A Randomized Controlled Trial of N-Acetylcysteine in the Treatment of Early-Onset Preeclampsia: Study Protocol

Abstract

Abstract Background Despite significant advancements in obstetric care, the incidence of preeclampsia remains a substantial public health challenge, and effective strategies to prevent the disease progression remain limited, particularly in low-resource settings. N-acetylcysteine (NAC), an antioxidant and glutathione precursor, has demonstrated anti-inflammatory and vasodilatory effects, making it a promising candidate for repurposing. However, robust evidence from well-powered randomized controlled trials is lacking. Objective This study will evaluate the impact of NAC on the time-to-disease progression in pregnant women with early-onset preeclampsia in Lagos, Nigeria. Methods This is the study protocol for a proof-of-concept, double-blind, randomized, controlled trial to be conducted between April 2026 to July 2028 at the maternity units of the two teaching hospitals in Lagos, Nigeria. At baseline, n=153 sexually active women aged 18 years or older diagnosed with early-onset preeclampsia at 24 to 34 weeks’ gestation will be randomised to receive either daily oral tablet containing 600 mg of NAC or a placebo tablet that is matched for appearance and the dosing regimen in addition to standard antenatal care from diagnosis (randomisation) until either 34 weeks’ gestation or delivery, whichever comes first. The primary endpoint is the time-to-progression (in days) of early-onset preeclampsia to severe disease. The data analysis will be conducted on an intention-to-treat basis. Kaplan-Meier estimates with a Log-rank test will be used to calculate and compare the time-to-disease progression for the treatment groups, while Cox proportional hazard models with a backwards conditional method will be used to compare the primary endpoint between the treatment arms while adjusting for other covariates for precision using hazard ratios (HRs) and 95% confidence intervals (95%CIs). Subgroup analyses will also be performed to assess the differential effects of significant covariates on the impact of NAC on disease progression. Statistical significance will be reported as P <0.05. Discussion This study will evaluate the efficacy of daily oral NAC compared to placebo in treating pregnant women with early-onset preeclampsia. If proven effective, NAC could offer a safe, affordable, and scalable intervention to reduce the burden of preeclampsia, particularly in resource-constrained settings. Registration PACTR202603712049354 (24th March 2026); https://pactr.samrc.ac.za/TrialDisplay.aspx?TrialID=3571 Author Summary Preeclampsia is a serious complication of pregnancy that can lead to life-threatening outcomes for both mothers and babies, especially in low-resource settings. Although improvements in obstetric care have been made, there are still limited options to prevent the progression of early disease to more severe forms. N-acetylcysteine (NAC), a widely available and inexpensive medication with antioxidant and anti-inflammatory properties, has shown promise in early studies, but strong clinical evidence is lacking. In this study, we describe a randomized controlled trial designed to test whether NAC can slow the progression of early-onset preeclampsia in pregnant women in Lagos, Nigeria. Participants will receive either NAC or a placebo alongside standard care, and we will measure how long it takes for the disease to worsen. By using rigorous study methods, including blinding and intention-to-treat analysis, we aim to generate reliable evidence on the effectiveness of NAC in this context. If NAC is found to be effective, it could provide a safe, affordable, and scalable treatment option to improve maternal and newborn outcomes, particularly in settings where healthcare resources are limited.