| Protocol No: | ECCT/25/03/03 | Date of Protocol: | 26-11-2024 |
| Study Title: | Evaluating the safety and efficacy of Imatinib in combination with Artemether and Lumefantrine for the treatment of Uncomplicated Malaria: a three-part trial. |
| Study Objectives: |
General Objective
The general objective of the trial is to evaluate the safety, tolerability, and efficacy of AL+IM in the treatment of uncomplicated malaria in adults and pediatric (above 12months) age groups.
Specific Objective
The primary objectives of this study are elaborated below:
i. To determine if the triple combination AL+IM (ALIM) exhibits non-inferior safety and tolerability as compared to the SOC (AL) alone
in adults, and all age groups above 12 months
ii. To determine if the addition of IM to AL allows for the complete clearance of P. falciparum after only 2 days of dosing in adults and pediatric age groups above 12 months
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| Laymans Summary: |
1.Why should you do this study?
Treatment options for malaria are continuously being challenged. The P. falciparum parasite has been found to take longer to eliminate during the standard three-day treatment, and in some cases be totally resistant to medication, even Artemisinin combined therapies (ACT), which are currently the gold standard of treatment. An initial trial in Vietnam found that the drug Imatinib, when used in combination with ACT, greatly improved the treatment of malaria, eliminating the parasite and improving the fever experienced by patients.
2. What questions are we trying to answer?
We propose to use Imatinib in combination with ACTs to treat malaria, while evaluating if this combination is safe and effective in adults and all childhood age groups above 12 months of age. Furthermore, we would like to know if indeed, when imatinib is used with ACTs, the malaria parasite can be eliminated in 2 days.
3. Where is the study taking place?
This study in going to take place in public health facilities in western Kenya, located in the Kisumu, Busia and/or Siaya counties.
4. How many participants does it involve and how will they be selected?
The study will be conducted in three parts:
1)
In Part 1, to establish in a small number of adult study participants the safest, and effective dose of Imatinib to use in combination with ACTs we will enroll 30 participants in the control (standard of care) group and 120 (4 groups of 30) participants in the (AL+IM) treatment groups in the first Part of the study.
2)
In Part 2, we anticipate recruiting an additional 516 adult participants (172 in each of three cohorts) (i.e. a control, a 3-day ALIM treatment cohort and a 2-day ALIM treatment cohort).
3)
In Part 3, like Part 1, we shall evaluate the safety, and efficacy of ALIM in each of three age groups i.e., 10-18yrs, 5-9yrs and 12-60 months at two different IM concentrations. In each of these three age-groups we shall recruit a control cohort (30 children on AL for 3 days), an intervention group (30 children) on treatment for 3 days and another group (30 children) on treatment for 2 days. Part 3 will only begin recruitment after Part 1 is successfully completed.
Study participants shall be recruited from the health facilities when they present for treatment of uncomplicated Malaria. We shall request informed consent from the approached participants. Participation is voluntary. We shall approach both adult male patients (18-55 years old) and adult female patients (18-55 years old) that are either postmenopausal (defined as amenorrhea for the last consecutive 12 months), actively on birth control, and/or test negative on a pregnancy test. In the case of post-pubertal girls below the age of 18yrs, we shall also require a negative pregnancy test.
5. What does the study involve for those taking part?
Study participants will be treated with ACTs (Artemether & Lumefantrine) alone or in combination with Imatinib and monitored for treatment.
In Part 1 of the trial (involving adults), we shall ask the participants to be admitted at the study hospital for at least 1-2 days. To determine the elimination of the malaria parasite, we shall draw blood samples of the participants at the following intervals:
i. 0hrs, 4hrs, 6hrs, 12hrs, 18hrs (on Day 0)
ii. 24hrs, 36hrs (on Day 1)
iii. 48hrs, 60hrs (on Day 2)
iv. 72hrs (on Da7 4)
v. Day 7 follow up
vi. Day 21 follow up
vii. Day 35 follow up
In Part 2 of the trial (involving adults), we shall also ask participants to be admitted at the hospital for 1-2 days. We shall draw blood samples from the participants at the following intervals:
i. 0hrs, 12hrs (on the first day, Day 0)
ii. 24hrs, 36hrs (on Day 1)
iii. 48hrs, 60hrs (on Day 2)
iv. Day 7 follow up
v. Day 21 follow up
vi. Day 35 follow up
In Part 3 (involving children), we shall withdraw the samples at 0hr, 48hrs and 72hrs during which time they will be admitted at the study hospital, and during follow up on days 7, 21 and 35.
6. What are the risks and benefits of taking part?
Risks: It is the first time we are combining Imatinib with Artemether and Lumefantrine. Hence there may be previously unknown side effects, much as these individual drugs are quite safe at the dose and duration we intend to administer them.
Benefits: Potential benefits include a shorter duration of illness, accelerated elimination of the parasite, faster resolutions of symptoms with lower chances of illness caused by the same parasite’s recrudescence (as would be the case when it is not totally eliminated)
7. How will the study benefit society?
Imatinib as an additional option to the drugs used to treat malaria will greatly strengthen the available treatment interventions. Uniquely, unlike all other malaria drugs, the mode of action of Imatinib targets the red blood cell which the malaria parasite cannot mutate. Hence it is difficult (if ever possible) for the parasite to develop resistance to Imatinib.
8. When does the study start and finish?
We intend to start this recruitment into this study in the first quarter of 2025 and complete it by fourth quarter of 2027. The duration of the trial shall ultimately depend on study participant recruitment.
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| Abstract of Study: |
In a phase 2 clinical trial performed in Vietnam, 400 mg imatinib mesylate (IM) in combination with the standard of care (SOC), which at the time was 120 mg dihydroartemisinin (DHA) and 960 mg piperaquine (PPQ) per day, was shown to be safe and well tolerated in male patients aged 16-55, infected with P. falciparum malaria. Additionally, IM+DHA+PPQ was shown to reduce the parasite density and pyrexia in patients infected with P. falciparum malaria faster than in patients treated with the SOC (DHA+PPQ) alone.
This protocol will expand upon the initial results obtained in Vietnam, to evaluate the safety, tolerability, and efficacy of the use of the combination of Artemether + Lumefantrine + Imatinib mesylate (ALIM), and its ability to eliminate the parasites after 2 days of dosing in Kenya. It shall also evaluate this triple combination in a broader age group, compared to the initial trials, to eventually include a 12-60 months children age group which together with the 1-5yr age group are the most affected by malaria morbidity and mortality, accounting for 80% of the burden.
The implementation of the study shall be in three incremental parts:
Part 1: This shall be an adaptive trial design that will seek to ensure no serious adverse events occur when IM is added to the SOC (AL) during the standard 3 days of dosing and the adequate dose, if possible, that can effectively treat malaria in a 2 dose regimen. During this part of the trial, study participants will be followed-up over 35 days, to determine adequate clinical and parasitic response. IM dosing will begin at 600mg/day in cohort 2a for three days. If no parasites are observed via microscopy/PCR corrected analysis between days 7 and 35 (i.e., no recrudescence), then 600mg IM + AL will be administered for only 2 days in cohort 2b and recrudescence determined on samples collected between days 7- and 35-days post admission. If no significant increase in recrudescence is observed, then the dose of imatinib will be reduced to 400mg/day and the procedure will be repeated. However, if parasites are detected in the initial 600mg/day group or a significant increase in recrudescence is observed after 2-day dosing, the dose of IM will be escalated to 800mg/day.
Part 2: The amount of IM that eliminates all viable parasites after 2 days of dosing will have been identified in the previous Part 1. Using this dose, a larger sample of 516 participants above the age of 18 years will be split evenly between three groups: a control (AL for 3 days), a cohort 1 (AL+IM for 3 days) and a cohort 2 (AL+IM for 2 days). This part of the trial will confirm the effectiveness in larger numbers.
Part 3: Based upon the proven efficacy of ALIM in adults, an age de-escalation, dose escalation trial shall evaluate the safety, tolerability and efficacy of ALIM in the following age groups:
-10-17yrs age group
-5-9yrs age group
-12-60 months age group
In each of these age groups cohorts, we shall recruit 90-150 children, which shall include 30 participants on the SOC (AL for 3 days), an intervention group (30 participants) on treatment for 3 days receiving the standard dose of AL (calculated by weight) with IM at a lower dose of 260mg/m2/day, and another group (30 participants) on the AL+IM treatment for 2 days. If after 35 days of follow up malaria parasites are found, we shall recruit another intervention cohort on treatment for 2 days that will receive AL + IM at a higher dose of 340 mg/m2/day.
In all three parts of the study, measurements such as parasite density, body temperature, and adverse events will also be collected at the time intervals as indicated in the study methodology section.
All trial activities and associated tests will be performed using site SOPs and internationally accepted guidelines.
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