Drug Resistant Malaria Due to Plasmodium Falciparum Clinical Trial
Official title:
Assessment of Antimalaria Drugs Susceptibility Testing for an Effective Management of Infected Patients in Sub-Sahara Africa
The antimalarial drugs efficacy and safety study will be conducted in the Clinics and
hospital of the Cameroon Development Corporation (CDC) Estates, Tiko Health District,
located in a typical forest and rainfall area in the South West Region Cameroon. In this
study, 350 children aged 6 months to 5 years who are found to have uncomplicated symptomatic
malaria will be enrolled between October 2012 and March 2013. Participants will be
randomized to receive one of the following medications.
(i) DHA+PQ : dihydroartemisinin, 2.5 mg per kg, plus piperaquine phosphate, 20mg per kg
daily for 3 days; (ii) ART LUM : Artemether, 2mg per kg, plus lumefantrine 10mg, twice daily
for 3 days; (iii) AS+MQ: artesunate, 4 mg/kg/day, with mefloquine, 8 mg/kg/day orally once a
day for 3 days.
All study medications will be administered orally The Primary objective of this study are to
compare the efficacy, safety and tolerability of orally administered artemether plus
lumefantrine (ART+LUM), artesunate plus mefloquine (AS+MQ) and dihydroartemisinin plus
piperaquine (DHA+PQ) combinations in the treatment of uncomplicated falciparum malaria in
Cameroon in order to provide evidence that can be used to determining the optimum
antimalaria treatment policy in Cameroon. The secondary objectives are as follows (i) To
valuate the efficacy and safety of artemether plus lumefantrine (ART + LUM) and artesunate
plus mefloquine (AS + MQ) versus dihydroartemisinin plus piperaquine (DHA + PQ) combination
(ii) To compare the clearance of asexual parasites and gametocytes in each treatment arm
(iii) To assess the clearance of fever (iv) Assess effect of each treatment arm on anemia
This study is a randomized, double blinded clinical trial. After enrollment, participant
will be randomized to one of the three treatment regimen. The treatment outcome will be
assessed through a 42-day efficacy study. Participants who will exhibit early or late
treatment failure and those with adequate clinical response and parasitological failure on
day 14, 28 or 42 will be treated with quinine (25mg base per kg body weight per day in three
divided doses for five days). In addition to antimalarial drugs oral paracetamol (50mg/kg
body weight per day in three divided doses) will be administered for fever exceeding 37.5%.
Polymerase Chain Reaction (PCR) -corrected 28 day and 42 day efficacy will be evaluated for
each treatment episode.
Malaria incidence has increased two- to three-folds over the past four decades, and nearly
half the world's population now lives in regions endemic for malaria: In Asia, Africa, and
South America. A global annual estimate of 300-500 clinical cases of malaria and mortality
in the range of 1-2 million is reported, 90% of which occurs in sub-Saharan Africa. In
Cameroon, malaria remains the number one public health problem with more than one million
five hundred cases and three thousand one hundred and sixty two deaths in health facilities
per year. Indeed, 45-50% of consultations, 23% of hospitalizations and 35% of deaths among
children under 5 years are attributable to malaria Early diagnosis and treatment for malaria
remain the most acceptable strategy for malaria control. Mortality is rising and approaching
three million malarial deaths each year, in large parts because of increasing resistance to
antimalarial drugs. The emergence and spread of P. falciparum resistance to conventional
monotherapies such as chloroquine (CQ), amodiaquine (AQ), mefloquine (MQ),
sulfadoxine-pyrimethamine (SP) resulted in the request of more effective and accessible
antimalaria drugs to the entire population living in endemic areas.
In Cameroon, prior to 2002, CQ and SP were the first and second line antimalarial drugs
respectively. Studies conducted in different ecological settings in Cameroon revealed marked
decline of these drugs with 67% clinical failure for CQ alone . This led to an interim
adoption of AQ by the Ministry of Public Health. A series of randomised, open controlled
trial revealed that AQ was still effective when administered as monotherapy or in
combination with SP since only 10.2 %, 13.6 % and 0% clinical failures were recorded for AQ,
SP and SP+AQ respectively. However, studies conducted in Guinea Savannah showed decline
rates of these antimalarials drugs with clinical failures of 40%, 20%, and 13.6% for AQ, SP
and AQ+SP combination.
Widespread resistance of malaria parasite to these commonly available antimalaria drugs has
necessitated country to review and deploy new antimalarial drug policies to ensure effective
case management. The World Health Organization (WHO) currently recommends artemisinin-based
combination therapies (ACTs) as the best first-line treatment for uncomplicated falciparum
malaria, but studies to ensure that current regimens are optimal are incomplete.
Artemisinine-based combination therapies (ACTs) are most preferred for their enhancement of
efficacy and their potential to lower malaria incidence and the rate at which resistance
emerges and spread\. Due to their rapid clearance time, treating early cases of
uncomplicated malaria with ACTs may prevent its progression to severe malaria with
consequent reduction in severe cases and malaria mortality rate. Although the National
Malaria Control Programme (NMCP) of Cameroon adopted amodiaquine plus artesunate (AQ+AS) and
arthemether plus lumefantrine (ART+LUM) for the treatment of uncomplicated malaria in 2004,
there was no local data in support of the policy. In series of subtrials to constitute a
database of anti-malarial drug efficacy in Cameroon, AQ was proposed to be the most rational
partner of artesunate; likewise, a single arm study provided preliminary evidence of safety
and efficacy of AQ+AS but with low statistical power to detect rare events and no PCR
corrections to distinguish re-infection from recrudescence. Meta-analysis studies have shown
ART-LUM to be highly effective and safe when the twice daily doses (total of six doses) are
administered under supervision, but there are concerns that six doses of ART-LUM over three
days may reduce compliance. Nevertheless, relatively few numbers of patients complained of
physical fatigue during ART-LUM treatment but trials comparing it to order ACTs are few.
AS+AQ combination is less expensive and subsidized by the Cameroonian Government, it is
believed that its cure rate may be lower than that of ART-LUM because of parasite resistance
to AQ and as such, its inclusion in ACTs is likely going to fail. In addition, the minor,
transient side effects of AQ may lead to poor compliance and subsequent decline in AQ
efficacy. In Southeast Asia, where P. falciparum is the most drug-resistant in the world,
three-day artesunate-mefloquine treatment is generally the preferred treatment for
uncomplicated malarial infection. Studies in Laos, suggest that artesunate plus mefloquine
(AS-MQ) and ART-LUM combinations are both effective and are superior to CQ plus SP in the
treatment of uncomplicated falciparum malaria. However, ASMQ has been limited by the high
cost, the frequency of adverse effects associated with mefloquine, and the lack of a
formulation combining both antimalarials in a single tablet. In addition, reduced efficacy
of artesunate-mefloquine has been reported recently from the southeastern border of
Thailand.
Artemether plus lumefantrine has fewer adverse effects but is also relatively expensive. A
global analysis of a series of randomized studies of anti-malarial treatment efficacy
conducted in Cameroon between 2003 and 2007 ART-LUM to be the most effective ACT with no
treatment failure due to recrudescence (98.3% cure rate PCR corrected), followed by
dihydroartemisinin-piperaquine with 92.7% cure rate. After PCR adjustment, 28 days cure
rates was 91.7% for AS-SP 88.7% for artesunate-amodiaquine, and 76% for
artesunate-chlorproguanil-dapsone. Clinical trials in Cambodia and Vietnam suggest that the
dihydroartemisinin plus piperaquine (DHA+PQ) combination is highly effective against P.
falciparum parasites with few adverse effect in both children and adult. In Cambodia, the
28-days cure rates were 98.6% in children and 92.3% in adult and in Vietnam, using
dihydroartemisinin-piperaquine-trimethoprim combination, the 56-days cure rates in children
and adults were 97-98% (Tran et al., 2004). In addition, it is relatively inexpensive
compare to other ACTs, at 1 $ US per treatment course (Mutabingwa et al., 2005).
Therefore if it is demonstrated that DHA-PQ is an effective antimalaria in Cameroon, with
fewer adverse effects in comparison to AS-MQ and ART-LUM, it may be an alternative treatment
available to the Government of Cameroon with the advantages of being coformulated and
available at lower cost than the other ACTs.
In order to determine the comparative efficacy and adverse effects profile of antimalaria in
Cameroon, investigators propose to carry out an open randomised comparative clinical trial
of the combination of oral arthemether plus lumefantrine (ART+LUM) and artesunate plus
mefloquine (AS+MQ)versus dihydroartemisinine plus piperaquine (DHA+PQ) combinations in the
treatment of uncomplicated malaria.
Primary objective :
The objective of this study is to compare the efficacy, safety and tolerability of orally
administered arthemether plus lumefantrine (ART+LUM), artesunate plus mefloquine (AS+MQ) and
dihydroartemisinin plus piperaquine (DHA+PQ) combinations in the treatment of uncomplicated
falciparum malaria in Cameroon in order to provide evidence that can be used to determining
the optimum antimalaria treatment policy in Cameroon.
Secondary objectives :
- To valuate the efficacy and safety of artemether plus lumefantrine (ART + LUM) and
artesunate plus mefloquine (AS + MQ) versus dihydroartemisinin plus piperaquine (DHA +
PQ) combination
- To compare the clearance of asexual parasites and gametocytes in each treatment group
- To assess the clearance of fever
- To assess effect of each treatment arm on anemia
STUDY SITE AND DESIGN It is a randomized clinical trial comparing the efficacy of oral
dihydroartemisinin plus piperaquine to artemether plus lumefantrine and artesunate
mefloquine combinations. The formulation of the test will be unilateral (Null hypothesis:
DHA +PQ = ART+LUM or DHA + PQ = AS + MQ ; Alternative hypothesis: DHA +PQ > ART+LUM or DHA +
PQ> AS + MQ) The trial will be conducted in a typical forest and rainfall area located in
south-western Region of Cameroon. Patients will be recruited in the outpatient pediatric
unit of satellite clinics and references hospital under Cameroon Development Corporation
(CDC) administration, between October 2012 and March 2013
ELIGIBILITY
- Inclusion criteria : The inclusion criteria are; signs/symptoms of uncomplicated
malaria including axillary temperature ≥ 37.5; monoinfection with Plasmodium
falciparum; parasite count between 2000 and 200 000 per μl; haemoglobin level> 5 g/dL;
absence of signs/symptoms of severe malaria or other diseases requiring drugs with
antimalaria or antihistaminic activities; parent/guardian willingness to give their
consent
- Exclusion criteria: Exclusion of patients with the following criteria; Chronic disease
(HIV, malnutrition etc.), severe malaria, severe anaemia (haemoglobin level< 5 g/dL),
respiratory distress, inability to drink, convulsion etc., history of allergie to test
drugs; co-infection requiring drug with antihistaminic or antimalaria activities such
as cotrimoxazole
SAMPLING AND SAMPLE SIZE:
The minimum participant per arm was calculated to be 50 in order to detect reduction of
fever for at least 12 hrs, with the standard deviation of 18, and α and β values set at
0.05. However, the sample size will be increase by 10% in order to take account of
individuals lost of follow-up. Therefore the total number of participants to be enrolled in
this study is estimated to be at least 180 with 60 participants per treatment arm.
INITIAL EXAMINATION This will include a complete physical examination and blood sample
analysis. After finger pricking, samples of capillary blood will be used to prepare two
thick films, to determine haematocrit, to conduct the Rapid Diagnosis Testing (RDT),
impregnate an isocode stix (50 µl for DNA extraction) by depositing a drop of blood on this
filter paper while avoiding any contact with the finger. All slides, cassette and stix will
be labelled with patient's individual code numbers and date of collection. They will be air
dried and kept away from insects. The stix will be stored with a desiccant in individual
plastic bag. The microscopy slides will be stained and kept in slides boxes. Parasite
density will be counted on thick blood film stained with Giemsa then examined under the
microscope. The reading will be on 200 leukocytes and the result will be expressed in number
of asexual parasites per µl of blood by estimating the average white Blood Cell (WBC) count
of 8000/µl of blood. Anemia will be assessed by the measurement of hematocrit in heparinized
capillary tube, centrifuged for 5 minutes. Finger prick blood sample will be used to search
for the Plasmodium falciparum Histidin Rich Protein 2 (HRP2).The mutations responsible for
drug resistance will be identified on isolates of P. falciparum, collected on filter paper
by molecular biology techniques
TREATMENT REGIMEN
Upon arrival to the health facility, patients who will meet the inclusion criteria and give
their consent, will be randomly assigned to one of the following combination and doses: (i)
DHA+PQ : dihydroartemisinin, 2.5 mg per kg, plus piperaquine phosphate, 20mg per kg daily
for 3 days; (ii) ART+ LUM : Artemether, 2mg per kg, plus lumefantrine 10mg, twice daily for
3 days; (iii) AS+MQ: artesunate, 4 mg/kg/day, with mefloquine, 8 mg/kg/day orally once a day
for 3 days.
All drugs will be administered with water except for ART-LUM, which will be given with milk
to increase bioavailability. All doses will be administered under supervision. After drug
ingestion, the patient will be observed for at least 30 minutes. Children who will vomit
within this period will receive the same repeated doses. Patients with persistent vomiting
will be withdrawn from the study. After the procedure patients will be given a schedule for
routine follow-up visits. Parents/guardians will be informed to immediately return their
children/ to the assessment team at any time during or outside the follow-up periods if
symptoms return.
The personnel who will administer the doses will be different from those who will follow the
patient up and examine the blood smears.
Rescue treatment:
Children who will exhibited early or late treatment failure and those with adequate clinical
response and parasitological failure on day 14, 28. or 42 will be treated with quinine (25mg
base per kg body weight per day in three divided doses for five days), in accordance with
the Cameroon National Malaria Control Program and the WHO guidelines on antimalarial
treatment. In addition to antimalarial drugs oral paracetamol (50mg/kg body weight per day
in three divided doses) will be administered for fever exceeding 37.5oC. In the event of
concomitant bacterial infection, absent on day 0 but present during the follow up,
amoxicillin will be administered at 50mg per kg body weight per day for seven days
Non recommended treatment: antibiotics such as cotrimoxazole with antimalaria or
antihistaminic activities.
MONITORING FOR SAFETY, PARASITOLOGICAL AND CLINICAL RESPONSES The clinical response will be
monitored on days 1, 2, 3, 7, 14, 28 and D42. All patients will be followed up by means of
home or facility visit. Therapeutic efficacy will be evaluated in relation to three major
criteria: (1) the fever clearance time define as the time taken to attain a rectal
temperature below 38°C (ii) The proportion of negative thick smears on days 7, 14, 28, D42
and (iii) the number of early (D1-D3) and late (D4-D42) treatment failures. The clinical and
parasitological responses will be classified as early treatment failure, late treatment
failure or adequate clinical and parasitological response according to the WHO definition.
Other criteria include recrudescence of parasitemia, frequency of advert effects side
(pruritus, fatigue, headache, dizziness, nausea, vomiting, diarrhea, skin rash, palpitation,
bradycardia). Judging criteria will be evaluated by observers unaware of the treatment
administered. Rectal temperature will be taken with an electronic thermometer. Side effects
will be noted from the statements of parent/guardians. Parasite densities will be read
against 1000 leukocytes.
FOLLOW-UP PROCEDURE
Follow-up schedule Patients will be assessed daily during the scheduled follow-up. Adverse
effects will be assessed based on non-suggestive questioning by the investigators. After
patient enrolment at D0, clinical assessment will be made on day 1, 2, 3, 7, 14, 28 and 42
as recommended in the WHO protocol. Patients will be advised to return on any day outside
the schedule period (D8-D13) (D15-D27), and (D29-D41) if symptoms returned and not to wait
for scheduled visits. Blood films for parasite count and filters paper samples will be
examined on these days or on any other day when ever a child spontaneously returns. Routine
blood investigations (hematology and biochemistry) will be performed prior to (Day0) and
weekly for the 4 weeks of the study period. Haemoglobin will be typically reassessed on day
7, 14, 28, 42. Provision will be made ahead of time for locating patients at home if they do
not respond to schedules Study end-point Valid end point includes treatment failure,
completion of follow-up period without treatment failure, loss of follow-up, protocol
violation and severe adverse effects.
Statistical analysis The data will be analysed by means of Statistical Package for the
Social Sciences (SPSS). Qualitative variables will be compared using the X2 or Fisher's
exact test, and quantitative variables will be compared by analysis of variance or the
Kruskaul-Wallis test. The 95% confidence intervals of proportions will be calculated using
the binomial test and the level of significance (P) set at 0.05 for all statistical tests.
ETHICAL CONSIDERATION Tests drugs are included in national guidelines and are prescribed
daily in Cameroon. The aim of the study, the advantages and the constraints will be
explained in order to obtain the parent/guardian consent. Participation fee for all patients
(transportation, laboratory analysis) will be free of charge.
Data collection and analysis
Data will be collected on separate standardized questionnaires for enrollment and
monitoring. Follow-up questionnaires and patient case record forms will be handed to the
coordinator on daily basis, who will archive them after verification and data analysis.
Estimated Time to Complete Enrollment:
The total duration of the survey is estimated at 150 days based on 83 days of enrolment (an
average of 4 enrolments per day), 42 days for the follow-up of the last enrolled patient,
and 25 days for data analysis and report writing.
;
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator, Outcomes Assessor), Primary Purpose: Treatment
| Status | Clinical Trial | Phase | |
|---|---|---|---|
| Recruiting |
NCT02604966 -
P. Falciparum Resistance to Artemisinin in Vietnam
|
Phase 4 |