Field research in Tropical Medicine, and Mother and Child Health. Malaria, nutrition, neglected disease, HIV, TB, paediatrics, Epilepsy, access to treatment, treatments for children.
Reply to Eisenhut
To the Editor
Eisenhut [1] underlined the importance of the equivalence trial design for the comparison of rectal quinine
treatment with other quinine applications. Very few cerebral malaria studies have been able to enroll a sufficient number of patients to answer the primary outcome of mortality among patients, and most studies have focused on secondary outcomes. Analysis of mortality can only be realized through costly multicenter studies, which are beyond the reach of many clinicians working in resource-constrained countries.
Although quinine remains the main treatment for severe malaria in Africa, alternative and simple techniques, such as the rectal route, have received little support.
Since the first publications by Barennes in 1989 and 1994 [2, 3], only 2 randomized studies evaluating rectal quinine for the treatment of cerebral malaria have been performed [4, 5]. We acknowledge
that our recent study [4] had insufficient power to demonstrate equivalence between the 2 treatment groups; nonetheless, our study confirmed the efficacy of intrarectal quinine in the management of severe
malaria. Pooling data from similar studies allowed us to reach a sample size close to
that suggested by Eisenhut [1]. Pooling the Niger and Ugandan data revealed an interesting
but non–statistically significant trend toward higher mortality in the intravenous quinine group, compared with the rectal quinine group (15.4% [14 of 91 patients] vs. 8.4% [8 of 95 patients]; Pp.1). Furthermore, pooling data from similar studies in which intravenous quinine was administered to 327 patients in the same hospital from 2003 through 2007 [4, 6, 7] showed a trend of lower mortality in the intrarectal quinine group (8.4% [8 of 95 patients] vs. 15.9% [37 of 232 patients]; Pp.07) [7, 8].
However, we believe that the debate should focus on another topic. Less than 20% of deaths come to the attention of any formal health care system [8]. Therefore, hospital-based trials investigating severe malaria are affected by a survival bias, because only children who survive and seek care in a hospital can be evluated.
In our comparison of the 2 treatment modes, we noted that intravenous quinine is available only at hospitals and that intrarectal quinine could be available at the village level. Therefore, rectal quinine could be administered early, at the onset of illness, with a mean of 3.5 days before reaching the hospital [4]. In these situations, rectal quinine is likely to save more lives than intravenous quinine. Indeed, a study comparing the 2 routes should be performed at the community level, not at the hospital level. Eisenhut [1] also commented on the need to focus on comparison of safety, convenience, and cost implications. However, a study performed since his review [9] provide this information. We previously evaluated drug tolerance among 898
patients in a randomized study in Burkina Faso; the feasibility and acceptability of treatment at the community level have recently been evaluated in Niger, Mali, and Senegal [10–12].
We acknowledge the comments by Eisenhut [1]; however, our results highlight the important role that rectal quinine could play as early treatment in settings where there are often insurmountable challenges associated with transferring patients to medical centers that are better equipped to handle such cases.
Acknowledgments
Potential conflicts of interest. J.A. has received partial research funding from Impact Malaria, Sanofi-Aventis. All other authors: no conflicts.
Jane Achan,1 Hubert Barennes,2 Justus Byarugaba,1 and James K. Tumwine1
1Department of Pediatrics and Child Health, Makerere University, Kampala, Central Uganda; and 2Institut Francophone de Medecine Tropicale, Vientiane, Laos
Reference
1. Eisenhut M. The importance of equivalence trial design for comparison of rectal quinine with other quinine applications. Clin Infect Dis 2008; 46:1795–6 (in this issue).
2. Barennes H. Essai clinique du Quinimax en intra-rectal. Med Digest 1989; 15:1–4.
3. Barennes H. Is intrarectal injectable quinine a safe alternative to intramuscular injectable quinine? Trop Doct 1994; 24:32–3.
4. Achan J, Byarugaba J, Barennes H, Tumwine JK. Rectal versus intravenous quinine for the treatment of childhood cerebral malaria in Kampala, Uganda: a randomized, doubleblind clinical trial. Clin Infect Dis 2007; 45: 1446–52.
5. Barennes H, Munjakazi J, Verdier F, Clavier F, Pussard E. An open randomized clinical study of intrarectal versus infused Quinimax for the treatment of childhood cerebral malaria in Niger. Trans R Soc Trop Med Hyg 1998; 92: 437–40.
6. Aceng JR, Byarugaba JS, Tumwine JK. Rectal artemether versus intravenous quinine for the treatment of cerebral malaria in children in Uganda: randomised clinical trial. BMJ 2005; 330:334.
7. Namutangula B, Ndeezi G, Byarugaba JS, Tumwine JK. Mannitol as adjunct therapy for childhood cerebral malaria in Uganda: a randomized clinical trial. Malar J 2007; 6:138.
8. Breman JG. The ears of the hippopotamus: manifestations, determinants, and estimates of the malaria burden. Am J Trop Med Hyg 2001; 64(Suppl):1–11.
9. Eisenhut M, Omari A, MacLehose HG. Intrarectal quinine for treating Plasmodium falcparum malaria: a systematic review. Malar J 2005; 4:24.
10. Landais E, Poisson C, Condamine JL. Analysis of 1697 cases of childhood malaria treated using intra-rectal Quinimax (QIR) in the Tilaberi health district in Niger [in French]. Med Trop (Mars) 2007; 67:471–6.
11. Ndiaye JL, Tine RC, Faye B, et al. Pilot feasibility study of an emergency paediatric kit for intra-rectal quinine administration used by the personnel of community-based health care units in Senegal. Malar J 2007; 6:152.
12. Thera MA, Keita F, Sissoko MS, et al. Acceptability and efficacy of intra-rectal quinine alkaloids as a pre-transfer treatment of non–per os malaria in peripheral health care facilities in Mopti, Mali. Malar J 2007; 6:68.
Reprints or correspondence: Dr. James Tumwine, Paediatrics and Child Health, Makerere University Medical School, PO
Box 7072, Kampala 256, Central Uganda (jtumwine @imul.com). Clinical Infectious Diseases 2008; 46:1796–7
_ 2008 by the Infectious Diseases Society of America. All rights reserved. 1058-4838/2008/4611-0032$15.00
DOI: 10.1086/588055
The Importance of the Equivalence Trial Design for Comparison of Rectal Quinine Treatment with Other Quinine Applications
To the Editor—Achan et al. [1] reported on a randomized trial comparing intrarectal with intravenous quinine and found no difference in outcomes, such as coma recovery time and mortality, in the largest study (thus far) comparing rectal with other applications of quinine for treatment of cerebral malaria. The design and sample size calculation were based on the assumption that rectal quinine is superior to intravenous quinine with regard to parasite clearance time. However, in the treatment of cerebral malaria, parasite clearance is not a key outcome on which the design of such a comparison should be based. Mortality, coma recovery time, and neurological sequelae would be more important outcomes. Degree of parasitemia does not correlate with the amount of sequestration of parasites in the brain in cerebral malaria [2]. A previous systematic review [3] of data from 8 randomized, controlled trials found no difference in mortality and coma recovery time between rectal and other applications of quinine treatment. The comparison of a new with a traditional application of a drug should aim primarily at demonstration of equivalence for important primary outcomes and at comparison of safety, convenience, and cost implications [4]. For a sample size calculation for an equivalence trial with mortality as a primary outcome, with a difference in mortality of 2% as a range of equivalence and 8% mortality (as expected with standard quinine treatment of cerebral malaria), a sample size of at least 3863 persons in each treatment group would be required to demonstrate equivalence with a power of 80% and a 2-sided 95% CI for the difference in mortality [4]. For an equivalence trial with coma recovery time as a primary outcome, with a difference in coma recovery time of 4 h as a range of equivalence and 12 h as SD, at least 189 participants would be required in each group to demonstrate equivalence with 80% power and a 95% CI for the difference. The trial by Achan et al. [1] was therefore underpowered to investigate equivalence, and this and previous trials [3] of rectal quinine for the treatment of severe malaria did not support a statement about equivalence of 2 applications of quinine. Future trials should investigate equivalence in an appropriately powered trial that takes into account power calculations for equivalence trials as a basis in their design. Acknowledgments Potential conflicts of interest. M.E.: no conflicts. Michael Eisenhut Luton & Dunstable Hospital National Health Service Foundation Trust, Luton, United Kingdom References 1. Achan J, Byarugaba J, Barennes H, Tumwine JK. Rectal versus intravenous quinine for the treatment of childhood cerebral malaria in Kampala, Uganda: a randomized, double-blind clinical trial. Clin Infect Dis 2007; 45:1446–52. 2. Silamut K, Phu NH, Whitty C, et al. A quantitative analysis of the microvascular sequestration of malaria parasites in the human brain. Am J Pathol 1999; 155:395–410. 3. Eisenhut M, Omari AAA. Intrarectal quinine for treating Plasmodium falciparum malaria. Cochrane Database Syst Rev 2005:CD004009. 4. Jones B, Jarvis P, Lewis JA, Ebbutt AF. Trials to assess equivalence: the importance of rigorous methods. BMJ 1996; 313:36–9. Reprints or correspondence: Dr. Michael Eisenhut, Luton & Dunstable Hospital NHS Foundation Trust, Lewsey Rd., Luton LU40DZ, United Kingdom (michael_eisenhut@yahoo.com).
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