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Tolerability of malaria chemoprophylaxis in non-immune travellers to sub-Saharan Africa: multicentre, randomised, double blind, four arm study

BMJ 2003; 327 doi: https://doi.org/10.1136/bmj.327.7423.1078 (Published 06 November 2003) Cite this as: BMJ 2003;327:1078
  1. Patricia Schlagenhauf, research scientist (pat{at}ifspm.unizh.ch)1,
  2. Alois Tschopp, statistician2,
  3. Richard Johnson, research psychologist3,
  4. HansD Nothdurft, consultant in tropical and travel medicine4,
  5. Bernhard Beck, consultant in tropical and travel medicine5,
  6. Eli Schwartz, professor of tropical and travel medicine6,
  7. Markus Herold, resident1,
  8. Bjarne Krebs, resident44,
  9. Olivia Veit, resident5,
  10. Regina Allwinn, consultant in tropical and travel medicine7,
  11. Robert Steffen, professor of travel medicine1
  1. 1Division of Epidemiology and Communicable Diseases, Institute for Social and Preventive Medicine, University of Zurich, Zurich, Switzerland
  2. 2Department of Biostatistics, Institute for Social and Preventive Medicine, University of Zurich
  3. 3Military Performance Division, US Army Research Institute of Environmental Medicine
  4. 4Department of Infectious Diseases and Tropical Medicine, University of Munich
  5. 5Swiss Tropical Institute, Basel
  6. 6Chaim Sheba Medical Center, Tel Hashomer, University of Tel Aviv
  7. 7Institute for Medical Virology, J W Goethe University, Frankfurt/Main
  1. Correspondence to: P Schlagenhauf
  • Accepted 29 August 2003

Abstract

Objective To compare the tolerability of malaria chemoprophylaxis regimens in non-immune travellers.

Design Randomised, double blind, study with placebo run-in phase.

Setting Travel clinics in Switzerland, Germany, and Israel.

Main outcome measure Proportion of participants in each treatment arm with subjectively moderate or severe adverse events.

Participants 623 non-immune travellers to sub-Saharan Africa: 153 each received either doxycycline, mefloquine, or the fixed combination chloroquine and proguanil, and 164 received the fixed combination atovaquone and proguanil.

Results A high proportion of patients reported adverse events, even in the initial placebo group. No events were serious. The chloroquine and proguanil arm had the highest proportion of mild to moderate adverse events (69/153; 45%, 95% confidence interval 37% to 53%), followed by mefloquine (64/153; 42%, 34% to 50%), doxycycline (51/153; 33%, 26% to 41%), and atovaquone and proguanil (53/164; 32%, 25% to 40%) (P = 0.048 for all). The mefloquine and combined chloroquine and proguanil arms had the highest proportion of more severe events (n = 19; 12%, 7% to 18% and n = 16; 11%, 6% to 15%, respectively), whereas the combined atovaquone and proguanil and doxycycline arms had the lowest (n = 11; 7%, 2% to 11% and n = 9; 6%, 2% to 10%, respectively: P = 0.137 for all). The mefloquine arm had the highest proportion of moderate to severe neuropsychological adverse events, particularly in women (n = 56; 37%, 29% to 44% versus chloroquine and proguanil, n = 46; 30%, 23% to 37%; doxycycline, n = 36; 24%, 17% to 30%; and atovaquone and proguanil, n = 32; 20%, 13% to 26%: P = 0.003 for all). The highest proportion of moderate or severe skin problems were reported in the chloroquine and proguanil arm (n= 12; 8%, 4% to 13% versus doxycycline, n = 5; 3%, 1% to 6%; atovaquone and proguanil, n = 4; 2%, 0% to 5%; mefloquine, n = 2; 1%, 0% to 3%: P = 0.013).

Conclusions Combined atovaquone and proguanil and doxycyline are well tolerated antimalarial drugs. Broader experience with both agents is needed to accumulate reports of rare adverse events.

Footnotes

  • Contributors PS and RS designed the study, with statistical input from AT and RJ and were responsible for centre coordination and study management. PS, HDN, BB, ES, MH, BK, OV, and RA obtained ethical approval, recruited participants, and collated the data at their respective centres. AT managed data entry and did the data analysis. RJ analysed moods and feelings. PS drafted the paper. PS and RS will act as guarantors for the paper.

  • Funding Pfizer, GlaxoSmithKline, Roche, and Zeneca provided the drugs free of charge. GlaxoSmith Kline and Roche provided research grants. The guarantors accept full responsibility for the conduct of the study, had access to the data, and controlled the decision to publish.

  • Competing interests PS has received speakers' honorariums and travel expenses from Roche and GlaxoSmithKline. She acted as a consultant to Roche in a drug safety database evaluation. RS has received speakers' honorariums and travel expenses from GlaxoSmithKline, Roche, and Pfizer. He is also a member of the advisory board of GlaxoSmithKline for malaria prophylaxis related questions. BB has received a speaker's honorarium and travel expenses from GlaxoSmithKline. HN has received speakers' honorariums and travel expenses from GlaxoSmithKline on different occasions. He has been principal or coinvestigator in several vaccine trials sponsored by GlaxoSmithKline.

  • Ethical approval Approval was obtained from the ethics committees of all five participating centres in Zurich, Basel, Munich, Frankfurt, and Tel-Aviv.

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