Imatinib added to artemether-lumefantrine for uncomplicated P. falciparum malaria

Evaluating the Safety and Efficacy of Imatinib in Combination With Artemether and Lumefantrine for Treatment of Uncomplicated Malaria

This trial tests whether adding imatinib to standard artemether-lumefantrine helps people with uncomplicated Plasmodium falciparum malaria clear infections faster and limit drug-resistant parasites.

Quick facts

• Phase: PHASE2
• Study type: Interventional
• Enrollment: 1116 (estimated)
• Ages: 1 Year to 55 Years
• Sex: All
• Sponsor: Victoria Biomedical Research Institute (other)
• Drugs / interventions: Imatinib
• Locations: 1 site (Kisumu)
• Trial ID: NCT07559370 on ClinicalTrials.gov

What this trial studies

The trial adds imatinib to the standard artemether-lumefantrine (AL) regimen to block parasite egress from infected red blood cells by inhibiting the host Syk kinase, a mechanism expected to trap and kill parasites without directly targeting the parasite. The study begins with a dose-finding phase in adults (varying doses starting at 400 mg twice daily with provisions to reduce to 600 mg or 400 mg once daily if needed) to identify a safe regimen, then proceeds to a larger randomized confirmation phase in adults and a pediatric enrollment arm for children aged 12 months to under 18 years. Participants must be admitted for 48–72 hours for monitoring and have symptomatic mild-to-moderate P. falciparum malaria with parasite density ≥5,000/µL. The trial is being conducted in Kenya at the Victoria Biomedical Research Institute and affiliated clinical sites.

Who should consider this trial

Good fit: Ideal candidates are symptomatic patients with mild-to-moderate P. falciparum malaria and parasite counts ≥5,000/µL, adults aged 18–55 (with appropriate birth-control or post-menopausal status) for the adult phases, and children aged 12 months to under 18 for the pediatric arm, who can be admitted for 48–72 hours and have not taken antimalarials in the prior 4 weeks.

Not a fit: Patients with severe malaria, very low parasite density, pregnant women, people with significant unrelated health problems, or those who recently received antimalarial treatment are unlikely to benefit from participation.

Why it matters

Potential benefit: If successful, the combination could clear infections faster and reduce the emergence and spread of drug-resistant malaria.

How similar studies have performed: This host-directed use of imatinib for malaria is novel: preclinical and mechanistic data support the idea, but large clinical successes with this exact approach have not yet been established.

Eligibility criteria

Inclusion Criteria:

For Part 1 and 2 of the study design, all individuals must meet all the inclusion criteria below:

* Patients diagnosed with symptomatic mild to moderate P. falciparum malaria with a parasite density of \>= 5000 parasites/μl
* Adult male, age 18-55 years old or adult female, age 18-55 years that are post-menopausal, or test negative on a pregnancy test and will be on active birth control through to the end of the follow up period.
* Provision of informed consent and agrees to hospital admission for 48-72hrs
* Good health condition other than malaria
* The patient has not taken anti-malarial drugs in the past 4 weeks

For Part 3 of the trial, all individuals must meet all the inclusion criteria below:

* Patients diagnosed with symptomatic mild to moderate P. falciparum malaria and a parasite density of \>= 5000 parasites/μl
* Age 12 months to below 18 years
* Presented by parent or legally accepted representative (LAR) who has consented to the participation of the child in the trial and agrees to hospital admission for 48-72hrs.
* Hb levels \> 5mg/dL
* Child has not taken anti-malarial drugs in the past 6 weeks.

Exclusion Criteria:

* Prospective study participant, LAR and/or impartial witness (where applicable) declines to provide informed consent.
* Symptoms and signs of severe or complicated malaria including:

  * significant confusion or impaired consciousness (including unarousable coma)
  * multiple convulsions (more than two episodes within 24 hours),
  * respiratory distress
  * circulatory collapse (systolic blood pressure \<80mm Hg with evidence of impaired perfusion)
  * clinical jaundice plus evidence of other vital organ dysfunction
  * simultaneous infection of unrelated origin
* Parasite density \> 200,000 parasites /μl
* In the case of female participants: currently pregnant or lactating
* Other neurological or psychiatric symptoms or disorders
* Abnormal bleeding
* Resting heart rate lower than 55 or higher than 100 bpm
* History of cardiac disease
* Signs, symptoms and laboratory results of impairment of vital organs such as liver, lungs, kidney and cardiovascular system
* Abnormal blood chemistry:

  * hemoglobin \< 9.0 g/dL in adults or \< 5.0 g/dL in children 12 months-18 years
  * WBC not in the range of 4800-10,000/mm3
  * RBC if \< 4.0x106/ mm3
  * Platelet \< 1.3x105/ mm3
  * ALAT not in the normal range (4 to 36 U / l)
  * ASAT not in the normal range (8 to 33 U / l)
  * Total bilirubin 0.1 to 1.2 mg / 100 ml
  * Serum protein if \< 5.5 g/dL
* 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 attend/meet study staff on follow up visits
* Concomitant use of medicines, including:

  * medicines used to treat high cholesterol (such as atorvastatin, lovastatin, simvastatin);
  * medicines used to treat hypertension and heart problems (such as diltiazem, nifedipine, nitrendipine, verapamil, felodipine, amlodipine);
  * medicine used to treat HIV (antiretroviral medicines) including 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 including barbiturates (such as phenobarbital), carbamazepine or phenytoin;
  * medicines used after organ transplantation and in autoimmune diseases (such as cyclosporin, tacrolimus);
  * nefazodone (used to treat depression);
  * aprepitant (used to treat nausea);

Where this trial is running

Kisumu

• Victoria Biomedical Research Institute — Kisumu, Kenya (RECRUITING)

Study contacts

• Principal investigator: Dr. Quentin Awori MBChB — Victoria Biomedical Research Institute
• Study coordinator: Dr. Quentin Awori, MBChB

Conditions: Malaria, Uncomplicated malaria, Artemether-lumefantrine combination therapy, Imatinib mesylate, Drug-resistant malaria, Parasite egress blockade