Clinical Trial Details
— Status: Active, not recruiting
Administrative data
| NCT number |
NCT05186363 |
| Other study ID # |
SMCMOZPHASE2 |
| Secondary ID |
INV-033337 |
| Status |
Active, not recruiting |
| Phase |
Phase 4
|
| First received |
|
| Last updated |
|
| Start date |
January 8, 2022 |
| Est. completion date |
December 1, 2023 |
Study information
| Verified date |
October 2023 |
| Source |
Malaria Consortium |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
We describe a Type II hybrid effectiveness-implementation study design which evaluates the
effects of a clinical intervention on relevant outcomes whilst collecting information on
implementation. It is designed to determine feasibility and effectiveness of an innovative
intervention, as well as the protective efficacy of the drugs used. The study consists of
three components: 1) Conducting a cluster randomized controlled trial (cRCT) through
household surveys establishing confirmed malaria cases in children; 2) Conducting a
prospective cohort study to determine the chemoprevention efficacy of
sulfadoxine-pyrimethamine and amodiaquine (SPAQ) and whether drug concentrations or parasite
resistance influence the duration of protection; and 3) Conducting a resistance markers study
in children 3-59 months to measure changes in resistance marker prevalence over time.
Description:
This implementation research study uses a convergent mixed-methods approach. SMC will be
implemented in four monthly cycles between December 2021 and February 2022. The research will
involve the following components:
1. Conducting a cluster randomized controlled trial (cRCT) through passive surveillance to
establish confirmed malaria cases in children
2. Conducting a prospective chemoprevention efficacy cohort study to determine if SPAQ
provides 28 days of protection from infection and whether drug concentrations and/or
resistance influence the duration of protection
3. Conducting a resistance markers study in children 3-59 months in the two research
districts plus the two standard intervention districts to measure changes in resistance
marker prevalence over time.
Four districts will be involved in the study: the two intervention districts from phase 1
(Mecubúri and Malema) and two districts where SMC has not previously been implemented (Lalaua
and Muecate). The cRCT will only be implemented in the two new districts. The chemoprevention
efficacy cohort study will only be conducted in one of the two new districts, which will be
selected based on operational feasibility. The estimated target population for SMC in the
study districts is 114,000 children aged 3-59 months.
Methods
1. Cluster randomized controlled trial (cRCT) To assess the effectiveness of SMC using a
cluster randomized control trial (cRCT) in two districts in Nampula province.
Study design and sample selection The effectiveness of SPAQ (on an intention to treat
basis) for prevention of clinically-significant cases of malaria among children aged
3-59 months in this setting will be investigated using a cRCT.
This trial will comprise of two arms: one control arm and one intervention arm. Informed
consent for childrens' participation in the trial will be obtained from caregivers.
Clusters will be selected for the intervention arm at the level of comunidades or
communities. The study will be powered to have an 80% chance of detecting, as
significant at the 5% level using a two-tailed test, a 40% reduction in incidence (based
on that assumption that efficacy of SPAQ in Northern Mozambique, where prevalence of
resistance alleles in circulating parasites is high, is half that found in studies in
West African settings). It will assume that study participants, in the absence of SMC,
would experience 0.2 clinical episodes per child per high-transmission season
(corresponding to the SMC round) of sufficient severity to present to a health facility.
Sample size calculation for chi square test comparing two independent proportions in a
cluster randomized design with the proportion of sample with the expected outcome: 0.80;
Statistical power: 80 %; Confidence level: 95% (α=0.05); Assumed proportions of children
developing confirmed case of malaria during follow-up: Intervention arm: 0.2; Control
arm: 0.12 (Corresponding to protective effect of 40%); Ratio of children in control arm:
intervention arm (K-ratio): 1.5; Assumed intra-cluster correlation (ICC) of malaria
outcomes: 0.23; Selected cluster size: 15; Estimated total required sample size:n =
2,850, of which 1,710 in the control and 1,140 in the intervention arms; Estimated total
number of clusters: n = 190, of which 114 in the control and 76 in the intervention
arms. A total of 76 communities will be selected at random from a list of all
communities with probability proportional to population size for inclusion in the
intervention arm. Afterwards, 114 communities will be selected at random from among the
remaining for inclusion in the control arm. All eligible children in the intervention
areas will receive SMC as per the standard protocol. In all areas selected for inclusion
in the control and intervention arms, 15 households will be selected at random from a
household list in each community. In each household, one eligible child will be selected
at random from among the eligible children and included into the study. The participant
sampling frame was designed to ensure overall efficiency of the study in terms of number
of clusters, overall sample size and number of communities receiving SMC. Attack rates
in the intervention and control districts will be compared to ensure these are similar
across the selected intervention and control areas. In the control arm, households will
be randomly sampled by researchers from selected communities with one eligible child
recruited at random in each household. After caregivers provide consent, children will
be recruited and a short baseline questionnaire will be administered to collect
individual data on each child and to confirm their eligibility. In the intervention arm,
a researcher will follow a pair of community distributors as they administer SMC.
Households in selected communities will be randomly sampled from those visited by the
distributors. Before SMC is administered, consent sought, one eligible child will be
recruited and a short baseline questionnaire will be administered to collect individual
data and to confirm their eligibility. Blood samples will be taken and subsequent
hemoglobin concentration measured using a Hemocue machine. Children recruited into the
study presenting at clinics will be identified using information on their SMC record
cards, and data on clinic visits including suspected malaria cases and results of rapid
diagnostic tests (RDTs) will be matched to baseline questionnaire data to build a
database for analysis. Date of clinic attendance and confirmation of malaria cases using
rapid diagnostic tests will be recorded to allow for calculation of follow-up time and
time to malaria events for fitting of Cox proportional hazards regression model.
2. Chemoprevention efficacy cohort study The aims of this study component is to ascertain
whether current dosing regimens of sulfadoxine, pyrimethamine and amodiaquine given
during SMC sufficiently protect against Plasmodium falciparum infection in children of
3-59 months for 28 days. The study design is similar to what has been proposed as a
standard chemoprevention efficacy study (CPES) protocol. The aim is not only to explore
if chemoprevention failure takes place, but if this is as a result of recrudescent
infections, new infections or under-dosing. As proposed by the standard CPES protocol,
both malaria thick smears and dry blood spots (DBS) will be taken at day 0, day 2, day
7, day 14, day 21 and day 28 after administration of the first three-day dose of SPAQ,
which will be administered through directly observed therapy (DOT). In addition to what
is proposed by the standard CPES protocol, all DBS samples on day 0 and day 28 will be
processed in order to ascertain low density parasitemia estimates through qualitative
polymerase chain reaction (qPCR). If sufficient DNA exists, day 0 and day 28 qPCR
genotypes will be compared. If children are found to have malaria infections, presence
of the same haplotype would indicate a recrudescent infection. If different haplotypes
are present, this would indicate a new infection after SPAQ administration. The qPCR
methodology is designed to amplify only parasites that have freshly emerged from the
liver. DBSs will also be processed for parasitemia estimations and genotyping on days 2,
7, 14 and 21 if a child's thick smear on those days was positive or, retrospectively, if
subsequent DBSs are Plasmodium falciparum positive. A DBS will also be collected
whenever a child has fever and is malaria positive on a rapid diagnostic test (RDT).
Drug level, qPCR parasite estimation and genotyping will also take place. Assuming a 3%
breakthrough infection rate sampling 494 children will provide a 95% confidence interval
of 1.7% to 4.9%. Assuming a 99% response rate and 1% loss to follow up a sample size of
500 children is considered appropriate. Finger pricks will be conducted by trained
nurses or health personnel both for thick blood smears and for DBS. Dose, weight, age,
length of mid-upper arm circumference, tympanic temperature, location, time and date
will be recorded for each child on day 0 and all subsequent time points on day 2, 7, 14,
21 and day 28 when the follow up slides and DBS will be taken. Thick blood smears and
DBS will be prepared for processing by a trained laboratory technician. All thick smears
and DBSs will be sent to a suitable laboratory with high-sensitivity pharmacology
capacity for microscopy and qPCR analyses. A questionnaire exploring if the child
received other treatment or experienced any disease since SPAQ administration will be
co-administered every time a sample is taken. Caregivers will be reminded at each visit
to the household to seek care at a health facility or from a community health worker if
the child becomes febrile. A system will be put in place to record RDT results and any
treatments received. On day 28, data collectors will also administer a questionnaire to
each caregiver to explore the child's illness history over the duration of the study.
The laboratory will send the processed data back to Malaria Consortium, where the
relevant mutations distributions and proportions will be analyzed comparing
parasitological efficacy between groups of mutations. The drug levels will be analyzed
as a cohort by mean, median and standard deviation and determine any correlations with
treatment outcomes, in particular drug concentrations on day 7. Day 28 positivity will
be correlated to antimalarial drug resistance genotype.
3. Resistance markers study The aim of this study component is to continue to monitor
prevalences of SP and AQ resistance and any increase in resistance prevalence after one
annual round of SMC (in the two new phase 2 study districts) or two annual rounds of SMC
(in the two phase 1 districts) as assessed via molecular markers in the population. A
specific objective is to detect prevalence over time in the proportion of symptomatic
children with an RDT residing in the districts where SMC is implemented who carry
parasites with mutations compared to children living in similar districts without SMC.
Trends of SP and AQ resistance will be monitored in the two original intervention
districts, as well as in the two research districts. A health facility-based,
cross-sectional survey will be conducted before SMC project implementation (base line)
and after one complete round of SMC distribution (end line). Monitoring the prevalence
of alleles associated with resistance to drugs is, by standard protocol, done by
collecting samples from symptomatic children with evidence of infection. The sample
collection will be performed in four selected first level of care health facilities in
each study district. The key markers to be monitored are: dihydrofolate reductase
(dhfr): codons 108, 51, 59 and 164; dihydropteorate synthetase (dhps): codons 431, 437,
540, 581 and 613; Pf chloroquine resistance transporter gene (pfcrt): codons 72-76; Pf
multidrug resistance gene 1 (pfmdr1): codons 86, 184 and 1246 and Plasmepsin 2 (plm2).
The sample size for the survey was determined using a World Health Organization protocol
for drug efficacy testing with the intention to estimate changes in prevalence of SP and
AQ resistance markers with enough precision to provide reassurance that there has been
no important increase, while having adequate power to detect changes if they occur. A
sample of 300 children per district (150 each at base line and end line) is expected to
result in 90% power to detect a difference at 5% level between baseline and end line.
The total sample size will therefore be 1,500, with 750 children to be sampled at both
baseline and end line.
