Characteristics of included studies [ordered by study ID]
Gordeuk 1992a
|
| Methods | Cross-over trial
Generation of allocation sequence: not specified
Allocation concealment: unclear
Blinding: double blind
Inclusion of all randomized participants: 100% (28/28) for the initial period used in this analysis; 3/28 withdrawn after first 72 h |
|
| | Participants | Number: 28
Description: adults aged 15 to 56 years; partially immune with asymptomatic P. falciparum |
|
| | Interventions | Iron-chelating agent vs placebo
1. DFO B (100 mg/kg/day)
2. Placebo (normal saline)
Subcutaneous infusion over 72 h, then cross-over; initial period only used in this analysis |
|
| | Outcomes | 1. Mean parasite concentration
2. Rate of parasite clearance (graph)
3. Side effects |
|
| | Notes | Location: Zambia
Date: February to August 1990
Sources of support: Ciba-Geigy donated DFO |
|
|
Gordeuk 1992b
|
| Methods | Generation of allocation sequence: not specified
Allocation concealment: central randomization by pharmacy staff
Blinding: double blind
Inclusion of all randomized participants: 100% |
|
| | Participants | Number: 83 children
Description: < 6 years; cerebral malaria; P. falciparum parasitaemia; unrousable coma |
|
| | Interventions | Iron-chelating agent plus antimalarial drugs vs placebo plus antimalarial drugs
1. DFO mesylate (100 mg/kg/day)
2. Placebo (5% dextrose)
Continuous infusion over 72 h; added to standard quinine and sulfadoxine-pyrimethamine treatment |
|
| | Outcomes | 1. Mortality
2. Time to recovery of full consciousness (Glasgow Coma Scale: 5)
3. PCT (ring form decrease to < 22/mm3)
4. Rate of parasite clearance (graph) |
|
| | Notes | Location: Macha Mission Hospital, S. Province, Zambia
Date: 1990-1
Sources of support: Ciba-Geigy donated DFO; Macha Mission Hospital pharmacy prepared the placebo
Paired sequential design used for first 30 participants enrolled; study too small to detect reduction in mortality |
|
|
Gordeuk 1993
|
| Methods | Generation of allocation sequence: not specified
Allocation concealment: unclear
Blinding: double blind
Inclusion of all randomized participants: 100% |
|
| | Participants | Number: 37
Description: adult rural Zambians with asymptomatic P. falciparum |
|
| | Interventions | Iron-chelating agent vs placebo
1. DFO B (100 mg/kg/day)
2. Placebo (normal saline)
Continuous subcutaneous infusion over 72 h |
|
| | Outcomes | Mean parasite concentration (graph) |
|
| | Notes | Location: Macha, S. Province, Zambia
Date: Aug 1990 to Feb 1991
Sources of support: Ciba-Geigy provided DFO
First 10 days of study used, day 11 participants with persisting parasitaemia offered DFO (not randomized) |
|
|
Mohanty 2002
|
| Methods | Generation of allocation sequence: random-number table
Allocation concealment: serial numbering
Blinding: double blind
Inclusion of all randomized participants: 100% |
|
| | Participants | Number: 45
Description: aged 13 to 84 years with P. falciparum infection and fever |
|
| | Interventions | Iron-chelating agent plus antimalarial drugs vs placebo plus antimalarial drugs
1. Deferiprone (75 mg/kg/day in 12 hourly divided doses) plus antimalarial regimen for 10 days
2. Placebo capsules plus antimalarial regimen for 10 days
Antimalarial regimen: standard quinine and doxycycline therapy plus supportive therapy |
|
| | Outcomes | 1. Mortality
2. Coma recovery
3. Parasite clearance |
|
| | Notes | Location: KEM hospital, Mumbai, India
Date: 1996-7 |
|
|
Thuma 1998a
|
| Methods | Generation of allocation sequence: not specified; block randomization
Allocation concealment: centrally randomized by pharmacy staff
Blinding: double blind (only pharmacist knew code)
Inclusion of all randomized participants: 100% |
|
| | Participants | Number: 352
Description: Zambian children aged < 6 years; asexual forms of P. falciparum; unrousable coma (Blantyre Coma Scale < 5); normal cerebrospinal fluid |
|
| | Interventions | Iron-chelating agent plus antimalarial drugs vs placebo plus antimalarial drugs
1. DFO B (100 mg/kg/day)
2. Placebo (5% dextrose)
Continuous IV infusion over 72 h; added to standard quinine treatment (7-day regimen); also used a quinine loading dose of 20 mg/kg |
|
| | Outcomes | 1. Mortality
2. Coma recovery (time to Blantyre Coma Scale: 5)
3. Parasite clearance time (ring form decrease to < 20/cubic mm)
4. Fever clearance time (temperature decrease to 37.8 ºC)
5. Parasite clearance day 3
6. Adverse effects |
|
| | Notes | Location: Macha Mission Hospital, S. Province (rural) and University Teaching Hospital, Lusaka (urban), Zambia
Date: 1992-4
Sources of support: Ciba-Geigy donated DFO
Initially to include 600 children but stopped by safety committee |
|
|
Thuma 1998b-i
|
| Methods | Cross-over trial
Generation of allocation sequence: not specified; block randomization
Allocation concealment: unclear
Blinding: double blind (only pharmacist knew code)
Inclusion of all randomized participants: 12/13; 13 enrolled, 1 removed after 24 h (12 completed trial period) |
|
| | Participants | Number: 13
Description: adult (male) Zambians; asymptomatic
P. falciparum parasitaemia |
|
| | Interventions | Iron-chelating agent vs placebo
1. Deferiprone (75 mg/kg/day)
2. Placebo
Administered sequentially every 8 h for 72 h; 3 days wash out, then cross-over; initial trial period only used in review |
|
| | Outcomes | 1. Mean parasite concentration (graph)
2. Toxicity and side effects |
|
| | Notes | Location: Macha Mission Hospital, Zambia
Date: September to December 1993
Sources of support: University of Toronto synthesized deferiprone; Novopharm Ltd, Toronto prepared capsules; Pharmacy Dept, Hospital for Sick Children, Toronto prepared placebo capsules
1 of 2 trials (along with Thuma 1998b-ii) reported in 1 publication |
|
|
Thuma 1998b-ii
|
| Methods | Cross-over trial
Generation of allocation sequence: not specified; block randomization
Allocation concealment: unclear
Blinding: double blind (only pharmacist knew code)
Inclusion of all randomized participants: 10/12; 12 enrolled, 2 dropped out (1 at 3 days, 1 at 7 days), 10 completed the study |
|
| | Participants | Number: 12
Description: adult (male) Zambians; asymptomatic P. falciparum parasitaemia |
|
| | Interventions | Iron-chelating agent vs placebo
1. Deferiprone (100 mg/kg/day)
2. Placebo
Given orally every 6 h for 96 h; 24 h wash out then, cross-over; initial trial period only used in review |
|
| | Outcomes | 1. Mean parasite concentration (graph)
2. Toxicity and side effects |
|
| | Notes | Location: Macha Mission Hospital, Zambia
Date: September to December 1993
Sources of support: University of Toronto synthesized deferiprone; Novopharm Ltd, Toronto prepared capsules; Pharmacy Dept, Hospital for Sick Children, Toronto prepared placebo capsules
1 of 2 trials (along with Thuma 1998b-ii) reported in 1 publication |
|
|
DFO: desferrioxamine; P. falciparum: Plasmodium falciparum.
Characteristics of excluded studies [ordered by study ID]
|
| Study | Reason for exclusion |
|---|
| | Bunnag 1992 | Open pilot study |
| | Gordeuk 1990 | Correspondence with first author confirmed that this abstract describes preliminary research conducted prior to Gordeuk 1992b, which is included in this review |
| | Looareesuwan 1996 | In an initial toxicity check, 13 patients were treated with artesunate alone (2.4 mg/kg by intravenous, then 1.2 mg/kg by intravenous every 12 h for 8 doses) or the same regimen of artesunate plus desferrioxamine (DFO) continuous infusion over 72 h. Once it was clear little toxicity was occurring, another 18 patients were treated similarly in a randomized single-blind trial. However, because the initial 13 patients had similar baseline characteristics to the subsequent 18 patients, the results were combined. Thus 2 data sets are combined, but 1 is the result of a nonrandomized study |
| | Traore 1991 | Pilot trial with just 3 patients as controls |
|
|
Comparison 1. Desferrioxamine (DFO) vs placebo (plus standard antimalarial regimen): severe malaria
|
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|
| | 1 Death | 2 | 435 | Risk Ratio (M-H, Fixed, 95% CI) | 1.40 [0.89, 2.18] |
| | 2 Persistent seizures (> 3) | 1 | | Risk Ratio (M-H, Fixed, 95% CI) | Totals not selected |
| | 3 Parasite clearance at day 3 | 1 | | Risk Ratio (M-H, Fixed, 95% CI) | Totals not selected |
| | 4 Phlebitis | 1 | | Risk Ratio (M-H, Fixed, 95% CI) | Totals not selected |
| | 5 Recurrent hypoglycaemia | 1 | | Risk Ratio (M-H, Fixed, 95% CI) | Totals not selected |
|
|
Comparison 2. Deferiprone vs placebo: asymptomatic malaria
|
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|
| | 1 Abdominal pain | 2 | 44 | Risk Ratio (M-H, Fixed, 95% CI) | 1.29 [0.38, 4.35] |
| | 2 Headache | 2 | 44 | Risk Ratio (M-H, Fixed, 95% CI) | 8.0 [1.08, 59.05] |
| | 3 Dizziness | 2 | 44 | Risk Ratio (M-H, Fixed, 95% CI) | 5.0 [0.63, 39.65] |
| | 4 Myalgia | 1 | | Risk Ratio (M-H, Fixed, 95% CI) | Totals not selected |
| | 5 Malaise | 1 | | Risk Ratio (M-H, Fixed, 95% CI) | Totals not selected |
|
|
Comparison 3. Deferiprone vs placebo (plus standard antimalarial regimen): symptomatic malaria
|
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|
| | 1 Death | 1 | | Risk Ratio (M-H, Fixed, 95% CI) | Totals not selected |
| | 2 Coma recovery time | 1 | | Mean Difference (IV, Fixed, 95% CI) | Totals not selected |
| | 3 Parasite clearance time | 1 | | Mean Difference (IV, Fixed, 95% CI) | Totals not selected |
|
|
Table 1. Detailed search strategies
|
| Search set | CIDG SRa | CENTRAL | MEDLINEb | EMBASEb | LILACSb |
| | 1 | iron | iron | iron | iron | iron |
| | 2 | chelat* | chelat* | chelat* | chelat$ | chelat$ |
| | 3 | 1 and 2 | 1 and 2 | 1 and 2 | 1 and 2 | 1 and 2 |
| | 4 | malaria | deferiprone | deferiprone | deferiprone | deferiprone |
| | 5 | 3 and 4 | desferrioxamine | desferrioxamine | desferrioxamine | desferrioxamine |
| | 6 | — | deferoxamine | deferoxamine | deferoxamine | deferoxamine |
| | 7 | — | 3 or 4 or 5 or 6 | IRON CHELATING AGENTS | IRON CHELATING AGENT | 3 or 4 or 5 or 6 |
| | 8 | — | malaria | 3 or 4 or 5 or 6 or 7 | 3 or 4 or 5 or 6 or 7 | malaria |
| | 9 | — | 7 and 8 | malaria | malaria | 7 and 8 |
| | 10 | — | — | 8 and 9 | 8 and 9 | — |
| | 11 | — | — | Limit 10 to humans | Limit 10 to humans | — |
|
|
aCochrane Infectious Diseases Group Specialized Register.
bSearch terms used in combination with the search strategy for retrieving trials developed by The Cochrane Collaboration (Higgins 2006); upper case: MeSH or EMTREE heading; lower case: free text term.
|
Table 2. Desferrioxamine (DFO) vs placebo for severe malaria: coma recovery time
|
| Trial | Outcome description | Rate of recoverya | Median timeb | Notes |
| | Gordeuk 1992b | Time from start of treatment to a sustained coma score 5 (Glasgow Coma Scale); reported as median recovery time (continuous) rather than survival data | 1.3 times faster in DFO group than in placebo group (95% CI 0.7 to 2.3) | DFO: 20.2 h (41 participants)
Placebo: 43.1 h (42 participants)
P = 0.38 | Adjusted results: deep coma (50 participants)
Recovery of full consciousness during the 72-h study period was analysed in all 83 participants |
| | Thuma 1998a | Time from start of treatment to coma score 5 (Blantyre Coma Scale); reported as median recovery time (continuous) rather than survival data | 1.2 times faster in DFO group than in placebo group (P = 0.21) | DFO: 18.1 h (143 participants)
Placebo: 19.0 h (158 participants)
95% CI 0.97 to 1.6 | 2 study sites used in the trial, but treated as 1 for analysis |
|
|
CI: confidence interval.
aRate of recovery of full consciousness. bMedian time to recovery.
|
Table 3. Desferrioxamine (DFO) vs placebo for severe malaria: parasite clearance time
|
| Trial | Outcome description | Rate of clearance | Mean 50% time | Notes |
| | Gordeuk 1992b | Rate of clearance | 2.0 times faster in DFO group than in placebo group (95% CI 1.2 to 3.6)
Significantly increased with the addition of DFO (P = 0.01) | — | Survival graph provided, but too small to interpret and no information from which hazard ratio could be determined |
| | Thuma 1998a | Rate of clearance reported, but no explanation of 'rate'
Trial author provided data for parasite clearance time provided (but treated as continuous data and only mean given (no standard deviation) and parasite clearance on day 3 after correspondence | 1.1 times faster in placebo group than DFO group (P = 0.24) | DFO: 24.6 h (145 participants)
Placebo: 24.3 h (155 participants) | 2 study sites used in the trial, but treated as 1 for analysis |
|
|
Table 4. Desferrioxamine (DFO) vs placebo for asymptomatic malaria: parasitaemia
|
| Trial | Outcome description | Change in mean PCa | Notes |
| | Gordeuk 1992a | Mean parasite concentration over initial trial period (72 h) (graph)
Decrease in geometric mean concentrations of parasites in both treatment groups during the initial trial period | DFO: significant decrease (P = 0.0001); 12 participants
Placebo: significant decrease (P = 0.002); 12 participants
Change with DFO compared to placebo: P = 0.005 | Cross-over trial; initial period only used |
| | Gordeuk 1993 | Mean parasite concentration over 72 h (graph) | DFO: significant decrease (P = < 0.001); 16 participants
Placebo: no significant decrease; 21 participants
During the week following treatment (days 3 to 10), parasitaemia remained significantly lower in the DFO group (P = 0.009) | — |
|
|
aChange in mean parasite concentration.
|
Table 5. Desferrioxamine (DFO) vs placebo for asymptomatic malaria: adverse effects
|
| Trial | Outcome description | Local effects | Systemic effects | Notes |
| | Gordeuk 1992a | Adverse effects detected during study period | Mild swelling and pain at site of needle insertion
DFO group: 22/25 subcutaneous administrations
Placebo group: 10/25 subcutaneous administrations
P < 0.05 | None reported | Participants examined and questioned regarding adverse effects twice daily. Facilities not available in study area for formal ophthalmologic and otologic evaluations |
| | Gordeuk 1993 | Adverse effects detected during study period | None reported | None reported | Participants examined and questioned regarding adverse effects twice a day |
|
|
Table 6. Deferiprone versus placebo for asymptomatic malaria: parasitaemia
|
| Trial | Outcome description | Mean at start | Mean at 72 h | Notes |
| | Thuma 1998b-i | Mean parasite concentration over initial trial period (72 h) (graph) | Deferiprone: 102/µL (SEM range 52 to 202); 6 participants
Placebo: 149/µL (SEM range 91 to 244): 7 participants | Deferiprone: 90/µL (SE 15); 5 participants
Placebo: 250/µL (SE 150); 7 participants | Cross-over trial; initial period only used
No significant decrease in parasites in either group
Trial designed to look for 80% reduction in parasite density (deferiprone vs placebo), but to show even 40% reduction would require 8 participants in each study arm; antiplasmodial effect of deferiprone not found due to a type II error |
| | Thuma 1998b-ii | Mean parasite concentration over initial trial period (72 h) (graph) | Deferiprone: 248/µL (SEM range 112 to 552); 6 participants
Placebo: 124/µL (SEM range 70 to 219); 6 participants | — | Cross-over trial; initial period only used
No significant decrease in parasites in either group
Antiplasmodial effect of deferiprone possibly not found due to type II error (explanation as in Thuma 1998b-i) |
|
|
SEM: standard error of measurement.
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