Safety and Efficacy of Imatinib in Combination With Artemether-Lumefantrine for Uncomplicated Malaria

Official title

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

Overview

This study is investigating an innovative approach to treating uncomplicated malaria by adding a drug called Imatinib to the current standard of care, Artemether + Lumefantrine (AL). The researchers hope this combination, known as ALIM, will clear infections faster and stop the spread of drug-resistant parasites that are becoming a major threat in Africa

Detailed description

Most antimalarial drugs work by directly attacking the Plasmodium falciparum parasite, but this approach carries a fundamental weakness: the parasite can slowly rewrite its own biology to shrug off these chemical assaults. Imatinib, a drug already proven safe in cancer treatment for over two decades, takes a radically different tack. Instead of targeting the invader, it targets the human red blood cell that the parasite infects. Specifically, Imatinib inhibits a human enzyme called Syk kinase a key that the parasite turns to pry open the cell and burst forth into the bloodstream. By jamming this lock, the drug traps the parasite inside the cell, where toxic byproducts accumulate and ultimately kill it. Because the parasite cannot alter human biology the way it alters its own, researchers believe resistance to Imatinib will be extraordinarily difficult if not impossible for malaria to evolve.

To test this promising strategy, a clinical trial is now underway at the Alupe sub county hospital in Busia County, Kenya, a region bearing some of the nation's highest malaria burdens. The study unfolds in three cautious phases. First, between ninety and two hundred ten adults will receive varying doses of Imatinib starting at 400 milligrams twice daily to determine the safest regimen. If side effects prove too severe, the dose will be lowered to 600 or 400 milligrams once per day. Once the optimal dose is identified, the second phase will enroll 516 adults to confirm that adding Imatinib to the standard artemether lumefantrine (AL) regimen is as safe as AL alone, and to test whether a two day course works as well as the conventional three days. Finally, because children under five account for nearly eighty percent of malaria deaths, the third phase will extend the trial to younger participants from twelve months to seventeen years using weight based dosing.

Participants who enroll must remain in the hospital for forty eight to seventy two hours of close observation. Medical staff will draw frequent blood samples, often via finger prick, to count parasites and monitor liver and kidney health. After discharge, patients return for follow up visits on days seven, twenty one, and thirty five to ensure the infection has not recurred. To compensate for time and lost wages, each participant receives 1,500 Kenyan shillings per day, and the study covers all travel and medical expenses.

Safety is reinforced by clear boundaries. Although Imatinib is already FDA approved and widely used for cancer, its combination with AL is novel. To avoid dangerous drug interactions, anyone taking medications for high cholesterol, high blood pressure, or HIV cannot enroll. Pregnant or breastfeeding women are also excluded, as Imatinib can harm a developing fetus, and female participants must use birth control throughout the trial.

The study operates under rigorous ethical oversight. It has been reviewed by the Jaramogi Oginga Odinga Teaching and Referral Hospital and the Pharmacy and Poisons Board, while an independent Data Safety Monitoring Board composed of doctors and scientists will continuously review the data to determine whether the trial remains safe to proceed. All participant information is protected under the Kenyan Data Protection Act, ensuring personal privacy is never compromised. Overall, the trial expects to enroll between 906 and 1,116 participants by the end of 2027, with the ultimate goal of delivering a more powerful, resistance proof tool for malaria elimination.

Interventions

• Drug Artemether lumefantrine tablets
  There is no difference
• Drug Artemether Lumefantrine and Imatinib Mesylate
  There is no difference

Primary outcome measures

• Dose of Imatinib (in mg) Required to Eliminate Viable Parasites [Time frame: 48 hours post-first dose]
• Number of Participants with Treatment-Emergent Adverse Events (TEAEs) by Severity Grade [Time frame: Up to Day 35]
• Number of Participants with PCR-Corrected Recrudescence [Time frame: Day 35]

Secondary outcome measures (3)

• Change from Baseline in Parasite Density (parasites/μL) [Time frame: Days 1, 2, and 3]
• Change from Baseline in Body Temperature (°C) [Time frame: Days 1, 2, and 3]
• Percentage Reduction in Parasite Density from Baseline [Time frame: Days 1, 2, and 3]

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);

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

Kenya · 1 center

• Victoria Biomedical Research Institute — Kisumu

Identifiers

NCT: NCT07559370 · VIBRI-ALIM01

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗