Impact of Artemisinin-based Combination Therapy and Quinine on Treatment Failure and Resistance in Uncomplicated Malaria
Condition: Malaria
MeSH terms: Malaria
Study type: Interventional
Phase: Phase 3

Summary: 
      This is a bi-centric phase IIIb, randomized, open label, 3-arm clinical trial performed to
      investigate the impact of retreatment with an Artemisinin-Based Combination (ACT), for
      example Arthemeter-Lumefantrine (AL) in Uganda (Ug) and artesunate-amodiaquine (ASAQ) in
      RDCongo, on malaria incidence and its potential selection of resistant strains.

      Patients will be followed-up for efficacy and safety during 42 days after treatment with the
      first line therapy recommended by the national authorities(arthemeter-lumefantrine in Uganda
      and artesunate-amodiaquine in RDCongo) and retreated the patients either with the same ACT or
      an other ACT or oral Quinine + clyndamicin.

      The investigators hypothesize that (re)treatment with the first line ACT treatment beyond 14
      days is as efficacious as any other rescue treatment, without the risk of selecting drug
      resistant strains.
    

Detailed description: 
      RATIONALE Following the World Health Organization (WHO) guidelines, most African countries
      have opted for ACT. Several clinical trials on ASAQ, an ACT, completed in Africa have shown
      an efficacy > 90% (3-5). Furthermore, after The polymerase chain reaction (PCR) analysis,
      over 75 % of ASAQ & AL treatment failures have been classified as new infections, while
      recrudescences have low parasite densities. ASAQ is safe and easy administered, with a good
      treatment adherence. Therefore, effectiveness may be close to efficacy . ASAQ has now been
      developed as fixed-dose combination and registered. The Democratic Republic of Congo (DRC)
      has also chosen ASAQ as first-line treatment for uncomplicated malaria.

      Efficacy of the 6 dose regimen of AL has been demonstrated in semi-immune and non-immune
      populations in Asia and Africa to be consistently greater than 95%, with rapid parasite and
      symptom clearance and significant gametocidal effect. In Uganda, AL has already been chosen
      as first-line treatment for uncomplicated malaria.

      In DRC and Uganda, quinine is the rescue treatment for malaria. It is cheap, widely available
      and generally considered to be effective but is not popular due to the unwanted side effects.
      Quinine has a very short half life, therefore repeated dosing is required. In an efficacy
      study of quinine and artemisinin for uncomplicated malaria in Vietnam, recrudescence rates
      were 16% after 7 days of quinine monotherapy. In studies conducted in Gabon, Plasmodium
      falciparum in Vitro sensitivity to quinine was high and had not changed over the past decade.
      Although quinine monotherapy shows high efficacy in the setting of clinical trials, it has
      considerable disadvantages, mainly because of its poor tolerability and the prolonged
      treatment course. Poor adherence carries a high risk of treatment failure, particularly
      because quinine causes a syndrome of adverse effects known as cinchonism that includes
      primarily tinnitus, nausea, and vertigo. Other reported side effects are high tone hearing
      impairment, dizziness, hypotension as well as headache and visual disturbances. As result of
      these side effects, some studies have reported poor compliance to treatment. A randomized
      trial in Thailand reported 71% adherence Such poor adherence to the 7-days regimen is
      associated with a high risk of treatment failure, which can contribute to the development and
      spread of resistance. Furthermore, in field circumstances patients are often re-treated with
      the recommended first line drug, i.e. ASAQ.

      As quinine is effective against all species of malaria including chloroquine-resistant
      strains of P. falciparum, it is widely used for the treatment of severe malaria. Therefore,
      it should be protected from resistance by a rational use, as its effectiveness in
      uncomplicated malaria is lower than ACT.

      Rationale Considering the facts that: over 90% of treatment failure to ASAQ or AL are new
      infections, parasitaemia is low in case of recrudescence occurring from day 14 and in
      real-life situations patients are re-treated with the same first line drug, there is the need
      to assess the role of the first line treatment as rescue treatments. This efficacy will be
      compared to quinine + clindamycin and another ACT treatment in line with the WHO guideline,
      and another ACT treatment to provide clear guidelines. The investigators hypothesize that
      re-treatment with the first line ACT treatment beyond 14 days is as efficacious as any other
      rescue treatment, without the risk of selecting drug resistant strains. Furthermore, a
      prolonged follow up will allow the assessment of the epidemiological, parasite related risk
      factors for repeated malaria infection and to collect samples for immunological risk factors
      for repeated malaria attacks.

      TRIAL OBJECTIVES AND PURPOSE

      Efficacy

      The primary objective is:

        1. to show that, in children aged 12 to 59 months with recurrent uncomplicated P.
           falciparum malaria within 42 days of treatment with an artemisinin-based combination
           therapy (ASAQ in DRC or AL in Uganda), the PCR adjusted efficacy at 28 days after
           re-treatment with the same artemisinin-based combination therapy is at least 90% and

        2. to estimate the relative efficacy of re-treatment with the same artemisinin-based
           combination compared to treatment with quinine and treatment with another
           artemisinin-based combination therapy (ASAQ after first line AL treatment or AL after
           first line ASAQ treatment).

      Secondary objectives are:

        1. To evaluate the PCR-unadjusted efficacy at 28 days of re-treatment with the same
           artemisinin-based combination therapy and to compare it to treatment with quinine +
           clindamycin and treatment with another artemisinin-based combination therapy (ASAQ after
           first line AL treatment or AL after first line ASAQ treatment).

        2. To evaluate and compare the efficacy of AL, ASAQ and quinine + clindamycin as rescue
           treatment for a recurrent P. falciparum malaria episode occurring 2 weeks after the
           administration of the first line treatment, with and without PCR adjustment.

        3. To evaluate and compare the 42 days clinical efficacy of AL (Uganda) and ASAQ (RDC) for
           the first line treatment of uncomplicated P. falciparum malaria, with and without PCR
           adjustment.

        4. To evaluate and compare the efficacy of the different rescue treatment regimens in terms
           of fever clearance time, asexual parasite clearance time, gametocytaemia at day 7, 14,
           21 and 28, and, Hemoglobin changes between day 0 and days 14 and 28.

      Additional objectives are:

        1. To evaluate the selection of Plasmodium falciparum pfmdr1 alleles following therapy with
           quinine + clindamycin, AL and ASAQ.

        2. To assess epidemiological, parasitological and host related predictors for recurrent
           malaria infections, an adjacent study that will be developed in a separate nested study
           protocol.

      Safety To evaluate the safety and tolerability of AL, ASAQ and quinine + clindamycin when
      used as rescue treatments.

      DRUG TO BE TESTED Quinine Quinamax® (Sanofi) + Clindamycin Dalacin® (Pfizer): in this study
      the investigators will use Dalacin syrup (75mg/5ml) and dry Quinamax® tablets (125mg) of whom
      the dosage is not adapted to children below 9 kg. The latter explains why children below 12
      months will be exclude from our study

      Artemether-lumefantrine (AL) AL of Novartis, marketed under the trademarks Riamet® and
      Coartem®, was registered in Switzerland in 1999, it is pre-qualified by the WHO and has since
      received marketing authorisation in several endemic and non-endemic countries. A recent
      review showed that the drug combination is highly efficacious against sensitive and multidrug
      resistant falciparum malaria as it offers the advantage of rapid clearance of parasites by
      artemether and the slower elimination of residual parasites by lumefantrine.

      Amodiaquine artesunate ASAQ is safe, easy to use and efficacious and the second most used ACT
      worldwide. DRC, through the National Malaria Control Program has complied with the WHO
      recommendation by recommending since 2005 ASAQ as first line treatment for uncomplicated
      malaria. In a study conducted in 2004 in the eastern part of the country, the efficacy of
      ASAQ was estimated at 93% after PCR adjustment. Twenty five trials (11,700 patients) carried
      out in Sub-Saharan Africa show a PCR-adjusted efficacy at day 28 of 94%. ASAQ is currently
      the second most used ACT globally (co formulated Co-arsucam® or ASAQ Winthrop®,
      Sanofi-Aventis. A study has been conducted in Burkina Faso in children under 5 and has shown
      that co-formulated ASAQ is well tolerated and its efficacy was 93% after PCR correction. The
      investigators will use this co-formulated ASAQ Winthrop® of Sanofi-Aventis, age dosed and put
      on the market since March 2007. This product has been pre-qualified by the WHO.

      STUDY DESIGN This is a bi-centre, phase IIIb, randomized, open label, 3-arm trial.
    

Intervention name(s): Artemether/Lumefantrine; Artesunate/Amodiaquine; Quinine + Clindamycin
Intervention type(s): Drug; Drug; Drug
Intervention description(s): Tablets containing 20 mg of Artemether and 120 mg of Lumefantrine. Each dose to be taken with high-fat food or drinks (for example milk).
Weight in kg Number of tablet per dose Age 5 to < 15 kg 1 tablet per dose 15 to < 25 kg 2 tablets per dose 25 to < 35 kg 3 tablets per dose; Age (Weight in Kg) Dose Treatment duration 2 to 11 months (= 4,5 to < 9kg):1 tablet (25 mg/675mg) for 3 days
1 to 5 years (= 9 kg to < 18 kg)1 tablet(25mg/67,5mg)for 3 days; this arm consist to 7 days treatment of 60 patients with quinine tablet 125mg + clindamycin syrup as follow;
Quinine:
9 to < 11 kg: ½ tablets 12 to < 19 kg: 1 tablets per dose 20 to < 27 kg: 1½ tablets per dose 28 to < 35 kg: 2 tablets per dose
Clindamycin syrup:
10 mg/kg twice daily
Other intervention name(s): Coartem®; Co-arsucam®; Quinimax® tablet 125mg; Dalacin® syrup 75mg/5ml
Intervention MeSH terms: Artesunate; Lumefantrine; Artemether; Amodiaquine; Artemether, Lumefantrine Drug Combination; Quinine; Clindamycin; Clindamycin palmitate; Clindamycin phosphate
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: retreatment; artemisinin-based combination; malaria; resistant