Impact of Artemisinin-based Combination Therapy and Quinine on Treatment Failure and Resistance in Uncomplicated Malaria (QuinAct)
|First Submitted Date ICMJE||June 9, 2011|
|First Posted Date ICMJE||June 16, 2011|
|Last Update Posted Date||October 22, 2014|
|Start Date ICMJE||May 2012|
|Primary Completion Date||June 2014 (Final data collection date for primary outcome measure)|
|Current Primary Outcome Measures ICMJE
||Late Parasitological Failure [ Time Frame: Day4-Day28 ]
Parasitaemia after day 3 in the absence of fever (axillary temperature <37.5°C)
|Original Primary Outcome Measures ICMJE
|Change History||Complete list of historical versions of study NCT01374581 on ClinicalTrials.gov Archive Site|
|Current Secondary Outcome Measures ICMJE
|Original Secondary Outcome Measures ICMJE
|Current Other Outcome Measures ICMJE||Not Provided|
|Original Other Outcome Measures ICMJE||Not Provided|
|Brief Title ICMJE||Impact of Artemisinin-based Combination Therapy and Quinine on Treatment Failure and Resistance in Uncomplicated Malaria|
|Official Title ICMJE||A Randomized Clinical Trial to Measure the Impact of Retreatment With an Artemisinin-based Combination on Malaria Incidence and Its Potential Selection of Resistant Strains|
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.
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
The primary objective is:
Secondary objectives are:
Additional objectives are:
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.
|Study Type ICMJE||Interventional|
|Study Phase||Phase 3|
|Study Design ICMJE||Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Completed|
|Completion Date||June 2014|
|Primary Completion Date||June 2014 (Final data collection date for primary outcome measure)|
|Eligibility Criteria ICMJE||
Patients with at least one of the following criteria will be excluded:
|Ages||12 Months to 59 Months (Child)|
|Accepts Healthy Volunteers||No|
|Contacts ICMJE||Contact information is only displayed when the study is recruiting subjects|
|Listed Location Countries ICMJE||Congo, Uganda|
|Removed Location Countries|
|NCT Number ICMJE||NCT01374581|
|Other Study ID Numbers ICMJE||UA-IHU-2010-01 version 1|
|Has Data Monitoring Committee||Yes|
|U.S. FDA-regulated Product||Not Provided|
|IPD Sharing Statement||Not Provided|
|Responsible Party||Jean-Pierre Van geertruyden, Universiteit Antwerpen|
|Study Sponsor ICMJE||Universiteit Antwerpen|
|PRS Account||Universiteit Antwerpen|
|Verification Date||October 2014|
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP