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ABSTRACT |
 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The authors are aware of the fact that there is no standard definition of nonimmune status. Travel to malaria-endemic areas places nonimmune individuals at risk of infection with Plasmodium falciparum and of complications of malaria. This is particularly the case where chemoprophylaxis is not used or is ineffective. As a result, a significant number of patients return from travel with imported malaria. It has been estimated that 
16,000 cases of imported malaria occur in Europe each year.2 Deaths from falciparum malaria also occur; for example, in the United Kingdom, > 2,000 cases of imported malaria are reported annually, with an average of 9 cases being fatal.3
A number of treatments are currently used in cases of imported malaria in industrialized countries. A survey in France in 20012 found that, even for uncomplicated falciparum malaria, intravenously quinine was the most commonly used treatment in 41% of cases. Mefloquine (in 18% of cases) and atovaquone-proguanil (Malarone), used in 14% of cases, were the next most commonly used therapies. Quinine and mefloquine have both been associated with potentially severe side effects. Quinine causes highly unpleasant adverse effects, and mefloquine is associated with severe neuropsychological problems,4 especially when used at a curative dose. Discontinuation because of adverse reactions has been reported in 11% of patients receiving mefloquine for the treatment of imported uncomplicated falciparum malaria in France.2 Atovaquone-proguanil, whereas effective and well tolerated as prophylaxis and in the treatment of falciparum malaria in endemic countries, has been relatively little studied in the treatment (rather than prophylaxis) of malaria in nonimmune travelers, and there are few data on its effectiveness against other Plasmodium species.5
Against this background, there remains a need for additional effective, well-tolerated treatments for imported uncomplicated falciparum malaria. Artemether-lumefantrine (co-artemether) is the first artemisinin-based combination therapy registered in industrialized countries. This fixed combination treatment has been extensively studied in endemic countries, mainly in Southeast Asia6–9 and sub-Saharan Africa,10–13 and the six-dose regimen has been shown to be associated with high parasitologic cure rates and rapid clearance of parasites and resolution of fever in these settings. However, experience with the six-dose regimen of artemether-lumefantrine in nonimmune patients is limited. Here we report the results of a multicenter, open-label, non-comparative study in which adult nonimmune travelers with imported uncomplicated falciparum malaria (or mixed infections including P. falciparum) were treated with the six-dose regimen of artemether-lumefantrine.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Key exclusion criteria were signs/symptoms indicative of severe/complicated malaria (as defined by the World Health Organization14); known hypersensitivity to the study medication; having received artemisinin derivatives within the previous 7 days; and concurrent use of other treatment/prophylaxis for malaria.
Methods. This was an open-label, non-comparative study performed at 16 centers in Europe and Colombia. The single center in Colombia was in Villavicencio, in an area without endemic malaria. This center had a history of treating nonimmune patients, typically patients from non-endemic areas who had to move to endemic areas either in search of employment or as a result of conflict.15 It was included in the study after a protocol amendment (the original protocol included only European centers) to accelerate recruitment of patients, which before the amendment had been slower than anticipated.
Treatment. Doses of 80 mg artemether and 480 mg lumefantrine (four tablets, each containing 20 mg artemether and 120 mg lumefantrine) were given on diagnosis and at 8, 24, 36, 48, and 60 hours. Patients were followed up for 28 days after diagnosis. Most patients took their medication with fat-containing food.
Efficacy evaluations.
Efficacy was assessed in terms of parasitologic cure rates at 7 and 28 days, time to fever clearance, time to parasite clearance, and the proportion of patients with P. falciparum gametocytes at each evaluation on days 0, 1, 2, 3, 7, and 28. Confidence intervals on proportions were calculated using the exact Pearson-Clopper method. Time to fever and parasite clearance were analyzed using Kaplan-Meier estimation (with appropriate censoring for patients lost to follow-up). The original sample size was chosen on the basis that, assuming at most a 10% recrudescence rate and requiring a precision of ± 5% (95% CI), 140 patients would be needed.
Pharmacokinetics. It was planned for one 2-mL blood sample to be collected from all patients on Day 3, 4–10 hours after the last dose of study medication, for determination of lumefantrine and desbutyl-lumefantrine. In addition, it was planned to take a blood sample from any patient with treatment failure to assess drug levels. The blood sample was drawn by venipuncture into a heparinized tube. Blood was centrifuged without delay at 1,000 rpm for 15 minutes, and the plasma was transferred in polypropylene tubes and stored at -70°C until shipment for analysis. Samples were shipped to the analytical center packed with dry ice. In practice, samples were available for 27 patients, and only 1 patient with treatment failure had a sample for determination of lumefantrine and desbutyl-lumefantrine.
A subset of 15 patients (recruited at the Colombian center after closure of the main study) had more extensive blood sampling for pharmacokinetic analysis. In these patients, samples were taken pre-dose and 2–4 hours after study medication doses 2, 3, 4, and 5 on Day 3 (72 hours after first dose), Day 4 (96 hours after first dose), and on Day 7 (168 hours after first dose). Lumefantrine and desbutyl-lumefantrine plasma concentrations were measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods at Novartis Pharma, BAPK-F, Rueil-Malmaison, France. These methods were developed by the sponsor and were fully validated. The lower limit of quantitation (LLOQ) of the methods was 50 ng/mL for lumefantrine and 5 ng/mL for desbutyl-lumefantrine. Pharmacokinetic parameters (derived from extensive samplings in the subset of 15 patients) were determined using model-independent methods (WinNonlin Pro., Version 4.0.1; Pharsight Corp., Mountain View, CA).
Safety assessments. Safety was assessed in terms of adverse events and laboratory parameters. Adverse events were summarized in terms of all adverse events occurring after baseline and in terms of treatment-emergent signs and symptoms (TESS; i.e. adverse events occurring after baseline but before reappearance of asexual parasites in the blood).
Blood samples to assess clinical laboratory parameters (hematology: hematocrit; hemoglobin; red blood cell count; white blood cell count; platelet count; and biochemistry: glucose; bilirubin; creatinine [serum]; ALT [SGPT]; and alkaline phosphatase) were taken at baseline and Day 28. Laboratory values were analyzed in terms of summary statistics for changes from baseline, shift tables based on the normal ranges, and shift tables based on National Cancer Institute Common Toxicity Criteria (NCI CTC) where these were available.
At baseline and Days 1, 2, and 3 (e.g., 6–10 hours after last dose), a standard 12-lead ECG (25 mm/s) was recorded followed by a tracing for rhythm evaluation using standard ECG recording equipment. The ECGs were analyzed qualitatively and quantitatively including measurements of the PQ- and QT-interval and the duration of the QRS-complex. QTc-interval was calculated by using the formulae of Bazett16 and Fridericia.17 ECGs were reviewed in a blinded manner by cardiologists at a Clinical Research Organization (eResearch Technology, Philadelphia, PA) to guarantee the quality and homogeneity of the interpretation of these data.
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RESULTS |
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Demographic and disease characteristics at baseline are shown in Table 1
. Patients were predominantly men (69%) and young to middle-aged (median, 37 years). Median body weight was 73.0 kg (range, 41–119 kg), with 65% of patients weighing > 65 kg (including 20 patients, 12.1%, who weighed > 90 kg). Most patients had pure falciparum malaria, with only 5% having mixed infections. Other Plasmodium species detected on admission were P. vivax (in two patients) and P. malariae (in six patients), but were not found subsequently. In another three patients, P. vivax was first detected at their final evaluation (Day 28, Day 13, and Day 15).
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Efficacy.
Efficacy results are shown in Table 2. Results are presented for the per protocol (PP) population (defined as all patients who completed the study and did not have major protocol violations). It was originally planned to analyze efficacy primarily on the intention-to-treat (ITT) population (all patients with confirmed malaria who received at least one dose of study drug). The pre-specified ITT analysis, however, counted patients who had incomplete documentation of parasite counts after parasite clearance as treatment failures. An unexpectedly high proportion of patients in the study had incomplete documentation of parasite counts after parasite clearance, most commonly because of discontinuation before the Day 28 visit. This would have led to an underestimation of the parasitologic cure rate in the ITT population. The PP population was therefore considered to provide the most relevant parasitologic cure rates.
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The parasitologic cure rate at 28 days was 96.0% (95% CI, 90.8%, 98.7%). In addition to the two patients who did not clear parasites by Day 7, three patients had late reappearance of parasites (at Days 22, 24, and 28). All three of these patients were treated successfully with atovaquone-proguanil (Malarone), and one patient also received chloroquine. All three patients had been infected in sub-Saharan Africa, but in different countries: Kenya, the Gambia, and either Rwanda or Angola.
Subgroup analysis according to body weight category in the PP population showed 28-day parasitologic cure rates of 100% (95% CI, 92.5%, 100.0%) in patients of body weight 
65 kg and 93.4% (95% CI, 85.3%, 97.8%) in patients weighing > 65 kg. The median weight of the five patients with treatment failure was 85 (range, 73–97 kg) versus 70.5 kg (range, 47–115 kg) in the 119 patients who were successfully cured.
The effects of age on treatment outcome were not examined by subgroup analysis (there were very few patients > 60 years of age in the study); the patients in the PP population who had treatment failure ranged between 21 and 62 years of age.
Of the three patients who vomited and replaced doses of artemether-lumefantrine, two were cured at Day 28, and the other was discontinued from the study because of a protocol violation (incomplete documentation of parasite counts after clearance). This latter patient also violated the protocol by only taking three doses of study medication.
Median times to parasite clearance and fever clearance were 41.5 (95% CI, 40.0, 42.6) and 36.8 hours (95% CI, 24.5, 40.0), respectively. Between baseline and Day 3, > 20% of the patients had P. falciparum gametocytes. No patient had gametocytes after Day 7.
Safety and tolerability. There were no deaths or life-threatening adverse events (AEs) during the study. Six patients had AEs that needed prolonged hospitalization. In three of the patients, the AEs were primarily related to malaria (in two cases to the severity of the signs/symptoms of the initial infection and in the other to recrudescence). The pattern of AEs in two of the remaining three patients (anemia, thrombocytopenia, liver function test abnormalities, hematuria, malaise, and abdominal pain in one patient and hepatocellular damage in the other) also suggests an association with malaria, particularly with one patient who discontinued artemether-lumefantrine treatment after the second dose and received intravenously quinine as antimalarial rescue medication from Day 0 to Day 3 because of complications of malaria. The endocarditis reported in one patient seems to have been a coincidental infection. None of the three patients, including one with reported progression of malaria, who had either hepatocellular damage or liver function test (LFT) abnormalities had serum transaminase levels greater than NCI CTC Grade 2. One patient had NCI CTC Grade 3 serum bilirubin levels at baseline, but at Day 28, this had decreased to NCI CTC Grade 1. Resolution of all of the AEs that needed prolonged hospitalization was reported, with the exception of the malaria (reported on Day 22) in one patient, for which no further information was available.
The most common AEs (those reported in at least 5% of patients) are shown in Table 3. In total, 75% of patients reported at least one adverse event. The most frequent AEs reported were headache, insomnia, diarrhea, vertigo, malaise, and cough. Most of the common AEs, such as headache, malaise, and gastrointestinal disturbances such as diarrhea, nausea and vomiting, together with anorexia and vertigo and chills, were probably related to signs and symptoms of malaria. The proportions of patients experiencing common AEs that were suspected by the investigators to be related to study treatment are also shown in Table 3. It can be seen that insomnia was the most frequently reported adverse event considered to be treatment-related. For the other common adverse events, only a small proportion were considered to be treatment-related. No allergic reactions were reported in any of the patients.
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ECG evaluations revealed only very small and clinically irrelevant changes in mean and median QTc, as calculated using either Bazett’s or Fridericia’s formula. The proportions of patients with predefined QTc signal values are shown in Table 4. The majority of patients had QTc increases from baseline of < 30 ms. There were no patients with absolute QTc values (using either formula) of > 500 ms, and none of the patients had QTc increases from baseline of > 60 ms according to both formulae. One patient had an increase from baseline of > 60 ms in QTc interval calculated using Bazett’ s formula from 393 ms at baseline to 456 ms at Day 2. Two patients had an increase from baseline of > 60 ms in QTc interval calculated using Fridericia’s formula. One patient had an increase of 71 ms from baseline to Day 2 (from 331 to 402 ms). The only AE reported by this patient was mild vertigo from Day 2 to Day 3. The other had a QTc increase of 64 ms from 401 ms to 465 ms at Day 1. Days 2 and 3 QTc values were both within the normal range, at 420 and 427 ms, respectively. This patient reported mild vertigo on Day 1 but otherwise experienced no AEs.
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For the 15 patients who provided more detailed pharmacokinetic data, plasma concentration-time profiles for lumefantrine and its metabolite desbutyl-lumefantrine are shown in Figure 1. Pharmacokinetic parameters for both compounds are shown in Table 5. The metabolite-to-parent ratio was 0.36% ± 0.15% (Cmax) and 0.33% ± 0.19% (AUC(0-t)). Linear regression analyses of log-transformed pharmacokinetic parameters (Cmax and AUC(0-t)) against body weight did not show any significant relationship between body weight and the pharmacokinetic parameters (R2 = 0.22, P = 0.078 for Cmax and R2 = 0.13, P = 0.182 for AUC(0-t) for lumefantrine and R2 = 0.08, P = 0.303 and R2 = 0.002, P = 0.866, respectively, for desbutyl-lumefantrine). All 15 patients achieved parasite clearance without recrudescence and with no gametocytes present at end of study. This was despite a large range of individual exposure levels to lumefantrine (Cmax from 2.12 to 11.2 µg/mL and AUC (0-t) from 98.8 to 761 µg · h/mL) and desbutyl-lumefantrine (Cmax from 0.006 to 0.034 µg/mL and AUC(0- t) from 0.276 to 2.76 µg · h/mL). Therefore, no relationship between drug exposure levels and parasite clearance could be established. Neither descriptive analysis nor linear regression analyses of QTc changes from baseline (calculated using either the Bazett or Fridericia formula) showed any significant relationship between the pharmacokinetic parameters and QTc changes from baseline.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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At baseline, patients tended to have relatively low parasite counts. There was a wide range of time between returning from travel and diagnosis of malaria; the median was 12 days, but one patient had apparently been infected for at least 240 days before diagnosis. The majority of infections were pure P. falciparum. Mixed infections with other species (P. vivax and P. malariae) were found in < 5% of patients. Data from Thailand suggest mixed infections (P vivax and P. falciparum) cause more anemia, but this fact does not seem relevant in the present context to influence the interpretation of our data.18
Most patients completed the study as planned, but there was a relatively high rate of premature discontinuation and of protocol violations. This was unexpected on the basis of studies with artemether-lumefantrine in malaria-endemic countries. Most patients who discontinued prematurely were lost to follow-up or did so as a result of protocol violations, specifically as incomplete documentation of parasite counts after initial clearance. It seems that a significant proportion of patients failed to return to the study centers once their malaria symptoms had resolved. This high rate of discontinuation and protocol violations led us to present the efficacy analysis based on the PP population, rather than the planned primary analysis based on an ITT population, providing the most representative parasitologic cure rate.
The original intention to conduct a study comparing the most commonly used drugs such as mefloquine, atovaquone/proguanil, and artemether/lumefantrine proved not to be feasible because of declining numbers of nonimmune malaria patients in industrialized countries. In addition, it also became evident that atovaquone-proguanil was used extensively as a chemoprophylactic agent and was therefore less likely to be used as drug of choice for treatment.
Treatment was effective, with a high 28-day parasitologic cure rate. Two patients did not clear parasites by Day 7, and three patients had late reappearance of parasites (at Days 22, 24, and 28). The observed 28-day parasitologic cure rate was comparable with those seen in trials in endemic countries (ranging from 94% to 97%, although analysis populations were not always defined as in this study),6,9,10,12,13 suggesting that treatment is as effective in the nonimmune population as in semi-immune patients. Gametocytes also appeared to be cleared rapidly.
The 28-day parasitologic cure rate was chosen as the primary efficacy endpoint on the basis of WHO recommendations in place at the time the study was designed. It is therefore possible that not all cases of recrudescence were detected, because those occurring later than Day 28 would have been missed. A recent publication reporting a comparative study of artemether-lumefantrine and artesunate plus amodiaquine performed in Zanzibar12 found that the Day 28 and Day 42 parasitologic cure rates for artemether-lumefantrine (uncorrected for re-infection) were 93% and 77%, respectively. This difference was largely caused by re-infection: the adjusted cure rates after polymerase chain reaction analysis to identify new infections were 97% at Day 28 and 92% at Day 42. Re-infection should not be an issue in non-malarious areas, but a 42-day follow-up period would still have been preferable in this study to detect late recrudescence. In practice, however, a follow-up period of > 28 days would seem to be impracticable in the European setting, as shown by the proportion of patients who were lost to follow-up in this study.
Artemether-lumefantrine was well-tolerated, with most reported AEs appearing to be related to malaria. Laboratory evaluations were consistent with malaria and its resolution. ECG evaluations were performed because of the chemical similarity between lumefantrine and halofantrine, an antimalarial known to be associated with prolongation of the QTc interval.8 The possibility of a cardiotoxic effect of lumefantrine has been extensively studied in in vitro and in vivo studies. These studies unequivocally showed that lumefantrine lacks the cardiotoxicity of halofantrine.7,8,19 In this study, no significant effects on cardiac safety in terms of QTc interval were observed; changes in QTc interval and rates of QTc prolongation were low and consistent with those previously observed.
The pharmacokinetic data obtained in this study suggest that lumefantrine and desbutyl-lumefantrine concentrations are not strongly correlated with body weight. No clear relationship between lumefantrine or desbutyl-lumefantrine levels and either parasite clearance or changes in QTc interval were apparent. However, the higher median body weight in patients with treatment failures (although based on very few patients) highlights the need for additional data to ensure that the dose does not need to be adapted in overweight patients. No allergic reactions were seen, although these have been reported elsewhere.20
In conclusion, the six-dose regimen of artemether-lumefantrine is a good choice for treating acute uncomplicated falciparum malaria in nonimmune patients, with a high efficacy, a rapid resolution of clinical symptoms, and a good tolerability. It may prove to be the most appropriate option when considering the range of treatments available in industrialized countries, particularly when some alternative therapies such as quinine and mefloquine are associated with tolerability problems. Another alternative, atovaquone-proguanil, although apparently well tolerated, has not been well studied in the treatment of malaria in the nonimmune population,21,22 but may be as effective as artemether-lumefantrine. The results of this study also underline the fact that all nonimmune patients treated for malaria need to be informed about the possibility of reappearance of parasite and clinical recrudescence for several weeks after treatment.
Received January 8, 2007. Accepted for publication July 15, 2007.
Acknowledgments: The authors thank the other investigators, namely A. Stich, Medical Mission Hospital, Wurzburg, Germany; D. Malvy, University Hospital, Bordeaux, France; T. Debord, Hôpital Bégin, St-Mandé, France; F. Castelli, Institute of Infectious and Tropical Diseases, University of Brescia, Brescia, Italy; H.J. Furrer, Inselspital, Bern, Switzerland; B. Marchou, Hôpital Purpan, Toulouse, France; D. Overbosch, Havenziekenhuis and Institute for Tropical Diseases, Rotterdam, The Netherlands; and the late K. Markwalder, University Hospital, Zurich, Switzerland. In addition, we thank all the staff involved in the collaborating centers and the patients who participated. We also thank H. Reinhart, Novartis Switzerland, and M.-N. Bizot and L. Masson, Novartis Pharma SAS, Rueil-Malmaison, France, for expert technical assistance in analyzing lumefantrine and desbutyl-lumefantrine in plasma samples; M. Wilkie, Novartis Pharmaceuticals Corporation, East Hanover, NJ, for participating in the conduct of the study; M. Wibberg and T. Widmayer, Datamap GmbH, Freiburg, Germany, for conducting the analyses; and P. D. Hunt, Novartis Horsham Research Centre, Horsham, UK, for assistance with the manuscript.
Financial support: This study was supported by Novartis Pharma AG, Basel, Switzerland.
Disclosure: Some of the authors wish to disclose that they are employees of Novartis Pharma or have received grants or honoraria from Novartis. This statement is made in the interest of full disclosure and not because the authors consider this a conflict of interest.
* Address correspondence to Christoph Hatz, Swiss Tropical Institute, Socinstrasse 57, 4002 Basel, Switzerland. E-mail: christoph.hatz{at}unibas.ch 
Authors’ addresses: Christoph Hatz, Swiss Tropical Institute, Socinstrasse 57, 4002 Basel, Switzerland, Telephone: 41–0–61–2848255, Fax: 41–0–61–2718654. Jaime Soto, FADER/Cibic, Calle 60 A No. 5, 54 Suite 201, Bogota, Colombia, Telephone: 57–0–1–3482171, Fax: 57–0–1–3476093. Hans Dieter Nothdurft, Abteilung für Infektions- und Tropenmedizin der Universität München, Leopoldstrasse 5, D-80802 München, Germany, Telephone: 49–0–89–21803830, Fax: 49–0–89–336038. Thomas Zoller, Universitätsklinikum Charité, Medizinische Klinik mit Schwerpunkt Infektiologie, Campus Virchow-Klinikum, Augustenburger Platz 1, D-13353 Berlin, Germany, Telephone: 49–0–30–450653806, Fax: 49–0–30 450553906. Thomas Weitzel, Tropeninstitut Berlin, Spandauer Damm 130, 14050 Berlin, Germany, Telephone: 49–0–30–30116816, Fax: 49–0–30–30116888. Louis Loutan, Unité de Médecine des Voyages et des Migrations, Hopitaux Universitaires de Genève, Rue Micheli-du-Crest 24, 12011 Genève 14, Switzerland, Telephone: 41–0–22–3729615, Fax: 41–0–22–3729626. Francois Bricaire, Department of Tropical and Infectious Diseases, Pavillon Laveran, Groupe Hospitalier Pitié-Salpêtrière, 47 Bd de l ’ Hôpital, 75651 Paris Cedex 13, France, Telephone: 33–0–1–42160111, Fax: 33–0–1–42160165. Frederick Gay, Department of Tropical and Infectious Diseases, Pavillon Laveran, Groupe Hospitalier Pitié-Salpêtrière, 47 Bd de l’Hôpital, 75651 Paris Cedex 13, France, Telephone: 33–0–1–42160148, Fax: 33–0–1–42160165. Gerd-Dieter Burchard, Bernhard-Nocht-Institut für Tropenmedizin, Klinische Abteilung, Bernhard-Nocht-Strasse 74, D-20359 Hamburg, Germany, Telephone: 49–0–40–42818390, Fax: 49–0–40–42818394. Kim Andriano, Novartis Pharmaceuticals Corporation, One Health Plaza, East Hanover, NJ 07936–1080, Telephone: 862–778–8608, Fax: 973–781–3922. Gilbert Lefèvre, Novartis Pharma AG, Postfach, CH-4002 Basel, Switzerland, Telephone: 41–61–3246114, Fax: 41–61–3248940. Patricia Ibarra de Palacios, Novartis Pharma AG, Postfach, CH-4002 Basel, Switzerland, Telephone: 41–61–32–47540, Fax: 41–61–32–46537. Blaise Genton, Policlinique Médicale Universitaire, Rue du Bugnon 44, 1011 Lausanne, Switzerland, Telephone: 41–0–21–3144859, Fax: 41–0–21–3144857.
Reprint requests: Christoph Hatz, Swiss Tropical Institute, Socinstrasse 57, 4002 Basel, Switzerland. E-mail: christoph.hatz{at}unibas.ch.
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