Evaluation of Hydroxychloroquine Sulfate on Pregnancy Outcomes in Women with Antiphospholipid Antibodies: A Randomized Controlled Trial

The primary objective of the HYPATIA trial is to evaluate the effect of **hydroxychloroquine** (HCQ) on pregnancy outcomes in women with **antiphospholipid antibodies**. This is clinically relevant as antiphospholipid syndrome (APS) is associated with adverse pregnancy outcomes, and HCQ may offer a therapeutic benefit in improving these outcomes.

Secondary objectives include the collection of blood samples for pharmacokinetic and biomarker studies. These studies aim to provide insights into the drug's behavior in the body and its potential biological effects, which could further inform treatment strategies for women with APS.

The clinical trial focuses on evaluating the effect of hydroxychloroquine (HCQ) on pregnancy outcomes in women with **antiphospholipid antibodies**. The study population comprises exclusively female participants, specifically women with known antiphospholipid antibodies (aPL) or **antiphospholipid syndrome** (APS) who are planning pregnancy. The age range of the participants is categorized under code 3, which typically includes adults. The trial does not include male subjects or vulnerable populations. Participants were selected based on the presence of a positive test for anticardiolipin antibodies, lupus anticoagulant, or anti-beta 2 glycoprotein-I, confirmed on two or more occasions more than 12 weeks apart, with the last positive test within 12 months of study entry. Written informed consent was required for participation. The sponsor has not provided information regarding the total number of participants or specific lifestyle considerations such as diet or physical activity.

The clinical trial is designed as a **randomized**, **controlled**, and **double-blind** study to evaluate the efficacy of **hydroxychloroquine sulfate** in improving pregnancy outcomes in women with **antiphospholipid antibodies**. The trial will involve the administration of **hydroxychloroquine sulfate 200 mg film-coated tablets** or a placebo, with the active treatment being administered orally. The study is set to commence recruitment on April 1, 2023, and is expected to conclude by December 31, 2027. The trial will span a maximum treatment period of 21 days for each participant.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on the presence of antiphospholipid antibodies and other criteria. Following the screening, participants will be randomized to receive either the active treatment or placebo. The primary endpoint of the study is a composite of adverse pregnancy outcomes related to antiphospholipid antibodies, including pregnancy loss and premature birth. Secondary endpoints include various measures of neonatal and maternal health outcomes.

Study visits will include regular follow-up assessments to monitor the safety and tolerability of the treatment, as well as to collect data on pregnancy outcomes. The end-of-study visit will occur after the completion of the treatment period and will involve a comprehensive evaluation of both maternal and neonatal health. Participants are expected to be involved in the study for the duration of their pregnancy and up to six weeks postpartum. Conditions that may lead to early termination from the study include withdrawal of consent, significant adverse events, or any condition that, in the opinion of the investigator, warrants discontinuation of the study drug.

The clinical trial involves the administration of **Hydroxychloroquine sulfate** 200 mg film-coated tablets, which serve as the experimental medication. The active substance, **hydroxychloroquine sulfate**, is of chemical origin and is provided by Zentiva Pharma UK Limited. The pharmaceutical form of the medication is a film-coated tablet, designed for **oral use**. The maximum daily dose is 200 mg, with a total maximum dose of 128,000 mg over a treatment period of 21 days. The administration schedule is structured to ensure consistent dosing, and participant compliance is monitored throughout the trial to maintain adherence to the prescribed regimen.

The study also includes a **placebo** as a non-experimental treatment. The placebo is a white, circular, biconvex tablet, debossed with "200" on one side and plain on the other. It is used to provide a comparator treatment, ensuring the integrity of the trial's double-blind design. The placebo does not contain any active pharmaceutical ingredients and is administered in a manner identical to the experimental medication to maintain blinding. Compliance with the placebo administration is similarly monitored to ensure the reliability of the trial outcomes.

Efficacy in the clinical trial titled "HYPATIA: A prospective randomised controlled trial of HYdroxychloroquine to improve Pregnancy outcome in women with AnTIphospholipid Antibodies" will be assessed using both primary and secondary endpoints. The primary endpoint is a composite measure of three principal adverse pregnancy outcomes related to **antiphospholipid antibodies (aPL)**: one or more pregnancy losses (either before 10 weeks of gestation or beyond 10 weeks of gestation of a morphologically normal fetus as documented by ultrasound or direct examination) and premature birth of a morphologically normal neonate before 34 weeks due to preeclampsia, eclampsia, or recognized features of placental insufficiency.

Secondary endpoints include a range of pregnancy and neonatal outcomes such as pregnancy loss before 10 weeks, pregnancy loss beyond the 10th week of a morphologically normal fetus, premature birth of a morphologically normal neonate before 34 weeks due to specific conditions, gestational age at delivery, birth weight, delivery by Caesarean section, Apgar score less than 7 at 5 minutes, neonatal morbidity including bleeding or thrombotic complications, infections, congenital abnormalities, days to hospital discharge for mother and child, thrombotic events in the mother during pregnancy and up to 6 weeks postpartum, days of neonate in special care, and the safety and tolerability of hydroxychloroquine in both the mother and the neonate.