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Safety and efficacy of atovaquone and proguanil hydrochloride for the prophylaxis of Plasmodium falciparum Malaria in South Africa
CLINICAL
THERAPEUTICSWOL.
2 1, NO. 4, 1999
Safety and Efficacy of Atovaquone and Proguanil Hydrochloride for the Prophylaxis of Plasmodium falciparum Malaria in South Africa J. Dirk van der Berg, MBChB,l Cornelia S.J. Duvenage, MBChB,l Neil S. Roskell, MSC,~ and Trevor R. Scott, PhD3 ‘Department of Internal Medicine, 1 Military Hospital, Pretoria, South Africa, 2Glaxo WellcomeResearchand Development, Greenford, Middlesex, United Kingdom, and 3Glaxo WellcomeInc., ResearchTriangle Park, North Carolina
ABSTRACT The objective of this study was to determine the safety andefficacy of atovaquone and proguanil hydrochloride combination therapy for the prophylaxis of Plasmodiumfalciparum malaria in at-risk nonimmune subjectsin South Africa. This openlabel trial was conducted at researchsites in South Africa during the main malaria transmission season, February through July. The study volunteers were temporarily living in, or traveling to, a malariaendemicarea.They received 1 tablet of 250 mg atovaquoneand 100 mg proguanil hydrochloride once daily for up to 10 weeks. Subjects were monitored using sequential clinical and laboratory assessments. Thick blood smearswere stained and evaluated by a central laboratory. An immunochromatographictest for Pfalciparum was also used for on-site patient management.Prophylactic successwas summarizedusing a 95% confidence interval for the proportion Accepted for publication Printed in the USA. Reproduction in whole
0149.2918/99/$19.00
on March
8, 7999.
or part is not permitted.
of subjects who did not develop parasitemia or who withdrew due to a treatment-relatedadverseevent. A total of 175 subjects (15% women) were enrolled in the trial. The mean duration of drug exposure was 8.9 weeks. The combination of atovaquone and proguanil hydrochloride was well tolerated. The most frequently reported adverse events consideredpossibly related to study treatment were headache(7%), abdominal pain (2%), increased cough (2%), and skin disorder (2%). No seriousadverse events were reported, and no treatment-emergenteffects were noted for any laboratory variables. One subject who was noncompliant with therapy developed parasitemia,and 3 subjects withdrew due to a treatment-related adverse event (2 subjects with headache and 1 with nauseaand dizziness). The prophylaxis successrate was 97%. In this study, atovaquone and proguanil hydrochloride combination therapy had an excellent safety and efficacy profile for prophylaxis of P falciparum malaria in nonimmune subjects. Key words: atovaquone, proguanil, Malarone’“, Plasmodium falciparum, malaria. 741
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INTRODUCTION Despite decades of efforts to eradicate or reduce the incidence of malaria, it remains a major infectious disease associated with significant morbidity and mortality in tropical and subtropical areas of the world.’ According to the World Health Organization2 there are an estimated 300 million to 500 million people infected annually, resulting in 1.4 to 2.8 million deaths each year. However, the risk of malaria is not limited to permanent residents of endemic areas. Business travel, tourism, and increasing military deployment in these areas put significant numbers of people at risk for exposure and infection.‘,3,4 Among 910 US civilians who acquired malaria in 1992 after traveling to endemic areas, 8 1% had not completed a recommended chemoprophylactic regimen, and 7 deaths were attributed to malaria.5 Selection of appropriate chemoprophylaxis is complicated by the increasing prevalence of Plasmodium falciparum strains that are resistant to many of the currently available antimalarial drugs.“‘O In addition, adverse effects associated with some antimalarial drugs limit their use, particularly for prophylactic purposes. 3,4,9-20Consequently, efforts continue toward identifying and developing new antimalarial drugs for treatment and prophylaxis. Use of combination drug regimens has been proposed as a way to avoid the development of parasite resistance to newly introduced antimalarial drugs.’ One such combination, atovaquone and proguanil hydrochloride,” has recently been evalu*Trademark: Malarone’” (Glaxo Wellcome Research Triangle Park, North Carolina).
742
Inc.,
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ated for the treatment and prophylaxis of malaria. Atovaquone is a hydroxy-1,4naphthoquinone with a novel mode of antimalarial action.” In P fdcipurum, it selectively inhibits mitochondrial electron transport, 22 diminishes pyrimidine biosynthesis,23 and collapses mitochondrial membrane potential, 24ultimately preventing cell replication. Proguanil and its primary active metabolite cycloguanil are dihydrofolate reductase inhibitors.i4 Through this action, pyrimidine nucleotide pools are depleted, and nucleic acid synthesis and subsequent cell replication are blocked. The combination of atovaquone and proguanil hydrochloride has been shown to be highly effective for the treatment of P falciparum malaria, with an overall cure rate of 98.7% in 521 patients.25 The encouragingtreatmentresultsled to studiesof the combination of atovaquone and proguanil as a prophylactic agent for falciparum malaria.Shankset a126assessed 2 dosagesof the fixed-dose combinationof atovaquone and proguanil hydrochloride versus placebo in a randomized, doublemaskedstudy in 216 adult Kenyan volunteers. During the IO-week prophylaxis period, malariadeveloped in 52% of placebo recipients but in none of the subjectsreceiving either 1 or 2 combination tablets daily, each containing 250 mg of atovaquone and 100 mg of proguanil hydrochloride (100% efficacy). Lell et al27 conducted a double-masked, placebocontrolled study in 320 children residingin Gabon. Atovaquone and proguanil hydrochloride were administeredat reduced dosagesbasedon body weight category to children who weighed ~40 kg. During the 12 weeks of study drug administration, malaria occurred in 25 placebo recipients and in none of the atovaquone and proguanil hydrochloride recipients (100% ef-
J.D. VAN DER BERG ET AL.
ficacy) . Sukwa et alz8 conducteda doublemasked, placebo-controlled trial among 299 adult volunteers in Zambia. During the IO-week study, malaria occurred in 41 placebo recipients and in 2 subjects receiving 1 combination tablet daily (95% efficacy). In all thesestudies,the incidence of adverse events among the atovaquone and proguanil hydrochloride recipientswas similar to or lower than that among the placebo recipients. We conducted the present open-label study primarily to acquire additional safety and tolerance data from nonimmuneadult male and female volunteers receiving atovaquone and proguanil hydrochloride for the prophylaxis of malaria. Prophylaxis was indicated for thesevolunteers because they were temporarily residing in or traveling to malaria-endemic areasof South Africa. Efficacy in preventing P falciparum parasitemiawas also assessed.
SUBJECTS
AND METHODS
Study Population Healthy, nonimmune male and female volunteers between the agesof 16 and 65 years who were at risk for malarial infection were eligible for the trial. All were South African National DefenseForce personnel (soldiers, support personnel, and spouses).All participants provided written informed consent.Volunteerswere ineligible for enrollmentif they hadhad a splenectomy, had known hypersensitivity to atovaquoneor proguanil hydrochloride, or had clinically significant abnormalities on baselinehematology or clinical chemistry tests (including creatinine clearance ~30 mL/min or alanine aminotransferase >3 times the upper limit of normal). Female volunteersalsowere ineligible if they were
pregnant(or unwilling to avoid pregnancy) or lactating. All volunteers were required to have a negative result on a baseline (screening)rapid immunochromatographic test (ICT) for P falciparum malariaF9Participants who had recently moved to an endemic area had to be receiving antimalarial prophylaxis (chloroquine/proguanil or mefloquineat recommendeddoses)for 228 days before the start of treatment or for the duration of their stay (if ~28 days). Study Design Volunteers were screenedfor study eligibility through demographicdata, physical findings, and the results of pregnancy testing and routine hematology (ie, hemoglobin, hematocrit, platelets,meancorpuscular volume, red blood cells, total white blood cells, bands,basophils,eosinophils, lymphocytes, monocytes, and neutrophils) and clinical chemistry (ie, sodium, potassium, serum alanine aminotransferase,albumin, alkaline phosphatase, calcium, serum creatinine, creatinine clearance, serumy-glutamyltransferase,glucose[nonfasting], phosphorus,total bilirubin, total protein, urea nitrogen) assessments. Subjects were alsoscreenedfor the presenceof malarialinfection usingthe rapid ICI and a thick blood smear.With the exceptionof the ICT, which was conductedon site, all laboratory assessments wereconductedby a centralized laboratory (COVANCEISciCor). Volunteerscould enter the study on the basisof a negative ICT result. After enrollment, volunteers were seen daily for the dispensingof study medication, which consistedof 1 combinationtablet (250 mg atovaquone and 100 mg proguanil hydrochloride). Administration of the drug, which occurred approximately 45 minutes after a meal, was observed by 743
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study personnel. (Administration after mealshas been shown to enhanceabsorp tion of atovaquone.sO)Volunteerswho had recently moved to the endemic area and were receiving antimalarialprophylaxis received their first dose of the study drug 2 daysbefore the next weekly doseof chloroquine or mefloquine. Prior chemoprophylaxis was discontinuedafter the initial dose of study drug. Study subjectstraveling to an endemic area and not currently receiving prophylaxis began taking study drug 2 days before entering the endemic area. Participants were seen for extended clinic visits at weeks 5 and 10 of dosing. During these visits, a physical examination wasperformed, subjectswere queried regarding adverse events and concurrent medication use, and blood sampleswere collected for rapid 1CT. Hematology and clinical chemistry evaluations and thick blood smearsfor malaria testing were also obtained at week 10. Thick blood smears were obtained at any time during the study that malaria infection was suspected. Subjects were withdrawn from the trial if they missed more than 2 consecutive days of dosing, were prescribed concurrent medication with known antimalarial activity, or developed parasitemia during the treatment or follow-up phasesof the study. Patients developing parasitemia were treated with quinine and doxycycline and appropriate supportive care. The protocol for the study wasreviewed and approved by the institutional review boards of the South African Medical Services and the Medical Association of South Africa ResearchEthics Committee.
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safety population comprised all subjects who had received 21 dose of treatment. Summary statisticswere calculated for the demographic, clinical chemistry, and hematologic data.All adverseeventsnoted or mentioned were summarized by drug association,intensity, and seriousness. The primary efficacy end point was the successof prophylaxis during chemosuppression(weeks0 to 10). Prophylaxis was considered successfulif a subject with a negative baseline test result for malaria failed to develop malaria while receiving chemoprophylaxis. Prophylaxis was considered a failure if a subject with a negative baselinetest result for malaria either developed evidence of malaria (by ICT or blood smear)during weeks0 to 10 or withdrew from the study due to an adverse event that was considered treatment related by the investigator. The proportion of prophylactic successes was summarized using a 95% exact confidence interval.3’ Subjects were considered assessable if they (1) had a negative baseline blood smear;(2) received 21 doseof study treatment; (3) were compliant with the protocol while receiving medication; (4) did not receive concomitant medication with antimalarial activity; and (5) were either present at week IO, had a positive blood smearbefore week 10, or were withdrawn for a treatment-related adverse event. Therefore, subjects lost to follow-up or withdrawn from the study for reasons other than parasitemia or a treatmentrelated adverse event were considerednot assessable for efficacy. RESULTS
Data Analysis No hypothesis testing was performed on safety or demographic variables. The 744
The study was conducted at 4 research sites along the northern and eastern borders of South Africa in 1997 during the
J.D. VAN DER BERG ET AL.
main malaria transmissionseason(February through July). The volunteers consisted of South African National Defense Force personnel deployed to areaswhere there is usually a high rate of malaria transmission. A total of 175 volunteers were screened and enrolled in the trial, 113 (65%) of whom were included in the efficacy analysis. Reasonsfor exclusion from the assessablepopulation included failure to return for study visits (51 subjects, most of whom were soldiers redeployed to a remote area), noncompliance with dosing (1 subject), and concurrent antimalarial drug use (IO subjects). All 175 volunteers were included in the summaries of safety data. All subjectstested negative for malaria at the screening visit, as determined by both ICT and blood smear results. One hundred forty-nine men (85%) and 26 women (15%) were enrolled in the trial. The mean age of the men was 29 years; for women it was 34 years. Mean body weight for the men was 76 kg; for the women it was 71 kg. The mean duration of exposure to study drug was 8.9 weeks. Forty subjects (23%) reportedly had mi-
nor deviations from the prescribed study drug regimen (ie, missing rl but not >2 consecutive doses).
Safety Adverse events reported by 22% of study subjects during chemoprophylaxis are presentedin the table. The most commonly reported adverse events during chemoprophylaxis, irrespective of causality, were headache (10%) and a flulike syndrome (7%). More women (15%) than men (9%) reported headache,but the number of events was too smallto draw meaningful conclusions. Headache (7%) was the most commonly reported adverse event judged by study personnelto be possibly associatedwith study treatment. All adverseeventswere reported to be of mild or moderate intensity. No seriousadverse events were reported. Three subjects discontinued study drug due to an adverse experience (2 subjectswith headacheand 1 with nauseaand dizziness). No treatment-emergenteffects were observed in any of the hematologic or clinical chemistry variables measured. No fe-
Table. Adverse events reported by 22% of 175 subjectsduring chemoprophylaxis.
Adverse Event Headache Flulike syndrome Abdominal pain Pain Increased cough Diarrhea Skin disorder Acne Eye pain
All Reports (no., %) 18 12 6 6 4 3 3 3 4
(10) (7) (3) (3) (2) (2) (2) (2) (2)
Reports Possibly Associated with Study Drug (no., %) 12 (7) 0 (0) 4 (2)
2 (1) 3 (2) 1 (
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male volunteer was known to have become pregnant during the course of the study. Efficacy Parasitemia developed at dosing week 4 in 1 subject enrolled in the trial. This volunteer was known to be noncompliant, having missedmany dosesof study drug, and he was excluded from the efficacy analysis. Three of 113 assessable subjects withdrew due to a treatment-related adverse event. Thus the chemoprophylaxis successrate was 97% (95% confidence interval, 92% to 99%) in the assessable population. DISCUSSION AND CONCLUSIONS The results of this study provide additional support for prophylaxis againstfalciparum malaria with the combination of atovaquone and proguanil hydrochloride. Once-daily dosing with 250 mg atovaquone and 100 mg proguanil hydrochloride (1 tablet) for up to 10 weeks was well tolerated, with no serious adverse events noted. The 1 subject who developed malaria was noncompliant with therapy. Less than 2% of enrolled subjects discontinued prophylaxis due to a treatment-related adverse event. At the start of the study, none of the subjectshad immunity to malaria, and all were temporarily resident in or were traveling to an area where malaria was endemic. In a country such as South Africa, where malaria is both seasonal and focal and there is little acquired immunity, all such individuals may be at risk of death from uncontrolled parasitemia.‘” The safety and efficacy data from the presentopen-label trial are consistentwith 746
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the findings from 3 double-masked, placebo-controlled trials assessingthe drug combination for malaria prophylaxis.26-28The 3 controlled studies, conducted in Gabon, Zambia, and Kenya, used dosing regimens similar to the one used in our trial. The overall efficacy rate in those studies was 98%, and adverse events occurred with similar or lower rates in subjectsreceiving atovaquone and proguanil hydrochloride compared with subjects receiving placebo. According to White,9 the rapid development of drug resistanceto Pfalciparum may lead to recalcitrant malaria in parts of SoutheastAsia by the start of the next millennium. The potential for the rapid development of resistance to newly introduced compounds is of paramount concern. Current antimalarial treatment regimens are relying more heavily on combination drug therapy in an attempt to delay the appearanceof resistanceto 1 or both drugs, particularly when they are to be widely usedin a malaria-endemicarea. It hasbeen hypothesized that antimalarial combinations that expose parasites to drugs having different sitesof action may reduce the probability of the parasites’developing resistanceto both drug componentsX2Atovaquone and proguanil appear to be excellent partners for combination antimalarial dosing. These drugs act on the samestageof the parasite but, as previously discussed,have different sites of action. In clinical trials of atovaquoneand proguanil in the treatment of malaria, clinical resistance was demonstrated in approximately 30% of patients treated with atovaquone alone and more than 90% of patients treated with proguanil alone, but in fewer than 2% of patients treated with the combination of the two.2s,1’Additional experience with this combination will be
J.D. VAN DER BERG ET AL.
necessaryto fully explore the issueof antimalarial resistancein vivo. There has been speculationthat results obtained from “traveler” studiesconducted in nonimmune, young, healthy military personneltraveling to endemic areasmay not be generalizable to the population of nonmilitary travelers. Croft and Garners have suggestedthat general travelers are more likely to withdraw from or be noncompliant with malaria prophylaxis than military personneland that the stressesof intercontinental travel may put them at higher risk of drug-related adverseexperiences.We believe the results of our study are generalizable to nonmilitary travelers for a variety of reasons.First, our population was derived from a spectrumof military personneland not just young, fit male soldiers.Indeed, 15% of the study population were women with a meanage at study entry of 34 years. Our population also included individuals with concurrent stable medical conditions, including cardiovascular and gastrointestinal abnormalities, and individuals using concomitant medications, as would be expected among tourists and businesstravelers. Twentythree percent of study participantsreported minor deviations from the prescribeddosing regimen, as can also be expected of generaltravelers. Despitethesedeviations, the combination was highly efficacious. The significant stressesassociated with deployment away from family, potentially to areasof civil unrest, did not appear to lead to a higher incidence of adverse events comparedwith incidencesin previous placebo-controlled trials of atovaquone and proguanil hydrochloride for malaria prophylaxis .262* The resultsof this study, combinedwith the data from 3 previous double-masked, placebo-controlled prophylaxis trials, sug-
gest that the combination of atovaquone and proguanil hydrochloride has an excellent safety and efficacy profile for chemoprophylaxis against P falciparum malaria. ACKNOWLEDGMENTS This study was supportedby a grant from Glaxo Wellcome Inc., ResearchTriangle Park, North Carolina. The authors wish to thank the South African Medical Services, South African National Defense Force, and the volunteers who participated in this trial. The authors would also like to acknowledge the Clinical Research Department of Glaxo Wellcome South Africa for their role in facilitating the logistics of the study. They are grateful to Dr. Jeff Chulay for reviewing the manuscript. Address correspondence to: Trevor R. Scott, PhD, HIV/O1 Clinical Development, Glaxo Wellcome Inc., 5 Moore Drive, ResearchTriangle Park, NC 27709. REFERENCES 1. Olliaro P,CattaniJ, Wirth D. Malaria,the submergeddisease.JAMA. 1996;275: 230-233.
2. WorldHealthOrganization.World malaria situation in 1992. Wkly Epidemiol Rec. 1994;69:309-316. 3. Croft A, Gamer P.Mefloquine to prevent malaria: A systematic review of trials. BMJ. 1997;315:1412-1416. 4. Hoffman SL. Diagnosis, treatment, and prevention of malaria. Med Clin North Am. 1992:76:1327-1355.
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5. Zucker JR, Barber AM, Paxton LA, et al. Malaria surveillance-United States, 1992. MMWR Morb Mortal Wkly Rep. 1995;44(33-5): I- 15. 6. Bjorkman A, Phillips-Howard PA. The epidemiology of drug-resistant malaria. Truns R Sot Trop Med Hyg. 1990;84: 177-l 80.
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of seven cases. Ann Intern Med. 1986; 104:801-803. 17. Panisko DM, Keystone JS. Treatment of malaria-l 990. Drugs. 1990;39: 16s I 89. 18. Salako LA. Toxicity and side-effects of anti-malarials in Africa: A critical review. Bull WHO. 1984;62(Suppl):63-68.
7. Wernsdorfer WH. Epidemiology of drug resistance in malaria. Actu Trop. 1994;56: 143-156.
19. Stuiver PC, Ligthelm RJ, Goud ThJLM. Acute psychosis after mefloquine. Luncrt. 1989;2:282. Letter.
8. White NJ. Antimalarial drug resistance: The pace quickens. J Antinicrob Chemother. 1992;30:571-585.
20. Taylor D, Pitarangsi C, Echeverria P, et al. Campylobacter enteritis during doxycycline prophylaxis for malaria in Thailand. Lancet. 1988;2:578-579.
9. White NJ. The treatment NEJM. 1996;335:800-806.
of malaria.
10. World Health Organization. Practical chemotherapy of malaria. World Health Organization Tech Rep Ser. 1990;805: l-141. 11. Cook IF, Kish MY. Haematological safety of long-term malarial prophylaxis with dapsone-pyrimethamine. Med J Aust. 1985;143:129-141. 12. Hatton CSR, Peto TEA, Bunch C, et al. Frequency of severe neutropenia associated with amodiaquine prophylaxis against malaria. Lancet. 1986;1:411414. 13. Hellgren U, reactions to in Swedish prophylaxis.
Rombo L, Berg B. Adverse sulphadoxine/pyrimethamine travellers: Implications for BMJ. 1987;295:365-366.
14. Keystone JS. Prevention Drugs. 1990;39:337-354.
of malaria.
15. Krogstad DJ, Herwaldt BL. Chemoprophylaxis and treatment of malaria. NEJM. 1988;319:1538-1540. 16. Larrey D, Castot A, Pessayre D, et al. Amodiaquine-induced hepatitis: A report 748
21. Hudson AT, Dickins M, Ginger CD, et al. 566C80: A potent broad spectrum antiinfective agent with activity against malaria and opportunistic infections in AIDS patients. Drugs Exp Clin Res. 1991;17:427435. 22. Fry M, Pudney M. Site of action of the antimalarial hydroxynaphthoquinone, 2{ trans-4-(4’-chlorphenyl) cyclohexyl) -3. hydroxy- l,4-naphthoquinone (566C80). Biochem Pharmarol. 1992;43: 1545-l 553. 23. Hammond DJ, Burchell JR, Pudney M. Inhibition of pyrimidine biosynthesis de nova in Plasmodium falcipurum by 2-(4-tbutylcyclohexyl)-3-hydroxy1,4naphthoquinone in vitro. Mol Biochem Parasitol. 1985;14:97-109. 24. Srivastava IK, Rottenberg H, Vaidya AB. Atovaquone, a broad spectrum antiparasitic drug, collapses mitochondrial membrane potential in a malarial parasite. ./ Biol Chem. 1997;272:3961-3966. 35_. Looareesuwan S, Chulay JD, Canfield CJ, Hutchinson DB. Malarone (atovaquone hydrochloride): A review of its clinical development for treatment of malaria. Am J Trop Med Hyg. 1999;60:533-541.
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26. Shanks GD, Gordon DM, Klotz FW, et al. Efficacy and safety of atovaquone/proguanil for suppressive prophylaxis against Plasmodium falciparum malaria. Clin Infect Dis. 1998;27:494499. 27. Lell B, Luckner D, Ndjave M, et al. Randomized placebo-controlled study of atovaquone plus proguanil for malaria prophylaxis in children. Lancet. 1998351: 709-713. 28. Sukwa TY, Mulenga M, Chisaka N, et al. A randomized, double blind, placebocontrolled field trial to determine the efficacy and safety of Malarone (atovaquonel proguanil) for the prophylaxis of malaria. Am J Trop Med Hyg. 1999;60:521-525. 29. Valecha N, Sharma VP, Devi CU. A rapid immunochromatographic test (ICT) for di-
agnosis of Plasmodium Microbial
Infect
Dis.
falciparum. 1998;30:257-260.
Diagn
30. Haile LG, Flaherty JF. Atovaquone: A review. Ann Pharmacothel: 1993;27: 14881493. 31. Conover WJ. In: Practical Non-Parametric Statistics. New York: Wiley; 1980: 99-104. 32. Peto TEA, Newbold CI, Pasvol G. Qinghaosu, mefloquine, and pyrimethaminesulfadoxine in falcipantm malaria. Luncet. 1985;1:216. Letter. 33. Looareesuwan S, Viravan C, Webster HK, et al. Clinical studies of atovaquone, alone or in combination with other antimalarial drugs, for treatment of acute uncomplicated malaria in Thailand. Am J Trop Med Hyg.
1996;54:62-66.
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2 1, NO. 4, 1999
Safety and Efficacy of Atovaquone and Proguanil Hydrochloride for the Prophylaxis of Plasmodium falciparum Malaria in South Africa J. Dirk van der Berg, MBChB,l Cornelia S.J. Duvenage, MBChB,l Neil S. Roskell, MSC,~ and Trevor R. Scott, PhD3 ‘Department of Internal Medicine, 1 Military Hospital, Pretoria, South Africa, 2Glaxo WellcomeResearchand Development, Greenford, Middlesex, United Kingdom, and 3Glaxo WellcomeInc., ResearchTriangle Park, North Carolina
ABSTRACT The objective of this study was to determine the safety andefficacy of atovaquone and proguanil hydrochloride combination therapy for the prophylaxis of Plasmodiumfalciparum malaria in at-risk nonimmune subjectsin South Africa. This openlabel trial was conducted at researchsites in South Africa during the main malaria transmission season, February through July. The study volunteers were temporarily living in, or traveling to, a malariaendemicarea.They received 1 tablet of 250 mg atovaquoneand 100 mg proguanil hydrochloride once daily for up to 10 weeks. Subjects were monitored using sequential clinical and laboratory assessments. Thick blood smearswere stained and evaluated by a central laboratory. An immunochromatographictest for Pfalciparum was also used for on-site patient management.Prophylactic successwas summarizedusing a 95% confidence interval for the proportion Accepted for publication Printed in the USA. Reproduction in whole
0149.2918/99/$19.00
on March
8, 7999.
or part is not permitted.
of subjects who did not develop parasitemia or who withdrew due to a treatment-relatedadverseevent. A total of 175 subjects (15% women) were enrolled in the trial. The mean duration of drug exposure was 8.9 weeks. The combination of atovaquone and proguanil hydrochloride was well tolerated. The most frequently reported adverse events consideredpossibly related to study treatment were headache(7%), abdominal pain (2%), increased cough (2%), and skin disorder (2%). No seriousadverse events were reported, and no treatment-emergenteffects were noted for any laboratory variables. One subject who was noncompliant with therapy developed parasitemia,and 3 subjects withdrew due to a treatment-related adverse event (2 subjects with headache and 1 with nauseaand dizziness). The prophylaxis successrate was 97%. In this study, atovaquone and proguanil hydrochloride combination therapy had an excellent safety and efficacy profile for prophylaxis of P falciparum malaria in nonimmune subjects. Key words: atovaquone, proguanil, Malarone’“, Plasmodium falciparum, malaria. 741
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INTRODUCTION Despite decades of efforts to eradicate or reduce the incidence of malaria, it remains a major infectious disease associated with significant morbidity and mortality in tropical and subtropical areas of the world.’ According to the World Health Organization2 there are an estimated 300 million to 500 million people infected annually, resulting in 1.4 to 2.8 million deaths each year. However, the risk of malaria is not limited to permanent residents of endemic areas. Business travel, tourism, and increasing military deployment in these areas put significant numbers of people at risk for exposure and infection.‘,3,4 Among 910 US civilians who acquired malaria in 1992 after traveling to endemic areas, 8 1% had not completed a recommended chemoprophylactic regimen, and 7 deaths were attributed to malaria.5 Selection of appropriate chemoprophylaxis is complicated by the increasing prevalence of Plasmodium falciparum strains that are resistant to many of the currently available antimalarial drugs.“‘O In addition, adverse effects associated with some antimalarial drugs limit their use, particularly for prophylactic purposes. 3,4,9-20Consequently, efforts continue toward identifying and developing new antimalarial drugs for treatment and prophylaxis. Use of combination drug regimens has been proposed as a way to avoid the development of parasite resistance to newly introduced antimalarial drugs.’ One such combination, atovaquone and proguanil hydrochloride,” has recently been evalu*Trademark: Malarone’” (Glaxo Wellcome Research Triangle Park, North Carolina).
742
Inc.,
THERAPEUTICS”
ated for the treatment and prophylaxis of malaria. Atovaquone is a hydroxy-1,4naphthoquinone with a novel mode of antimalarial action.” In P fdcipurum, it selectively inhibits mitochondrial electron transport, 22 diminishes pyrimidine biosynthesis,23 and collapses mitochondrial membrane potential, 24ultimately preventing cell replication. Proguanil and its primary active metabolite cycloguanil are dihydrofolate reductase inhibitors.i4 Through this action, pyrimidine nucleotide pools are depleted, and nucleic acid synthesis and subsequent cell replication are blocked. The combination of atovaquone and proguanil hydrochloride has been shown to be highly effective for the treatment of P falciparum malaria, with an overall cure rate of 98.7% in 521 patients.25 The encouragingtreatmentresultsled to studiesof the combination of atovaquone and proguanil as a prophylactic agent for falciparum malaria.Shankset a126assessed 2 dosagesof the fixed-dose combinationof atovaquone and proguanil hydrochloride versus placebo in a randomized, doublemaskedstudy in 216 adult Kenyan volunteers. During the IO-week prophylaxis period, malariadeveloped in 52% of placebo recipients but in none of the subjectsreceiving either 1 or 2 combination tablets daily, each containing 250 mg of atovaquone and 100 mg of proguanil hydrochloride (100% efficacy). Lell et al27 conducted a double-masked, placebocontrolled study in 320 children residingin Gabon. Atovaquone and proguanil hydrochloride were administeredat reduced dosagesbasedon body weight category to children who weighed ~40 kg. During the 12 weeks of study drug administration, malaria occurred in 25 placebo recipients and in none of the atovaquone and proguanil hydrochloride recipients (100% ef-
J.D. VAN DER BERG ET AL.
ficacy) . Sukwa et alz8 conducteda doublemasked, placebo-controlled trial among 299 adult volunteers in Zambia. During the IO-week study, malaria occurred in 41 placebo recipients and in 2 subjects receiving 1 combination tablet daily (95% efficacy). In all thesestudies,the incidence of adverse events among the atovaquone and proguanil hydrochloride recipientswas similar to or lower than that among the placebo recipients. We conducted the present open-label study primarily to acquire additional safety and tolerance data from nonimmuneadult male and female volunteers receiving atovaquone and proguanil hydrochloride for the prophylaxis of malaria. Prophylaxis was indicated for thesevolunteers because they were temporarily residing in or traveling to malaria-endemic areasof South Africa. Efficacy in preventing P falciparum parasitemiawas also assessed.
SUBJECTS
AND METHODS
Study Population Healthy, nonimmune male and female volunteers between the agesof 16 and 65 years who were at risk for malarial infection were eligible for the trial. All were South African National DefenseForce personnel (soldiers, support personnel, and spouses).All participants provided written informed consent.Volunteerswere ineligible for enrollmentif they hadhad a splenectomy, had known hypersensitivity to atovaquoneor proguanil hydrochloride, or had clinically significant abnormalities on baselinehematology or clinical chemistry tests (including creatinine clearance ~30 mL/min or alanine aminotransferase >3 times the upper limit of normal). Female volunteersalsowere ineligible if they were
pregnant(or unwilling to avoid pregnancy) or lactating. All volunteers were required to have a negative result on a baseline (screening)rapid immunochromatographic test (ICT) for P falciparum malariaF9Participants who had recently moved to an endemic area had to be receiving antimalarial prophylaxis (chloroquine/proguanil or mefloquineat recommendeddoses)for 228 days before the start of treatment or for the duration of their stay (if ~28 days). Study Design Volunteers were screenedfor study eligibility through demographicdata, physical findings, and the results of pregnancy testing and routine hematology (ie, hemoglobin, hematocrit, platelets,meancorpuscular volume, red blood cells, total white blood cells, bands,basophils,eosinophils, lymphocytes, monocytes, and neutrophils) and clinical chemistry (ie, sodium, potassium, serum alanine aminotransferase,albumin, alkaline phosphatase, calcium, serum creatinine, creatinine clearance, serumy-glutamyltransferase,glucose[nonfasting], phosphorus,total bilirubin, total protein, urea nitrogen) assessments. Subjects were alsoscreenedfor the presenceof malarialinfection usingthe rapid ICI and a thick blood smear.With the exceptionof the ICT, which was conductedon site, all laboratory assessments wereconductedby a centralized laboratory (COVANCEISciCor). Volunteerscould enter the study on the basisof a negative ICT result. After enrollment, volunteers were seen daily for the dispensingof study medication, which consistedof 1 combinationtablet (250 mg atovaquone and 100 mg proguanil hydrochloride). Administration of the drug, which occurred approximately 45 minutes after a meal, was observed by 743
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study personnel. (Administration after mealshas been shown to enhanceabsorp tion of atovaquone.sO)Volunteerswho had recently moved to the endemic area and were receiving antimalarialprophylaxis received their first dose of the study drug 2 daysbefore the next weekly doseof chloroquine or mefloquine. Prior chemoprophylaxis was discontinuedafter the initial dose of study drug. Study subjectstraveling to an endemic area and not currently receiving prophylaxis began taking study drug 2 days before entering the endemic area. Participants were seen for extended clinic visits at weeks 5 and 10 of dosing. During these visits, a physical examination wasperformed, subjectswere queried regarding adverse events and concurrent medication use, and blood sampleswere collected for rapid 1CT. Hematology and clinical chemistry evaluations and thick blood smearsfor malaria testing were also obtained at week 10. Thick blood smears were obtained at any time during the study that malaria infection was suspected. Subjects were withdrawn from the trial if they missed more than 2 consecutive days of dosing, were prescribed concurrent medication with known antimalarial activity, or developed parasitemia during the treatment or follow-up phasesof the study. Patients developing parasitemia were treated with quinine and doxycycline and appropriate supportive care. The protocol for the study wasreviewed and approved by the institutional review boards of the South African Medical Services and the Medical Association of South Africa ResearchEthics Committee.
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safety population comprised all subjects who had received 21 dose of treatment. Summary statisticswere calculated for the demographic, clinical chemistry, and hematologic data.All adverseeventsnoted or mentioned were summarized by drug association,intensity, and seriousness. The primary efficacy end point was the successof prophylaxis during chemosuppression(weeks0 to 10). Prophylaxis was considered successfulif a subject with a negative baseline test result for malaria failed to develop malaria while receiving chemoprophylaxis. Prophylaxis was considered a failure if a subject with a negative baselinetest result for malaria either developed evidence of malaria (by ICT or blood smear)during weeks0 to 10 or withdrew from the study due to an adverse event that was considered treatment related by the investigator. The proportion of prophylactic successes was summarized using a 95% exact confidence interval.3’ Subjects were considered assessable if they (1) had a negative baseline blood smear;(2) received 21 doseof study treatment; (3) were compliant with the protocol while receiving medication; (4) did not receive concomitant medication with antimalarial activity; and (5) were either present at week IO, had a positive blood smearbefore week 10, or were withdrawn for a treatment-related adverse event. Therefore, subjects lost to follow-up or withdrawn from the study for reasons other than parasitemia or a treatmentrelated adverse event were considerednot assessable for efficacy. RESULTS
Data Analysis No hypothesis testing was performed on safety or demographic variables. The 744
The study was conducted at 4 research sites along the northern and eastern borders of South Africa in 1997 during the
J.D. VAN DER BERG ET AL.
main malaria transmissionseason(February through July). The volunteers consisted of South African National Defense Force personnel deployed to areaswhere there is usually a high rate of malaria transmission. A total of 175 volunteers were screened and enrolled in the trial, 113 (65%) of whom were included in the efficacy analysis. Reasonsfor exclusion from the assessablepopulation included failure to return for study visits (51 subjects, most of whom were soldiers redeployed to a remote area), noncompliance with dosing (1 subject), and concurrent antimalarial drug use (IO subjects). All 175 volunteers were included in the summaries of safety data. All subjectstested negative for malaria at the screening visit, as determined by both ICT and blood smear results. One hundred forty-nine men (85%) and 26 women (15%) were enrolled in the trial. The mean age of the men was 29 years; for women it was 34 years. Mean body weight for the men was 76 kg; for the women it was 71 kg. The mean duration of exposure to study drug was 8.9 weeks. Forty subjects (23%) reportedly had mi-
nor deviations from the prescribed study drug regimen (ie, missing rl but not >2 consecutive doses).
Safety Adverse events reported by 22% of study subjects during chemoprophylaxis are presentedin the table. The most commonly reported adverse events during chemoprophylaxis, irrespective of causality, were headache (10%) and a flulike syndrome (7%). More women (15%) than men (9%) reported headache,but the number of events was too smallto draw meaningful conclusions. Headache (7%) was the most commonly reported adverse event judged by study personnelto be possibly associatedwith study treatment. All adverseeventswere reported to be of mild or moderate intensity. No seriousadverse events were reported. Three subjects discontinued study drug due to an adverse experience (2 subjectswith headacheand 1 with nauseaand dizziness). No treatment-emergenteffects were observed in any of the hematologic or clinical chemistry variables measured. No fe-
Table. Adverse events reported by 22% of 175 subjectsduring chemoprophylaxis.
Adverse Event Headache Flulike syndrome Abdominal pain Pain Increased cough Diarrhea Skin disorder Acne Eye pain
All Reports (no., %) 18 12 6 6 4 3 3 3 4
(10) (7) (3) (3) (2) (2) (2) (2) (2)
Reports Possibly Associated with Study Drug (no., %) 12 (7) 0 (0) 4 (2)
2 (1) 3 (2) 1 (
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male volunteer was known to have become pregnant during the course of the study. Efficacy Parasitemia developed at dosing week 4 in 1 subject enrolled in the trial. This volunteer was known to be noncompliant, having missedmany dosesof study drug, and he was excluded from the efficacy analysis. Three of 113 assessable subjects withdrew due to a treatment-related adverse event. Thus the chemoprophylaxis successrate was 97% (95% confidence interval, 92% to 99%) in the assessable population. DISCUSSION AND CONCLUSIONS The results of this study provide additional support for prophylaxis againstfalciparum malaria with the combination of atovaquone and proguanil hydrochloride. Once-daily dosing with 250 mg atovaquone and 100 mg proguanil hydrochloride (1 tablet) for up to 10 weeks was well tolerated, with no serious adverse events noted. The 1 subject who developed malaria was noncompliant with therapy. Less than 2% of enrolled subjects discontinued prophylaxis due to a treatment-related adverse event. At the start of the study, none of the subjectshad immunity to malaria, and all were temporarily resident in or were traveling to an area where malaria was endemic. In a country such as South Africa, where malaria is both seasonal and focal and there is little acquired immunity, all such individuals may be at risk of death from uncontrolled parasitemia.‘” The safety and efficacy data from the presentopen-label trial are consistentwith 746
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the findings from 3 double-masked, placebo-controlled trials assessingthe drug combination for malaria prophylaxis.26-28The 3 controlled studies, conducted in Gabon, Zambia, and Kenya, used dosing regimens similar to the one used in our trial. The overall efficacy rate in those studies was 98%, and adverse events occurred with similar or lower rates in subjectsreceiving atovaquone and proguanil hydrochloride compared with subjects receiving placebo. According to White,9 the rapid development of drug resistanceto Pfalciparum may lead to recalcitrant malaria in parts of SoutheastAsia by the start of the next millennium. The potential for the rapid development of resistance to newly introduced compounds is of paramount concern. Current antimalarial treatment regimens are relying more heavily on combination drug therapy in an attempt to delay the appearanceof resistanceto 1 or both drugs, particularly when they are to be widely usedin a malaria-endemicarea. It hasbeen hypothesized that antimalarial combinations that expose parasites to drugs having different sitesof action may reduce the probability of the parasites’developing resistanceto both drug componentsX2Atovaquone and proguanil appear to be excellent partners for combination antimalarial dosing. These drugs act on the samestageof the parasite but, as previously discussed,have different sites of action. In clinical trials of atovaquoneand proguanil in the treatment of malaria, clinical resistance was demonstrated in approximately 30% of patients treated with atovaquone alone and more than 90% of patients treated with proguanil alone, but in fewer than 2% of patients treated with the combination of the two.2s,1’Additional experience with this combination will be
J.D. VAN DER BERG ET AL.
necessaryto fully explore the issueof antimalarial resistancein vivo. There has been speculationthat results obtained from “traveler” studiesconducted in nonimmune, young, healthy military personneltraveling to endemic areasmay not be generalizable to the population of nonmilitary travelers. Croft and Garners have suggestedthat general travelers are more likely to withdraw from or be noncompliant with malaria prophylaxis than military personneland that the stressesof intercontinental travel may put them at higher risk of drug-related adverseexperiences.We believe the results of our study are generalizable to nonmilitary travelers for a variety of reasons.First, our population was derived from a spectrumof military personneland not just young, fit male soldiers.Indeed, 15% of the study population were women with a meanage at study entry of 34 years. Our population also included individuals with concurrent stable medical conditions, including cardiovascular and gastrointestinal abnormalities, and individuals using concomitant medications, as would be expected among tourists and businesstravelers. Twentythree percent of study participantsreported minor deviations from the prescribeddosing regimen, as can also be expected of generaltravelers. Despitethesedeviations, the combination was highly efficacious. The significant stressesassociated with deployment away from family, potentially to areasof civil unrest, did not appear to lead to a higher incidence of adverse events comparedwith incidencesin previous placebo-controlled trials of atovaquone and proguanil hydrochloride for malaria prophylaxis .262* The resultsof this study, combinedwith the data from 3 previous double-masked, placebo-controlled prophylaxis trials, sug-
gest that the combination of atovaquone and proguanil hydrochloride has an excellent safety and efficacy profile for chemoprophylaxis against P falciparum malaria. ACKNOWLEDGMENTS This study was supportedby a grant from Glaxo Wellcome Inc., ResearchTriangle Park, North Carolina. The authors wish to thank the South African Medical Services, South African National Defense Force, and the volunteers who participated in this trial. The authors would also like to acknowledge the Clinical Research Department of Glaxo Wellcome South Africa for their role in facilitating the logistics of the study. They are grateful to Dr. Jeff Chulay for reviewing the manuscript. Address correspondence to: Trevor R. Scott, PhD, HIV/O1 Clinical Development, Glaxo Wellcome Inc., 5 Moore Drive, ResearchTriangle Park, NC 27709. REFERENCES 1. Olliaro P,CattaniJ, Wirth D. Malaria,the submergeddisease.JAMA. 1996;275: 230-233.
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