Pregnancy Clinical Trial
Official title:
A Randomised Double Blind Clinical Trial of Amodiaquine (AQ) and Sulphadoxine-pyrimethamine (SP) Used Singly and in Combination (AQ+SP) Compared With Chloroquine (CQ) in the Treatment of Falciparum Malaria Infection in Pregnancy
Malaria in pregnancy is potentially fatal to both the mother and the foetus particularly in the primigravidae. Implementation of appropriate control and preventive measures is challenged by the fact that malaria infection in pregnancy is often asymptomatic and parasitized red blood cells sequestrated in the placental microcirculation may not be detectable in the peripheral blood. In addition, the widespread prevalence of parasites resistant to chloroquine and sulphadoxine-pyrimethamine (SP) and, the safety concerns about newer antimalarials, poverty and inadequate supply have made antimalarial treatment options available to pregnant women very limited. These have necessitated an urgent search for alternative safe and efficacious treatment options for pregnant women. The objective of this study is to assess the efficacy, safety and tolerability of four antimalarial treatment options in rural Ghana within a programme setting.
Primary objective:
To determine the effect of AQ, SP and the AQ+SP combination compared with CQ treatment on
the prevalence of peripheral parasitaemia on days 14 and 28 post treatment.
Secondary objectives:
1. To compare the incidence of adverse events in the treatment groups.
2. To compare the effect of study drugs on maternal haemoglobin on 14 and 28 days post
treatment, and at delivery.
3. To compare the effect of study drugs on peripheral and placental parasite densities at
delivery.
4. To compare the effect of study drugs on birth weight at delivery.
5. To assess the effect modifications of gestational age, parity, gravidity, prior
antimalarial use, presence or absence of symptoms at enrolment, baseline parasite
density and baseline Hb on the parasitological and haematological responses to the test
drugs.
6. To assess the accuracy of the OptiMAL antigen test for detecting peripheral
parasitaemia compared to microscopy.
7. To compare the overall incidence of adverse pregnancy outcomes (abortion, stillbirth,
congenital abnormality, prematurity and intrauterine deaths) in the study group to
local rates obtained from St Theresa's Hospital's records.
Study location and population:
The study was carried out at the St. Theresa's Hospital in the Nkoranza district of the
Brong Ahafo Region of Ghana. The St. Theresa's hospital is a general district hospital. It
has a bed capacity of 80 and provides all basic medical services including adult medicine,
paediatrics, surgery and obstetrics and gynaecology. The study enrolled pregnant women of
all parities attending the St. Theresa's Hospital's antenatal clinic with a gestational age
of 16 weeks and above between March 2003 and September 2004.
Methods:
Antennal screening and enrolment:
All pregnant women who attended antenatal clinics were screened for malaria antigens with
OptiMAL dipsticks. Those with a positive antigen test were considered eligible, and after
informed consent had been obtained from them 5mls of venous blood was drawn from an
antecubital vein for baseline measurements of haemoglobin, white blood cell counts (total
and differential), bilirubin, alanine aminotransferase, aspartate aminotransferase and
gamma-glutamyl transferase and for making filter paper blood spots. Women were then assessed
clinically and obstetrically with the view to enrolling them into the study. Pregnancy
viability and gestational age were confirmed with ultrasound scanning by the study clinician
or the principal investigator. Pregnant women with positive malaria antigen tests confirmed
microscopically were randomised into four treatment arms if they satisfied all inclusion
criteria.
Follow-up schedule:
Field workers visited the study women in their homes following the initial supervised drug
administration at the antenatal clinic on post treatment days 3, 7, 14 and 28 and performed
the following routines.
- Day 3 and Day 7: Obtained venous blood for filter paper blood spots, white cell and
malaria parasite counts, and recorded any side effects.
- Day 14 and Day 28: Obtained venous blood for white cell and malaria parasite count,
measurement of alanine and aspartate transaminases, bilirubin and for filter paper
blood spots and recorded any side effects.
Subsequently, pregnant women were seen at the antenatal clinic monthly and, for those with
32 weeks and above of gestation fortnightly. At these visits, they were actively screened
for peripheral parasitaemia using OptiMAL dipstick test. At any time before delivery if the
test was negative, the woman remained on daily haematinics. If women who were already
enrolled had positive antigen test confirmed by microscopy, they received another course of
the treatment they were initially assigned to. Women were enrolled in the study only for the
first episode of malaria detected during the antenatal visit. At delivery, midwives recorded
birth weights and any stillbirths, perinatal deaths or congenital abnormalities. They also
made slides from peripheral, placental and cord blood and sampled maternal blood for
haemoglobin measurements. Any record of a congenital deformity was verified and confirmed by
a clinician. The women and their babies were visited at home at six weeks post delivery to
record any neonatal adverse events such as deaths or severe morbidity.
Outcome measures:
Primary
1. Prevalence of parasitaemia on days 14 and 28 post treatment.
Secondary
1. Incidence of adverse drug events within seven days following treatment.
2. Proportions of pregnant women withdrawn from the study due to the occurrence of adverse
drug events (clinical and laboratory) by day 7 following initiation of treatment.
3. Change in maternal haemoglobin concentrations at days 14 and 28 following treatment.
4. Prevalence of peripheral parasitaemia at delivery.
5. Prevalence of placental parasitaemia at delivery.
6. Proportions of abnormal biochemistry and white blood cell values on days 14 and 28 post
treatment.
7. Sensitivity, specificity, positive and negative predictive values, likelihood ratios,
and the area under receiver operating characteristic (ROC) curve for the OptiMAL
antigen test.
8. Incidences of adverse pregnancy outcomes in the study group.
9. Prevalence of postpartum parasitaemia.
10. Prevalence of postpartum anaemia.
Sample Size:
This was based on the assumption of a 28-day parasitological clearance of 90% for AQ, SP and
the AQ+SP combination, and 78% for chloroquine (α = 5% power = 90%). Allowing for a 15% loss
to follow-up, 225 pregnant women were recruited into each of the 4 treatment arms of the
study giving a total study size of 900 pregnant women.
Data and safety monitoring board:
A data and safety monitoring board (DSMB) was constituted for the project. The board was
responsible for:
- Regular monitoring of the data and safety issues concerned with the study.
- Reviewing the PI's reports on serious adverse events and making recommendations on
further progress of the study.
- Reviewing the statistical analysis plan prior to breaking the study drug codes.
;
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double-Blind, Primary Purpose: Treatment
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