Antimalaria Drugs Susceptibility Testing for an Effective Management of Infected Patients in Sub-Sahara Africa
Condition: Drug Resistant Malaria Due to Plasmodium Falciparum
MeSH terms: Malaria; Disease Susceptibility
Study type: Interventional
Phase: Phase 3

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Arthemeter-lumefantrine; Artesunate mefloquine; Dihydroartemisinin piperaquine; Paracetamol; Amoxicillin; Quinine
Intervention type(s): Drug; Drug; Drug; Drug; Drug; Drug
Intervention description(s): Randomization codes were computer-generated by an offsite investigator and provided to a study nurse responsible for treatment allocation. All other study personnel were blinded to the treatment assignments, and patients were not informed of their treatment regimen. Participants from Group 1: AL, Group 2 : DHAP, Group3 : ASMQ were also given appointment card for days 1, 2, 3, 7, 14, 21, 28, 35 and 42 for clinical examination and blood smears. Blood was taken on filter paper on each of these visits.; Artequin® is an antimalarial drug presented as infant co-formulation of two separate drugs; Malacur®. is an antimalarial drug presentad as co-formulation of two separate drugs; Paracetamol, is an antipyretic drug, presented as tablets or syrup in infants formulation; Amoxicillin is an antibiotic with no reported activity on plasmodium; quinine sulphate is an antimalaria drug administered as a second line or rescue drug
Other intervention name(s): Cofantrine®; Artequin®; Malacur®; Paracetamol syrup; Clamoxyl® 125 mg/5mL; Quinine sulphate
Intervention MeSH terms: Acetaminophen; Amoxicillin; Artesunate; Lumefantrine; Piperaquine; Artenimol; Mefloquine; Quinine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary purpose: Treatment