Effect of Imatinib on Suppression of Malaria Parasites in Patients With Uncomplicated Plasmodium Falciparum Malaria (MIM)

The purpose of this study is to determine the efficacy and safety of imatinib in combination with dihydroartemisinin plus piperaquine in the treatment uncomplicated P. falciparum malaria in adult male patients.

Study Overview

• Status: Completed
• Conditions: Plasmodium Falciparum Malaria
• Intervention / Treatment: Drug: Imatinib combination therapy; Drug: Dihydroartemisinin-piperaquine

Detailed Description

An exploratory study to examine the efficacy and safety of imatinib mesylate in combination with dihydroartemisinin plus piperaquine on suppression of parasitemia in patients with uncomplicated Plasmodium falciparum malaria. In vitro studies of P. falciparum parasitized erythrocytes demonstrate that inhibitors of the protein tyrosine kinase SYK prevent malaria parasite egress from infected red blood cells and thereby terminate the parasite's life cycle. Although no potent syk kinase inhibitors were approved for human use at the time of initiation of this study, a bcr-abl tyrosine kinase inhibitor (imatinib mesylate (Gleevec®)) that also exhibits off-target inhibition of syk tyrosine kinase, has been FDA-approved for treatment of a number of human malignancies including chronic myelogenous leukemia and GIST. Because imatinib can be taken daily for many years without significant toxicity, it can be used to obtain a preliminary indication of whether inhibition of erythrocyte syk kinase can suppress parasitemia in patients with P. falciparum malaria. In a phase 1 clinical trial on the same patient population, anti-malaria activity was observed with imatinib, with little or no accompanying toxicity. Because dihydroartemisinin plus piperaquine constitute the currently used standard-of-care therapy for malaria in Southeast Asia, the above trial will test the safety and efficacy of the combination of imatinib plus dihydroartemisinin and piperaquine in treatment of uncomplicated malaria. In this pilot study, the rate of decrease in peripheral blood parasitemia in 30 adult male patients with uncomplicated malaria will be compared to the same rate of decrease in parasitemia in 30 adult male patients treated solely with dihydroartemisinin plus piperaquine.

• Study Type: Interventional
• Enrollment (Actual): 15
• Phase: Phase 1

Contacts and Locations

Study Locations

• Vietnam
  • Quang Tri
    • Huong Hoa, Quang Tri, Vietnam, 520000
      • A Tuc

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 50 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Gender: only adults are selected for the trial; note that female subjects cannot be women of child-bearing age.
• Age: 18-50 years.
• Target disease: Uncomplicated Plasmodium falciparum malaria

Exclusion Criteria:

• symptoms and signs of complicated malaria
• including continuous high fever of over 390C, psychiatric disorders, confusion, other neurological symptoms, symptoms and signs of functional impairment of the organs such as lungs, kidneys or cardiovascular system;
• symptoms and signs of liver damage or kidney damage
• symptoms and signs of another complicating infection such as pneumonia, dengue fever, and other bacterial infection.
• P. falciparum > 25.000 / mm3

• WBC <4000 and >10.000 /mm3

  • RBC < 3.5x106/mm3
  • Platelets < 40.000 /mm3
• Hemoglobin < 10 g/dL
• ALT more than 200% of the upper limit (56 units/L)
• AST more than 200% of the upper limit (40 units/L)
• Blood creatine more than 75% of the upper limit (men: 1.2 mg/dL, women 1 mgdL)
• Serum total protein < 6 g/L
• Glycemia < 50 mg/dL> 200 mg/dL
• Standard urine test Serious alterations
• Concomitant treatments

Antimalarial Drugs Anticoagulant therapy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Imatinib combination therapy; Administration of imatinib (400 mg/day) plus dihydroartemisinin (40 mg/day) plus piperaquine (320 mg/day) to uncomplicated adult male malaria patients. Normal health parameters will be monitored continuously to evaluate safety and the decrease in peripheral blood parasitemia with time will be quantitated to assess efficacy.	Drug: Imatinib combination therapy; Imatinib plus dihydroartemisinin plus piperaquine; Other Names: Gleevec; Glivec
Active Comparator: dihydroartemisinin plus piperaquine; Administration of dihydroartemisinin (40 mg/day) plus piperaquine (320 mg/day) to uncomplicated adult male malaria patients. Normal health parameters will be monitored continuously to evaluate safety and the decrease in peripheral blood parasitemia with time will be quantitated to assess efficacy.	Drug: Dihydroartemisinin-piperaquine; Standard of care; Other Names: Eurartesim; Artekin; Diphos; Timequin; Duocotecxin; Malacur; Ridmal

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to Parasite Clearance	Parasite clearance was determined by assessing the parasite count in blood, using thin film, thick film and qPCR analysis	From baseline to the time point when the blood parasite count is zero (up to a maximum of 5 days)
28-day Cure Rate	28-day cure rate was defined as the percentage of participants with blood parasite count of zero after 28 days of treatment and no evidence of recurrent infection with the same parasite genotype after reduction of the asexual parasitemia. Follow up after treatment will only be performed in the case of complete clearance of parasites at D5 due to Imatinib treatment.	Day 28

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Frequency of adverse events	Adverse events (AEs) are defined as events possibly related to the study drug as judged by physician that occur within 1 week of beginning treatment with imatinib.; Incidence, severity, drug-relatedness, seriousness of adverse events; Laboratory values (biochemistry and haematology); Vital signs	Within 1 week of beginning treatment with imatinib

Collaborators and Investigators

• Sponsor: HuLow
• Collaborators: University of Turin, Italy; Purdue University; Università degli Studi di Sassari; Hue University
• Investigators: Principal Investigator: Huynh D Chien, MD, PhD, Hue University; Principal Investigator: Philip S Low, PhD, Purdue University

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2015
• Primary Completion (Actual): December 2, 2016
• Study Completion (Actual): February 2, 2017

Study Registration Dates

• First Submitted: November 16, 2015
• First Submitted That Met QC Criteria: November 23, 2015
• First Posted (Estimate): November 25, 2015

Study Record Updates

• Last Update Posted (Actual): February 11, 2021
• Last Update Submitted That Met QC Criteria: February 8, 2021
• Last Verified: February 1, 2021

More Information

Terms related to this study

• Keywords: Plasmodium falciparum; imatinib mesylate; antimalarials; Uncomplicated malarial
• Additional Relevant MeSH Terms: Infections; Vector Borne Diseases; Parasitic Diseases; Protozoan Infections; Malaria; Malaria, Falciparum; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Antiprotozoal Agents; Antiparasitic Agents; Antimalarials; Imatinib Mesylate; Piperaquine; Artenimol
• Other Study ID Numbers: HuLow-201605