of Obstetrics and Gynecology  
Maastricht University Medical Centre  
P.O. Box 5800  
6202 AZ Maastricht, The Netherlands  
Principal 
investigator  
 
MUMC 
Prof. Dr. RFPM Kruitwagen, Maastricht UMC  
Department of Obstetrics and Gynecology  
Maastricht University Medical Centre  
P.O. Box 5800  
6202 AZ Maastricht, The Netherlands  
Zuyderland Medical Centre 
Dr. H. Mertens 
Department of Obstetrics and Gynecology 
P.O. Box 5500 
6130 MB Sittard, The Netherlands 
Sponsor   
Academisch Ziekenhuis Maastricht 
Contact person:  
Prof. Dr. RFPM Kruitwagen, Maastricht UMC  
Department of Obstetrics and Gynecology  
Maastricht University Medical Centre  
P.O. Box 5800  
6202 AZ Maastricht, The Netherlands 
Subsidising party   
Vifor pharma  


 
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Independent expert   
(s)  
Dr. T. van Gorp, gynecologist Maastricht UMC+ 
Laboratory sites  
Klinisch chemisch lab, Maastricht UMC  
Contact: Loe Donselaar  
Klinisch chemisch lab, Orbis Medical Centre, Sittard  
Contact: Dr. J. ten Cate  
Radboud University Nijmegen Medical Centre  
  
Hepcidinanalysis.com 
Contact: S. Klaver  
Pharmacy  
Pharmacy Maastricht UMC  
Basic Pharma  
   
Name  
Signature  
Date  
Sponsor or legal representative:  
  Prof. dr. J.G. Nijhuis, Maastricht UMC 
   
  
 
09APRIL 
2016 
[Coordinating Investigator/Project 
leader/Principal Investigator]:  
   
Prof. Dr. RFPM Kruitwagen, Maastricht UMC  
   
    
  
 
09APRIL 
2016 
  
 
 


 
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List of abbreviations and relevant definitions .......................................................................................... 6 
Summary .................................................................................................................................................. 7 
1. 
INTRODUCTION AND RATIONALE .......................................................................................... 9 
2. 
OBJECTIVES ................................................................................................................................ 11 
3. 
STUDY DESIGN ........................................................................................................................... 12 
4. 
STUDY POPULATION ................................................................................................................ 13 
4.1 
Population .............................................................................................................................. 13 
4.2 
Inclusion criteria .................................................................................................................... 13 
4.3 
Exclusion criteria ................................................................................................................... 13 
4.4 
Sample size calculation .......................................................................................................... 13 
5. 
TREATMENT OF SUBJECTS ..................................................................................................... 14 
5.1 
Investigational products ......................................................................................................... 14 
6. 
INVESTIGATIONAL PRODUCTS .............................................................................................. 15 
6.1 
Name and description of investigational products ................................................................. 15 
6.2 
Summary of findings from clinical and non-clinical studies ................................................. 15 
6.3 
Summary of known and potentional risks and benefits ......................................................... 15 
6.4 
Description and justification of route of administration and dosage ..................................... 17 
6.5 
Dosages, dosage modifications and method of administration .............................................. 17 
6.6 
Preparation and labelling of Investigational Medicinal Product ........................................... 18 
6.7 
Drug accountability ................................................................................................................ 18 
7. 
METHODS .................................................................................................................................... 18 
7.1 
Study parameters .................................................................................................................... 18 
7.1.1 Main study parameter ......................................................................................................... 18 
7.1.2 Secondary study parameters ............................................................................................... 19 
7.2 
Randomization, blinding and treatment allocation ................................................................ 19 
7.3 
Study procedures .................................................................................................................... 19 
7.4 
Withdrawal of subjects .......................................................................................................... 21 
7.5 
Replacement of subjects in case of withdrawal ..................................................................... 21 
7.6 
Premature termination of the study ........................................................................................ 21 
8. 
SAFETY REPORTING ................................................................................................................. 22 
8.1 
Temporary halt for reasons of subject safety ......................................................................... 22 
8.2 
Aes, SAEs and SUSARs ........................................................................................................ 22 
8.2.1 Adverse events (AE) ........................................................................................................... 22 
8.2.2 Serious adverse events (SAEs) ........................................................................................... 22 
8.2.3 Suspected unexpected serious adverse reactions (SUSARs) .............................................. 23 
8.3 
Annual safety report ............................................................................................................... 24 
9. 
STATISTICAL ANALYSIS .......................................................................................................... 24 
9.1 
Primary study parameter ........................................................................................................ 24 
9.2 
Baseline differences ............................................................................................................... 25 
9.3 
Multivariable analysis ............................................................................................................ 25 
9.4 
Secondary study parameters .................................................................................................. 25 
9.5 
Alpha ...................................................................................................................................... 26 
9.6 
Handling of missing values .................................................................................................... 26 
9.7 
Statistical analysis package .................................................................................................... 26 
9.8 
Interim analysis (if applicable) .............................................................................................. 27 
10. ETHICAL CONSIDERATIONS .................................................................................................. 27 
10.1 
Regulation statement .............................................................................................................. 27 


 
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10.2 
Recruitment and consent ........................................................................................................ 27 
10.3 
Benefits and risks assessment ................................................................................................ 28 
10.4 
Compensation for injury ........................................................................................................ 28 
11. ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION ................................. 28 
11.1 
Handling and storage of data and documents ........................................................................ 28 
11.2 
Monitoring and quality assurance .......................................................................................... 29 
11.3 
Annual progress report ........................................................................................................... 30 
11.4 
End of study report ................................................................................................................ 30 
11.5 
Public disclosure and publication policy ............................................................................... 30 
12. STRUCTURED RISK ANALYSIS .............................................................................................. 31 
12.1 
Potential issues of concern ..................................................................................................... 31 
12.2 
Synthesis ................................................................................................................................ 34 
13. REFERENCES .............................................................................................................................. 35 
 
  
 


 
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List of abbreviations and relevant definitions  
  
CCMO  
Central Committee on Research Involving Human Subjects  
COV  
Close out visit  
CTCM  
Clinical Trial Center Maastricht  
CV  
  
Curriculum Vitae  
(e)CRF  
(Electronic) case report form  
Euro-HRQoL Euro-health related quality of life  
Fe  
  
Iron  
GCP    
Good Clinical Practice  
GMP  
Good Manufacturing Practice  
Hb  
  
Hemoglobin  
IC  
  
Informed Consent  
ICH    
International conference on harmonisation  
IMV    
Interim monitoring visit  
IV  
  
Intravenous therapy  
MEMS  
Medication Event Monitoring System  
METC  
Medical Ethics Committee  
MFI    
Multidimensional Fatigue Inventory   
MUMC  
Maastricht University Medical Centre  
NaCl  
Sodium Chloride  
OMC  
Orbis Medical Centre  
(S) AE  
(Serious) Adverse Event  
SIV  
  
Site initiation visit  
SUSAR  
Suspected Unexpected Serious Adverse Reaction  
WMO  
Act Medical Research on Humans  
   
 
 


 
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Summary  
Rationale  
Anemia after caesarean section is often treated with iron therapy to ensure that the 
hemoglobin will return to normal more rapidly. Scientific evidence for this action is 
limited. Several studies, in which iron therapy was given after orthopaedic or cardiac 
surgery, show that after 6 to 10 weeks the hemoglobin was not significantly different 
between patients treated with oral preparations and patients treated with a placebo. 
These studies have not examined the hemoglobin level during the first few weeks after 
surgery including the quality of life analysis.   
The purpose of this double blind randomized controlled trial therefore is to examine the 
effect of both oral iron therapy and intravenous iron therapy on hemoglobin level and on 
the quality of life during the first few weeks postcaesarean in patients with a moderate 
anemia.   
Study design  
Double blind randomized controlled trial  
Study population  
Patients fulfilling the in- and exclusion criteria with a hemoglobin level between 5.0 and 
7.0 mmol/L after caesarean sections.  
Intervention  
Patients will be randomized into three groups:  
1. Treatment with ferrous fumarate 200 mg 2dd 1 capsule during 30 days. These 
patients also get once a placebo intravenously.  
2. Treatment with Ferinject®. These patients also obtain 60 placebo capsules for 30 
days. 
3. Placebo treatment: both a placebo intravenously and 60 placebo capsules for 30 
days.  
Main study parameters  
Primary objective: Hemoglobin levels after 3 and 6 weeks 
Secondary objectives:  


 
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• 
Quality of life after 1, 3 and 6 weeks  
• 
Side effects of the medication  
• 
Predictive value of other parameters such as CRP, transferrin, ferritin and 
hepcidin  
• 
Cost analysis  
Nature and extent of the burden and risks associated with participation, 
benefit and group relatedness  
The patient will have 3 extra blood tests to determine hemoglobin, CRP, ferritin and 
transferrin. In addition, 4 times the patient has to fill in a questionnaire about the quality 
of life. One time, fluid will be administered to the patient; this may be sodium chloride 
0.9% or Ferinject®. The needle for the infusion does not have to be inserted another time 
as this has already been done before every operation. In addition, the patient must take 
capsules for one month (ferrous fumarate vs. placebo). Not treating a patient (the group 
that gets an oral and intravenous placebo) will not entail significant risks, but may cause 
a longer time of fatigue and dizziness. Literature also shows that not treating a patient 
with a hemoglobin around 5 mmol/L is justified. The group treated with oral or 
intravenous iron preparations may have gastrointestinal side effects or skin reactions. 
No serious adverse events have been described. The occurrence of a serious allergic 
reaction to Ferinject® is extremely rare.  
The advantage of treating a patient may be that the hemoglobin level during the first 6 
weeks normalizes more rapidly, which may affect the quality of life during the first 6 
weeks postoperatively.  
  
  
  
  
  
 
 


 
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1. INTRODUCTION AND RATIONALE  
  
Anemia due to surgery is often treated with iron therapy to ensure that the hemoglobin 
will return to a normal value more rapidly. Several studies in orthopaedic and cardiac 
surgery, in which iron therapy was given postoperatively, show that after 6 to 10 weeks 
the hemoglobin was not significantly different between patients treated with oral 
preparations and patients treated with a placebo.1-5  Therefore, the scientific evidence for 
this treatment, especially in case of a moderate anemia (Hb 5.0 – 7.0 mmol/L), is 
limited. 
Annually there are also thousands of patients treated with either oral iron therapy or 
intravenous iron therapy after a caesarean section. Hospital wide protocols are available 
for the diagnosis and treatment of postpartum anemia, but not specifically for post 
caesarean anemia. The reason for giving iron preparations for a postoperative anemia is 
both patient and doctor-dependent. A patient with a hemoglobin level of 6.5 mmol / L 
without symptoms is less likely to receive iron supplementation than a patient with a 
hemoglobin level of 6.5 mmol / L with complaints (eg weakness, fatigue). In addition, 
one doctor will prescribe iron preparation more easily than another doctor does. In other 
words, there is no clear national or international guideline for the treatment of post 
caesarean anemia through iron suppletion. Giving iron supplements to patients can lead 
to side effects, and because of the fact that it is prescribed very frequently it leads also to 
high costs for medical care. Given the absence of good evidence, is giving iron post 
caesarean really necessary? And if so, which patients with a post caesarean anemia 
should get iron supplementation? Is the intravenous form superior to the oral form? Is 
measuring the hemoglobin level only enough to start therapy or should other blood 
values be determined for this decision?  
Several studies examined the effect of intravenous iron versus oral iron therapy for postpartum anemia 
in general. Breymann et al. concluded that iron carboxymaltose was not inferior to ferrous sulfate in 
terms of change in mean Hb from baseline to week 12.6 Van Wyck et al. found that ferritin was 
significantly higher in the i.v. iron treatment group compared to the oral iron treatment group 
(p = 0.004) two weeks after delivery, while Hb values did not differ between the groups.7 Seid et al., 
however, found that ferric carboxymaltose-treated subjects were significantly more likely to: (1) 
achieve a hemoglobin greater than 12 g/dL in a shorter time period with a sustained hemoglobin 
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attain higher serum transferrin saturation and ferritin levels. Drug-related adverse events occurred less 
frequently with ferric carboxymaltose.8 Also Froessler et al concluded that intravenous iron sucrose, 
restores iron stores faster than with oral ferrous sulfate.9 The major limitation of all these studies is that 
they also included vaginal births (this group was even dominant) and not caesarean sections alone. The 
treatment of a postsection anemia is potentially different from a postpartum anemia after vaginal birth 
and especially the way of administration.   
Some researchers believe that the characteristics of an anemia occurring after surgery 
probably fit better with an anemia due to chronic disease than an iron deficiency 
anemia.10,11 The anemia associated with a chronic disease is characterized by a low 
content of iron and transferrin in the plasma, resulting in a reduction in the 
erythropoiesis.12-14 Possible acute phase protein plays a role.15-19 This would explain 
why, in contrast to intravenous therapy, oral iron therapy is not effective in a 
postsurgery (so also post caesarean) anemia.  
In a prospective study, Iperen et al. examined the effects of larger and smaller surgery 
on erythropoiesis, iron metabolism and the acute phase response proteins.20 They found 
that both major and minor surgery induce a state of hypoferremia despite adequate iron 
stores. They conclude that giving oral iron in the first weeks after surgery is not 
effective (if iron stores are normal before surgery). Also Cutress et al. drew this 
conclusion after examining the importance of oral iron therapy in patients undergoing 
surgery for breast cancer.21 They concluded that because of the operation and the 
associated inflammatory response a disturbance occurs in the serum iron indices which 
may lead to inadequate supply of iron to the bone marrow and thus a disturbance in the 
red blood cell synthesis. This phenomenon does not appear to be related to the amount 
of bloodloss but to the inflammatory response, causing a blockage of iron mobilization. 
That’s why no effect is to be expected of giving postoperative oral iron. Giving 
intravenous iron circumvents this problem.  
Bisbe et al. compared ferric carboxymaltose with ferrous oral glycine sulphate for 
postoperative anaemia after total knee arthroplasty. They found that postoperative IV 
ferric carboxymaltose provided significant benefit over oral ferrous glycine sulphate, 
particularly in patients with preoperative iron deficiency, severe postoperative anemia, 
or both.22  
As mentioned earlier, in Dutch hospitals oral and intravenous iron preparations are often 
prescribed for post caesarean patients with moderately low hemoglobin levels, although 


 
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this is not scientifically well-fetched. The purpose of this randomized controlled trial is 
to get an answer to these questions in patients with post caesarean anemia.  
1. What is the effect of oral iron therapy on hemoglobin levels in the first weeks 
postoperatively?  
2. What is the effect of intravenous iron therapy on hemoglobin level in the first weeks 
postoperatively?  
3. What is the effect of oral iron therapy on quality of life in the first weeks 
postoperatively? 
4. What is the effect of intravenous iron therapy on quality of life function in the first 
weeks postoperatively?  
In addition, some of the iron-metabolism related parameters that may be of value in 
predicting the effect of iron supplementation will be determined (transferrin, CRP, 
ferritin, hepcidin). It will also be taken into consideration whether or not this is 
proportionate to the side effects of medication including the inconvenience of taking 
medication, and the associated costs.  
 
 
2. OBJECTIVES  
  
Primary objective:  
Comparison of the hemoglobin level 3 and 6 weeks postoperatively between the 
different groups  
  
Secondary objectives:  
• 
Comparison of quality of life after 1, 3 and 6 weeks postoperatively between the 
different groups  
• 
Comparison of the side-effects of various drugs  
• 
Is there a “subgroup” of patients who have the greatest effect of the medication used 
(eg patients with low ferritin)  
• 
Is there a “subgroup” of patients who respond better to ferinject than ferrous 
fumarate and vice versa (eg patients with elevated CRP).  
• 
What are the costs of taking oral iron or intravenous iron  
   
 


 
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3. STUDY DESIGN  
  
The study will be a double blind randomized controlled trial.  
Patients undergoing a primary caesarean section in the Maastricht University Medical 
Centre and the Orbis Medical Centre in Sittard will be informed about the study, both in 
writing and orally.  A schematic overview of assessments is given in the schedule at the 
end of the protocol (annex 1). 
If the patient has signed the informed consent the patient data will be entered in a 
database and then the pre-operative blood will be taken (standard and extra). If the 
postoperative hemoglobin level is between 5-7 mmol/L the patient will be randomized 
and two extra blood tubes will be taken. Randomization will be done by the computer 
and the first questionnaire will be completed. The patient characteristics will be copied 
from the electronic patient record. Subsequently, each patient will receive an infusion 
with a placebo or with Ferinject® (depending on which group the patient ended up). The 
patients will not know the actual treatment, because the infusion line and the flask with 
NaCl or Ferinject® will be packed. Also the venflon will be covered by a gauze. So both 
the patient and the doctor will not know if a placebo or the Ferinject® itself is given. The 
patient will receive 60 capsules to take home, which need to be taken two times daily. 
This can be ferrous fumarate or a placebo. To verify compliance, patients will use a 
dispenser which count how often it is opened. Postoperatively, the hemoglobin will be 
determined another two times: after 3 and 6 weeks. At 3 weeks the research nurse will 
do this at the patient’s home and the second time this will be obtained in the hospital 
where it can be combined with the regular control. The research nurse will call the 
patient after 1 week to ask how things are going and whether the second questionnaire 
has been completed. If the nurse visits the patient after 3 weeks, she will ensure that the 
questionnaires about the quality of life after 1 and 3 weeks were completed. The day the 
patient will come for the regular check at 6 weeks, she will also be seen by the research 
nurse who will check whether the last questionnaire was also completed. At this 
appointment the hemoglobin and other blood-values will also be determined.  
During the pre-operative visit the informed consent will be signed. Normally this will be 
at the time of admission. The maximum time period between the pre-operative visit and 
the actual surgery may be 72 hours. In case the scheduled surgery is postponed to a time 


 
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point outside the allowed time window, the first pre-operative hemoglobin of the patient 
will be determined again.  
 
  
4. STUDY POPULATION  
  
4.1 Population  
The study will be performed in the Maastricht University Medical Centre and the 
Zuyderland Hospital, Heerlen, the Netherlands. Patients fulfilling the below mentioned 
in- and exclusion criteria will be asked to participate in the study. 
 
4.2 Inclusion criteria  
• Postoperative hemoglobin is between 5-7 mmol / L after a terme (>37 weeks) 
primary Caesarean section 
 
4.3 Exclusion criteria  
• Pre-eclampsia / HELLP syndrome 
• Malignancy during pregnancy or during the first six weeks postpartum 
• Infections 
• Per of posteroperative blood transfusion 
• Hematologic disorder (hemoglobinopathy; hemochromatosis) 
• Erythropoiesis-stimulating agents < 3months ago  
• Myelosuppressive therapy in history 
• Hepatitis 
• HIV 
• Alcohol abuses 
• Legal incapacity 
• Not understanding Dutch 
• Previous allergic reaction to oral or intravenous iron 
 
4.4 Sample size calculation  
This study will examine whether intravenous iron gives an improvement of the 
hemoglobin content 3 weeks postoperatively in patients with a hemoglobin between 5-7 
mmol / L after caesarean sections, compared with giving oral iron, as well as placebo. 


 
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Based on the assumption that a minimum of 0,5 mmol/L difference in the hemoglobin 
level is thought to be of clinical importance and a standard deviation of 0,7 mmol/L 
(based on a retrospective analysis and a comparable study 4) it was determined that, with 
an alpha of 5% and a power of 80%, for each group 32 patients are needed. For 3 groups 
this means 96 patients. Allowing for patients lost to follow-up, the study number was set 
on 120 patients to guarantee adequate numbers of patients in each group.  
   
A retrospective analysis performed at the Maastricht University Medical Centre between 
1 January 2015 and June 30 2015, showed that 66 patients had a primary caesarean 
section. If we exclude the patients that had an operation on Friday (because during the 
weekends the study-medication cannot be prepared) the remaining number were 46 
patients. Of these 46 patients, 31 people had a hemoglobin level between 5.0 and 7.0 
mmol / L.  If we assume that 70% of patients want to participate in the study, this will 
lead to 44 patients per year to randomize at the MUMC+. The other participating 
hospital (Zuyderland Sittard-Heerlen) has a double amount of deliveries including 
Caesarean sections which means that we need at maximum 1,5 year to complete the 
study. 
 
 
5. TREATMENT OF SUBJECTS  
  
5.1 Investigational products  
Ferinject®, an intravenous iron, will be used as one of the investigational products. Also 
ferrous fumarate, an oral iron, will be used. There will be two placebos: NaCl and 
placebo capsules. 
Information about these products is given in chapter 6.  
Each patient will receive an infusion with a placebo or with Ferinject® (depending on 
which group the patient ended up). All patients receive 60 capsules to take home, which 
need to be taken two times daily. This can be ferrous fumarate or a placebo.   
All interventions that has to be done (blood, questionnaires etc) are given in chapter 7.3  
 
 


 
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6. INVESTIGATIONAL PRODUCTS  
  
6.1 Name and description of investigational products  
The following research products will be used.  
• Capsulated Ferrous fumarate: 200 mg ferrous fumarate contains 65 mg Fe + + 
Features: Iron is necessary for the synthesis of haem in hemoglobin.  
• Placebo capsules. The placebo will be made by Basic Pharma and are capsules 
filled with starch.  
• Ferinject®: Solution for injection/infusion 50 mg Fe ³/ml, vial of 2 ml, 10 ml or 20 
ml. Properties: In iron (III) carboxymaltose the iron is present in a complex with a 
carbohydrate polymer, which releases the iron at the iron transport and storage 
proteins in the body (ferritin, transferrin).  
• Flask of NaCl 0.9%  
  
6.2 Summary of findings from clinical and non-clinical studies  
The use of ferrous fumarate and Ferinject® is indicated for an iron deficiency anemia. 
For these indications, the used drugs in this study, are therefore registered in the 
Netherlands. Whether the use of ferrous fumarate is also indicated with postoperative 
anemia, is not evident. An overview of clinical and non-clinical studies on the use of 
ferrous fumarate and Ferinject® postoperatively is given in the introduction of this 
protocol.  
  
6.3 Summary of known and potentional risks and benefits  
Ferrous fumarate  
Side effects  
Gastrointestinal complaints such as nausea, stomach-ache, constipation and diarrhea. 
These effects are dose dependent. Iron solutions may cause discoloration of the teeth. 
Potential risks  
None  
Benefits  
Faster growth of hemoglobin level in iron deficiency  
  


 
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Placebo Capsules  
Side effects  
No known side effects  
Potential risks  
None  
Benefits  
No known benefits  
  
Ferinject®  
Side effects  
Common (1-10%): headache, dizziness, rash, nausea, abdominal pain, constipation, 
diarrhea. Injection site reactions. Transient decrease in the concentration of phosphorus 
in the blood, increased ALAT. Uncommon (0.1-1%): myalgia, arthralgia, paresthesia, 
hypotension, redness, taste disturbance, vomiting, dyspepsia, flatulence, itching, 
urticarial, pyrexia, fatigue, chest pain, rigors, malaise and peripheral edema. Increased 
aspartate aminotransferase, γ-GT and lactate dehydrogenase  
Potential risks  
Anaphylactic shock, this occurs very rarely  
Benefits  
Faster increase in hemoglobin levels in iron deficiency anemia when oral iron therapy 
has proved to be ineffective or cannot be used  
  
NaCl 0.9%  
Side effects  
With 250 ml NaCl 0.9%, one need not worry about side effects, below, side effects are 
described after larger amounts of NaCl  
Fluid retention in the arms and legs (peripheral edema), pulmonary congestion (when 
excessive therapy)  
Potential risks  
Too much sodium in the blood is sometimes accompanied by restlessness, muscle 
weakness, dullness, convulsions and possible unconsciousness (hypernatremia)  
Benefits  
As far as known, the use of NaCl in an iron deficiency anemia has no advantages   


 
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6.4 Description and justification of route of administration and dosage  
Ferrous fumarate is available in suspension form and in tablet form. In this study the 
tablet form will be used, also because this form is used in the current setting standard 
and we want to precisely examine the current situation. The tablets are capsulated to 
match placebo capsules used in this study. 
Ferinject® is only available as intravenous administration.  
  
6.5 Dosages, dosage modifications and method of administration  
Capsulated Ferrous fumarate  
200 mg ferrous fumarate contains 65 mg Fe + +  
Features: Iron is necessary for the synthesis of haem in hemoglobin  
Way of administration: oral  
Dosage: 200 mg 2x daily  
  
Placebo capsules  
Placebo capsule is a 200 mg capsule filled with starch. 
Features: None  
Way of administration: oral  
Dosage: 200 mg 2x daily  
  
Ferinject®  
Solution for injection / infusion ³ 50 mg Fe / ml, vial of 2 ml, 10 ml or 20 ml.  
Features: In iron (III) carboxymaltose the iron is present in a complex with a 
carbohydrate polymer, which releases the iron at the iron transport and storage proteins 
in the body (ferritin, transferrin).  
Way of administration: intravenous  
Dose: single dose of 1000 mg  
  
 
0.9% NaCl  


 
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1 flask containing 250 ml of fluid (each 500 ml of solution contains 4.5 g Sodium 
Chloride)  
Features: Used for the treatment of isotonic extracellular dehydration; the treatment of 
sodium deficit, as a medium or solvent of compatible drugs for parenteral administration 
Way of administration: intravenous  
Dosage: 250 ml  
  
6.6 Preparation and labelling of Investigational Medicinal Product  
The capsulated ferrous fumarate and placebo capsules will be supplied by Basic Pharma. 
This company provides randomized double-blind study medication, labeled according to 
the study protocol. The company provides a controlled distribution to the pharmacy of 
the participating hospitals. Ferinject® will be supplied by Vifor Pharma.  
  
6.7 Drug accountability  
  
Capsulated ferrous fumarate and matching placebo will be provided in bottles, packaged 
in cartons by Basic Pharma to the MUMC and OMC pharmacy. Basic Pharma has a 
GMP license, so all these things are recorded and traceable. Ferinject® will be provided 
by Vifor Pharma, also packaged in cartons. Three packages will be arranged by the 
MUMC and OMC pharmacy: package 1: NaCl, ferrous fumarate; package 2: NaCl, 
placebo capsules; package 3: Ferinject®, placebo capsules. Remaining Ferinject® will be 
returned to Vifor Pharma. Excess placebo and ferrous fumarate will be destroyed by the 
MUMC and OMC pharmacy.  
 
 
7. METHODS  
  
7.1 Study parameters  
7.1.1 Main study parameter  
Hemoglobin level after 3 and 6 weeks.  


 
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7.1.2 Secondary study parameters  
• 
Quality of life after 1, 3 and 6 weeks  
• 
Side effects of medication  
• 
Predictive value of other parameters such as CRP, transferrin, ferritin and 
hepcidin 
• 
Cost analysis  
  
7.2 Randomization, blinding and treatment allocation  
Randomisation is performed by the ALEA Screening and Enrollment Application 
Software of  Formsmsvision BV (Abcoude). Minimisation with stratification factor 
Hemoglobin (5.0-6.0 or 6.1-7.0), age (<60 years or >=60 years), ASA (1-2 or 3-5), type 
of surgery (laprotomic, laproscopic or vaginal and other) and amount of blood loss 
(<500 mL or >=500 mL) will be performed. The minimization method supported by 
ALEA is based on the minimization principles published in a paper by Pocock & 
Simon23.  
  
With the kit-number the pharmacy knows which package the patient should receive. It 
will be ensured that the infusion line and the flask with NaCl or Ferinject® will be 
packed. Also the venflon will be covered by a gauze. The placebo capsules will exactly 
resemble the capsulated ferrous fumarate tablets. 
 
7.3 Study procedures  
Interventions  
Blood  
Postoperative determination of the hemoglobin level is part of the regular care and will 
be performed on the first day after the operation.   
In this study we want to examine the blood three times more than in the regular care, 
namely 1 day and 3 and 6 weeks postoperatively.  At 1 day (after randomization and 
before treatment) it will be taken in the hospital. At 3 weeks the research nurse will visit 
the patient at home. At 6 weeks the patient will visit the hospital for the regular follow 
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Determination of other parameters in the blood will not lead to more discomfort of the 
patient.  
The lab results will be saved using an anonymous survey number.  
  
Administration of an infusion  
Each patient has postoperative IV, so no extra IV is needed for the study. The patient 
will receive either a flask NaCl (placebo) or a single dose of Ferinject® on the first or 
second day after the operation (24-48 hours postoperatively).  
  
Capsules  
The patient will start using capsules (either a placebo or ferrous fumarate) on the first or 
second day after the operation (24-48 hours postoperatively). 
Each patient is given 60 capsules to take home, where she has to take 1 capsule 2 times 
a day. 
  
Questionnaire  
Each patient will be asked to complete a questionnaire four times: after informed 
consent before starting treatment, and 1, 3 and 6 weeks postoperatively. This 
questionnaire is a combination of the EuroHRQoL and MFI questionnaires. Completing 
the questionnaire takes about 10-20 minutes and can be filled in via computer or on 
paper.  
This will be conducted as follows: the first questionnaire will be completed in the 
hospital the first day postoperatively before the study-medication is started. After 1 
week the research nurse will call the patient at home to ask how things are going and 
whether the second questionnaire has been completed. After 3 weeks the nurse visits the 
patient and will ensure that the questionnaires about the quality of life after 1 and 3 
weeks are completed. The day the patient will come for the regular check at 6 weeks, 
she will also be seen by the research nurse who will check whether the last questionnaire 
has also been completed.  
  
Data collection  
Patient characteristics. The following information will recorded:  
• Age  
• Morbidity  


 
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• Race  
• ASA score  
• Use of iron therapy preoperative (doses and duration of iron therapy) 
• Amount of blood loss during surgery  
  
7.4 Withdrawal of subjects  
Subjects can leave the study at any time for any reason if they wish to do so without any 
consequences. The investigator can decide to withdraw a subject from the study for 
urgent medical reasons. Participation in the study is entirely voluntarily. 
When necessary, the code of the administered medication can be broken to know with 
which medication the patient is treated.  
  
7.5 Replacement of subjects in case of withdrawal  
A dropout of 10-20% is taken into account. Results will still be included, unless the 
patient withdraws consent. Assessments that will be done at the withdrawal visit are 
adverse events, drug accountability and collect not-used study medication.  
  
7.6 Premature termination of the study  
  
Premature termination of the study may occur:  
a. 
if no positive decision is obtained with regard to the research or if the judgement 
of the competent medical research ethics committee that has assessed the research is 
irrevocably revoked;  
b. 
if a reasonable case can be made for terminating the research in the interests of 
the subjects' health. 
 
 
 
 
 


 
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8. SAFETY REPORTING  
  
8.1 Temporary halt for reasons of subject safety 
In accordance to section 10, subsection 4, of the WMO, the sponsor will suspend the study if there is 
sufficient ground that continuation of the study will jeopardise subject health or safety.  The sponsor 
will notify the accredited METC without undue delay of a temporary halt including the reason for such 
an action. The study will be suspended pending further review by the accredited METC. The 
investigator will take care that all subjects are kept informed. 
8.2 Aes, SAEs and SUSARs  
  
8.2.1 Adverse events (AE)  
Adverse events are defined as any undesirable experience occurring to a subject during 
the study, whether or not considered related to the investigational product. All adverse 
events reported spontaneously by the subject or observed by the investigator or his staff 
will be recorded  
  
8.2.2 Serious adverse events (SAEs)  
A serious adverse event is any untoward medical occurrence or effect that at any dose:   
- results in death;  
- is life threatening (at the time of the event);  
- requires hospitalisation or prolongation of existing inpatients’ hospitalisation;  
- results in persistent or significant disability or incapacity;  
- is a congenital anomaly or birth defect;  
- Any other important medical event that may not result in death, be life threatening, or      
require hospitalization, may be considered a serious adverse experience when, based 
upon  appropriate medical judgement, the event may jeopardize the subject or may 
require an  intervention to prevent one of the outcomes listed above.  
 
 
In the current study design, there is no expectation that the treatment will lead to Serious  
 
Adverse Events.  


 
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The sponsor will report the SAEs through the web portal ToetsingOnline to the 
accredited METC that approved the protocol, within 15 days after the sponsor has first 
knowledge of the serious adverse reactions.  
  
SAEs that result in death or are life threatening should be reported expedited. The 
expedited reporting will occur not later than 7 days after the responsible investigator has 
first knowledge of the adverse reaction. This is for a preliminary report with another 8 
days for completion of the report.  
 
8.2.3 Suspected unexpected serious adverse reactions (SUSARs)  
Adverse reactions are all untoward and unintended responses to an investigational 
product related to any dose administered.  
Unexpected adverse reactions are SUSARs if the following three conditions are met:  
1. the event must be serious (see chapter 9.2.2);  
2. there must be a certain degree of probability that the event is a harmful and an 
undesirable reaction to the medicinal product under investigation, regardless of the 
administered dose; 
3. the adverse reaction must be unexpected, that is to say, the nature and severity of the      
adverse reaction are not in agreement with the product information as recorded in: 
- Summary of Product Characteristics (SPC) for an authorised medicinal product;  
- Investigator’s Brochure for an unauthorised medicinal product.  
  
The sponsor will report expedited the following SUSARs through the web portal 
ToetsingOnline to the METC:  
- 
SUSARs that have arisen in the clinical trial that was assessed by the METC;  
- 
SUSARs that have arisen in other clinical trials of the same sponsor and with the 
same   medicinal product, and that could have consequences for the safety of the 
subjects involved in the clinical trial that was assessed by the METC.  
The remaining SUSARs are recorded in an overview list (line-listing) that will be 
submitted once every half year to the METC. This line-listing provides an overview of 
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main points of concern.  The expedited reporting of SUSARs through the web portal 
ToetsingOnline is sufficient as notification to the competent authority.  
  
The sponsor will report expedited all SUSARs to the competent authorities in other 
Member States, according to the requirements of the Member States.   
  
The expedited reporting will occur not later than 15 days after the sponsor has first 
knowledge of the adverse reactions. For fatal or life threatening cases the term will be 
maximal 7 days for a preliminary report with another 8 days for completion of the 
report. 
  
The research coordinator at the corresponding centre will report the incident within 24 
hours to the principal investigator followed by a written notification within 48 hours.  
  
8.3 Annual safety report  
A report of events, adverse events and serious adverse events will be combined with the 
annual progress report and be sent to the METC.  
  
8.4 Follow up of adverse events  
All adverse events will be continued until they disappear completely, or until a stable 
situation has been reached. Depending on the event, additional tests or medical 
procedures for followup can be required.  
 
 
9. STATISTICAL ANALYSIS  
  
9.1 Primary study parameter  
Primary study parameter is change in hemoglobin level (mmol/L) between baseline and 
either 3 or 6 weeks postoperatively. Differences in change between the two 
experimental groups, and between each experimental group and the control group will 
be tested by use of the  
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9.2 Baseline differences  
Differences in baseline characteristics are not expected in view of randomization. In 
order to check for any imbalances, values of variables measured at baseline (including 
hemoglobin) will be compared between groups (means for continuous variables, 
percentages for categorical variables). No statistical testing of baseline differences will 
be done since all differences will be due to chance.9.3 Multivariable analysis. In case of 
prognostically important baseline differences between groups, multivariable linear 
regression analysis will be carried out instead of the Student’s T-test.  
  
9.3 Multivariable analysis  
In case of prognostically important baseline differences between groups, multivariable 
linear regression analysis will be carried out instead of the Student’s T-test.       
  
9.4 Secondary study parameters  
Quality of life 
Each patient will be asked to complete three questionnaires at four times: at baseline 
after informed consent before starting iron treatment, and 1, 3 and 6 weeks 
postoperatively. The questionnaires are: 1) the EuroQoL, a generic health related quality 
of life questionnaire. In this questionnaire patients indicate their current health in five 
dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression 
2) the Multi-Dimensional Fatigue Questionnaire which is a 20-item self-reported 
instrument to measure fatigue. At baseline (first day postoperatively in the hospital but 
before the study-medication is started) patients will be asked to complete the 
questionnaires. At 1 week after start of the treatment, the research  nurse will call the 
patient at home to ask whether the second questionnaire has been completed.  After 3 
weeks the nurse visits the patient and will ensure that the questionnaires about the 
quality of life after 1 and 3 weeks are completed. At 6 weeks, the patient will visit the 
outpatient clinic and will also be seen by the research nurse who will check whether the 
last questionnaire has also been completed.   
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ANOVA.  
  
Side effects of the medication  
The next side effects will be registered: headache, constipation, diarrhea, nausea, 
dizziness, rash and stomach-ache. On questionnaire B, C, and D the patients can indicate 
whether there is any of these side effects. 
For each potential side effect, the percentage of patients reporting it will be compared 
between groups. Groups will be compared using the Chi-square test. 
  
Predictive value of other parameters 
We will determine for number of parameters whether they predict patients’ sensitivity to 
iron supplementation. These parameters are: CRP, transferrin, ferritin and hepcidin. The 
significance of these parameters will be determined by doing subgroup analyses among 
patients with either high or low values of the parameters (i.e. the similar analyses as in 
9.1 but within subgroups). 
  
Cost-analysis  
Resource use and costs of the intravenous and oral iron therapy will be measured. If relevant 
and appropriate, a cost-minimisation or a cost-effectiveness analysis will be performed. 
In that case, the analysis will include a time-horizon of 6 weeks and be performed from 
a health care perspective.  
  
9.5 Alpha  
We will employ an alpha of 5% (2-sided testing). 
  
9.6 Handling of missing values  
Missing values in the primary outcome parameter (hemoglobin) will be imputed by 
means of the last known observation. Missing values in baseline characteristics will be 
imputed by means of a multiple imputation procedure. 
  
9.7 Statistical analysis package  
Statistical analysis will be carried out using either SPSS or SAS. 


 
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9.8 Interim analysis (if applicable)  
Not applicable  
 
  
10. ETHICAL CONSIDERATIONS  
  
10.1 Regulation statement  
The study will be conducted according to the principles of the Declaration of Helsinki, 
version Fortaleza 2013 and in accordance with the Medical Research Involving Human 
Subjects Act (WMO).  
  
10.2 Recruitment and consent  
All patients who are scheduled for a primary caesarean section will be informed about 
the study by the physician who is arranging the procedure. A copy of the patient 
information and consent form will be given to the patient. About one week later the 
research nurse will call the patient, and ask her if there are any questions and if she likes 
to participate. When the patient likes to participate, the informed consent form will be 
signed on the day the patient visits the hospital for the scheduled operation by both the 
patient and one of the members of the research team. The ultimate responsibility will 
always lie with the investigator(s), but they can delegate this specific task. Who is 
authorized to obtain the informed consent will be noted in a delegation log. A standard 
operating procedure informs the members of the research team in which case (i.e. 
specific questions) they should contact the investigators or one of the doctors before the 
patient signs the informed consent. Medical responsibility will hereby be ensured. After 
signing, the patient will get a screening number and pre-operatively blood will be taken 
and stored. If the patient meets all inclusion criteria including post-operative Hb 5-7 
mmol/L, she can be randomized and hepcidin, transferrin, ferritin and CRP will be 
determined. If the patient does not meet all inclusion criteria including of post-operative 
Hb 5-7 mmol/L, she will not be randomized and the preoperatively stored blood will be 
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10.3 Benefits and risks assessment  
The expected risk of complications by treatment with Ferinject® or ferrous fumarate 
seem very low, but could improve quality of life.  
  
10.4 Compensation for injury  
The sponsor (also) has an insurance which is in accordance with the legal requirements 
in the Netherlands (Article 7 WMO and the Measure regarding Compulsory Insurance 
for Clinical Research in Humans of 23th June 2003). This insurance provides cover for 
damage to research subjects through injury or death caused by the study.  
1. € 450.000,-- (i.e. four hundred and fifty thousand Euro) for death or injury 
for each subject who participates in the Research;  
2. € 3.500.000,-- (i.e. three million five hundred thousand Euro) for death or 
injury for all subjects who participate in the Research;   
3. € 5.000.000,-- (i.e. five million Euro) for the total damage incurred by the 
organisation for all damage disclosed by scientific research for the Sponsor 
as ‘verrichter’ in the meaning of said Act in each year of insurance coverage.  
  
The insurance applies to the damage that becomes apparent during the study or within 4 
years after the end of the study.  
 
 
11. ADMINISTRATIVE ASPECTS, MONITORING AND 
PUBLICATION  
  
11.1 Handling and storage of data and documents  
  
Online patient questionnaires  
Patient-reported outcomes will be captured with electronic online questionnaires using 
Select Survey. This will reduce the percentage of missing data and errors in the 
collected data.   
  


 
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Randomization  
Randomization will be performed online in ALEA.   
  
Data management  
Data will be captured by means of an electronic CRF, called MACRO, provided by 
CTCM. With MACRO, the data will be captured and analyzed in a GCP compliant 
manner, including queries and audit trails. The database will be digitally archived for 15 
years after study closure. 
Before study start, all individuals that are authorized by the Principal Investigator to 
perform Data Entry will be trained on the eCRF. For every subject enrolled in this trial, 
the eCRF must be completed within a reasonable time period after data collection. All 
clinically significant results must be recorded on the eCRF. 
  
11.2 Monitoring and quality assurance  
Monitoring will be performed by trained and qualified monitors of the CTCM.  
According to Good Clinical Practice (GCP) guidelines, the main task of the monitor 
is ensuring that:  
• 
The rights and well-being of human subjects are protected  
• 
Reported trial data are accurate, complete and verifiable from source documents  
• 
The conduct of the trial is in compliance with the currently approved protocol, GCP 
and applicable regulatory requirements. Prior to the study start, a monitoring plan 
will be assembled, specifying the Source Document Verification Plan, the Drug 
Accountability Plan, the frequency of monitoring visits and frequency of checking 
the Trial Master Files/Investigator Site Files. Monitoring will be performed 
remotely (using the eCRF) and on site. 
  
There are several kinds of monitoring visits:  
• 
Site initiation visit (SIV): The SIV will be performed after all approvals have been 
obtained and prior to enrolling the first subject. There will be 1 SIV per site. 
• 
Interim monitoring visit (IMV): Several IMV’s will be performed during the trial. 
Frequency of visits is determined in the monitoring plan. 
• 
Close out visit (COV): The COV will be performed at the end of the trial, after 
collection of all data. There will be 1 COV per site. 


 
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Monitoring visits will be planned in accordance with the study site personnel. According 
to the ICH GCP guidelines, the investigator must enable the monitor during visits, 
providing him/her with all necessary information and documents. Furthermore, the 
investigator is obliged to answer all queries raised by the monitor in the eCRF in a 
timely manner.  
After each monitoring visit, a follow-up email with all action points will be sent to the 
site.  
These action points will be addressed at the beginning of the next monitoring visit. 
  
11.3 Annual progress report  
The investigator will submit a summary of the progress of the trial to the accredited 
METC once a year. Information will be provided on the date of inclusion of the first 
subject, numbers of subjects included and numbers of subjects that have completed the 
trials, serious adverse events/ serious adverse reactions, other problems and 
amendments.  
  
11.4 End of study report  
The principal investigator will inform the evaluative committee within 90 days after 
discontinuation of the study. The end of the study is defined as the day when the 
hemoglobin level of the last patient 6 weeks postoperatively is determined and the 
questionnaire has been filled out. After this, the analysis will take place. If the 
investigation is terminated earlier, the principal investigator will inform the METC with 
the reasons for the premature termination. Within one year after completion of the 
investigation, the investigator will send a research report with the results of the 
investigation to the METC, including abstracts or publications related to the 
investigation.  
  
11.5 Public disclosure and publication policy  
  
The data and conclusions that emerge from the study will be described in one or more 
articles for publication and submission to an international peer reviewed journal.  


 
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12. STRUCTURED RISK ANALYSIS  
  
12.1 Potential issues of concern  
  
Ferinject  
  
a. Level of knowledge about mechanism of action  
Ferinject provides usable iron transport-and-storage proteins.  
Research showed that Fe from ferinject was very quickly eliminated from the blood and 
transferred to the bone marrow and deposited in the liver and spleen.  
  
b. Previous exposure of human beings with the test product(s) and/or products with a 
similar biological mechanism  
The efficacy and safety of Ferinject has been studied in different therapeutic areas 
necessitating intravenous iron to correct iron deficiency. See also SPC.  
  
c. Pharmacokinetic considerations  
Positron emission tomography demonstrated that 59Fe and 52Fe from Ferinject was 
rapidly eliminated from the blood, transferred to the bone marrow, and deposited in the 
liver and spleen. 
After administration of a single dose of Ferinject of 100 to 1,000 mg of iron in ID 
patients, maximum total serum iron levels of 37 µg/mL up to 333 µg/mL are obtained 
after 15 minutes to 1.21 hours respectively. The volume of the central compartment 
corresponds well to the volume of the plasma (approximately 3 litres). 
The iron injected or infused was rapidly cleared from the plasma, the terminal half-life 
ranged from 7 to 12 hours, the mean residence time (MRT) from 11 to 18 hours. Renal 
elimination of iron was negligible.   
  
d. Study population  
Patients have had a primary caesarean section and have a postoperative hemoglobin 
between 5-7 mmol / L. Infections, disease during pregnancies will be excluded. See also 
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e. Interaction with other products  
As with all parenteral iron preparations the absorption of oral iron is reduced when 
administered concomitantly. Therefore, if required, oral iron therapy should not be 
started for at least 5 days after the last injection of Ferinject.  
  
f. Can effects be managed?  
Administration of Ferinject in quantities exceeding the amount needed to correct iron 
deficit at the time of administration may lead to accumulation of iron in storage sites 
eventually leading to haemosiderosis. Monitoring of iron parameters such as serum 
ferritin and transferrin saturation may assist in recognising iron accumulation. If iron 
accumulation has occurred, treat according to standard medical practice, e.g. consider 
the use of an iron chelator.  
  
  
Capsulated ferrous fumarate  
  
Capsules (European Pharmacopoeia standard) are filled with 2 tablets of 100 mg ferrous 
fumarate and starch 1500. The use of a capsule around the ferrous fumarate will not 
change the effect of ferrous fumarate. See also the IMPD for the capsulated ferrous 
fumarate.  
  
a. Level of knowledge about mechanism of action  
Ferrous fumarate provides usable for iron transport-and-storage proteins.  
  
b. Previous exposure of human beings with the test product(s) and/or products with a 
similar biological mechanism  
The efficacy and safety of ferrous fumarate has been studied in different therapeutic 
areas necessitating oral iron to correct iron deficiency. See also SPC  
  
c. Pharmacokinetic considerations  
In the acid conditions of the gastric contents, ferrous fumarate is dissociated and ferrous 
ions are liberated. These irons are absorbed in the proximal portion of the duodenum. 


 
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The ferrous iron absorbed by the mucosal cells of the duodenum is oxidised to the ferric 
form, and this is bound to a protein to form ferritin. Ferritin in the mucosal cells releases 
iron into the blood, where it is bound to transferrin and passed into the iron stores - 
liver, spleen, and bone marrow. These stores are a reserve of iron for synthesis of 
haemoglobin, myoglobin, and iron containing enzymes. Iron is lost from the body 
through loss of cells in urine, faeces, hair, skin, sputum, nails, and mucosal cells, and 
through blood loss. Ferrous fumarate has the same pattern of absorption and excretion 
as dietary iron. 
  
d. Study population  
Patients have had a primary caesarean section and have a postoperative hemoglobin 
between 5-7 mmol / L. Infections, oncologic diseases during pregnancy, HELLP 
syndrome, pre eclampsia will be excluded. See also chapter 4.3  
  
e. Interaction with other products  
Iron reduces the absorption of penicillamine, bisphosphonates, ciprofloxacin, 
entacapone, levodopa, levofloxacin, levothyroxine (thyroxine) (give at least 2 hours 
apart), moxifloxacin, mycophenolate, norfloxacin, ofloxacin, zinc. 
Absorption of both iron and antibiotic may be reduced if Fersamal is given with 
tetracycline.Absorption of oral iron is reduced by calcium salts, Magnesium salts (as 
magnesium trisilicate), Trientine. 
Chloramphenicol delays plasma iron clearance, incorporation of iron into red blood 
cells and interferes with erythropoiesis. Some inhibition of iron absorption may occur if 
it is taken with cholestyramine, tea, eggs or milk. 
Avoid concomitant use of iron with dimercaprol. 
Oral iron antagonises hypotensive effect of methyldopa.  
  
f. Can effects be managed?  
In case of overdose  
Supportive and symptomatic measures include ensuring a clear airway, monitor cardiac 
rhythm, BP and urine output, establishing IV access and administering sufficient fluids 
to ensure adequate hydration. Consider whole bowel irrigation. If metabolic acidosis 
persists despite correction of hypoxia and adequate fluid resuscitation, an initial dose of 
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by arterial blood gas monitoring (aim for a pH of 7.4). Consider the use of 
desferrioxamine, if /the patient is symptomatic (other than nausea), serum iron 
concentration is between 3-5 mg/L (55-90 micromol/L) and still rising. Haemodialysis 
does not remove iron effectively but should be considered on a supportive basis for 
acute renal failure as this will facilitate removal of the iron-desferrioxamine complex.  
  
  
Ferrous fumarate placebo capsules(see also IMPD): Containing starch 1500 
  
a. Level of knowledge about mechanism of action 
Starch 1500 and the capsule has no pharmologic action  
  
b. Previous exposure of human beings with the test product(s) and/or products with a 
similar biological mechanism  
Placebo capsules with starch 1500 have been used in more studies without any effects. 
  
c. Pharmacokinetic considerations Not applicable  
  
d. Study population  
Patients have had a primary caesarean section operation and have a postoperative 
hemoglobin between 5-7 mmol / L. Infections, oncologic diseases during pregnancy 
will be excluded. See also chapter 4.3  
  
e. Interaction with other products  
No interactions  
  
f. Can effects be managed?  
Not applicable  
  
12.2 Synthesis  
The group treated with oral or intravenous iron preparations may have side effects on 
gastrointestinal region or skin reactions.  


 
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The use of ferrofumaraat can give the following adverse events: mild constipation in 1-
10%, diarrhea in 0.1-1%. Skin reactions occur only in 0.01-0.1%. Nausea, stomach pain, 
vomiting and anorexia are also reported. We don’t expect other risk/adverse events 
because it has already been used for many years. No serious adverse events have been 
described.For ferinject the next adverse events are described: headache, dizziness, 
nausea, abdominal pain, constipation, diarrhea and skin rash in 1-10%. Uncommon (0.1-
1%): myalgia, arthralgia, paresthesia, hypotension, redness, taste disturbance, vomiting, 
dyspepsia, flatulence, itching, urticarial, pyrexia, fatigue, chest pain, rigors, malaise and 
peripheral edema. Increased aspartate aminotransferase, γ-GT and lactate 
dehydrogenase. Dyspnoe only in 0.01-0.1%.The occurrence of a severe allergic reaction 
to Ferinject® is extremely rare, but cardiopulmonary resuscitation will always be 
available. People with previous allergic reactions to oral or intravenous iron are 
excluded from the study. Other risks or adverse events are not to be expected because 
ferinject has been given for several years.  
Not treating a patient (the group that only receives oral and intravenous  placebo) will 
not entail major risks, but may cause a longer time of fatigue and dizziness. Literature 
also shows that not treating a patient with a hemoglobin around 5 mmol/L is 
justified1,2,3. Because not treating patients with an intense low hemoglobin level (<5 
mmol/Hg) can lead to more risks, they are excluded from the study.    
The patient does not have to undergo an invasive procedure: the load is relatively small 
and does not entail major risks, while the results of the study may lead to better use of 
medication for the patient, hence fewer side effects and less costs for care.  
  
 
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Annex 1. Assessment schedule  
  
Visits and Timepoints 1 Pre-operative 
Surgery 
Post-operative 
Week 1 
Week 3 
Week 6 
Withdrawal  
 
Screening 
 
 
Telephone call 
Home visit 
 
 
Assessments 
Day - 3 to -1 
Day 0 
Day 1, within 24-48 
hours after surgery 
Day 7 
Day 21 
Day 42 
 
Informed consent 
X 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
Demography (age, race) 
X2 
 
 
 
 
 
 
Relevant Medical History / Current medical conditions 
X2 
 
 
 
 
 
 
ASA score 
X2 
 
 
 
 
 
 
Type of surgery 
 
X2 
 
 
 
 
 
Amount of blood loss during surgery 
 
X2 
 
 
 
 
 
Hb 
X 
 
X 
 
X 
X 
 
Transferrin, Ferritin, CRP 
X 
 
X2 
 
X 
X 
 
Hepcidin 
X 
 
X2 
 
X 
X 
 
QoL questionnaires 
 
 
X2 
X 
X 
X 
 
(Serious) Adverse events 
 
 
X2 
X 
X 
X 
X 
Randomization 
 
 
X2 
 
 
 
 
Dispense studymedication 
 
 
X2 
 
 
 
 
Drug accountability 
 
 
X2 
 
X 
X 
X 
Collect not-used study medication 
 
 
 
 
 
X 
X 
1 Due to logistic reasons adjustments in timepoints can occur 
 
 
 
 
 
 
 
2 Only if post-operative Hb is within 5 and 7 mmol/L