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Mefloquine/doxycycline trials

During INTERFET, a large number of Australian Army soldiers who were taking doxycycline for prophylaxis against malaria developed the disease (see History). Doxycycline must be taken on a daily basis and evidence from studies in other militaries had identified compliance with taking the medication as a major issue. For this reason Defence needed to look at other options, including the then second line medication, mefloquine, to improve the protection of ADF personnel against malaria.

Mefloquine was registered in Australia by the Therapeutic Goods Administration (TGA) for malaria prophylaxis (prevention) in 1993, seven years before the field trials were conducted in Timor-Leste. As a weekly dose it had previously been shown to have better compliance than daily medications during studies in Australian tourists. Although adverse events were similar for those using mefloquine for malaria prevention compared with those using doxycycline, the drug appeared to have neuropsychiatric side effects that researchers were concerned could impact on operational effectiveness. Studies of other military populations showed mefloquine to be as well tolerated and have better compliance than daily anti-malarial medications when used over shorter periods than the typical ADF deployment. Nevertheless, it was important to understand the effects of these medications in the ADF population to inform the most appropriate anti-malarial regimen for force protection rather than just change the policy. As such, the AMI sought approval to conduct trials (field tests) of mefloquine in ADF troops deploying to Timor-Leste from 2001-2002.

The ADF trials of malaria medications were done according to strict ethical and scientific standards.  The test protocols were carefully reviewed prior to the trial by the then Australian Defence Medical Ethics Committee (ADMEC), a committee of impartial experts charged with being certain that such testing is both ethically permissible and scientifically correct. Detailed written records were kept at all phases of the trial with this information later analysed and the results presented in scientific publications to document the trial's findings.

The objective of this study was to compare the side effects and effectiveness of mefloquine with those of doxycycline under typical field conditions. Both of these medications were already registered and in use in Australia across the broader population. The study population was drawn from battalion groups deploying to Timor-Leste during April – October 2001 and October 2001 - May 2002.

Participation in the study was optional and voluntary. Efforts were made to ensure deploying personnel were fully informed of the risks and benefits of participation before they made their decision.  They were given a written information sheet and a verbal briefing, and were asked to sign a consent form. Those who chose to participate were also advised of the option to opt out or withdraw from the trials at any time with no detriment to their career or future health care.

Participation in the trials was not a pre-requisite for deployment.  To provide deploying personnel with appropriate protection against malaria, those who chose to not participate in the trials were prescribed antimalarial medication in accordance with extant health policy.  In most cases these individuals would have been prescribed doxycycline; however in accordance with the extant policy those who could not tolerate doxycycline would have been prescribed mefloquine.

Each participant was assessed prior to starting the study, while on deployment and before return to Australia. Participants were also assessed if they developed any side effects or experienced any adverse events. In this study, 1,157 soldiers took mefloquine and 388 took doxycycline. As expected some were unable to tolerate the specific malaria medication to which they were assigned. Those having adverse side effects were examined by medical and nursing officers, the medication was ceased, and the findings recorded while in Timor-Leste.

In several instances, soldiers intolerant of their medication had to be switched to an alternative. Soldiers not reporting side effects were still questioned about such symptoms and blood samples were taken from some trial participants to be certain that there were no chemical or blood problems that developed without symptoms. The most commonly reported adverse effects of both drugs were sleep disturbance, headache, tiredness and nausea. There were three serious neuropsychiatric events reported in people taking mefloquine. Two of these individuals had undisclosed medical conditions that would have prevented the prescription of mefloquine if they had been known to medical staff.

Overall, the study found that mefloquine was generally well tolerated and concluded that it should continue to be used for those who cannot tolerate doxycycline. No lasting serious adverse events were noted during these trials.  Follow up occurred over weeks to months following return from Timor-Leste for late malaria infections or additional symptoms.

This study was published in the Medical Journal of Australia and is available at the Medical Journal of Australia site.

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