Improving Treatment Outcomes in Chronic Myeloid Leukaemia Patients Using Imatinib and Artesunate Combination Therapy
Phase: PHASE2
Conditions: Chronic Myeloid Leukemia (CML)
Sponsor: Obafemi Awolowo University

 
 
STUDY PROTOCOL 
 
 
 
 
IMART TRIAL 
 
 
 
 
IMPROVING TREATMENT OUTCOMES IN CHRONIC MYELOID LEUKAEMIA 
 PATIENTS USING IMATINIB AND ARTESUNATE COMBINATION THERAPY. 
 
 
 
 
 
 
 
 
 
 
10th March, 2025 
 
 
 
 
 

Research Objectives 
The general objective of this study is to evaluate the synergistic effect of imatinib and 
Artesunate on the clinical outcome of chronic phase and imatinib-resistant CML patients. The 
specific objectives are to: 
a. 
Assess the safety of artesunate use beyond its traditional antimalarial dosing period in 
CML patients. 
b. 
Compare treatment outcomes between patients on imatinib alone and patients on 
imatinib plus artesunate at 3, 6 and 12-months of follow-up. 
c. 
Determine the effect of imatinib and artesunate combination on the achievement of 
major molecular remission [MMR] in CML patients with sub-optimal response to 
imatinib. 
d. 
Determine the effect of artesunate on imatinib pharmacokinetics following 
coadministration of the two drugs. 
 
Details 
(a). 
Study population: The population will be consenting Philadelphia chromosome-
positive (Ph+) or Breakpoint Cluster Region, Abelson murine Leukaemia (BCR-ABL) 
positive chronic phase CML patients accessing imatinib at the OAUTHC, Ile-Ife following 
Simon’s design (Mander & Thompson, 2010) 
Inclusion criteria: Newly diagnosed chronic phase CML patients between 18 years and 85 
years with written informed consent and patients with sub-optimal response to imatinib 
therapy will be recruited for the study. 
Exclusion criteria: Patients with documented hypersensitivity to artesunate, cardiovascular 
disease, pregnancy and inability to give consent will be excluded. Patients currently on any 
medication(s) that can interact with imatinib or affect its pharmacokinetics parameters (like 
rifampicin and ketoconazole) will be excluded.  
 
(b). 
Study design: The study is a prospective randomized phase II clinical trial of 
artesunate and imatinib combination therapy in chronic phase CML patients. Patients will be 
recruited and followed up for at least 6 months of imatinib therapy. Newly diagnosed CML 
patients recruited for the study will be assigned to Group A or B by randomization already 
generated before recruitment starts using the Clinical Trial Randomization Tool. 
• Group A: 25 newly diagnosed, imatinib naive, chronic phase CML (CP-CML) 
patients placed on a standard dose of imatinib [400mg daily] alone.  
• Group B: 25 newly diagnosed, imatinib naive, CP-CML patients placed on standard-
dose imatinib [400mg daily] plus artesunate [200mg daily for 14 days every month] 
• Group C shall be 25 imatinib-exposed CML patients who have shown evidence of 
sub-optimal response to imatinib therapy. This group shall have standard-dose 
imatinib [400mg daily] plus artesunate [2mg/kg/day or 4mg/kg/day daily for 14 days 

every month]. Patients will be randomized to either doses called Group C2 or Group 
C4. 
Suboptimal response as defined by inability to achieve complete haematologic response 
(CHR) at 3months, major cytogenetic response (MCyR) at 6months, complete 
cytogenetic response (CCyR) at 12months or major molecular response (MMR) at 
18months (Morotti et al., 2015). 
(c). 
Tests: The following investigations will be conducted at the time of recruitment and as 
stated: Full blood count (monthly), Renal function test (monthly), Liver function test 
(monthly), and Bcr-Abl testing (every three months).  
 
(d). 
Sample Collections for pharmacokinetics analysis and imatinib levels 
 
Groups A: Baseline imatinib PK then imatinib levels monthly  
 
Group B: Baseline imatinib PK then imatinib and artesunate levels monthly 
 
Group C: Baseline imatinib PK then imatinib and artesunate levels monthly 
2mls of blood samples will be withdrawn from all the patients at pre-determined time 
intervals (0min, 15min, 30mins, 60mins, 120mins & 360mins) into EDTA tubes this will be 
further processed to obtain plasma and this will be stored at -20oC.  
(e). 
Pharmacokinetic analysis: A bio-analytical LC-MS/MS will be developed and 
validated according to ICH guidelines to simultaneously determine the amount of imatinib, 
its metabolite (N-desmethylimatinib) and artesunate and its metabolite (dihydroartemisin). 
This method will be used to quantify the amount of these drugs in the plasma of the patients 
at 3months, 6months and 12months of follow-up. 
(f). 
Study End points: The primary endpoint will be the achievement of Major Molecular 
remission (MMR/MR3) with bcr/abl-1 gene transcript ≤0.1 and deep molecular response 
(MR4) with bcr/abl-1 gene transcript ≤0.01 at 12 months. The secondary endpoints will 
include plasma imatinib levels at 6 and 12 months, disease progression and adverse events 
relating to long-term use of artesunate. 
(h). 
Statistical analysis: The cumulative incidence of molecular response rate at 12 
months, the primary end point, will be estimated using the Kaplan–Meier method. Secondary 
endpoints regarding patient characteristics and safety indices will be estimated with the use of 
paired-sample tests. Confidence intervals will be estimated at the 95% confidence level and 
2-sided P <0.05 will be considered to indicate statistical significance.