Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT01704508 |
| Other study ID # |
Eurartesim-2012 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
Phase 4
|
| First received |
|
| Last updated |
|
| Start date |
November 2012 |
| Est. completion date |
July 2016 |
Study information
| Verified date |
August 2015 |
| Source |
Bandim Health Project |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Plasmodium falciparum causes malaria and approximately 665 000 deaths each year. chloroquine
and sulphadoxine-pyrimethamine resistant P. falciparum are widespread. An artemisinin
derivative combined with lumefantrine, amodiaquine or piperaquine is therefore recommended
for the treatment of malaria in Africa. However, artemisinin resistance appears to be
developing and resistance/tolerance to amodiaquine and lumefantrine exists. We are presently
conducting a study in Guinea-Bissau. Preliminary data indicates that the effectiveness and
availability of artemether-lumefantrine (AL), the 1st line drug, is poor. Consequently there
is a need for another treatment option. Dihydroartemisinin-piperaquine (DP) has been shown to
be efficacious and well tolerated in several African countries and is therefore such an
option. A clinical trial comparing the safety and efficacy of artemether-lumefantrine and
dihydroartemisinin-piperaquine is therefore needed.
Parents to children seeking Bandim Health Centre (CSB) with symptoms compatible with malaria
will be informed of the study. If accepting and the child fulfil the inclusion criteria, the
child will be randomised to treatment with either AL or DP. The treatment will be given
supervised at the health centre in the morning and the evening on day 0, day 1, and day 2.
At each visit and in the morning on day 3, the child will be examined, the mother asked for
any symptoms and signs of side-effects, the temperature measured. Furthermore, a blood sample
will be taken for examination of malaria parasites. On day 0 samples for measurement of
antimalarial drugs and for genotyping of the parasites will be taken on filterpaper. In a
subgroup of 50 children a blood sample for in vitro culturing and for analysis of the number
of leucocytes will also be taken.
After having finished the treatment the children will be followed on day 7 and then once a
week until day 42. At each visit the condition of the child will be examined and a
bloodsample taken for examination of parasites in the blood. Furthermore, a filterpaper
bloodsample will be collected for measurement of the drug concentration of if the child has
recrudescence for genotyping of the parasites. On day 0, 3 and 42 the haemoglobin level will
be examined.
The result of the two treatments will be evaluated by comparing the number of children with
recurrent parasitaemia, both corrected and uncorrected (recrudescence vs. reinfections). This
will be presented as adequate clinical and parasitological response rates PCR-corrected and
PCR-uncorrected. Furthermore, the chance in haemoglobin level from day 0 till day 3 and till
day 42 will be compared. The concentration of the antimalarial drug in the blood samples
taken at the visit before the re-parasitaemia will be capered to the concentrations in
children without re-parasitaemia.
Assuming a 20% loss to follow up a total of 346 children should be included. For the children
included, health care and medications at Bandim Health Centre will be free during the study
period but no other gifts or payments will be made.
Results will be presented to the staff at the Bandim health centre and the ministry of Health
and will be published in an international peer reviewed journal.
Description:
Background Plasmodium falciparum causes malaria and approximately 665 000 deaths each year.
Previously chloroquine (CQ) and sulphadoxine-pyrimethamine were the principle drugs for the
treatment of malaria. Due to widespread resistance to these drugs1, the World Health
Organization recommends that P. falciparum in Africa should be treated with artemisinin +
amodiaquine, artemether + lumefantrine (AL) or dihydroartemisinin + piperaquine2 (DP).
However, resistance to artemisinins appears to be developing3,4, resistance to amodiaquine
exists2 and treatment with AL rapidly selects for parasites with increased tolerance (5 times
higher inhibitory concentration) to lumefantrine5-7.
In Guinea-Bissau, CQ remained efficacious until replaced by AL. This is explained by the use
of a unique well tolerated high dose treatment schedule 8-10. Since the introduction of AL in
2008, the number of children with malaria has increased manyfold in Bissau in contrast with
other African countries. Our data suggests that this increase is due unavailability of AL,
poorer than expected effectiveness of AL and to an increased use of the second-line drug
quinine. Quinine is typically given for 3 instead of 7 days and has very poor efficacy when
used thus11. To counter this Guinea-Bissau needs an alternative cheap and easily dosed 2nd
line drug that can also be used when AL is not available or when funding for AL no longer
exists.
Dihydroartemisinin+piperaquine is a safe and well tolerated artemisinin based combination12.
DP is taken once daily and has been shown to be highly efficacious (>95%) in several African
settings13,14. DP also protects from re-infection for longer than AL14. As such this is a
drug that could become an attractive treatment option in Guinea-Bissau. It has however, never
been used in the country.
Aim Conduct an efficacy study with artemether + lumefantrine and dihydroartemisinin +
piperaquine
1. To measure the efficacy and safety of AL and DP in children aged 6 months to 12 years
suffering from uncomplicated P. falciparum malaria.
2. To determine the capacity of each drug combination to protect against re-infection.
3. To differentiate recrudescence from re-infections using PCR based methods
4. To determine whole blood concentrations of lumefantrine and piperaquine the week before
reparasitaemia
5. To determine haemoglobin values on days 0, 3 and 42
6. To determine differential white blood cell counts on days 0, 3, 7, 14 and 21
7. To determine genetic polymorphisms in P. falciparum causing reparasitaemia,
8. To culture parasites from 50 children for further characterisation of P. falciparum
geno- and phenotypes.
2. Methods Study design This will be an open label, randomized, non inferiority trial
conducted at the Bandim health centre, Guinea-Bissau. Children with uncomplicated
malaria who meet study inclusion criteria will be enrolled, randomised to treatment with
either AL or DP, treated on site and monitored for 42 days. The follow up will consist
of a fixed schedule of check-up visits and corresponding clinical and laboratory
examinations. The proportion of children experiencing therapeutic failure during the
follow-up period will be used to estimate the efficacy of the study drugs. PCR analysis
will be used to distinguish between a true recrudescence due to treatment failure and
episodes of re-infection.
Study Site and population Children aged 6 months to 12 years with uncomplicated P.
falciparum malaria that attend the Bandim health centre.
Timing and duration of the study The study will start in November 2012 and continue
until 350 children are included. If this is not achieved in one year the study will run
for 2 years.
Inclusion criteria A) Age ≥6 months, and <13 years. B) Mono-infection with P. falciparum
detected by microscopy. C) Parasitemia of 1.000-200.000/µl asexual forms. D) Axillary
temperature ≥37.5 ˚C or a history of fever within 24 hours. E) Ability to swallow oral
medication.
F) Ability and willingness to comply with the study protocol for the duration of the
study and to comply with the study visit schedule. G) Informed consent from a parent or
guardian
Exclusion criteria A) Signs or symptoms of severe malaria including the following
symptoms Prostration. Impaired consciousness. Respiratory distress. Repeated generalised
convulsions (three or more per 24 hours or 2 witnessed seizures in 24 hours).
Circulatory collapse. Abnormal bleeding. Jaundice. Haemoglobinuria (dark red/black
urine). Severe anaemia (Haemoglobin <5g/dl). Hyperparasitaemia (>200.000/ µl asexual
forms) B) Presence of general danger signs in children under 5 including the following
Prostration. Respiratory distress. Haemoglobin <5g/dl. Two or more convulsions within 24
hours. Persistent vomiting C) Presence of severe malnutrition. D) Any evidence of
chronic disease or acute infection other than malaria. E) Regular medication which may
interfere with antimalarial pharmacokinetics. F) History of hypersensitivity reactions
or contraindications to AL, DP or quinine.
G) Domicile outside the study area.
Loss to follow up If a child is not seen on the day of follow up the child will be
sought at home on two consecutive days and if possible contacted by mobile phone. At
each subsequent weekly follow up three new attempts to see the child will be made.
3. Treatment Antimalarial treatment Treatment with AL will be given according to a
6-dose regime. Treatment with DP will be given according to a 3 dose regime. Tablets of
AL (20 mg artemether and 120 mg lumefantrine) will be obtained from the manufacturer.
Tablets of DP (Eurartesim®) with 160mg/20mg or 320mg/40mg obtained from Sigma-Tau.
Block Randomization Identical slips of paper specifying treatment arm AL or DP will be
put into an envelope. Each envelope will contain 20 slips from each group and children
will randomly select one slip.
Concomitant treatment and medication that should not be used Paracetamol will be used to
treat fever. Iron and vitamin supplementation will be given if required. Prior treatment
with an antimalarial drug will not be considered as exclusion criteria. Children taking
any drug with antimalarial activity (including antibiotics such as tetracycline or
azithromycin) during the study period will be withdrawn.
Rescue treatment If children vomit twice, they will receive therapy with quinine
intramuscularly and will be withdrawn from the study. Any child with signs of severe or
complicated malaria will be treated according to recommendations of the attending nurse.
If a child meets criteria for early treatment failure, he or she will receive parenteral
quinine. If a child meets criteria for late treatment failure he or she will be
re-treated with AL.
4. Evaluation Criteria Efficacy and safety evaluation Treatment outcomes will be early
treatment failure, late clinical failure, late parasitological failure or adequate
clinical and parasitological response as defined by the WHO2.
Safety end points The incidence of any adverse event including neutropenia will be
documented. All children will be asked routinely about previous symptoms and about
symptoms that have emerged since the previous follow up visit. When clinically
indicated, children will be evaluated and treated appropriately. All adverse events will
be recorded in the case record forms.
Clinical evaluation All children will be evaluated by an attending study nurse and the
examination will include a physical examination, body weight, body (axillary)
temperature as shown in table 3
Microscopic examination Two thick and thin blood films for parasite counts and species
identification will be obtained as shown in table 3 and whenever a child returns to the
Bandim health centre. Slides will be stained using freshly prepared Giemsa and examined
with 1000 x magnification. The number of asexual parasites per 200 white blood cells
will be counted or, if parasitaemia is high, the number of white blood cells per 500
parasites will be counted. Parasite density will be assessed independently by 2
qualified microscopists. Discordant results will be read a third time.
Genotyping, antimalarial drug concentration, haemoglobin and white blood cell count
100µL of blood will be collected on Whatman 3MM filter-paper using a capillary tube on
day 0, 7, 14, 21, 28, 35, 42 and whenever reparasitaemia is detected. Filter-papers will
be dried and then placed inside separate sealed plastic bags. Filter-papers and bags
will be labelled with study number date and follow up day. The samples will be stored at
-20˚C. Blood samples will be obtained at the same time that blood is taken for
microscopy.
In order to differentiate recrudescence from a re-infection genotyping using sequential
analysis of pfglurp, pfmsp1 and pfmsp2 will be done21.
The proportion of resistance associated genotypes in resistance associated genes
including pfcrt, pfmdr1, pfmrp1 and pfcmu will be determined. Genotyping will be done at
Karolinska Institutet, Stockholm, Sweden and/or Universidade do Minho, Portugal.
Drug concentrations will be assessed on the week prior to reparasitaemia at Mahidol
University Bangkok using high performance liquid chromatography (HPLC).
Haemoglobin concentration will be determined on day 0, 3 and 42 using a haemocueTM At
the same time that blood sampling for microscopy is done on Day 0, exactly 200μL of
blood will also be taken for in vitro culturing from 50 patients. The blood will be put
into medium and grown in vitro in an incubator at 37 ˚C. When a culture is established
it will be frozen in liquid nitrogen for transport to Sweden or Portugal where extensive
drug assays will be carried out.
5. Study Assessment Screening and enrolment As part of the routine medical services
provided at the health centre, all children with symptoms suggestive of malaria will be
screened for malaria using a rapid diagnostic test. Positive tests are confirmed by
microscopy. Children fulfilling inclusion critera will be invited to participate in the
study following informed consent.
Follow up Children will be given a unique personal identification number and be given
treatment after informed consent. The basic follow up schedule is shown below.
Treatments, information to the children, clinical observations and adverse events will
be recorded in the clinical record forms. The children will come to the health centre on
days 0, 1, 2, 3, 7, 14, 21, 28, 35 and 42. If a child is not seen at the health centre
he/she will be visited at home.
6. Data Management The principle investigator will ensure that the study protocol is
strictly adhered to and that data are correctly collected and recorded on the case
record form. Data will be entered into an EpiData database during the study.
7. Sample size The PCR corrected day 42 ACPR of AL was 97% in 2008 ( = before the
national recommendation was changed in favour of A). It is likely that DP should be as
efficacious as AL and it is therefore appropriate to conduct a non-inferiority trial13.
Assuming 97% ACPR for both treatments, 5% significance level (alpha), 80% power (1-beta)
and a non-inferiority limit (d) of 5% 144 children are required in each arm. Assuming a
20% loss to follow up a total of 346 children should be included.
Analysis of data The data will be analysed using survival estimates of per protocol
treatment failure rates but also intention to treat treatment failure rates. Final
analysis will include a description of included children, proportions of adverse events
and any serious adverse events, the proportion of children withdrawn or lost to follow
up, the cumulative PCR corrected and uncorrected success and failure rates on day 42 and
the proportion of early, late clinical and late parasitological treatment failures.
