Randomized, Double-Blind, Placebo-Controlled Trial of Hydroxychloroquine Sulfate in Women with Recurrent Pregnancy Loss

The primary objective of this study is to evaluate the difference in **live birth rate (LBR)** among women with **Recurrent Pregnancy Loss** (RPL) who are treated with **Hydroxychloroquine (HCQ)** compared to those receiving a placebo. This is assessed using an Intention to Treat (ITT) analysis, which includes all participants regardless of adherence to the treatment protocol. The clinical relevance of this objective lies in its potential to provide evidence for a therapeutic option that could improve LBR in women experiencing RPL, a condition associated with significant emotional and physical burden.

Secondary objectives include:

• Assessing the difference in LBR for women treated with HCQ versus placebo, excluding cases of pregnancy loss due to chromosome abnormalities, ectopic pregnancy, neglect of treatment, induced abortion, or early withdrawal from treatment (Per Protocol (PP) analysis).
• Evaluating birth weight, duration of pregnancy, Apgar score five minutes after birth, and the number of days admitted to a neonatal department. This aims to determine if HCQ treatment can reduce preterm birth, perinatal morbidities, and low birth weight, or if it increases perinatal complications compared to placebo.
• Investigating immune and inflammatory profiles in women treated with HCQ versus placebo, and comparing women with live births to those with another pregnancy loss. This includes analyzing pre-pregnancy inflammatory levels to identify high responders and understanding pregnancy complications to identify high-risk groups early.
• Monitoring metabolic activity using ultra-low dose FDG-PET/CT scans in a sub-study, focusing on the uterus and immune-related tissues such as bone marrow, spleen, thymus, and lymph nodes, to correlate metabolic activity with inflammation grade.

The clinical trial focuses on women experiencing **Recurrent Pregnancy Loss** (RPL), specifically targeting those with a history of unexplained RPL. The study population comprises exclusively female participants, as male subjects are not included. The age range of participants is categorized under code "3," which typically represents adults, although specific age details are not provided. The trial does not involve a vulnerable population. Participants were selected based on their history of confirmed consecutive pregnancy losses, with criteria including at least four losses prior to gestational age 22+0 or at least three losses with a minimum of one occurring in the second trimester. The sponsor has not provided information regarding the total number of participants or specific lifestyle considerations such as diet or physical activity. The trial aims to assess the difference in live birth rate among women treated with Hydroxychloroquine compared to those receiving a placebo, following an intention-to-treat analysis.

The clinical trial is designed to evaluate the efficacy of **hydroxychloroquine sulfate** in treating **Recurrent Pregnancy Loss**. This is a randomized, double-blind, placebo-controlled trial, which aims to monitor the difference in live birth rate among women treated with hydroxychloroquine compared to those receiving a placebo. The trial will include 186 women who meet the inclusion criteria of having experienced at least three or four confirmed consecutive pregnancy losses prior to gestational age 22+0, with specific conditions regarding second-trimester losses. The trial is set to conclude after the inclusion and follow-up of these participants, which will extend to either a pregnancy loss or six months post-live birth.

The trial is expected to run from April 1, 2017, to December 31, 2027. Participants will be involved in the study for a maximum treatment period of 80 days, with a daily dose of 200 mg of hydroxychloroquine administered orally. The study visits will include an initial screening visit to confirm eligibility, followed by regular follow-up visits to monitor the participants' health and pregnancy status. The end-of-study visit will occur after the completion of the follow-up period. Participants who become pregnant less than two months after starting the medication or do not achieve pregnancy within one year will be replaced 1:1 by new patients.

Conditions that may lead to early termination from the study include non-compliance with the study protocol, adverse reactions to the medication, or withdrawal of consent by the participant. The trial is categorized as a Phase 4 therapeutic exploratory trial, and it is not considered a low-intervention study. The primary endpoint is the live birth rate, and the trial will employ an intention-to-treat analysis to ensure comprehensive data evaluation.

The clinical trial involves the administration of **Plaquenil**, a film-coated tablet containing **hydroxychloroquine sulfate** as the active substance. The pharmaceutical form is a film-coated tablet, and the medication is administered orally. The dosage is set at 200 mg per day, with a maximum total dose of 112,000 mg over the course of the treatment period, which spans up to 80 days. The tablets are encapsulated in gelatin capsules and provided in containers of 100 units. The active substance, hydroxychloroquine sulfate, is of chemical origin and is classified under the ATC code P01BA02. The product is manufactured by SANOFI A/S and is authorized for use in Denmark.

The study also includes a placebo treatment, which consists of **lactose monohydrate**. This substance serves as the comparator treatment in the trial, providing a control for evaluating the efficacy of the experimental medication. The placebo does not have a specified pharmaceutical form or route of administration, as it is used solely for blinding purposes in the study. The role of the placebo is to ensure that the trial remains double-blind, allowing for an unbiased assessment of the treatment outcomes.

Efficacy in the clinical trial titled "Hydroxychloroquine treatment for Recurrent Pregnancy Loss: a randomized double-blind placebo-controlled trial" will be assessed by monitoring the difference in live birth rate (LBR) among women treated with **Hydroxychloroquine (HCQ)** compared to those receiving a placebo. The primary endpoint is the live birth rate, which will be evaluated through an intention-to-treat (ITT) analysis. The trial will conclude after the inclusion and follow-up of 186 women, with follow-up extending to either pregnancy loss or six months post-live birth. Women who become pregnant less than two months after starting the medication or do not achieve pregnancy within one year will be replaced on a 1:1 basis by new participants. The trial is designed to ensure comprehensive data collection and analysis to determine the efficacy of HCQ in improving live birth rates in women with recurrent pregnancy loss.