<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT04501289</url>
  </required_header>
  <id_info>
    <org_study_id>FETHA/REC/VOL1/2017/482</org_study_id>
    <nct_id>NCT04501289</nct_id>
  </id_info>
  <brief_title>Low Dose Magnesium Sulphate Versus Standard Pritchard Regimen In Management Of Severe Preeclampsia/Eclampsia</brief_title>
  <official_title>Low Dose Magnesium Sulphate Versus Standard Pritchard Regimen In Management Of Severe Preeclampsia/Eclampsia: A Randomised Controlled Trial</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Adebayo Joshua Adeniyi</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Alex Ekwueme Federal University Teaching Hospital</source>
  <oversight_info>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Background - Preeclampsia/eclampsia, a pregnancy specific multi-systemic disease, is&#xD;
      associated with considerable maternal and perinatal morbidity and mortality. Prevention&#xD;
      and/or treatment of convulsion with magnesium sulphate, among others, is life-saving. Despite&#xD;
      different regimens that have been tried, the minimum effective dose of MgSO4 for the&#xD;
      prevention of eclampsia in patients with preeclampsia and treatment of convulsion in those&#xD;
      with eclampsia has not been determined.&#xD;
&#xD;
      Objectives - To compare the maternal and perinatal outcomes and maternal side effects in&#xD;
      eclamptic and preeclamptic participants treated with low dose regimen of MgSO4 with those&#xD;
      treated with the Pritchard regimen.&#xD;
&#xD;
      Materials and Methods - This will be a prospective, single blinded randomized controlled&#xD;
      study of low dose versus Pritchard regimens of MgSO4. Participants will be randomly assigned&#xD;
      to the either arm of the study. Efficacy and adverse effects of the drug on the mother and&#xD;
      baby will be noted. Data will be collated, tabulated and then statistically analysed using&#xD;
      the statistical package for social sciences (SPSS) Results - Conclusion will be drawn and&#xD;
      recommendation made from the findings in the study.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Introduction Preeclampsia complicates 5-7% of all pregnancies globally. However,&#xD;
      hospital-based studies in Nigeria have reported rates ranging between 1.2% and 6.3%, while a&#xD;
      study in Abakaliki recorded 0.99% for severe preeclampsia and 0.76% for eclampsia. Severe&#xD;
      preeclampsia and eclampsia are associated with increased maternal and perinatal morbidity and&#xD;
      mortality. The World Health Organization (WHO) estimates that about 63,000 maternal deaths&#xD;
      occur annually from preeclampsia/eclampsia and associated complications, with 98% of these&#xD;
      deaths occurring in developing countries. Perinatal adverse outcomes are usually due to&#xD;
      prematurity associated with preterm delivery, as well as intrauterine fetal death from&#xD;
      intrauterine growth restriction and placental abruption. Early recognition therefore,&#xD;
      combined with prompt management, is often required for good maternal and perinatal outcome.&#xD;
&#xD;
      The definitive treatment for severe preeclampsia or eclampsia is delivery of the placenta. In&#xD;
      affected women, positive maternal and perinatal outcomes depend on the woman having timely&#xD;
      access to a treatment package which include effective inpatient monitoring, optimal timing of&#xD;
      childbirth, presence of skilled attendant at birth and administration of antihypertensive as&#xD;
      well as anticonvulsive therapy. Of all the anticonvulsants that have been tried in the&#xD;
      management of preeclampsia and eclampsia, magnesium sulphate (MgSO4) has been established as&#xD;
      the anticonvulsant of choice both for prevention of convulsions in severe preeclampsia and&#xD;
      for prevention of recurrent convulsions in eclampsia. It has been shown to be superior to&#xD;
      diazepam, phenytoin, and lytic cocktail (a mixture of chlorpromazine, promethazine and&#xD;
      pethidine) in reducing the occurrence of eclamptic convulsion and the associated maternal&#xD;
      morbidity and mortality. It also has beneficial effects on fetuses, reducing the risks of low&#xD;
      Apgar scores in the 1st and 5th minutes, the risk of cerebral haemorrhage, as well as the&#xD;
      need for intubation and admission into newborn intensive care units.&#xD;
&#xD;
      Magnesium sulphate belongs to the class of electrolytes anti-dysrrhythmic drugs. It is a&#xD;
      sterile, non-pyrogenic concentrated solution of magnesium sulphate heptahydrate in water for&#xD;
      injection. It is administered by the intravenous (IV) or intramuscular (IM) routes as an&#xD;
      electrolyte replenisher or anticonvulsant. It has been adjudged to be the most effective,&#xD;
      safe and low-cost anticonvulsant drug for pre-eclampsia and eclampsia. Though the mechanism&#xD;
      of action is not completely understood, several hypotheses have been put forward to explain&#xD;
      its beneficial effects in patients with preeclampsia and eclampsia. These include dilatation&#xD;
      of cerebral blood vessels thereby reducing cerebral ischaemia, blockade of the&#xD;
      N-methyl-D-aspartate receptors in the brain and also causing peripheral vasodilatation.&#xD;
      However, despite its endorsement by the W.H.O. and its widespread availability, MgSO4 is&#xD;
      still underused and incorrectly administered in many low resource settings. This has been&#xD;
      discovered to be due to a number of provider factors and the complexity of treatment regimens&#xD;
      being used.&#xD;
&#xD;
      The most commonly used MgSO4 regimens are those given intramuscularly and/or intravenously&#xD;
      from the diagnosis of severe preeclampsia and eclampsia to 24 hours post delivery or post&#xD;
      last seizure episode, whichever occurs later. Though these regimens have been found to be&#xD;
      effective, they involve administering large doses of the drug. This usually leads to high&#xD;
      cost of treatment to the affected patients as well as difficulties in monitoring such&#xD;
      patients for drug toxicity (which include neurological deficit and cardiac arrest),&#xD;
      especially in developing countries where manpower and facilities are limited. Therefore,&#xD;
      several attempts have been made either to shorten the duration of administration or reduce&#xD;
      the dosage of MgSO4 with the aim of achieving optimal efficacy, while reducing the side&#xD;
      effects of the drug and the cost of management. These include those in which the loading dose&#xD;
      and maintenance doses were reduced in quantities; those involving reduction of maintenance&#xD;
      dose to 12 hours and those involving giving only the loading dose. No particular regimen has&#xD;
      been generally adopted as the minimum effective dose, although several lower doses have&#xD;
      proved to be effective. Because of their effectiveness which has been demonstrated over time,&#xD;
      it has been suggested that lower doses of MgSO4 may suffice for prophylaxis for patients with&#xD;
      severe preeclampsia as well as treatment for those with eclampsia, without jeopardising&#xD;
      efficacy.&#xD;
&#xD;
      Though the reason for the success recorded with the low dose regimen used in Dhaka was&#xD;
      attributed to the low body mass index of the population, several other studies in other&#xD;
      places with varying dosages and different weight distribution have also recorded varying&#xD;
      degrees of success. Therefore small body mass index (BMI) alone may not be enough to explain&#xD;
      the whole phenomenon. Some authorities have also shown that there is no association between&#xD;
      treatment failures and patients' BMI. or with serum magnesium levels. A systematic review in&#xD;
      Nigeria in 2016 supported the fact that there were no studies that had demonstrated the&#xD;
      lowest effective dose of MgSO4 to manage preeclampsia/eclampsia. Another systematic review&#xD;
      also recommended further studies to identify the minimum effective dose of MgSO4 for the&#xD;
      management of preeclampsia/eclampsia. Therefore, any regimen that will involve minimal cost&#xD;
      and side effects; and at the same time be as effective as the current doses being&#xD;
      administered, will go a long way in reducing the challenges of affordability of the drug and&#xD;
      that of its side effects. It is against this background that this study is being carried out&#xD;
      to compare the efficacy of a lower dose of MgSO4 in patients with severe pre-eclampsia and&#xD;
      eclampsia to that of the Pritchard's regimen among our women population with a view to&#xD;
      recommending it for use if the efficacy is found to be comparable.&#xD;
&#xD;
      Study background The study will be carried out at the Obstetric and Gynaecology division of&#xD;
      Alex Ekwueme Federal University Teaching Hospital, Abakaliki, Ebonyi State, South-east,&#xD;
      Nigeria. The department of Obstetrics and Gynaecology is one of the clinical departments in&#xD;
      the hospital. There are 52 obstetric bed spaces including antenatal and postnatal wards. The&#xD;
      department has five teams which are sub-divided into two units each. Each unit is manned by&#xD;
      at least two consultants. Resident doctors are distributed to cover all the units. The&#xD;
      department runs antenatal clinics managed by the consultants and resident doctors, assisted&#xD;
      by midwives and other health workers. Antenatal clients are booked daily on every week day&#xD;
      and are assigned consultants according to the units/teams running antenatal clinic each day.&#xD;
      The average antenatal booking is about 4,200 clients per annum, while the total antenatal&#xD;
      clinic attendance averages 21,000 per annum, with an average annual delivery rate of 3,100.&#xD;
      The department has established protocols for management of specific cases which are in&#xD;
      accordance with international best practices, and are displayed in the labour wards,&#xD;
      antenatal ward and the accident and emergency unit of the hospital. These protocols serve as&#xD;
      guides as patient care is still individualised.&#xD;
&#xD;
      For cases of severe preeclampsia and eclampsia, the departmental protocol is to stabilise the&#xD;
      patient and deliver through the most expeditious route, though considerations may be given in&#xD;
      certain cases of severe preeclampsia to allow for fetal growth for one or two weeks provided&#xD;
      maternal and fetal clinical and laboratory parameters are stable. One of the steps taken&#xD;
      during the period of stabilization is the administration of MgSO4 so as to avoid fits or its&#xD;
      recurrence. The most commonly used MgSO4 regimen in the department is the Pritchard regimen&#xD;
      in which MgSO4 is given as intravenous loading dose of 4g over 10 minutes, while 5g is&#xD;
      administered intramuscularly in each buttock statim. Then 5g of MgSO4 is then administered&#xD;
      intramuscularly every 4 hours until 24 hours after delivery or 24 hours after the last&#xD;
      seizure episode, whichever occurs later, provided no sign of toxicity from the previous dose&#xD;
      is noted. This is chosen because it involves less man-power for administration and monitoring&#xD;
      of the patients.&#xD;
&#xD;
      Study population Participants to be included in this study will be women with severe&#xD;
      preeclampsia and eclampsia that will be admitted and managed at the study facility who meet&#xD;
      the inclusion criteria. Detailed history will be obtained and thorough examination will be&#xD;
      carried out on all patients. Relevant investigations, which include blood group and Rhesus&#xD;
      type, complete blood count, platelet count, liver function tests, kidney function tests,&#xD;
      coagulation profile and urine analysis for proteinuria, will be carried out.&#xD;
&#xD;
      Sample size determination The minimum sample size will be determined using statistical&#xD;
      formula for non-inferiority study design.&#xD;
&#xD;
      N= 2×[Z1-α/2+Z1-β]2 × P × (1-P) do N = number of patients per group Z = the standard normal&#xD;
      deviate for a one or two sided study, usually set at 1.96.&#xD;
&#xD;
      d0 = clinically acceptable margin of equivalence which will be set at 0.05 P = proportion of&#xD;
      patients in both arms who developed convulsion following administration of MgSO4 from a&#xD;
      previous related study (0.2)50 α = type I error = ≤5% β = type II error =≤ 20% N = 2 ×&#xD;
      (1.96+0.845)2 × 0.2(1-0.2) 0.05 N = 2 × 7.868 × 0.2 × 0.8 0.05 N = 2.517768 0.05 N = 50.36 ≈&#xD;
      50 This will represent the number of patients per group. Twenty percent of this minimum&#xD;
      sample size will be added to correct for any attritions that may occur in the course of the&#xD;
      study. The final sample size on each arm of the study will now be 60.&#xD;
&#xD;
      Participants' selection The participants will be randomized by means of a computer generated&#xD;
      random numbers, by a statistician, using the software Research Randomizer®. Using this&#xD;
      software, sixty numbers will be randomly generated from a pool of one hundred and twenty&#xD;
      numbers (1-120) and these numbers will be assigned to group A (low dose) while the remaining&#xD;
      sixty numbers will automatically be assigned to group B (Pritchard).&#xD;
&#xD;
      Group A: will receive 4g of 20% intravenous (I.V.) MgSO4 (Magphate®) given over 10 minutes,&#xD;
      followed by 3g of 50% intramuscular (I.M.) MgSO4 in each buttock statim. Then, maintenance&#xD;
      doses will be given as 2.5g of 50% MgSO4 administered intramuscularly 4 hourly for 24 hours,&#xD;
      for those with severe preeclampsia and for 24 hours post delivery or post last seizure&#xD;
      episode, whichever occurs last, for participantsts with eclampsia (low dose regimen).&#xD;
&#xD;
      Group B: will receive loading dose as 4g of 20% MgSO4 I.V. over 10 minutes, followed by 5g of&#xD;
      50% MgSO4 I.M. in each buttock. Maintenance doses will be given as 5g of 50% MgSO4 I.M. 4&#xD;
      hourly in alternate buttock until 24 hours for patients with eclampsia and for 24 hours after&#xD;
      delivery or after last fit, whichever occurs later, for patients with eclampsia (Pritchard&#xD;
      regimen).&#xD;
&#xD;
      These numbers (1-120) will be inscribed on brown envelopes and a piece of paper with the&#xD;
      inscription 'low dose' or 'Pritchard' will be placed with the respective drug accordingly&#xD;
      inside these envelopes and sealed. All the envelopes will be kept in a locker that will be&#xD;
      made accessible to all the members of the research team. Participants will be made to know&#xD;
      what the drug is meant to do for them during the counselling session and the possible side&#xD;
      effects but will not know which arm of the study they belong (single blinding).&#xD;
&#xD;
      Participants, who meet the inclusion criteria, having signed the informed consent form, will&#xD;
      be given sequential study numbers and the corresponding numbered opaque sealed envelope will&#xD;
      then be allocated to the study cohorts.&#xD;
&#xD;
      Drug administration Participants allocated to the low dose arm, loading dose of magnesium&#xD;
      sulphate will be administered starting with 4g of 20% MgSO4 I.M. over 10 minutes by the&#xD;
      researcher/assistant, followed by 3g of 50% MgSO4 I.M. in each buttock statim. This will then&#xD;
      be followed by administration of 2.5g of 50% MgSO4 I.M. 4 hourly in alternate buttock for 24&#xD;
      hours, for patients with severe preeclampsia and for 24 hours after delivery or last fit,&#xD;
      whichever occurs later for patients with eclampsia. For those on the Prichard regimen, the&#xD;
      loading dose will be given as 4g of 20% I.V. over 10 minutes, followed by 5g of 50% MgSO4&#xD;
      I.M. in each buttock. This will then be maintained by 5g of 50% I.M. MgSO4 4 hourly for 24&#xD;
      hours for patients with severe preeclampsia and for 24 hours after delivery or last&#xD;
      convulsion, whichever occurs later, for cohorts with eclampsia. Participants' vital signs&#xD;
      will be checked before MgSO4 administration. Toxicity will also be checked for as earlier&#xD;
      outlined. If maintenance dose is found to be contraindicated in any of the patients based on&#xD;
      her clinical status or presence of signs of toxicity, such participants will be excluded from&#xD;
      the study. .&#xD;
&#xD;
      Monitoring Participants will be monitored clinically for signs of toxicity. This will be done&#xD;
      by checking for deep tendon reflex which should be present, respiratory rate which should be&#xD;
      not be less than 16 cycles per minute and hourly urine output which should be at least 30ml&#xD;
      per hour. One gram of calcium gluconate will be provided for each patient on MgSO4 to be&#xD;
      given in case of toxicity. For those who fit while on the low dose, 2g of 20% MgSO4 will be&#xD;
      administered intravenously over 10 minutes while the patient is converted to the Pritchard&#xD;
      regimen. Other causes of convulsion will also be sought for. If any of the participants on&#xD;
      Pritchard regimen fits, she will be given 2g of 20% MgSO4 intravenously over 10 minutes while&#xD;
      re-evaluating the woman for other possible causes of convulsion.&#xD;
&#xD;
      Statistical analysis Data will be collated, tabulated and then statistically analysed using&#xD;
      the statistical package for social sciences (SPSS) (IBM) software (version 22, Chicago USA).&#xD;
      Continuous variable will be presented as mean ± standard deviaton (SD), while categorical&#xD;
      variables will be presented as numbers and percentages. Chi-square test will be used for&#xD;
      comparison between groups of qualitative variables while normal z-test, risk ratio and&#xD;
      confidence interval at 95% will be used for comparison between groups of quantitative&#xD;
      variables. A difference with a p-value &lt;0.05 will be considered statistically significant.&#xD;
&#xD;
      Ethical consideration Ethical clearance was obtained from the Research and Ethics committee&#xD;
      of Alex Ekwueme Federal University Teaching Hospital, Abakaliki, Nigeria. A signed-written&#xD;
      consent will be obtained from each participant before recruitment into the study. The&#xD;
      participants will be made to understand that declining participation will have no&#xD;
      consequences in her obtaining adequate care. The participants will be assured that their&#xD;
      identity would be kept in confidence by the investigator.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">May 8, 2017</start_date>
  <completion_date type="Actual">January 22, 2018</completion_date>
  <primary_completion_date type="Actual">December 27, 2017</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>The participants in the study will be randomized into two study groups in ratio 1:1. Participants in group 1 will receive 4g of 20% intravenous (I.V.) MgSO4, followed by 3g of 50% intramuscular (I.M.) MgSO4 in each buttock statim. Then, maintenance doses will be given as 2.5g of 50% MgSO4 I.M. 4 hourly for 24 hours, for patients with severe preeclampsia and for 24 hours post-delivery or post last seizure episode, for patients with eclampsia; while those in group 2 will receive loading dose as 4g of 20% MgSO4 I.V., followed by 5g of 50% MgSO4 I.M. in each buttock. Maintenance doses will be given as 5g of 50% MgSO4 I.M. 4 hourly in alternate buttock until 24 hours for participants with eclampsia and for 24 hours after delivery or after last fit, whichever occurs later, for those with eclampsia</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Single (Participant)</masking>
    <masking_description>Participants will be informed of the drug to be administered and the duration but were unaware of the dosage of the drug to be administered to them. However, the investigator knew the dosage each study cohort received</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Convulsion</measure>
    <time_frame>Within 24 hours of administration</time_frame>
    <description>Occurrence of convulsion for participants with severe preeclampsia and recurrence of convulsion for cohorts with eclampsia</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Maternal side effects of MgSO4</measure>
    <time_frame>Within 24 hours of administration</time_frame>
    <description>Deep tendon reflex</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>MgSO4 toxicity</measure>
    <time_frame>Within 24 hours of administration</time_frame>
    <description>Urine output less than 30ml/hr</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Respiratory depression</measure>
    <time_frame>Within 24 hours of administration</time_frame>
    <description>Respiratory rate less than 12 cycles/min</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Maternal complication 1</measure>
    <time_frame>Before delivery of baby</time_frame>
    <description>Abruptio bplacentae</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Maternal complication 2</measure>
    <time_frame>Within 24 hours of delivery</time_frame>
    <description>Primary postpartum hemorrhage</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Maternal complication 3</measure>
    <time_frame>Within 24 hours of delivery</time_frame>
    <description>Mortality</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Fetal outcome 1</measure>
    <time_frame>At delivery</time_frame>
    <description>Apgar score</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Fetal outcome 2</measure>
    <time_frame>At delivery</time_frame>
    <description>Neonatal intensive care admission</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">114</enrollment>
  <condition>Preeclampsia/Eclampsia</condition>
  <arm_group>
    <arm_group_label>Low dose magnesium sulphate</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Experimental - participants in this arm will be pregnant women with severe preeclampsia/eclampsia who will receive low dose magnesium sulphate</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Magnesium sulphate Pritchard regimen</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Experimental - participants in this arm will be pregnant women with severe preeclampsia/eclampsia who will receive Pritchard regimen of magnesium sulphate</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Low dose magnesium sulphate</intervention_name>
    <description>Participants in this arm will receive 4g of 20% intravenous (I.V.) MgSO4 (Magphate®) given over 10 minutes, followed by 3g of 50% intramuscular (I.M.) MgSO4 in each buttock statim. Then, maintenance doses will be given as 2.5g of 50% MgSO4 administered intramuscularly 4 hourly for 24 hours, for participants with severe preeclampsia and for 24 hours post delivery or post last seizure episode, whichever occurs last, for cohorts with eclampsia.</description>
    <arm_group_label>Low dose magnesium sulphate</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Pritchard regimen</intervention_name>
    <description>Participants in this arm will receive loading dose as 4g of 20% MgSO4 I.V. over 10 minutes, followed by 5g of 50% MgSO4 I.M. in each buttock. Maintenance doses will be given as 5g of 50% MgSO4 I.M. 4 hourly in alternate buttock until 24 hours for patients with eclampsia and for 24 hours after delivery or after last fit, whichever occurs later, for cohorts with eclampsia.</description>
    <arm_group_label>Magnesium sulphate Pritchard regimen</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Pregnant women with diagnosis of severe preeclampsia/eclampsia&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Administration of MgSO4 before admission.&#xD;
&#xD;
          -  Administration of diazepam or phenytoin before admission&#xD;
&#xD;
          -  Maternal complications such as disseminated intravascular coagulation, cerebrovascular&#xD;
             accident, renal disease, HELLP syndrome and aspiration pneumonitis.&#xD;
&#xD;
          -  Multiple gestation&#xD;
&#xD;
          -  Gestational ages below 28 weeks&#xD;
&#xD;
          -  Postpartum eclampsia&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <gender_based>Yes</gender_based>
    <gender_description>Pregnant women with gestational age of 28 weeks and above</gender_description>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>49 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Joshua A Adebayo, MB;BS; FWACS</last_name>
    <role>Principal Investigator</role>
    <affiliation>Alex Ekwueme Federal University Teaching Hospital, Abakaliki</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Alex Ekwueme Federal University Teaching Hospital</name>
      <address>
        <city>Abakaliki</city>
        <state>Abakaliki LG</state>
        <country>Nigeria</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Nigeria</country>
  </location_countries>
  <verification_date>August 2020</verification_date>
  <study_first_submitted>August 2, 2020</study_first_submitted>
  <study_first_submitted_qc>August 2, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">August 6, 2020</study_first_posted>
  <last_update_submitted>August 2, 2020</last_update_submitted>
  <last_update_submitted_qc>August 2, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">August 6, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>Alex Ekwueme Federal University Teaching Hospital</investigator_affiliation>
    <investigator_full_name>Adebayo Joshua Adeniyi</investigator_full_name>
    <investigator_title>Doctor, Consultant, Department of Obstetrics and Gynaecology, Principal Investigator</investigator_title>
  </responsible_party>
  <keyword>Preeclampsia</keyword>
  <keyword>Eclampsia</keyword>
  <keyword>Magnesium sulphate</keyword>
  <keyword>Convulsion</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Pre-Eclampsia</mesh_term>
    <mesh_term>Eclampsia</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Magnesium Sulfate</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>Individual participant data would be made available by the corresponding author on request</ipd_description>
    <ipd_info_type>Study Protocol</ipd_info_type>
    <ipd_info_type>Statistical Analysis Plan (SAP)</ipd_info_type>
    <ipd_info_type>Informed Consent Form (ICF)</ipd_info_type>
    <ipd_info_type>Clinical Study Report (CSR)</ipd_info_type>
    <ipd_info_type>Analytic Code</ipd_info_type>
    <ipd_time_frame>20 years</ipd_time_frame>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT04501289
org study id: FETHA/REC/VOL1/2017/482
nct id: NCT04501289
lead sponsor: 
is fda regulated drug: No
is fda regulated device: No
Background - Preeclampsia/eclampsia, a pregnancy specific multi-systemic disease, is
      associated with considerable maternal and perinatal morbidity and mortality. Prevention
      and/or treatment of convulsion with magnesium sulphate, among others, is life-saving. Despite
      different regimens that have been tried, the minimum effective dose of MgSO4 for the
      prevention of eclampsia in patients with preeclampsia and treatment of convulsion in those
      with eclampsia has not been determined.

      Objectives - To compare the maternal and perinatal outcomes and maternal side effects in
      eclamptic and preeclamptic participants treated with low dose regimen of MgSO4 with those
      treated with the Pritchard regimen.

      Materials and Methods - This will be a prospective, single blinded randomized controlled
      study of low dose versus Pritchard regimens of MgSO4. Participants will be randomly assigned
      to the either arm of the study. Efficacy and adverse effects of the drug on the mother and
      baby will be noted. Data will be collated, tabulated and then statistically analysed using
      the statistical package for social sciences (SPSS) Results - Conclusion will be drawn and
      recommendation made from the findings in the study.
Introduction Preeclampsia complicates 5-7% of all pregnancies globally. However,
      hospital-based studies in Nigeria have reported rates ranging between 1.2% and 6.3%, while a
      study in Abakaliki recorded 0.99% for severe preeclampsia and 0.76% for eclampsia. Severe
      preeclampsia and eclampsia are associated with increased maternal and perinatal morbidity and
      mortality. The World Health Organization (WHO) estimates that about 63,000 maternal deaths
      occur annually from preeclampsia/eclampsia and associated complications, with 98% of these
      deaths occurring in developing countries. Perinatal adverse outcomes are usually due to
      prematurity associated with preterm delivery, as well as intrauterine fetal death from
      intrauterine growth restriction and placental abruption. Early recognition therefore,
      combined with prompt management, is often required for good maternal and perinatal outcome.

      The definitive treatment for severe preeclampsia or eclampsia is delivery of the placenta. In
      affected women, positive maternal and perinatal outcomes depend on the woman having timely
      access to a treatment package which include effective inpatient monitoring, optimal timing of
      childbirth, presence of skilled attendant at birth and administration of antihypertensive as
      well as anticonvulsive therapy. Of all the anticonvulsants that have been tried in the
      management of preeclampsia and eclampsia, magnesium sulphate (MgSO4) has been established as
      the anticonvulsant of choice both for prevention of convulsions in severe preeclampsia and
      for prevention of recurrent convulsions in eclampsia. It has been shown to be superior to
      diazepam, phenytoin, and lytic cocktail (a mixture of chlorpromazine, promethazine and
      pethidine) in reducing the occurrence of eclamptic convulsion and the associated maternal
      morbidity and mortality. It also has beneficial effects on fetuses, reducing the risks of low
      Apgar scores in the 1st and 5th minutes, the risk of cerebral haemorrhage, as well as the
      need for intubation and admission into newborn intensive care units.

      Magnesium sulphate belongs to the class of electrolytes anti-dysrrhythmic drugs. It is a
      sterile, non-pyrogenic concentrated solution of magnesium sulphate heptahydrate in water for
      injection. It is administered by the intravenous (IV) or intramuscular (IM) routes as an
      electrolyte replenisher or anticonvulsant. It has been adjudged to be the most effective,
      safe and low-cost anticonvulsant drug for pre-eclampsia and eclampsia. Though the mechanism
      of action is not completely understood, several hypotheses have been put forward to explain
      its beneficial effects in patients with preeclampsia and eclampsia. These include dilatation
      of cerebral blood vessels thereby reducing cerebral ischaemia, blockade of the
      N-methyl-D-aspartate receptors in the brain and also causing peripheral vasodilatation.
      However, despite its endorsement by the W.H.O. and its widespread availability, MgSO4 is
      still underused and incorrectly administered in many low resource settings. This has been
      discovered to be due to a number of provider factors and the complexity of treatment regimens
      being used.

      The most commonly used MgSO4 regimens are those given intramuscularly and/or intravenously
      from the diagnosis of severe preeclampsia and eclampsia to 24 hours post delivery or post
      last seizure episode, whichever occurs later. Though these regimens have been found to be
      effective, they involve administering large doses of the drug. This usually leads to high
      cost of treatment to the affected patients as well as difficulties in monitoring such
      patients for drug toxicity (which include neurological deficit and cardiac arrest),
      especially in developing countries where manpower and facilities are limited. Therefore,
      several attempts have been made either to shorten the duration of administration or reduce
      the dosage of MgSO4 with the aim of achieving optimal efficacy, while reducing the side
      effects of the drug and the cost of management. These include those in which the loading dose
      and maintenance doses were reduced in quantities; those involving reduction of maintenance
      dose to 12 hours and those involving giving only the loading dose. No particular regimen has
      been generally adopted as the minimum effective dose, although several lower doses have
      proved to be effective. Because of their effectiveness which has been demonstrated over time,
      it has been suggested that lower doses of MgSO4 may suffice for prophylaxis for patients with
      severe preeclampsia as well as treatment for those with eclampsia, without jeopardising
      efficacy.

      Though the reason for the success recorded with the low dose regimen used in Dhaka was
      attributed to the low body mass index of the population, several other studies in other
      places with varying dosages and different weight distribution have also recorded varying
      degrees of success. Therefore small body mass index (BMI) alone may not be enough to explain
      the whole phenomenon. Some authorities have also shown that there is no association between
      treatment failures and patients' BMI. or with serum magnesium levels. A systematic review in
      Nigeria in 2016 supported the fact that there were no studies that had demonstrated the
      lowest effective dose of MgSO4 to manage preeclampsia/eclampsia. Another systematic review
      also recommended further studies to identify the minimum effective dose of MgSO4 for the
      management of preeclampsia/eclampsia. Therefore, any regimen that will involve minimal cost
      and side effects; and at the same time be as effective as the current doses being
      administered, will go a long way in reducing the challenges of affordability of the drug and
      that of its side effects. It is against this background that this study is being carried out
      to compare the efficacy of a lower dose of MgSO4 in patients with severe pre-eclampsia and
      eclampsia to that of the Pritchard's regimen among our women population with a view to
      recommending it for use if the efficacy is found to be comparable.

      Study background The study will be carried out at the Obstetric and Gynaecology division of
      Alex Ekwueme Federal University Teaching Hospital, Abakaliki, Ebonyi State, South-east,
      Nigeria. The department of Obstetrics and Gynaecology is one of the clinical departments in
      the hospital. There are 52 obstetric bed spaces including antenatal and postnatal wards. The
      department has five teams which are sub-divided into two units each. Each unit is manned by
      at least two consultants. Resident doctors are distributed to cover all the units. The
      department runs antenatal clinics managed by the consultants and resident doctors, assisted
      by midwives and other health workers. Antenatal clients are booked daily on every week day
      and are assigned consultants according to the units/teams running antenatal clinic each day.
      The average antenatal booking is about 4,200 clients per annum, while the total antenatal
      clinic attendance averages 21,000 per annum, with an average annual delivery rate of 3,100.
      The department has established protocols for management of specific cases which are in
      accordance with international best practices, and are displayed in the labour wards,
      antenatal ward and the accident and emergency unit of the hospital. These protocols serve as
      guides as patient care is still individualised.

      For cases of severe preeclampsia and eclampsia, the departmental protocol is to stabilise the
      patient and deliver through the most expeditious route, though considerations may be given in
      certain cases of severe preeclampsia to allow for fetal growth for one or two weeks provided
      maternal and fetal clinical and laboratory parameters are stable. One of the steps taken
      during the period of stabilization is the administration of MgSO4 so as to avoid fits or its
      recurrence. The most commonly used MgSO4 regimen in the department is the Pritchard regimen
      in which MgSO4 is given as intravenous loading dose of 4g over 10 minutes, while 5g is
      administered intramuscularly in each buttock statim. Then 5g of MgSO4 is then administered
      intramuscularly every 4 hours until 24 hours after delivery or 24 hours after the last
      seizure episode, whichever occurs later, provided no sign of toxicity from the previous dose
      is noted. This is chosen because it involves less man-power for administration and monitoring
      of the patients.

      Study population Participants to be included in this study will be women with severe
      preeclampsia and eclampsia that will be admitted and managed at the study facility who meet
      the inclusion criteria. Detailed history will be obtained and thorough examination will be
      carried out on all patients. Relevant investigations, which include blood group and Rhesus
      type, complete blood count, platelet count, liver function tests, kidney function tests,
      coagulation profile and urine analysis for proteinuria, will be carried out.

      Sample size determination The minimum sample size will be determined using statistical
      formula for non-inferiority study design.

      N= 2×[Z1-α/2+Z1-β]2 × P × (1-P) do N = number of patients per group Z = the standard normal
      deviate for a one or two sided study, usually set at 1.96.

      d0 = clinically acceptable margin of equivalence which will be set at 0.05 P = proportion of
      patients in both arms who developed convulsion following administration of MgSO4 from a
      previous related study (0.2)50 α = type I error = ≤5% β = type II error =≤ 20% N = 2 ×
      (1.96+0.845)2 × 0.2(1-0.2) 0.05 N = 2 × 7.868 × 0.2 × 0.8 0.05 N = 2.517768 0.05 N = 50.36 ≈
      50 This will represent the number of patients per group. Twenty percent of this minimum
      sample size will be added to correct for any attritions that may occur in the course of the
      study. The final sample size on each arm of the study will now be 60.

      Participants' selection The participants will be randomized by means of a computer generated
      random numbers, by a statistician, using the software Research Randomizer®. Using this
      software, sixty numbers will be randomly generated from a pool of one hundred and twenty
      numbers (1-120) and these numbers will be assigned to group A (low dose) while the remaining
      sixty numbers will automatically be assigned to group B (Pritchard).

      Group A: will receive 4g of 20% intravenous (I.V.) MgSO4 (Magphate®) given over 10 minutes,
      followed by 3g of 50% intramuscular (I.M.) MgSO4 in each buttock statim. Then, maintenance
      doses will be given as 2.5g of 50% MgSO4 administered intramuscularly 4 hourly for 24 hours,
      for those with severe preeclampsia and for 24 hours post delivery or post last seizure
      episode, whichever occurs last, for participantsts with eclampsia (low dose regimen).

      Group B: will receive loading dose as 4g of 20% MgSO4 I.V. over 10 minutes, followed by 5g of
      50% MgSO4 I.M. in each buttock. Maintenance doses will be given as 5g of 50% MgSO4 I.M. 4
      hourly in alternate buttock until 24 hours for patients with eclampsia and for 24 hours after
      delivery or after last fit, whichever occurs later, for patients with eclampsia (Pritchard
      regimen).

      These numbers (1-120) will be inscribed on brown envelopes and a piece of paper with the
      inscription 'low dose' or 'Pritchard' will be placed with the respective drug accordingly
      inside these envelopes and sealed. All the envelopes will be kept in a locker that will be
      made accessible to all the members of the research team. Participants will be made to know
      what the drug is meant to do for them during the counselling session and the possible side
      effects but will not know which arm of the study they belong (single blinding).

      Participants, who meet the inclusion criteria, having signed the informed consent form, will
      be given sequential study numbers and the corresponding numbered opaque sealed envelope will
      then be allocated to the study cohorts.

      Drug administration Participants allocated to the low dose arm, loading dose of magnesium
      sulphate will be administered starting with 4g of 20% MgSO4 I.M. over 10 minutes by the
      researcher/assistant, followed by 3g of 50% MgSO4 I.M. in each buttock statim. This will then
      be followed by administration of 2.5g of 50% MgSO4 I.M. 4 hourly in alternate buttock for 24
      hours, for patients with severe preeclampsia and for 24 hours after delivery or last fit,
      whichever occurs later for patients with eclampsia. For those on the Prichard regimen, the
      loading dose will be given as 4g of 20% I.V. over 10 minutes, followed by 5g of 50% MgSO4
      I.M. in each buttock. This will then be maintained by 5g of 50% I.M. MgSO4 4 hourly for 24
      hours for patients with severe preeclampsia and for 24 hours after delivery or last
      convulsion, whichever occurs later, for cohorts with eclampsia. Participants' vital signs
      will be checked before MgSO4 administration. Toxicity will also be checked for as earlier
      outlined. If maintenance dose is found to be contraindicated in any of the patients based on
      her clinical status or presence of signs of toxicity, such participants will be excluded from
      the study. .

      Monitoring Participants will be monitored clinically for signs of toxicity. This will be done
      by checking for deep tendon reflex which should be present, respiratory rate which should be
      not be less than 16 cycles per minute and hourly urine output which should be at least 30ml
      per hour. One gram of calcium gluconate will be provided for each patient on MgSO4 to be
      given in case of toxicity. For those who fit while on the low dose, 2g of 20% MgSO4 will be
      administered intravenously over 10 minutes while the patient is converted to the Pritchard
      regimen. Other causes of convulsion will also be sought for. If any of the participants on
      Pritchard regimen fits, she will be given 2g of 20% MgSO4 intravenously over 10 minutes while
      re-evaluating the woman for other possible causes of convulsion.

      Statistical analysis Data will be collated, tabulated and then statistically analysed using
      the statistical package for social sciences (SPSS) (IBM) software (version 22, Chicago USA).
      Continuous variable will be presented as mean ± standard deviaton (SD), while categorical
      variables will be presented as numbers and percentages. Chi-square test will be used for
      comparison between groups of qualitative variables while normal z-test, risk ratio and
      confidence interval at 95% will be used for comparison between groups of quantitative
      variables. A difference with a p-value <0.05 will be considered statistically significant.

      Ethical consideration Ethical clearance was obtained from the Research and Ethics committee
      of Alex Ekwueme Federal University Teaching Hospital, Abakaliki, Nigeria. A signed-written
      consent will be obtained from each participant before recruitment into the study. The
      participants will be made to understand that declining participation will have no
      consequences in her obtaining adequate care. The participants will be assured that their
      identity would be kept in confidence by the investigator.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: The participants in the study will be randomized into two study groups in ratio 1:1. Participants in group 1 will receive 4g of 20% intravenous (I.V.) MgSO4, followed by 3g of 50% intramuscular (I.M.) MgSO4 in each buttock statim. Then, maintenance doses will be given as 2.5g of 50% MgSO4 I.M. 4 hourly for 24 hours, for patients with severe preeclampsia and for 24 hours post-delivery or post last seizure episode, for patients with eclampsia; while those in group 2 will receive loading dose as 4g of 20% MgSO4 I.V., followed by 5g of 50% MgSO4 I.M. in each buttock. Maintenance doses will be given as 5g of 50% MgSO4 I.M. 4 hourly in alternate buttock until 24 hours for participants with eclampsia and for 24 hours after delivery or after last fit, whichever occurs later, for those with eclampsia
primary purpose: Treatment
masking: Single (Participant)
masking description: Participants will be informed of the drug to be administered and the duration but were unaware of the dosage of the drug to be administered to them. However, the investigator knew the dosage each study cohort received
measure: Convulsion
time frame: Within 24 hours of administration
description: Occurrence of convulsion for participants with severe preeclampsia and recurrence of convulsion for cohorts with eclampsia
measure: Maternal side effects of MgSO4
time frame: Within 24 hours of administration
description: Deep tendon reflex
measure: MgSO4 toxicity
time frame: Within 24 hours of administration
description: Urine output less than 30ml/hr
measure: Respiratory depression
time frame: Within 24 hours of administration
description: Respiratory rate less than 12 cycles/min
measure: Maternal complication 1
time frame: Before delivery of baby
description: Abruptio bplacentae
measure: Maternal complication 2
time frame: Within 24 hours of delivery
description: Primary postpartum hemorrhage
measure: Maternal complication 3
time frame: Within 24 hours of delivery
description: Mortality
measure: Fetal outcome 1
time frame: At delivery
description: Apgar score
measure: Fetal outcome 2
time frame: At delivery
description: Neonatal intensive care admission
arm group label: Low dose magnesium sulphate
arm group type: Experimental
description: Experimental - participants in this arm will be pregnant women with severe preeclampsia/eclampsia who will receive low dose magnesium sulphate
arm group label: Magnesium sulphate Pritchard regimen
arm group type: Experimental
description: Experimental - participants in this arm will be pregnant women with severe preeclampsia/eclampsia who will receive Pritchard regimen of magnesium sulphate
intervention type: Drug
intervention name: Low dose magnesium sulphate
description: Participants in this arm will receive 4g of 20% intravenous (I.V.) MgSO4 (Magphate®) given over 10 minutes, followed by 3g of 50% intramuscular (I.M.) MgSO4 in each buttock statim. Then, maintenance doses will be given as 2.5g of 50% MgSO4 administered intramuscularly 4 hourly for 24 hours, for participants with severe preeclampsia and for 24 hours post delivery or post last seizure episode, whichever occurs last, for cohorts with eclampsia.
arm group label: Low dose magnesium sulphate
intervention type: Drug
intervention name: Pritchard regimen
description: Participants in this arm will receive loading dose as 4g of 20% MgSO4 I.V. over 10 minutes, followed by 5g of 50% MgSO4 I.M. in each buttock. Maintenance doses will be given as 5g of 50% MgSO4 I.M. 4 hourly in alternate buttock until 24 hours for patients with eclampsia and for 24 hours after delivery or after last fit, whichever occurs later, for cohorts with eclampsia.
arm group label: Magnesium sulphate Pritchard regimen
criteria: 
gender: Female
gender based: Yes
gender description: Pregnant women with gestational age of 28 weeks and above
minimum age: 18 Years
maximum age: 49 Years
healthy volunteers: No
last name: Joshua A Adebayo, MB;BS; FWACS
role: Principal Investigator
affiliation: Alex Ekwueme Federal University Teaching Hospital, Abakaliki
facility: 
country: Nigeria
responsible party type: Sponsor-Investigator
investigator affiliation: Alex Ekwueme Federal University Teaching Hospital
investigator full name: Adebayo Joshua Adeniyi
investigator title: Doctor, Consultant, Department of Obstetrics and Gynaecology, Principal Investigator
mesh term: Pre-Eclampsia
mesh term: Eclampsia
mesh term: Magnesium Sulfate
sharing ipd: Yes
ipd description: Individual participant data would be made available by the corresponding author on request
ipd info type: Study Protocol
ipd info type: Statistical Analysis Plan (SAP)
ipd info type: Informed Consent Form (ICF)
ipd info type: Clinical Study Report (CSR)
ipd info type: Analytic Code
ipd time frame: 20 years