Triple Antimalarial Combination to Accelerate the Parasite Clearance and to Prevent the Selection of Resistant Parasites

Study Overview
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Brief Summary
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The purpose of this study is to provide a new drug combination for a better treatment of P. falciparum for a faster parasite clearance and to counteract artemisinin resistance.

Detailed Description
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According to WHO, resistance to artemisinin derivatives (ART) is emerging in many areas of the Greater Mekong Region as a delayed parasite clearance following a standard treatment by artemisinin combined therapy (ACT). Artemisinin resistance is often accompanied by the resistance to the partner drugs such as piperaquine (PPQ), mefloquine (MEF), amodiaquine (AQ) and lumefantrine (LF). The slow and incomplete clearance of parasites following ACT treatment is considered to permit the selection of resistant parasites. The availability of new, more efficient treatments accelerating the clearance of parasites is therefore needed to counteract the selection of ART resistant strains. Imatinib (IMA) has been demonstrated to increase the efficacy of ART in a synergic fashion. This positive effect is further potentiated by low concentrations of PPQ. IMA is active both on the intra-erythrocyte asexual forms and on gametocytes. It is therefore expected that the combination DHA-PPQ-IMA should lead to faster and radical clearance of the parasites, therefore reducing the frequency of healthy carriers and transmission.

Official Title
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Triple Antimalarial Combination (Imatinib-DHA-PPQ) to Accelerate the Parasite Clearance and to Prevent the Selection of Resistant Parasites

Conditions
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Plasmodium Falciparum Malaria (Drug Resistant)

Intervention / Treatment
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* Drug: Imatinib
* Drug: Dihydroartemisinin-piperaquine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients diagnosed with mild to moderate P. falciparum malaria Adult male, age 18-55 years Good health conditions other than malaria The patient did not take anti-malarial drugs in the past 4 weeks Exclusion Criteria: unable to provide Informed Consent or Patient History Form symptoms and signs of severe or complicated malaria including: continuous high fever over 39 °C, confusion, convulsions parasitemia<150.000 parasites /microliter other neurological or psychiatric symptoms or disorders abnormal bleeding resting hearth rate lower than 60 and higher than 100 bpm abnormal ECG, history of cardiac diseases male adults with corrected QT intervals > 450ms signs, symptoms and laboratory results of impairment of vital organs such as liver, lungs, kidney and cardiovascular system hemoglobin < 9.0 gm/100ml symptoms and signs of infection such as pneumonia, dengue fever, and other viral or bacterial infection. patients with symptoms of gastrointestinal infections or any sign of malabsorption that may interfere with drug absorption concomitant infection by plasmodium species other than P. falciparum inability to meet daily with local doctor during period of clinical trial concomitant medicines like: medicines used to treat high cholesterol in the blood (such as atorvastatin, lovastatin, simvastatin); medicines used to treat hypertension and heart problems (such as diltiazem, nifedipine, nitrendipine, verapamil, felodipine, amlodipine); medicined used to treat HIV (antiretroviral medicines): protease inhibitors (such as amprenavir, atazanavir, indinavir, nelfinavir, ritonavir), non-nucleoside reverse transcriptase inhibitors (such as efavirenz, nevirapine); medicines used to treat microbial infections (such as telithromycin, rifampicin, dapsone); medicines used to help you fall asleep: benzodiazepines (such as midazolam, triazolam, diazepam, alprazolam), zaleplon, zolpidem; medicines used to prevent/treat epileptic seizures: barbiturates (such as phenobarbital), carbamazepine or phenytoin; medicines used after organ transplantation and in autoimmune diseases (such as cyclosporin, tacrolimus); sex hormones, including those contained in hormonal contraceptives (such as gestodene, progesterone, estradiol), testosterone; - glucocorticoids (hydrocortisone, dexamethasone); - omeprazole (used to treat diseases related to gastric acid production); paracetamol (used to treat pain and fever); theophylline (used to improve bronchial air flow); nefazodone (used to treat depression); aprepitant (used to treat nausea);

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: interventional
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: imatinib-Dihydroartemisinin-piperaquine<br>triple combination | Drug: Imatinib<br>* triple combination for the treatment of malaria<br>* Other names: Glivec;|
| Active Comparator: Dihydroartemisinin-piperaquine<br>standard of care | Drug: Dihydroartemisinin-piperaquine<br>* standard malaria treatment<br>* Other names: Duocotecxin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Occurrence of Adverse Events | Occurrence of Adverse Events over 42 days observation period | From baseline to day 42 | 
| Occurrence of Severe Adverse Events | Occurrence of Severe Adverse Events over 42 days observation period | From baseline to day 42 | 
| Occurrence of Abnormal Physical Symptoms | Occurrence of Abnormal Physical Symptoms (Clinical Abnormalities) over 42 days observation period | From baseline to day 42 | 
| Occurrence of Abnormal Laboratory Values | Occurrence of Abnormal Laboratory Values over 42 days observation period | From baseline to day 42 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency of residual parasitemia: % of patients with >1000 parasites/ ul at day 3 and 28 | Parasitemia is determined by assessing the parasite count in blood, using thin film, thick film and qPCR analysis. | day 3 and day 28 | 
| Frequency of fever and malaria symptoms | Percentage of patients with fever or malaria symptoms observed at Phisical Visit at day 3 and 28. | day 3 and day 28 | 
| Mean parasitemia in the control and investigational arms | Mean parasitemia by assessing the parasite count in blood, using thin film, thick film and qPCR analysis, expressed as parasites / ul at day 2, 3 and 5 measured in the control and investigational arms | day 2 and day 5 | 
| Parasite half-life measured at 12 and 24 hours | Mean parasite clearance half-life calculated using parasitemia measured at baseline, 12 and 24 hours post-treatment | from baseline to 24 hours post-treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Imatinib Mesylate, piperaquine phosphate, dihydroartemisinin