Preeclampsia Intervention 4 – A double blind phase III randomised controlled trial assessing metformin to prolong gestation in preterm preeclampsia

The primary objective of this study is to evaluate whether the administration of 3 grams of **metformin** ER daily can effectively prolong gestation in pregnancies complicated by preterm **preeclampsia** diagnosed between 22+0 and 33+6 weeks in women undergoing expectant management, compared to placebo. Prolonging gestation in such cases is clinically significant as it may reduce neonatal morbidity and mortality associated with preterm birth.

Secondary objectives include:

• Determining whether 3 grams of metformin ER daily can reduce the time from birth to discharge from neonatal care in neonates born to women with preterm preeclampsia, compared to placebo.
• Assessing whether 3 grams of metformin ER daily can increase neonatal birthweight in neonates born to women with preterm preeclampsia, compared to placebo.

The clinical trial focuses on a study population comprising **pregnant women** diagnosed with **preeclampsia**. The participants are exclusively female, aged 18 years and older, with a gestational age ranging from 22+0 to 33+6 weeks, carrying a singleton pregnancy. The trial involves women undergoing expectant management, where delivery is not anticipated within 48 hours. The sponsor has not provided the total number of participants. The selection criteria include a confirmed diagnosis of preeclampsia by the attending clinician and written consent from the participant. The trial does not specify any particular lifestyle considerations such as diet or physical activity. The study population is considered vulnerable due to the nature of the condition and the gestational period involved.

The clinical trial is designed as a **randomized**, **double-blind**, **controlled** study to evaluate the efficacy of **metformin hydrochloride** in prolonging gestation in pregnancies complicated by preterm **preeclampsia**. The trial will involve the administration of 3 grams of metformin ER daily, compared to a placebo, in women diagnosed with preterm preeclampsia between 22+0 and 33+6 weeks of gestation. The primary endpoint is the prolongation of gestation, measured from randomization to delivery. Secondary endpoints include the length of neonatal stay and neonatal birthweight.

Participants will be involved in the study from the screening visit through to the end-of-study visit, with the estimated trial duration extending until March 31, 2028. The inclusion visit will confirm eligibility based on criteria such as a confirmed diagnosis of preeclampsia, gestational age, and the decision for expectant management. Follow-up visits will monitor the health of the mother and fetus, adherence to the treatment regimen, and any adverse events. The end-of-study visit will occur after delivery to assess the primary and secondary endpoints.

Participant involvement is expected to last until delivery, with the possibility of early termination if delivery is anticipated within 48 hours, or if any safety concerns arise. The trial will commence recruitment on August 1, 2023, and will continue until the required sample size is achieved. The study is not classified as low intervention and is categorized as a Phase III trial, ensuring rigorous assessment of the intervention's efficacy and safety.

The clinical trial involves the administration of **Glucophage SR 500mg prolonged release tablet**, which contains the active substance **metformin hydrochloride**. This medication is formulated as a prolonged-release tablet, designed to be taken orally. The dosage regimen for the trial specifies a maximum daily dose of 3 grams, with a total maximum dose of 315 grams over the treatment period. The treatment duration is set for a maximum of 15 days. The pharmaceutical product is manufactured by Merck Serono Limited and is authorized under the marketing authorization number PL 11648/0054 in the United Kingdom. The trial aims to assess the efficacy of metformin in prolonging gestation in pregnancies complicated by preterm preeclampsia.

In addition to the experimental treatment, the study includes the use of a placebo, identified as **Glucophage XR 500 mg RM Placebo**. The placebo is designed to match the experimental medication in appearance and administration route, ensuring the double-blind nature of the trial. The placebo is administered orally, in a manner consistent with the experimental treatment, to maintain the integrity of the study's control group. The placebo does not contain any active pharmaceutical ingredients and serves as a comparator to evaluate the effects of the metformin treatment.

Efficacy in this clinical trial will be assessed by evaluating the primary and secondary endpoints. The primary endpoint is the **prolongation of gestation**, which is defined as the duration in days and hours from randomization to delivery. This measurement will consider pregnancies with intrauterine fetal demise as interval censored, calculated from the time of randomization to the last visit before delivery when the fetus was confirmed to be alive, and from randomization to delivery.

Secondary endpoints include the length of neonatal stay and neonatal birthweight. The length of neonatal stay is measured in days and hours from birth to discharge from neonatal care, encompassing both hospital and home-based care. If the infant is not admitted to neonatal care, the length of stay will be recorded as zero. Neonatal birthweight will be measured in grams.