A phase 3 trial for the evaluation of a triple combination of anti-malarial therapy (imatinib + dihydroartemisinin + piperaquine) for treatment of uncomplicated malaria

Rationale and Goals

According to the World Health Organization (WHO), resistance to artemisinin derivatives is emerging in many areas of the Greater Mekong Region as evidenced by a delayed parasite clearance following a standard treatment with an artemisinin combination therapy (ACT). Artemisinin resistance is often accompanied by concurrent resistance to its partner drugs such as piperaquine (PPQ), mefloquine (MEF), amodiaquine (AQ) and lumefantrine (LF). The availability of new more efficient treatments that are efficacious against these partially resistant malaria parasites is therefore a major need in the effort to counteract ACT resistance.  

Imatinib has been demonstrated to block parasite egress from infected erythrocytes while concurrently increasing the cytotoxicity of artemisinins in a synergistic fashion. This positive effect is further potentiated by low concentrations of piperaquine.  A major advantage of using imatinib in in an artemisinin combination therapy (ACT) derives from the fact that it is an FDA-authorized drug that has been shown to be safe in both children and adults, even during very prolonged use for the treatment of CML and GIST. Imatinib also undergoes rapid intestinal absorption, reaching peak plasma concentrations after only 1-2 hours and displaying a prolonged half time (16-20 hours). Additionally, imatinib targets the host protein tyrosine kinase, Syk.  Because the malaria parasite cannot mutate a host protein, the evolution of resistance to imatinib therapy should be extremely unlikely. 

It is therefore not surprising that the combination of imatinib plus dihydroartemisinin plus piperaquine (IMA+DHA+PPQ) in a Phase 2 clinical trial led to a more efficient clearance of the parasites and enhanced efficacy against parasites that exhibit delayed parasite clearance.  To replicate these results and validate the superiority of an IMA+DHA+PPQ over the standard DHA+PPQ therapy, a phase 3 clinical trial will be performed.


Trial endpoints 
The primary purpose of this Phase 3 trial is to determine if the triple combination of imatinib+DHA+PPQ exhibits non-inferior safety and enhanced efficacy as compared to the DHA+PPQ standard of care in patients with uncomplicated Plasmodium falciparum malaria. 

The primary and secondary clinical endpoints are as follows: 

• Primary endpoints

1. No significant increase in the number or severity of adverse events when compared to SOC
2. Accelerated parasite clearance compared to patients receiving the SOC
3. Accelerated decrease in fever compared to patients receiving the SOC 
   
   

• Secondary endpoints 

1. Reduction in percent of patients experiencing delayed parasite clearance (DPC; viable parasites present 24 hours after administration of 3rd treatment)
2. Avoidance of 2nd increase in fever (i.e. 2nd pyrexia spike)
3. Faster clearance of parasites in patients with highest initial parasite density
4. Reduction in percent of patients experiencing treatment failure (i.e. parasites still present at ≥28 days out - clinical treatment failure)
   
   

Planned Analysis 

     Primary endpoints: 

1. Null hypothesis:  Participants receiving the new drug combination (IMA+DHA+PPQ) will exhibit a significant increase in the number or severity of adverse events as compared to participants receiving the SOC (DHA+PPQ)
   
   Alternative hypotheses:  Participants receiving the new drug combination (IMA+DHA+PPQ) will exhibit no significant difference in the number or severity of adverse events as compared to participants receiving the SOC (DHA+PPQ)
   
   
2. Null hypothesis:  New drug combination (IMA+DHA+PPQ) will not reduce the parasite density at a faster rate compared to the SOC (DHA+PPQ) 
   
   Alternative hypotheses:  New drug combination (IMA+DHA+PPQ) will reduce the parasite density at a faster rate compared to the SOC (DHA+PPQ) 
   
   
3. Null hypothesis:  New drug combination (IMA+DHA+PPQ) will not reduce pyrexia faster than the SOC (DHA+PPQ) 
   
   Alternative hypotheses:  New drug combination (IMA+DHA+PPQ) will reduce pyrexia faster than SOC (DHA+PPQ) 
   
   Secondary endpoints: 

1. Null hypothesis:  Participants receiving the new drug combination (IMA+DHA+PPQ) will exhibit a similar percentage of delayed parasite clearance (DPC; viable parasites present 24 hours after administration of the 3rd treatment) as those patients administered SOC (DHA+PPQ)
   
   Alternative hypotheses:  Participants receiving the new drug combination (IMA+DHA+PPQ) will exhibit a smaller percentage of delayed parasite clearance (DPC; viable parasites present 24 hours after administration of the 3rd treatment) as those patients administered SOC (DHA+PPQ)
   
   
2. Null hypothesis:  New drug combination (IMA+DHA+PPQ) will not reduce the number of participants exhibiting a 2nd spike in body temperature as those given SOC (DHA+PPQ)
   
   Alternative hypotheses:  New drug combination (IMA+DHA+PPQ) will reduce the number of participants exhibiting a 2nd spike in body temperature as those given SOC (DHA+PPQ)
   
   
3. Null hypothesis:  New drug combination (IMA+DHA+PPQ) will not reduce the percent parasite density in participants with a high starting parasite density compared to participants who start with a low parasite density.
   
   Alternative hypotheses:  New drug combination (IMA+DHA+PPQ) will reduce the percent parasite density in participants with a high starting parasite density compared to participants who start with a low parasite density.
   
   
4. Null hypothesis:  Participants receiving the new drug combination (IMA+DHA+PPQ) will exhibit a similar percentage of treatment failure (i.e. parasites still present at ≥28 days out) as those patients administered SOC (DHA+PPQ)
   
   Alternative hypotheses:  Participants receiving the new drug combination (IMA+DHA+PPQ) will exhibit a smaller percentage of treatment failure (i.e. parasites still present at ≥28 days out) as those patients administered SOC (DHA+PPQ) 

Analysis of datasets 

The following deidentified data will be supplied for analysis: 

• Age
• Sex
• Parasite density
• Body temperature
• Number and severity of adverse events 
  
  

General description of statistical methods 


Projected timeline 

2022 Q4 – Protocols submitted to Vietnam Ministry of Health and local IRBs 

2023 Q1 – Vietnam Ministry of Health and local IRB approvals 

2023 Q2 – Delivery of study drug, final pre-visit to study sites 

2023 Q3 – Enrollment of 1st patient (malaria cases greatly increase during start of rainy season ~July) 

2024 Q3 – Enrolled 65 total participants (half of total) 

2024 Q4 – Interim statistical analysis 

2025 Q3 – Enrolled 130 total participants (complete enrollment) 

2025 Q4 – Final statistical analysis and drafting of manuscript 

2026 Q1 – Publication of study results in peer-review journal