Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT04501289 |
| Other study ID # |
FETHA/REC/VOL1/2017/482 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
May 8, 2017 |
| Est. completion date |
January 22, 2018 |
Study information
| Verified date |
August 2020 |
| Source |
Alex Ekwueme Federal University Teaching Hospital |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
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.
Description:
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.
