Background
Methods
Study design
Subjects
Study procedure
Early treatment failure (ETF)
| ● Signs of severe malaria/clinical deterioration requiring rescue medication on Days 0, 1, 2 or 3, in the presence of P. falciparum parasitaemia* |
● Last available asexual P. falciparum parasite count on Day 2 greater than the first available parasite count at baseline irrespective of axillary, oral, or rectal temperature | |
● Parasitaemia (P. falciparum) on Day 3 with fever†
| |
● Last available P. falciparum parasite count on Day 3 ≥ 25% of the first available parasite count at baseline | |
Late treatment failure
| |
Late clinical failure (LCF) | ● Signs of severe malaria/ clinical deterioration requiring rescue medication after Day 3 in the presence of P. falciparum parasitaemia, without previously meeting any of the criteria of ETF |
● Presence of P. falciparum parasitaemia and fever† on any day from Day 4 onward, without previously meeting any of the criteria of ETF | |
Late parasitologic failure | ● Presence of P. falciparum parasitaemia on any day from Day 7 onward and the absence of fever without previously meeting any of the criteria of ETF or LCF |
Laboratory assessment
Statistical analysis
-
Subjects who withdrew from the study due to any reason other than treatment failure were censored on the day of the last available blood smear measurement.
-
Subjects who received an anti-malarial concomitant medication for treatment of a reinfection (in a PCR-corrected analysis) were censored at the visit date if the anti-malarial was given after collection of the blood smear on that day. Otherwise, the subject was censored on the day of the last available blood smear measurement taken prior to the visit. Note that in a PCR-uncorrected analysis, this type of censoring only occurred when a subject was treated at a visit based on symptoms but later found not to have parasitaemia.
Results
Cohort 1
Cohort 2
Subject disposition and demographics
AZCQ
|
AL
| |
---|---|---|
N = 124
|
N = 131
| |
Male (n, %) | 74 (59.7) | 66 (50.4) |
6 months to <5 years (n, %) | 123 (99.2) | 129 (98.5) |
5 years (n, %)* | 1 (0.8) | 2 (1.5) |
Age (years) mean (SD) | 2.4 (1.3) | 2.7 (1.0) |
Range | 0.5-5.0 | 0.5-5.0 |
Weight (kg) mean (SD) | 12.5 (3.1) | 12.8 (2.5) |
Range | 6.1-19.0 | 6.9-18.0 |
Height (cm), mean (SD) | 90.2 (11.6) | 92.7 (9.5) |
Range | 59.0-115.0 | 66.3-116.0 |
Body mass index (kg/m2) mean (SD) | 15.2 (1.6) | 14.9 (1.6) |
Range | 9.5-20.7 | 8.4-20.3 |
Baseline disease characteristics
Efficacy results
Percentage of subjects with ACPR
*
(95% CI)
†
|
MITT population
|
PP population
| ||
---|---|---|---|---|
AZCQ N = 120
|
AL N = 126
|
AZCQ N = 114
|
AL N = 124
| |
Day 7 | 94.17 (89.55, 98.78) | 99.21 (97.25, 100.00) | 98.25 (95.39, 100.00) | 100.00 (−) |
ACPR % difference‡, 95% CI†
| -5.04 (-9.93, -0.15) | -1.75 (−) | ||
Day 14 | 92.47 (87.30, 97.64) | 99.21 (97.24, 100.00) | 96.46 (92.59, 100.00) | 100.00 (−) |
ACPR % difference‡, 95% CI†
| -6.74 (-12.15, -1.32) | -3.54 (−) | ||
Day 21 | 91.59 (86.04, 97.14) | 98.37 (95.65, 100.00) | 95.53 (91.10, 99.96) | 99.16 (97.03, 100.00) |
ACPR % difference‡, 95% CI†
| -6.78 (-12.82, -0.75) | -3.63 (-8.40, 1.14) | ||
Day 28§
| 89.27 (82.77, 95.77) | 98.37 (95.59, 100.00) | 93.08 (87.32, 98.84) | 99.16 (96.97, 100.00) |
ACPR % difference‡, 95% CI†
| -9.10 (-16.02, -2.18) | -6.08 (-12.10, -0.05) | ||
Day 35 | 89.27 (82.68, 95.86) | 96.19 (91.85, 100.00) | 93.08 (87.22, 98.95) | 96.96 (92.90, 100.00) |
ACPR % difference‡, 95% CI†
| -6.92 (-14.59, 0.76) | -3.87 (-10.79, 3.04) | ||
Day 42 | 87.55 (80.08, 95.03) | 96.19 (91.79, 100.00) | 91.29 (84.31, 98.28) | 96.96 (92.84, 100.00) |
ACPR % difference‡, 95% CI†
| -8.63 (-17.08, -0.18) | -5.66 (-13.55, 2.22) |
Percentage of subjects with ACPR
*
(95% CI)
†
|
MITT population
|
PP population
| ||
---|---|---|---|---|
AZCQ N = 120
|
AL N = 126
|
AZCQ N = 114
|
AL N = 124
| |
Day 7 | 94.17 (89.55, 98.78) | 99.21 (97.25, 100.00) | 98.25 (95.39, 100.00) | 100.00 (−,-) |
ACPR % difference‡, 95% CI†
| -5.04 (-9.93, -0.15) | -1.75 (−.-) | ||
Day 14 | 89.08 (83.05, 95.11) | 96.79 (93.28, 100.00) | 92.89 (87.69, 98.08) | 97.56 (94.42, 100.00) |
ACPR % difference‡, 95% CI†
| -7.71 (-14.54, -0.88) | -4.67 (-10.6, 1.25) | ||
Day 21 | 67.87 (59.02, 76.72) | 82.96 (75.91, 90.01) | 70.56 (61.67, 79.45) | 83.62 (76.65, 90.60) |
ACPR % difference‡, 95% CI†
| -15.09 (-26.24, -3.94) | -13.07 (-24.21, -1.92) | ||
Day 28 | 51.55 (42.07, 61.02) | 73.31 (65.10, 81.52) | 54.28 (44.57, 63.98) | 73.90 (65.71, 82.08) |
ACPR % difference‡, 95% CI†
| -21.79 (-34.14, -9.39) | -19.62 (-32.16, -7.08) | ||
Day 35 | 44.67 (35.24, 54.11) | 62.91 (54.00, 71.82) | 47.04 (37.31, 56.77) | 63.41 (54.49, 72.34) |
ACPR % difference‡, 95% CI†
| -18.24 (-31.05, -5.43) | -16.38 (-29.42, -3.33) | ||
Day 42 | 37.80 (28.58, 47.02) | 56.29 (47.12, 65.46) | 39.80 (30.24, 49.36) | 56.74 (47.54, 65.94) |
ACPR % difference‡, 95% CI†
| -18.49 (-31.33, -5.65) | -16.94 (-30.04, -3.83) |
Pharmacokinetic results
Study day
|
Time post dose (hrs)
| |||
---|---|---|---|---|
Mean (% CV) azithromycin serum concentrations*
| ||||
Cohort 1
|
Cohort 2
|
Cohorts 1 and 2 combined
| ||
0 | 0 | 0 N = 52 | 0 N = 119 | 0 N = 171 |
2 | 0 | 216 (39) N = 49 | 195 (93) N = 114 | 201 (78) N = 163 |
2 | 3 | 1160 (44) N = 49 | 906 (58) N = 111 | 938 (54) N = 160 |
2 | 8 | 609 (48) N = 49 | 467 (59) N = 115 | 510 (56) N = 166 |
7 | NS | 44.7 (67) N = 48 | 26.9 (75) N = 118 | 320 (77) N = 166 |
Mean (% CV) chloroquine plasma concentrations*
| ||||
0 | 0 | 0 N = 44 | 0 N = 107 | 0 N = 151 |
2 | 0 | 172 (35) N = 49 | 131 (53) N = 110 | 144 (48) N = 159 |
2 | 3 | 430 (36) N = 48 | 331 (44) N = 107 | 362 (43) N = 155 |
2 | 8 | 367 (43) N = 49 | 295 (40) N = 106 | 318 (43) N = 155 |
7 | NS | 54.5 (67) N = 49 | 35.1 (53) N = 112 | 41.0 (65) N = 166 |
Mean (% CV) desethylchloroquine plasma concentrations*
| ||||
0 | 0 | 0 N = 43 | 0 N = 103 | 0 N = 146 |
2 | 0 | 95.1 (77) N = 49 | 77.5 (67) N = 110 | 82.9 (72) N = 159 |
2 | 3 | 170 (48) N = 49 | 138 (48) N = 107 | 148 (49) N = 156 |
2 | 8 | 160 (58) N = 49 | 147 (58) N = 104 | 151 (58) N = 153 |
7 | NS | 66.9 (94) N = 49 | 38.5 (87) N = 112 | 46.8 (97) N = 161 |
Safety results
System organ class preferred term, n (%)
|
AZCQ N = 124
|
AL N = 131
|
---|---|---|
Gastrointestinal disorders | ||
Vomiting* | 38 (30.6) | 13 (9.9) |
Abdominal pain†
| 4 (3.2) | 14 (10.7) |
Diarrhoea | 4 (3.2) | 8 (6.1) |
Infections and infestations | ||
Infection parasitic | 37 (29.8) | 31 (23.7) |
Malaria | 26 (21.0) | 19 (14.5) |
Upper respiratory tract infection | 9 (7.3) | 12 (9.2) |
Bronchitis | 4 (3.2) | 9 (6.9) |
Respiratory tract infection | 2 (1.6) | 8 (6.1) |
General disorders and administration site conditions | ||
Pyrexia | 17 (13.7) | 27 (20.6) |
Respiratory, thoracic and mediastinal disorders | ||
Cough | 15 (12.1) | 13 (9.9) |
Metabolism and nutrition disorders | ||
Decreased appetite | 9 (7.3) | 5 (3.8) |
Nervous system disorders | ||
Skin and subcutaneous tissue disorders | ||
Pruritus | 8 (6.5) | 2 (1.5) |