Ferric Derisomaltose (Iron Isomaltoside) Versus Iron Sucrose for Treatment of Iron Deficiency in Pregnancy

Intravenous Iron Isomaltoside Versus Iron Sucrose for Treatment of Iron Deficiency in Pregnancy: A Randomized Comparative Trial

Ion deficiency anemia (IDA) is associated with poor neonatal outcomes and maternal morbidity. Iron replacement may be done with oral iron or intravenous iron, with intravenous iron being utilized later in pregnancy or if there is an inadequate response to oral iron in the first trimester. In Canada, iron sucrose has been used, however iron isomaltoside is as safe as other formulations of IV iron but can replete iron stores with a single visit. Replenishing iron stores reduces both maternal and neonatal risks and is supported by current guidelines. Iron status may play a role in depression, as well as anemia, bleeding and blood transfusion.

The goal of this clinical trial:

• Correct IDA with fewer visits and less impact on the healthcare system
• Improve the health and well being of all pregnant women who are experiencing moderate to severe iron deficiency anemia.

IDA is associated with poor neonatal outcomes and maternal morbidity. This clinical trial will compare IV iron isomaltoside to IV iron sucrose for correction of IDA, along with the potential impacts to the patient: physical, emotional and convenience. The study will also take into consideration the financial and resource impacts to the healthcare system, as well as determine the validity of using iron isomaltoside in second and third trimester pregnancy.

The trial will be a randomized, comparative, single center, phase III trial with a 1:1 allocation ratio. There will be two groups involved in this trial. Group 1: A single dose of IV iron isomaltoside. Group 2: Standard iron sucrose therapy.

Eligible participants will be screened for IDA during the initial appointment (greater or equal to 13 weeks gestational age) with the obstetrical care provider. Discussion/awareness about the study will be discussed at their appointment or over the telephone with the obstetrical care provider. This information will only be discussed if the patient requires IV iron repletion in second or third trimester pregnancy.

Enrollment inclusion/exclusion criteria must be met for the participant to receive the information about the study.

Study personnel will discuss the clinical trial, including obtaining informed consent with the eligible participant. Baseline vital signs and blood work will be documented from the previous patient visit where IDA was diagnosed. Documentation and data collection will occur at 3 other points within the clinical trial: Post iron infusion (approximately 30 days after infusion), during delivery and at 6 weeks postpartum.

Standard community blood work requisitions will be used for blood work and blood tests that occur within the community or health clinic setting. Standard Physician orders or Pre Printed orders will be followed for tests, bloodwork and medication administration while in hospital at the delivery admission. Participant duration will be from intake (approximately 13 weeks gestation to 6 week follow up post delivery of infant). The follow up at the 6 week appointment will be the end point for the participation of the study. A total of approximately 231 days of involvement within the study duration for each participant.

The study will be completed 36 months after the enrollment of the first participant or when all patients have been recruited to satisfy the sample size calculation.

The sample size is calculated based on the primary endpoint (achievement of Hb≥110 g/L after iron intervention). As iron isomaltoside has a faster rise in hgb (weeks 1 to 5) with fewer visits, it is assumed that 5% of iron isomaltoside and 15% of iron sucrose participants will have hgb <110 g/L at delivery. Given the 10% difference between groups of patients achieving a hgb ≥110g/L in the iron isomaltoside group, it is calculated that at a p of 0.05 and a power of 80%, 140 participants are required in each treatment group.

The primary endpoint of this trial is the correction of anemia, defined as Hgb greater or equal to 110 g/L at trial post iron infusion (30 days post iron infusion (with measured hemoglobin levels during delivery and at six weeks postpartum).

The secondary endpoint is the change in quality of life questionnaires from baseline, post iron infusion, at delivery and 6 weeks postpartum through standard Redcap tools. Additionally, any adverse event will be documented with appropriate follow up care.

Participant subjective data will also be collected based on tolerance of IV iron, pregnancy related symptoms and quality of life comparing pre iron infusion, post iron infusion, at delivery and again at 6 weeks post delivery. Participants will also be required to answer questions related to convenience of appointment for iron infusion(s), accessibility to the infusion appointments and post birth bonding with baby.

Analysis will be performed after data collection is complete using the latest version of RStudio. Qualitative variables will be expressed as counts, percentages, quantitative variables as mean +/- standard deviation or median (interquartile range [IQR] depending on the variable distribution. Comparison of continuous variables will be performed using the two sided Student's t test or Mann Whitney U test (where appropriate), and the chi squared test or Fisher's exact test (where appropriate) to compare category variables. The Kaplan Meier method will be used for the graphical assessment of time related events. Analysis of the primary efficacy and safety endpoints will be by intention to treat.

Participants who withdraw either due to medical condition or expressed withdrawal will be set as censored. No data relating to the withdrawal will be utilized in the data analysis. The proportion of endpoints will be analyzed using logistic regression. Continuous secondary endpoints will be analyzed by linear regression. For analyzing missing data, model based multiple imputations will be used for both primary and secondary outcomes.

Eligible pregnant women with iron deficiency will be recruited through the Department of Obstetrics and Gynecology Department, or through health care providers that maintain obstetrical care privileges at RGH.

Treatments arms will be allocated through a blocked randomization list prepared by an online tool. Moreover, the randomization will be stratified by Hgb level in increments of 10g/L to pursue equal distribution of the two groups. The sequence list will not be accessible to the investigators. Participants will be randomly assigned to receive either IV iron isomaltoside or IV iron sucrose. IV iron sucrose is the comparator because it is currently the formulation used for IDA during second and third trimester pregnancy in Regina, Saskatchewan, Canada. Products will be stored as per the product monograph and as per requirements and guidelines set out by the Saskatchewan Health Authority.

The Saskatchewan Health Authority will ensure that the written agreement to perform trial related monitoring, audits, Research Ethics Board reviews and regulatory inspections, and provide direct access to source data and/or documents of this clinical trial, as required. Data and source documents must be readily available to the Research Ethics Board, Health Canada, Therapeutic Products Directorate, inspectors, clinical trial team members, including investigators and/or obstetrical care providers for the purposes of compliance with regulatory requirements of the clinical protocol and purposes relating to treatment, care and follow up of adverse drug reactions or by means of trace back/lookback as required. Source data and documentation include patient records whether hard copy or electronic, blood work, appointment dates and times, test and procedure results relating to this clinical trial. All source documents must be accessible during the clinical trial period and after the clinical trial has completed.

Inclusion Criteria:

• 18 years of age and over
• Pregnancy with Gestational age ≥13 weeks
• Iron deficiency anemia defined as:
• Hemoglobin less than or equal to 110g/L and
• Serum ferritin less than 30ng/mL or
• Iron Saturation (Iron/TIBC) less than 20%
• Willing to participate and attend all planned follow up visits
• Willing to sign informed consent form
• Willing to attend appointments for iron infusion and follow up visits
• Willing to attend all planned bloodwork appointments

Exclusion Criteria:

• Pregnancy GA less than 13 weeks
• History of anemia caused by thalassemia or other haematologic disorder other than iron deficiency anemia ,
• Known serious hypersensitivity to other parental iron products
• Iron overload or disturbances in utilization of iron (i.e, haemochromatosis and haemosiderosis)
• Decompensated liver cirrhosis or active hepatitis
• History of multiple allergies
• Active acute or chronic infections
• Treated with IV iron products or blood transfusion within 4 weeks prior to inclusion
• Current participation in any other interventional trial
• Multiple gestation pregnancy
• Significant comorbidities (asthma requiring daily therapy or other lung diseases)
• Heart disease
• Kidney disease
• Rheumatologic disease
• Cancer
• Known hypersensitivity to iron sucrose or any excipients
• Known hypersensitivity to iron isomaltoside or any excipients.