Evaluation of Intravenous Ferric Carboxymaltose Versus Oral Ferrous Sulfate and Ascorbic Acid in Post-Caesarean Iron Deficiency Anemia and Postpartum Depression

The primary objective of this study is to assess the effect of **intravenous (IV) iron** versus oral iron treatment on the prevalence of postpartum depression at 8 weeks postpartum in women with moderate iron deficiency anemia following a cesarean delivery. This is clinically relevant as postpartum depression can significantly impact maternal health and infant care, and addressing iron deficiency may offer a therapeutic benefit.

Secondary objectives include:

• Evaluating the effect of IV iron treatment compared to oral iron treatment on biological parameters markers of anemia.
• Evaluating the effect of IV iron treatment compared to oral iron treatment on clinical parameters at 8 weeks postpartum.
• Evaluating the effect of IV iron treatment compared to oral iron treatment on clinical parameters at 6 months postpartum.
• Assessing potential adverse effects of treatment.
• Evaluating compliance with oral iron treatment.
• Conducting a medical-economic analysis with a cost-consequence approach.

The clinical trial involves a study population of **women** who have undergone a **caesarean delivery** and are experiencing moderate postpartum **iron deficiency anaemia**. The participants are aged 18 years and older, with a gestational age at delivery of at least 32 weeks. The trial exclusively includes female subjects, and the population is not considered vulnerable. Participants were selected based on specific health criteria, including a postoperative hemoglobin level between 8.0 g/dL and 10.0 g/dL, measured within 72 hours after delivery, and either a ferritinemia level of 100 ng/mL or less, or a transferrin saturation of 20% or less. The trial does not include male subjects, and there is no information provided regarding the total number of participants or specific lifestyle considerations such as diet or physical activity. The sponsor has not provided the total number of participants involved in the study.

The clinical trial is designed to evaluate the effect of intravenous (IV) iron versus oral iron treatment on the prevalence of postpartum depression in women with moderate iron deficiency **anemia** following a cesarean delivery. This is a multicentric, randomized, open-label, controlled trial with two parallel groups. The trial is categorized as a phase IV study and is considered low intervention due to the use of authorized medications with established safety and efficacy profiles. The trial is expected to commence recruitment on March 1, 2024, and conclude by March 1, 2027.

Participants will be randomly assigned to receive either IV iron in the form of **ferric carboxymaltose** or oral iron, specifically **dried ferrous sulfate** or a combination of **ascorbic acid and ferrous sulfate**. The trial will involve a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, cesarean delivery, and specific hematological parameters. The primary endpoint is the prevalence of postpartum depression symptoms at 8 weeks postpartum, assessed using the Edinburgh Postpartum Depression Scale (EPDS).

Study visits will include the initial screening, followed by treatment administration and monitoring visits. Participants will be assessed at 8 weeks postpartum for primary and secondary endpoints, including hemoglobin levels, serum ferritin, and EPDS scores. The end-of-study visit will occur at 6 months postpartum to evaluate long-term outcomes such as persistent postpartum depression and maternal-infant bonding. The expected duration of participant involvement is up to 6 months, with treatment compliance monitored over an 8-week period. Conditions that may lead to early termination from the study include adverse reactions to the treatment or withdrawal of consent by the participant.

The clinical trial involves the administration of three distinct treatments to evaluate their effects on postpartum depression in women with moderate iron deficiency anemia following a caesarean delivery. The first treatment is **TIMOFEROL 50 mg**, a **coated tablet** containing **dried ferrous sulfate** as the active substance. This pharmaceutical form is administered **orally** with a maximum daily dose of **50 mg** and a total dose not exceeding **2800 mg** over a treatment period of up to **8 weeks**. The product is manufactured by **Laboratoire des Réalisations Thérapeutiques Elerte** and is not a pediatric formulation.

The second treatment is **TIMOFEROL, gélule**, a **hard capsule** formulation containing a combination of **ascorbic acid** and **ferrous sulfate**. Similar to the first treatment, it is administered **orally** with a maximum daily dose of **50 mg** and a total dose limit of **2800 mg** over a maximum treatment period of **8 weeks**. This product is also produced by **Laboratoire des Réalisations Thérapeutiques Elerte** and is not intended for pediatric use.

The third treatment is **Ferinject 50 mg/ml**, a **dispersion for injection/infusion** containing **ferric carboxymaltose** as the active ingredient. This treatment is administered via **injection** with a maximum daily and total dose of **1000 mg** over a single treatment period of **1 week**. The product is manufactured by **Vifor France** and is not formulated for pediatric use. This treatment serves as the test product in the trial, while the oral formulations of TIMOFEROL act as comparator treatments.

Efficacy in the clinical trial titled "Treatment of anaemia after caesarean with intravenous versus oral iron and postpartum depression: a multicentric randomized open-labelled controlled trial (IRON-DEP)" will be assessed using both primary and secondary endpoints. The primary endpoint is the prevalence of postpartum depression (PPD) symptoms at 8 weeks postpartum, defined by an Edinburg Postpartum Depression Scale (EPDS) score of 11 or higher, measured through a self-assessment questionnaire.

Secondary endpoints include various parameters measured at 8 weeks postpartum, such as the average hemoglobin (Hb) level, the proportion of women with Hb levels below 12.0 g/dL, mean serum ferritin levels, and the proportion of women with serum ferritin below 20 ng/mL. Additionally, the average change in Hb level from inclusion to 8 weeks postpartum will be evaluated. The average EPDS score, the proportion of patients with symptoms of moderate depression (EPDS score between 11 and 13), and marked depression (EPDS score of 13 or higher) will also be assessed. Other secondary endpoints include the need for a transfusion of packed blood cells during the 8 weeks postpartum and the average fatigue score measured by the Multidimensional Fatigue Inventory score-20 (MFI-20).

Further assessments at 6 months postpartum will include the occurrence of long-term PPD, evaluated by the proportion of women with an EPDS score of 11 or higher, the average EPDS score, and the average change in the EPDS score between 8 weeks and 6 months postpartum. The average fatigue score (MFI-20) and its variation between 8 weeks and 6 months postpartum will also be measured. Additionally, the bond between mother and child will be assessed using the Mother-Infant Bonding Scale (MIBS).

Immune reactions during intravenous iron administration and up to 30 minutes after stopping it, as well as skin pigmentation secondary to intravenous iron extravasation within 8 weeks of delivery, will be monitored. Gastrointestinal side effects in both the intravenous and oral iron groups, such as constipation, abdominal pain, dyspepsia, muscle cramps, nausea, and vomiting, will be recorded within 8 weeks postpartum. Treatment compliance will be evaluated by determining if more than 80% of the prescribed treatment was taken during the 8 weeks of treatment. The estimated total cost of healthcare use will be assessed at inclusion, 8 weeks, and 6 months postpartum using the EQ-5D-5L.