Trial Country | Treatment regimen | Randomized | TF | Data to derive TF | Definitions of outcomes used in studies |
P. vivax | |||||
Dunne 2005a India |
Azithromycin 1 g/day for 3 days Primaquine from day 7 to 20 |
98 | 12/97 | 85/97 parasitological success (clinical response 86/97) | No systematic evaluation of outcome. Parasitological failure defined as RI (recrudescence after clearance), RII (reduction in parasitaemia by > 75% of baseline without clearance, RIII (failure to reduce parasitaemia to < 25% of baseline) but no clear clinical consequence to parasitological failure (eg RII failure at day 7). “Patients who the investigator felt were not responding to therapy were given alternative therapies at their discretion.” Clinical response: Resolution of fever, without relapse at day 28. |
Chloroquine 0.6 g on day 0 to 1, 0.3 g on day 2 Primaquine from day 7 to 20 |
102 | 1/102 | 101 parasitological success (clinical response 101/102) | ||
Pukrittayakamee 2001 Thailand |
Azithromycin 0.5 g/day for 3 days | 20 | 10/18 |
P. vivax cure: 8/18 Note: P. falciparum 6/18 |
Treatment failure: persistence of fever and parasitaemia for > 7 days or persistence of parasitaemia in the absence of fever for > 2 weeks. Reappearance of infection after clearance within 28 days. |
Tetracycline 250 mg 4x/day for 7 days | 27 | 4/18 | P. vivax cure: 14/18 | ||
Doxycycline 200 mg/day for 7 days | 25 | 8/18 | P. vivax cure: 10/18 | ||
Clindamycin 300 mg 4x/day for 7 days | 20 | 5/12 | P. vivax cure: 7/12 | ||
P. falciparum | |||||
Dunne 2005b India |
Azithromycin 1 g/day for 3 days | 16 | 9/14 | 9 had RI (3), RII (3) or RIII (3) failures (5/15 clinical cure) | No systematic evaluation of outcome. Treatment failure defined in terms of RI (recrudescence after clearance of parasitaemia), RII (reduction in parasitaemia to < 25% of baseline levels without clearance), and RIII (failure to reduce parasitaemia to < 25% of baseline levels), but time of evaluation and clinical consequences for type of resistance level not reported. Clinical response not defined (but one of the main outcomes). Term 'Eradication' used in table, not defined. “Any participant who, in the opinion of the investigator, had not sufficiently improved received additional antimalarial therapy.” |
Chloroquine 0.6 g on day 0 to 1, 0.3 g on day 2 | 16 | 11/15 | 11 had RI (9), RII (1) or RIII (1) failures (clinical cure 4/15) | ||
Azithromycin 1 g/day for 3 days, Chloroquine 0.6 g on day 0 to 1, 0.3 g on day 2 | 64 | 2/63 | 2 had RII (1) or RIII (1) failures (clinical cure 61/63) | ||
Krudsood 2000 Thailand |
Azithromycin 0.5 g/day, Artesunate 200 mg/day for 3 days | 67 | 24/55 | 24 RI response, 31 cure | 28‐day cure rate used. Sensitive: no reappearance of asexual forms of P. falciparum within 28 day follow‐up. Resistance: Resistance at level I (reappearance after day 7), II (parasitaemia at day 7), and III (failure to reduce parasitaemia by > 75% of initial count or clinical deterioration after 48 hours). |
Artesunate 200 mg/day for 3 days and mefloquine 10 mg/kg on day 0 to 1, 5 mg/kg on day 2 | 67 | 1/55 | 1 RI response, 54 cure | ||
Artesunate 200 mg/day for 3 days | 68 | 34/61 | 34 RI response, 27 cure | ||
Miller 2006 Thailand |
Azithromycin 0.5 g 2x/day and quinine 10 mg/kg 3x/day for 3 days | 10 | 1/10 | 1 R1 response, 9 cure | Cure: clearance of P. falciparum parasitaemia without recrudescence of malaria in a 28‐day period. |
Azithromycin 0.5 g 2x/day and quinine 10 mg/kg 3x/day for 5 days | 20 | 0/20 | All cure | ||
Azithromycin 0.5 g 3x/day and quinine 10 mg/kg 3x/day for 3 days | 20 | 0/20 | All cure. Note: this arm was not randomized | ||
Doxycycline 100 mg 2x/day for 7 days and quinine 10 mg/kg 3x/day for 7 days | 10 | 0/10 | All cure | ||
Na‐Bangchang 1996 Thailand |
Azithromycin 0.5 g at start, 0.25 g at 24 and 48 hours, and artemether 300 mg at start | 30 | 23/27 | 4/27 were sensitive, 23 RI response | Rate of treatment failure (RI‐RIII, WHO 1973). |
Doxycycline 100 mg 2x/day for 5 days and artemether 300 mg at start and 100 mg after 12 hrs | 30 | 14/30 | 16/30 sensitive, 14 RI response | ||
Noedl 2006 Thailand |
Azithromycin 0.75 g 2x/day and artesunate 100 mg 2x/day for 3 days | 27 | 2/25 | 23/25 cure. 2 RI | 28 day cure. Treatment failure divided in RI: clearance of asexual parasites within 7 days after start treatment, followed by recrudescence; RII: decrease in parasite count < 25% of baseline value within 48 hours but failure to clear parasites by day 7; RIII: failure of the parasite count to decrease to < 25% of the baseline value within 48 hours (WHO 1973). |
Azithromycin 1 g/day and artesunate 200 mg/day for 3 days | 27 | 3/27 | 24/27 cure, 3 RI | ||
Azithromycin 0.75 g 2x/day and quinine 10 mg/kg 2x/day for 3 days | 16 | 4/15 | 11/15 cure, 1 RI and 3 RIII | ||
Azithromycin 0.5 g 3x/day and quinine 10 mg/kg 3x/day for 3 days | 27 | 2/25 | 23/25 cure, 2 RI | ||
Pfizer 74841 India |
Azithromycin 1 g/day and chloroquine 600 mg/day for 3 days | 83 | 12/73 | 61 eradicated | Outcome: Asexual parasite clearance rate at day 28. No further definition given. Term 'eradication' used in table, not defined. |
Azithromycin 0.5 g/day and chloroquine 0.6 g/day for 3 days | 67 | 20/59 | 39 eradicated | ||
Sulfadoxine‐pyrimethamine 1500mg/75 mg at start, chloroquine 0.6 g on day 0 to 1, 0.3 g on day 2 | 79 | 4/72 | 68 eradicated | ||
Pfizer 82563 Kenya |
Azithromycin 1 g/day and chloroquine 0.6 g/day for 3 days | 7 | 1/5 | 1 RIII failure which cleared by day 7 (Eradication: 5/5) |
Eradication: Clearance of asexual parasitaemia within 7 days of initiation of treatment, without subsequent recurrence through day 28. Failure: RI: clearance of asexual parasitaemia before day 7, followed by recurrence on or after day 7. RII: marked reduction (< 25% of baseline) of asexual parasitaemia but no clearance prior to and up to day 7. RIII: no marked reduction ( > 25% of baseline) of parasitaemia within 48 hours. If a subject remained parasitaemic on day 7, curative treatment was provided. Terms of eradication and failure not mutually exclusive for RIII resistance: we used failure (RI‐RIII) for consistency with other studies. |
Chloroquine 0.6 g/day for 3 days | 7 | 2/7 | 1 RIII failure which cleared by day 7, and one RI failure (the other RI failure mentioned was the untreated RIII failure) (Eradication: 5/7) PCR adjusted: 1/7 |
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Pfizer 82576 Ghana, Kenya, Mali, Uganda, Zambia |
Azithromycin 1 g/day and chloroquine 0.6 g/day for 3 days | 114 | 5/103 | 5 late treatment failures (4.85%) PCR adjusted: 2/103 |
Primary outcome table presumably PCR‐adjusted; data for PCR‐unadjusted results on day 28 not clearly presented. Percent early and late treatment failure used (assuming the investigators follow WHO 2003) but this may not be reliable because the trial ended at day 42. Two RIII failures in 1 g azithromycin/chloroquine arm reported, but not labelled as early treatment failures. |
Azithromycin 0.5 g/day and chloroquine 0.6 g/day for 3 days | 9 | NR | |||
Mefloquine 750 mg at start, 500 mg after 6 hours | 115 | 2/103 | 1 early treatment failure and 1 late treatment failure (1.94%) PCR adjusted: 1/103 |
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Pfizer 84227 Columbia/Surinam |
Azithromycin 1 g/day and chloroquine 0.6 g/day for 3 days | 114 | 48/112 | 64 eradicated PCR partially adjusted: 68/112 (35 analysed) |
Primary endpoint asexual parasite clearance rate at day 28, not further defined. “Treatment when persistent or recurrent parasitaemia”, but time point of evaluation for treatment not defined. Used 'eradicated': asexual parasite clearance rate on day 28 among evaluable subjects. |
Azithromycin 0.5 g/day and chloroquine 0.6 g/day for 3 days | 14 | NR | |||
Atovaquone 1000 mg/day and proguanil 400 mg/day for 3 days | 116 | 1/113 | 112 eradicated PCR adjusted: 113/113 |
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Pfizer 84240 Indonesia |
Azithromycin 1 g/day and chloroquine 0.6 g/day for 3 days | 13 | 9/13 | 4 eradicated PCR partially adjusted 4/13 eradicated (5 analysed) |
Eradication: Clearance of asexual Pf parasitaemia within 7 days of initiation of treatment, without subsequent recurrence through day 28. Failure: failure to achieve clearance of Pf asexual parasitaemia within 7 days of initiation of treatment or subsequent recurrence through day 28 after achieving clearance. Subjects with persistent or recurrent parasitaemia during the follow up period were treated with antimalarial drugs and were withdrawn from further participation in the study. |
Azithromycin 0.5 g/day and chloroquine 0.6 g/day for 3 days | 7 | NR | |||
Sulfadoxine‐Pyrimethamine 1500mg/75 mg at start, chloroquine 0.6 g on day 0 to 1, 0.3 g on day 2 | 12 | 3/10 | 7 eradicated PCR adjusted: 8/10 |
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Pfizer 367653 Burkina Faso, Ghana, Kenya, Mali, Senegal, Zambia |
Azithromycin 1 g/day and chloroquine 0.6 g/day for 3 days | 113 | 1/107 | As per correspondence with Pfizer PCR adjusted: 0/107 |
Eradicated: clearance of asexual P. falciparum parasitaemia within 7 days of initiation of treatment, without subsequent recrudescence through day 28. Failure: Failure to achieve clearance of asexual P. falciparum parasitaemia within 7 days of initiation of treatment or subsequent recrudescence through day 28 after achieving initial clearance. |
Mefloquine 750 mg at start, 500 mg after 6 to 10 hours | 116 | 1/111 | As per correspondence with Pfizer PCR adjusted: 1/111 |
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Sykes 2009 Tanzania |
Azithromycine 20 mg/kg/day and artesunate 4 mg/kg/day for 3 days | 129 | 69/119 | Day 28 partially PCR‐adjusted: 40/119 (6 not tested) Day 42:TF 76/115, partially PCR‐adjusted: 42/115 (5 not tested) |
Parasitological failure: the presence of asexual malaria parasites after treatment (after day 3) on or before day 28, irrespective of symptoms. |
Artemether 20 mg and lumefantrine 120 mg 2x/day for < 15 kg and 40 mg/240 mg 2x/day for ≥15 kg for 3 days | 132 | 24/120 | Day 28 partially PCR‐adjusted: 12/120 (3 not tested) Day 42: TF 41/119, partially PCR adjusted: 17/119 (4 not tested) |
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Thriemer 2010 Bangladesh |
Azithromycin 1.5 g/day and artesunate 200 mg/day for 3 days. Children < 35 kg: azithromycin 30 mg/kg/day, and artesunate 4 mg/kg/day for 3 days | 152 | 13/142 | Day 28: PCR‐adjusted: 8/142 Day 42: TF 22/142, PCR‐adjusted: 8/142 |
Primary endpoint was cure: adequate clinical and parasitological response as defined by WHO criteria by day 42. Day 28 data kindly provided by the authors. |
Artemether 80 mg and lumefantrine 480 mg 2x/day for 3 days. Children < 35 kg: artemether 4 mg/kg and lumefantrine 24 mg/kg 2x/day for 3 days | 76 | 1/69 | Day 28: PCR‐adjusted: 0/69 Day 42: TF 6/69, PCR‐adjusted: 2/69 |
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Excluded studies | |||||
Krudsood 2002 Thailand |
Azithromycin 0.5 g/day and dihydroartemisinin 80 mg/day for 3 days | 82 | 20/66 | 46 cure | 28 day cure rate: the proportion of patients who cleared asexual parasitaemia within 7 days of initiation of treatment without subsequent recrudescence within 28 days. |
Mefloquine 10 mg/kg on day 1,2; 5 mg/kg on day 3; dihydroartemisinin 80 mg/day for 3 days | 88 | 68/68 | All cure | ||
Pfizer 282919 India/Columbia |
Azithromycin 2 g/day and chloroquine 0.6 g/day for 3 days | 110 | 5/107 | As per presentation ASTMH December 08, New Orleans PCR‐adjusted: 3/107 |
Parasitological clearance day 28 (PCR unadjusted), and eradication not defined. |