Evaluation of Prednisolone Efficacy in Women with Unexplained Recurrent Miscarriages: A Randomized, Placebo-Controlled Trial

The primary objective of the PREMI trial is to assess the effect of **prednisolone** administration during early pregnancy in women with unexplained recurrent miscarriages, with a specific focus on the live birth rate as the primary outcome measure. This is clinically relevant as it aims to determine whether prednisolone can improve pregnancy outcomes in this patient population, potentially offering a therapeutic option for a condition with limited treatment strategies.

Secondary objectives include evaluating the ongoing pregnancy rate, the miscarriage rate, and assessing side-effects and adverse events such as congenital birth defects, low birth-weight, and maternal side-effects. These secondary outcomes are crucial for understanding the broader implications of prednisolone use in this context, ensuring a comprehensive evaluation of both efficacy and safety.

The clinical trial focuses on women aged 18 to 39 who have experienced **unexplained recurrent miscarriages**. The study population is exclusively female, with no male participants included. Participants are selected based on having had two or more miscarriages, excluding molar and ectopic pregnancies, and no underlying cause for these miscarriages was identified after examination. The trial does not provide information on the total number of participants. The sponsor has not disclosed any specific lifestyle considerations such as diet or physical activity. The trial population is considered vulnerable, given the sensitive nature of the medical condition being studied. The sponsor has not provided further details regarding the selection process or additional criteria beyond those mentioned.

The clinical trial is designed to evaluate the efficacy of **prednisolone** administration during early pregnancy in women experiencing unexplained recurrent miscarriages. This study is structured as a randomized, double-blind, placebo-controlled trial, ensuring that neither the participants nor the researchers know who is receiving the active treatment or the placebo, thus minimizing bias. The trial is expected to span from October 2023 to July 2027, with the primary outcome measure being the live birth rate.

Participants will undergo a series of study visits, beginning with an inclusion visit where eligibility is confirmed based on criteria such as age (18-39 years), a history of two or more miscarriages, and the absence of an identified underlying cause for these miscarriages. Following the inclusion visit, participants will be randomly assigned to receive either **prednisolone** or a placebo, administered orally. The treatment period will last up to eight weeks, with a maximum daily dose of 20 mg and a total dose not exceeding 945 mg for **prednisolone**.

Throughout the trial, participants will attend regular follow-up visits to monitor their health and the progress of the pregnancy. These visits are crucial for collecting data on the primary and secondary endpoints, ensuring participant safety, and assessing the treatment's effectiveness. The end-of-study visit will occur after the last study subject has completed their final visit, and all necessary data has been gathered.

Participant involvement is expected to last for the duration of the pregnancy, with the possibility of early termination from the study if advised by the Data Safety Monitoring Board (DSMB) due to feasibility issues, slow inclusion rates, or safety concerns. The trial's success will be determined by the completion of all planned visits and the collection of comprehensive data, contributing valuable insights into the management of unexplained recurrent miscarriages.

The clinical trial involves the administration of **prednisolone**, a corticosteroid, as the experimental medication. Prednisolone is provided in tablet form, with each tablet containing the active substance **prednisolone**. The route of administration is oral, and the maximum daily dose is 20 mg. The total maximum dose over the treatment period is 945 mg for one group and 940 mg for another, with a maximum treatment period of 8 weeks. The trial aims to evaluate the effect of prednisolone on the live birth rate in women with unexplained recurrent miscarriages.

The study also includes a **placebo** as a comparator treatment. The placebo is formulated as a tablet, composed of an in-house base granulate serving as a binding and filling agent, talc as a glidant, and magnesium stearate as a lubricant. The base granulate is made from lactose, potato starch, and gelatine spirit. Talc is heated to 250°C for 30 minutes to eliminate spores of **Clostridium tetani**. The placebo is administered orally, mirroring the administration schedule of the experimental medication to maintain blinding and ensure the integrity of the trial results.

The efficacy of the clinical trial titled "Prednisolone administration in women with unexplained REcurrent MIscarriages" will be assessed by evaluating the primary outcome measure, which is the live birth rate. This trial aims to compare the effect of **prednisolone** administration during early pregnancy with a placebo in women experiencing unexplained recurrent miscarriages. The primary endpoint for efficacy assessment is defined as the completion of the last visit by the last study subject, with all data gathered. Secondary endpoints include recommendations from the Data Safety Monitoring Board (DSMB) to stop the trial due to feasibility issues, slow inclusion rates, or safety concerns.