Study setting {9}
The trial is being conducted at the Department of Obstetrics and Gynecology at Copenhagen University Hospital, Amager-Hvidovre Hospital, which is a tertiary hospital with 7000 – 8000 yearly deliveries.
Healthy women who wish to participate and fulfill the inclusion criteria are enrolled at gestational age (GA) 14+0 – 21+0. The duration for each participant is approximately 18 weeks and involves four follow-up visits by a trial investigator at Amager-Hvidovre Hospital.
Eligibility criteria {10}
Pregnant women at GA 14+0 – 21+0 are eligible for inclusion if they fulfil the following criteria: s-ferritin <30 μg/L (0-29 μg/L) after 4 weeks of standard treatment; age ≥18 years; signed informed consent form.
Exclusion criteria: multiple pregnancies; history of anaemia not caused by iron deficiency; iron overload or disturbances in utilization of iron; previous hypersensitivity to IV iron or to any excipients in the investigational drug products; active asthma within the last 5 years; multiple allergies; known decompensated liver cirrhosis or active hepatitis; active acute or chronic infections (assessed by clinical judgement); rheumatoid arthritis with symptoms or signs of active inflammation; treated with IV iron products, blood transfusion or erythropoietin within 4 weeks prior to inclusion; participation in any other interventional trial where the trial drug has not passed 5 half-lives prior to inclusion; any other medical condition that, in the opinion of the Investigator, may cause the participant to be unsuitable for the completion of the trial or place the participant at potential risk from being in the trial; meeting RBC-transfusion criteria (Hb ≤6.9 g/dL= ≤4.3 mmol/L with intolerable symptoms of anaemia or an Hb ≤6.4 g/dL (≤4.0 mmol/L) regardless of anaemia symptoms; inability to read and understand the Danish language.
Who will take informed consent? {26a}
Trial investigators will obtain informed consent.
Additional consent provisions for collection and use of participant data and biological specimens {26b}
Not applicable
Interventions
Explanation for the choice of comparators {6b}
The choice of the comparator is based on current standard treatment of ID in pregnancy.
Intervention description {11a}
A: IV FDI administered at the baseline visit as a single dose of 1000 mg (if pre-pregnancy body weight <50 kg then 20 mg/kg pre-pregnancy body weight). The dose is diluted in 100 ml 0.9 % sodium chloride and is given over approximately 20 minutes.
- Fixed dose oral ferrous fumarate (100 mg elemental iron) with ascorbic acid 60 mg (27), once daily.
Criteria for discontinuing or modifying allocated interventions {11b}
If the participant has IDA at T6w or T12w defined as Hb <11 g/dL and s-ferritin <30 μg/L an additional dose of IV iron isomaltoside is allowed in both groups (not at T18w due to lack of AE monitoring). The maximum cumulative dose is set to 2000 mg for the individual participant.
Strategies to improve adherence to interventions {11c}
Compliance to oral treatment is encouraged at every follow up visit.
Relevant concomitant care permitted or prohibited during the trial {11d}
Iron supplementation other than study treatment is prohibited.
Provisions for post-trial care {30}
Not applicable
Outcomes {12}
The primary endpoint of this trial is a Hb ≥11.0 g/dL (≥6.8 mmol/L) at all trial visits post-baseline (T3w, T6w, T12w and T18w).
The secondary endpoints are Hb ≥11.0 g/dL (≥6.8 mmol/L) at each follow-up visit, change in Hb and other haematological indices of ID/IDA from baseline to each follow-up visit (e.g. reticulocytes, reticulocyte haemoglobin content (CHr), s-ferritin, s-transferrin, s-iron, hepcidin, and calculated transferrin saturation (TSAT)), incidence of hypophosphatemia (defined as serum [s]‑phosphate <2 mg/dL) from baseline to each follow-up visit, change in fatigue and quality of life questionnaires from baseline to each follow-up visit, presence of RLS at each follow-up visit, number of participants who receive an additional IV iron isomaltoside dose at T6w and/or T12w, reason for the additional IV iron isomaltoside dose (non-compliance, lack of effect), number of participants receiving RBC-transfusions and the number of RBC-units per transfused participant from baseline to final subject visit, type and incidence of AEs observed at any time until final subject visit, serious or severe hypersensitivity reaction starting at or after the first dose of randomised treatment, AEs of special interest (constipation, diarrhoea, flatulence, nausea, vomiting, abdominal pain, dyspepsia, dysguesia, and stool discoloration), number of participants who discontinue from the trial because of lack of response or intolerance of investigational drugs, foetal bradycardia related to infusion of IV iron isomaltoside at or after GA 26, change in biochemical safety parameters from baseline to each follow-up visit and compliance to treatment: at baseline in the IV group and at T6w and T18w in oral group.
Specific explorative endpoints registered between final subject visit up until 7 days postpartum will be extracted from medical records: Incidence of maternal antepartum haemorrhage, thromboembolic events, gestational diabetes mellitus, gestational hypertensive disorders, blood transfusions, prolonged labour, length of labour, oxytocin use, assisted delivery, unplanned caesarean section, postpartum haemorrhage, maternal blood loss at labour (ml), length of maternal and neonatal hospital admission, maternal death, incidence of intrauterine growth retardation, preterm birth, ante- or postnatal asphyxia, low birthweight, neonatal infection, neonatal anaemia, required paediatric assistance, admission to neonatal ward, congenital malformations, foetal or neonatal death GA at delivery, date of delivery and birthweight.
Clinical outcome measures
The FACIT-fatigue questionnaire has been validated in a mixed population of patients with IDA. The questionnaire consists of 13 items regarding fatigue. Each item has a response scale of 0 – 4, 0 being ‘not at all’ and 4 being ‘very much so’. The score for each item is added up to a summed score, where a low score equals more fatigue and higher score equals a better condition. Selected items are there for reversed when adding up the total score.
The Short Form 12 (SF 12) is used to evaluate quality of life (QoL). The SF-12 is derived from the more comprehensive SF-36. Both SF-12 and SF-36 cover the two summary measures of physical and mental health through eight domains/scales (physical functioning, physical role, bodily pain, general health, vitality, social function, emotional role, mental health) which in turn are covered by 12 items. Higher scores indicate better conditions.
RLS is evaluated by using the four diagnostic criteria (36) as a quantitative outcome which is either present or not present.
Participant timeline {13}
The participants will attend the baseline visit and 4 follow-up visits: T3w three weeks (± 2 days), T6w six weeks (± 3 days), T12w twelve weeks (± 1 week) and T18w eighteen weeks (± 1 week) from baseline (see figure 1 and 2).
Sample size {14}
The sample size calculations are based on the primary endpoint: Hb ≥11 g/dL (≥6.8 mmol/L) at all time points after baseline. It is assumed that 5 % and 17.5 % of the participants in the FDI and oral treatment groups respectively will have a Hb <11 g/dL at some point during the trial, corresponding to 95 % and 82.5 % will have a Hb ≥11 g/dL at all post-baseline visits. Using a significance level of 5 %, and setting the power to 80 %, 100 participants in each treatment group are required in order to detect the assumed difference between FDI and oral iron.
Recruitment {15}
The women will be recruited from the clinical setting. Standard clinical procedures for pregnant women at the trial site include 1st trimester screening for iron deficiency and anaemia by measuring Hb and serum ferritin. Women with ID or IDA are recommended intensified oral iron supplementation and repeated blood samples in the 2nd trimester. Women with persistent iron deficiency despite this standard oral treatment are contacted, informed about the trial and are invited to the baseline visit.
Assignment of interventions: allocation
Sequence generation {16a}
The procedure for preparing the randomisation list is approved by the Global Trial Responsible Statistician. The randomisation list is prepared by BioStata ApS, Birkeroed, Denmark and is not accessible to the investigators.
Concealment mechanism {16b}
The investigators consecutively invite all eligible participants to attend the baseline visit. At the baseline visit demographics and latest Hb level are entered in the electronic Case Report File (eCRF) prior to randomisation. Thereafter, the participant is randomised and proceeds to the allocated treatment.
Implementation {16c}
Please find description above.
Assignment of interventions: Blinding
Who will be blinded {17a}
This trial is open label.
Procedure for unblinding if needed {17b}
This trial is open label.