Open-labelled randomised controlled trial of 12 hours versus 24 hours modified Pritchard regimen in the management of eclampsia and pre-eclampsia in Ghana (MOPEP Study): Study protocol

Introduction Hypertensive disorders of pregnancy continue to be a major contributor to maternal and perinatal morbidity and mortality. Magnesium sulfate therapy is the standard of care for seizure prophylaxis and treatment for pre-eclampsia and eclampsia respectively, despite wide disparities in dosing regimens and routes of administration. This study compares the clinical efficacy of magnesium sulfate in the reduction of seizure occurrence or recurrence with the 12 hours versus 24 hours modified Pritchard regimens in the management of severe pre-eclampsia and eclampsia. Methods and analysis This study is an open labelled randomised controlled trial. The study participants are patients admitted to the Korle Bu Teaching Hospital (KBTH) in Accra, Ghana with a diagnosis of antepartum, intrapartum or postpartum eclampsia or pre-eclampsia with severe features. All study participants will be administered a loading dose of magnesium sulfate, followed by maintenance dosing. Participants in the control group will receive magnesium sulfate for 24 hours after diagnosis, while those in the treatment group will receive magnesium sulfate for 12 hours after diagnosis. The primary outcome of this study is the occurrence of a seizure any time after the completion of treatment in the assigned group. Secondary outcome measures include maternal health outcomes, magnesium sulfate toxicities and fetal health outcomes. Data collection was started in October 2018 with a target enrolment of 1245 participants with severe pre-eclampsia and 844 participants with eclampsia with a projected study period of 2-3 years. Ethics and dissemination Ethical approval was obtained from the KBTH Institutional Review Board (IRB) in Ghana. University of Michigan involvement is limited to protocol development and statistical analysis of de-identified data, and has been granted a Not Regulated Determination by the University of Michigan IRB. Results of the study will be shared at clinical forums at the KBTH and will be submitted for publication in an international peer-reviewed journal. Trial registration number Pan African Clinical Trial Registry through the South African Medical Research Council (PACTR201811515303983). An open-labelled randomised controlled trial in which the study arm will receive 12 hours of maintenance doses of magnesium sulfate and the control arm will receive 24 hours of maintenance doses of magnesium sulfate. Participants will be enrolled into study groups by simple randomisation using a computerised random number generation table. The KBTH is the country’s premier teaching hospital and serves as a national referral hospital for the southern half of the country. It is a tertiary hospital with a bed capacity of 2000 and an average daily outpatient department attendance of 1500 patients. The maternity unit conducts about 9500 deliveries per year. Current standard of care at KBTH is a modified Pritchard regimen of magnesium sulfate, with administration of a loading dose followed by 24 hours of maintenance dosing, starting at the time of diagnosis of eclampsia or pre-eclampsia with severe features. Accra is a cosmopolitan city with people of varied ethnic backgrounds and social status. It is expected that the sample will represent this diversity and be reflective of the nation. Participants will be patients receiving their prenatal care at KBTH, as well as referral cases from peri-urban and rural communities around Accra. An occurrence of a seizure is the primary outcome. In women with eclampsia, this will be a recurrent seizure and in women with pre-eclampsia with severe features, this will be their initial seizure. Regarding eclampsia, we assume that the recurrent seizure rate of women receiving 12 hours of magnesium will be halfway between the seizure rate of women receiving 24 hours of magnesium (13.2%) and women receiving no magnesium (27.9%) at 20.6%.17 To detect a difference between 20.6% recurrent seizure in the 12 hours group and 13.2% recurrent seizure in the 24 hours group, a total sample size of 804 (402 in each group) is needed, assuming a two-sided test, 5% significance level and 80% statistical power. Regarding pre-eclampsia, in the subgroup analysis of the Magpie Trial, women with severe pre-eclampsia have a 1.1% rate of seizure if treated with 24 hours of magnesium.10 In our current study, with a high-risk population, we anticipate a 6% rate of seizures in women who receive no magnesium based on study site department data. In absence of data from the literature, we assume that the seizure rate of women receiving 12 hours of magnesium will be halfway between the seizure rate of women receiving 24 hours of magnesium (1.1%) and women receiving no magnesium (6%) at 3.55%. To detect a difference between 3.55% seizures in the 12 hours group and 1.1% seizures in the 24 hours group, a total sample size of 1186 (593 in each group) is needed, assuming a two-sided test, 5% significance level and 80% statistical power. Assuming 5% lost to follow-up and intervention discontinuation, 844 women with eclampsia (422 in each group) and 1245 women with severe pre-eclampsia (623 in each group) were recruited. See figure 1 for Consolidated Standards of Reporting Trials (CONSORT) flow chart. Recruitment and enrolment. CONSORT flow diagram outlining participant flow through each stage of the randomised controlled trial (intervention allocation, follow-up and data analysis). CONSORT, Consolidated Standards of Reporting Trials. Conceptualisation and securing of appropriate Institutional Review Board (IRB) approvals and funding and organisation of trial materials lasted 18 months. Trial recruitment and follow-up is estimated to last 2–3 years starting October 2018. All women admitted to the maternity ward of KBTH as an antepartum, labouring or postpartum patient will be assessed by the on-call obstetric resident according to the standard clinical practice. Based on initial history and physical examination, vitals signs and laboratory values, clinical diagnoses will be made by the on-call obstetric team. If a patient has a clinical diagnosis of eclampsia or pre-eclampsia with severe features, she will be identified as a potential study participant. The on-call resident will review study inclusion and exclusion criteria. If a woman meets inclusion criteria, a research assistant will be notified to confirm inclusion/exclusion criteria and obtain informed consent (see consent form in suppplementary file). Participants will be enrolled into study groups by simple randomisation using a computerised random number generation table (Random Number Generator V.3.0.56 for Mac). Using the table of random sequence of numbers (1 vs 2), sequentially numbered printed data collection forms will be labelled (1=control group; 2=treatment group) by researcher TB. After a participant is recruited and consented by the research assistant, the research assistant will be given the next numbered data collection form indicating the randomisation group. The research assistants are not involved in the randomisation process and do not have access or knowledge of the next treatment allocation. A sticker will be placed on the participants’ chart to notify her clinical team of her participation and group assignment. The research assistant will commence data collection by extracting relevant demographic and clinical data, such as medical history, past obstetric history and history of the index pregnancy from the participant’s antenatal record and supplemented by direct interview of participants. During the hospitalisation, we will prospectively document events such as timing of magnesium sulfate doses, timing of any seizures, mode and timing of delivery, maternal complications and magnesium sulfate toxicities. Neonatal information will be collected, including gestational age at delivery, birth weight, outcome of delivery (live birth vs stillbirth), neonatal intensive care unit (NICU) admission, APGAR score at 1 and 5 min and status at discharge (alive vs dead). According to the standard protocol at KBTH, all participants will have a detailed history and physical examination done at the time of admission. Complete blood counts, clotting profile, liver and renal function tests and urine protein measurements will be performed. Strict fluid input and output monitoring will be done and recorded on the study fluids chart. All patients will have urethral catheterisation retained for continuous bladder drainage until the last dose of the magnesium sulfate. All participants will be monitored for the entire duration of MgSO4 treatment by the on-call obstetrics team at least every 4 hours for blood pressure, patellar reflexes, respiratory rate, urine output and occurrence of seizures. After completion of the MgSO4 injections, patients will have their blood pressure monitored every 4 hours until normalisation of blood pressure, and subsequent discharge. Apart from the duration of magnesium sulfate administration, all other clinical management of study participants will be carried out by the attending on-call obstetrician in accordance with the standard institutional care protocol at KBTH. This includes administration of antihypertensives, decision on timing and mode of delivery, induction of labour and initiation and interpretation of fetal monitoring. All doses of magnesium sulfate will be prepared and verified by the KBTH in accordance with standard hospital protocols. The loading doses will be constituted as 8 mL of 50% solution diluted with 12 mL of sterile saline to obtain 20 mL of 4 g MgSO4, to be administered slowly over 15–20 min. Maintenance doses will be constituted as 10 mL of 50% MgSO4 solution to obtain 5 g of MgSO4, to be given as deep intramuscular injection. All doses of magnesium sulfate will be administered by clinical hospital nursing staff in accordance with standard hospital protocols. The occurrence of a seizure after completion of the third maintenance doses (MD3) and sixth maintenance doses (MD6) for the study and control groups, respectively will be regarded as a treatment failure. These patients will have the 24 hours modified Pritchard protocol restarted and completed if clinical assessment permits further magnsium sulfate therapy. After treatment failure, the management of further magnesium Sulfate is at the clinical discretion of the attending on-call obstetrician. The occurrence of clinical evidence of toxicity (absent tendon reflexes, respiratory depression, coma) after initiation of maintenance doses that necessitate discontinuation of further maintenance doses will also be regarded as a treatment failure. In the case of MgSO4 toxicities, the plan of management will be to stop further administration of MgSO4 and inject 1 g of calcium gluconate (10 mL of 10% solution) intravenously. The decision to reinitiate magnesium Ssulfate is at the clinical discretion of the attending on-call obstetrician. The primary outcome of this study will be the clinical efficacy of the magnesium sulfate regimen, defined as the absence of a seizure any time after the completion of the MD3 until discharge in the treatment (12 hours) group and after the completion of the MD6 until discharge in the control (24 hours) group. Secondary outcome measures include: Maternal: Neonatal: Data will be entered into REDCap and analyses will be carried out using STATA. Primary study aim is to determine whether use of the 12 hours versus 24 hours modified Pritchard regimens of magnesium sulfate impact occurrence of seizure. First, bivariate analysis will be performed to determine whether there are baseline differences between conditions (12 hours regimen, 24 hours regimen) in terms of demographics, obstetric history, medical history and index pregnancy. Comparisons across regimens will be performed using independent samples t-tests for normally distributed continuous variables, Wilcoxon rank test for non-normally distributed continuous variables and χ2 and Fisher’s exact tests, where appropriate in the case of categorical variables. Next, the primary outcome of occurrence of a maternal seizure will be examined. Given the categorical nature of this outcome variable (yes seizure, no seizure), χ2 test of independence will be used to determine whether the probability of experiencing a seizure across conditions. Finally, analyses will be conducted to assess secondary maternal and neonatal outcomes. In the case of continuous outcome variables independent samples t-tests will be conducted to assess whether condition predicts the continuous secondary outcome of interest. In the case of categorical outcome variables, χ2 tests of independence will be conducted to determine whether the incidence of the categorical secondary outcome of interest differed by condition. For all analyses, Fischer’s exact test will be used instead of a χ2 test of independence should the incidence of an outcome occur in less than five individuals per condition and (Bonferroni) corrections will be applied to correct for multiple comparisons. Number needed to treat and number needed to harm will be calculated for primary and secondary outcomes. All tests will be two-tailed. Of note, outcome data will be collected for participants who discontinue or deviate from intervention protocols. With approval from the IRB through the KBTH, Dr Titus Beyuo (primary author) will oversee the management of data collection and data safety at KBTH in Accra, Ghana. Patients’ data collection forms will be initially identified by their ‘folder number’ as given at their KBTH admission, as well as their name. This will allow subsequent data collection and integration throughout their hospital course, as well as data quality control as needed. Data collection forms will only be used and accessed by authorised study co-investigators and research assistants. Data recorded on paper data collection forms will be reviewed by Dr Titus Beyuo and then entered into a secure electronic data organisation programme (REDCap) using a password protected computer. Only authorised study coinvestigators and research assistants will have access to this computer. The information entered into REDCap will only include unique study numbers and will not include participants names or any other personal identifying information. The paper data collection forms will be stored securely in a locked cabinet in a locked office in the Obstetrics and Gynecology Department at KBTH, under the direction of Dr Titus Beyuo. The records (data collection sheets) will be retained for the entire duration of the study, during which data will be accessible only by authorised investigators. After complete cleaning and quality assurance, identification numbers will be replaced by simple sequence numbers. This de-identified data will be exported from REDCap into STATA for statistical analysis. All authors will have access to the final study dataset. Monitoring for quality and regulatory compliance will be overseen by the KBTH Scientific and Technical Committee in Ghana. An independent Data and Patient Safety Board was established at KBTH, consisting of Professor K. Nkyekyer (consultant obstetrician and chairman), Professor K.A. Bugyei (clinical pharmacologist and member) and Dr Ayegua Hagan (statistician and member). The Data and Patient Safety Board was created to assess the progress of the clinical study, and will review cumulative study data to evaluate safety, study conduct and scientific validity and integrity of the study. Adverse events (anaphylaxis, allergic reaction to MgSO4, respiratory depression, coma) and severe adverse events (maternal morbidity or mortality secondary to anaphylaxis, allergic reaction to MgSO4, respiratory depression, coma) will be collected by the principal investigator, Dr Beyuo, and reported to the Data and Patient Safety Review Board. Dr Beyuo will also be responsible for communicating any adverse event or protocol modifications on behalf of the investigators to the Data and Patient Safety Board and the IRB. The study may be terminated ahead of schedule on recommendation of the Data and Patient Safety Board or by the IRB or by the investigators if interim analysis (planned for 6 months after initiation of study) shows greater than 1% difference in recurrent fits between the study and control arms. This research was done without patient involvement. Patients were not invited to comment on the study design, interpret results or contribute to the writing or editing of this document.