A randomised study to compare a fixed dose combination of artesunate plus amodiaquine versus a fixed dose combination of artemether plus lumefantrine in the treatment of repeated uncomplicated P. falciparum malaria attacks occurring during two years in children in Uganda: preliminary results. Adoke Yeka, MPH1, Moses R. Kamya, Ph.D.2, Valérie Lameyre MD3, Ambrose O. Talisuna PhD.1,4 1. Uganda Malaria Surveillance Project, Kampala, Uganda. - 2. Department of Medicine, Makerere College of Health Sciences, Kampala, Uganda. - 3. Access to Medicines Sanofi, Paris, France. - 4. Infectious Disease Research Collaboration (IDRC), Uganda
Study site: Nagongera Health Centre, Tororo district EIR > 500 / year
Objectives:
Results
To compare effectiveness and clinical & biological safety of 2 ACT given
• 413 children enrolled (ASAQ: 208; AL 205) • Baseline characteristics comparable between the 2 treatment groups • 6032 malaria episodes in 22 months • Median number of episodes: ASAQ= 16; AL=15
to two cohorts of children, over a 2-year period: Artesunate-amodiaquine fixed-dose combination Artemether-lumefantrine fixed-dose combination
Number of patients
Each cohort received the same ACT for each
400 350 300 250 200 150 100 50 0
malaria attack ocurring during the study period Primary end-point : To demonstrate the non-inferiority of PCR adjusted adequate clinical and parasitological response at D28 (WHO protocol in vivo D28 2003) of 2 fixed dose ACT combinations, based on the first malaria attack of each patient.
AL ASAQ E1
E2
E3
Secondary :
Efficacy
To compare the two groups of treatment in terms of:
• First malaria episode
For the first attack (directly observed administration) • D42 efficacy* • Parasitological and fever clearance*
Efficacy assessment D28
E6
E7
E8
E9
E10
E11
E12
E13
E14
N LCF (LATE CLINICAL FAILURE) LPF (LATE PARASITOLOGICAL FAILURE) ACPR (ADEQUATE CLINICAL AND PARASITOLOGICAL RESPONSE
• Evolution of gametocyte carriage* • D28 and D42 clinical and parasitological effectiveness*
E5
Primary endpoint Response to the treatment after PCR correction for the first attack - ITT
• Clinical and biological tolerability For repeated attacks (non observed administration)
E4
NA
E15
E16
E17
E18
E19
E20
E21
E22
E23
E24
E25
E26
Number of episode
ASAQ FDC N=198
AL FDC N=201
Total N=399
198 0 (0.0%) 5 (2.5%)
201 3 (1.5%) 3 (1.5%)
399 3 (0.8%) 8 (2.0%)
192 (97.0%)
194 (96.5%)
386 (96.7%)
1 (0.5%)
1 (0.5%)
2 (0.5%)
95% confidence interval [CI] of the difference [-0.030; 0.039].
• Ongoing PCR analysis for subsequent episodes
• Clinical and biological tolerability • Compliance* During the total follow up of the cohort
Clinical and biological safety • At least one TEAE
• Treatment incidence density*
Safety population
• Impact of repeated treatment on clinical and biological tolerability * data not shown
• Serious AEs: (all attacks) ASAQ N=208
AL N=205
Total N=413
P-value Chi² test
At least one AE (1st attack)
59 (28.4%)
66 (32.2%) 125 (30.3%)
0.397
At least one AE (all attacks)
120 (57.7%) 127 (62.0%) 247 (59.8%)
0.377
No unexpected AE
Methods: • Monocentre, randomized, comparative, investigator-blinded, phase IV study (June 2008-June 2010) • 400 children < 5 years old at inclusion followed-up during 22 months • Presenting uncomplicated Plasmodium falciparum malaria • Signed informed consent from parents or guardians • Treatment dose adapted to body weight range • Follow-up D42: clinical and parasitological efficacy, clinical and biological safety - In case of failure up to D14: rescue treatment with oral quinine - In case of failure after D14: re-treatment with the same ACT • Amendment decided by DSMB in May 2009 (after 10 months of follow up/median of 7 episodes) - Implementation of Insecticide Treated Bednets (1 per child +1 for its guardian) and training of parents - Wash out from ACT during 3 months if ALT>3ULN or if neutrophils <400/µl at D0 . Treatment of new malaria episode occurring during wash-out with oral quinine, 5 days (supervised).
• Possibly related TEAEs (all attacks): 1 subject in each group (severe increase in ALT)
• Number of patient who experienced TEAE per treatment group per episode
130 120 110 100 90 80 70 60 50 40 30 20 10 0
Safety population Total Liver function test abnormal Malaria Urnary tract infection Anaemia Agranulocytosis Accident Forearm fracture Road traffic accident Cardiac failure congestive Dehydration
AE
22 4 7 1 4 1 1 1 1 1 1
ASAQ (n=208) n 16 4 6 1 3 1 1 1 1 1 1
%
7,7 1,9 2,9 0,5 1,4 0,5 0,5 0,5 0,5 0,5 0,5
AE
9 8 0 0 0 1 0 0 0 0 0
AL (n=205) n 9 8 0 0 0 1 0 0 0 0 0
%
4,4 3,9 0,0 0,0 0,0 0,5 0,0 0,0 0,0 0,0 0,0
TOTAL (n=413) AE n % 31 12 7 1 4 2 1 1 1 1 1
256,1 122,9 61,5 10,2 30,7 20,5 10,2 10,2 10,2 10,2 10,2
No difference between treatment groups (p-value = 0.159) One patient died 3 weeks after ASAQ treatment (16th episode), due to severe malaria, severe anemia and congestive heart failure. Relationship with investigational product was excluded.
• AEs special interest: (all attacks)
AL ASAQ
Safety population Total Liver function test abnormal Neutropenia Agranulocytosis
ASAQ (n=208) AE n 15 11 3 1
14 11 3 1
% 6,7 5,3 1,4 0,5
AL (n=205) AE n 14 12 1 1
14 12 1 1
% 6,8 5,9 0,5 0,5
TOTAL (n=413) AE n % 29 23 4 2
286,8 235,6 41,0 20,5
All AESI were reversible. E1 E2 E3 E4 E5 E6 E7 E8 E9 E10 E11 E12 E13 E14 E15 E16 E17 E18 E19 E20 E21 E22 E23 E24
Incidence of adverse events decreases with the repetition of treatment in both groups
Conclusion
• Wash out from ACT: 2 patients for ALT>3ULN at D0; spontaneous
recovering during the first month without ACT; Both were reintegrated in the cohort after 3 months.
An unexpectedly high number of malaria attacks was seen in this study, despite distribution of IT bednets and information of parents. Because of this high number of malaria episodes treated, this study provides unique data on the safety and efficacy of repeated administrations of two widely-used ACTs. Efficacy results obtained at D28 after PCR correction are available for the first episode; showing that the efficacy of ASAQ FDC was non-inferior to that of AL FDC.PCR analysis for the subsequent episodes is still ongoing. This study showed comparable clinical and biological safety profiles for the two ACTs, with no issue related with repeated administrations.