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. 2011 Feb 16;2011(2):CD006688. doi: 10.1002/14651858.CD006688.pub2
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
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
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
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
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
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)
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
  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.