Simplified Treatment for Eclampsia Prevention using Magnesium sulfate

Introduction: The primary objective is to evaluate the non-inferiority of a simplified magnesium sulfate regimen [10 g intramuscular (IM) 12 hourly x 2 doses] compared with a standard magnesium sulfate regimen [either 4g intravenous (IV) loading dose, followed by a maintenance dose of 1g/hour until 24 hours (“Zuspan regimen”) or 4g IV plus 10 g IM loading dose, followed by 5 g IM 4 hourly until 24 hours (“Pritchard regimen”)] for the prevention of maternal eclamptic seizure.

Methods  and materials

This will be a phase III, multicountry, multicentre, two-arm, parallel, open-label, active-controlled, randomized, non-inferiority trial.  The study population will be women diagnosed with pre-eclampsia and with a clinical or laboratory indication for magnesium sulfate treatment before giving birth or within 24 hours of giving birth. Eligible, consenting women will be randomized to receive either 10 g of magnesium sulfate IM 12 hourly x 2 doses or a standard IV (Zuspan) or standard IM (Pritchard) magnesium sulfate regimen depending on the standard treatment protocol in the participating hospitals.  Standard IV regimen will be 4g IV as loading dose, followed by IV infusion of 1g per hour for 24 hours whereas standard IM regimen will be administered as 4g IV plus 10 g IM loading dose, followed by 5 g IM every 4 hours for 24 hours. Outcome measurements will be conducted in women and their babies until the time of hospital discharge or transfer to a higher care unit or death. The primary outcome will be the occurrence of maternal eclamptic seizure. Statistical methods: In order to demonstrate non-inferiority within a margin of 0.51%, with a power of 80% and with a significance level of 2.5%, a total of 11,596 women (5,798 per group) are needed assuming equal eclampsia prevalence of 0.97% in the standard treatment group and the simplified treatment group. Assuming 3% drop-outs due to exclusion of women after randomization and those who are not protocol-compliant, the estimated sample size will be 11,959 women. The first interim analysis will be conducted for the Data Safety Monitoring Committee (DSMC) to assess safety and futility when 2400 women (1200 per arm) have been recruited. Second interim analysis will be conducted when 6000 women (3000 per arm) have been recruited to assess safety, efficacy, and futility. Final noninferiority analysis will be performed when total sample size of 12000 women is achieved.

Utility

Lack of resources to administer IV medication and provide supportive care and/or repeated IM administration of magnesium sulfate may be associated with pain due to the large volume for injection and risk of infection at the injection site. These challenges have turned the attention of health care workers towards seeking and testing alternative dosage regimens for magnesium sulfate. This approach has largely been driven by the intention to improve coverage of a life-saving treatment for women with pre-eclampsia, minimize potential adverse effects, reduce resources that are required for administering the complex standard regimens, and to encourage task sharing among health care providers where necessary