drugset / Trial / NCT03241901
"Prolonging the Therapeutic Life Span of Artemisinin-based Combination Therapies (ACT) in Bagamoyo District, Tanzania"
Phase 4
Completed
280 enrolled
Muhimbili University of Health and Allied Sciences
Karolinska Institutet · collabThe University of Western Australia · collabUppsala University · collab
RandomizedParallel-groupSingle-blindTreatment
Summary
This clinical trial evaluates the advantage of prolonging the therapeutic life span of Artemether-lumefantrine from 3 days to 6 days, and addition of single low dose of Primaquine 0.25mg/kg. The study will have two arms, one that will receive standard treatment of uncomplicated malaria with Artemether-lumefantrine, and the other arm will receive the prolonged dose of 6 days together with single low dose primaquine. This approach is expected to provide strategies for malaria control in an era of imminent Plasmodium falciparum resistance.
Timeline
- Start
- 2017-07-27
- Primary completion
- 2017-12-28
- Completion
- 2018-02-17
Outcome
Missed primary endpoint
paper There was no difference in proportion of PCR positivity across the arms at day 5 (80/130 (61.5%) vs 89/134 (66.4%), p = 0.44) PMID 32576258 ↗
paper or day 7 (71/129 (55.0%) vs 70/134 (52.2%), p = 0.71). PMID 32576258 ↗
Publications
- Background Sisowath C, Stromberg J, Martensson A, Msellem M, Obondo C, Bjorkman A, Gil JP. In vivo selection of Plasmodium falciparum pfmdr1 86N coding alleles by artemether-lumefantrine (Coartem). J Infect Dis. 2005 Mar 15;191(6):1014-7. doi: 10.1086/427997. Epub 2005 Feb 8.
- Background Martensson A, Stromberg J, Sisowath C, Msellem MI, Gil JP, Montgomery SM, Olliaro P, Ali AS, Bjorkman A. Efficacy of artesunate plus amodiaquine versus that of artemether-lumefantrine for the treatment of uncomplicated childhood Plasmodium falciparum malaria in Zanzibar, Tanzania. Clin Infect Dis. 2005 Oct 15;41(8):1079-86. doi: 10.1086/444460. Epub 2005 Sep 13.
- Background Malmberg M, Ngasala B, Ferreira PE, Larsson E, Jovel I, Hjalmarsson A, Petzold M, Premji Z, Gil JP, Bjorkman A, Martensson A. Temporal trends of molecular markers associated with artemether-lumefantrine tolerance/resistance in Bagamoyo district, Tanzania. Malar J. 2013 Mar 18;12:103. doi: 10.1186/1475-2875-12-103.
- Background Mideo N, Bailey JA, Hathaway NJ, Ngasala B, Saunders DL, Lon C, Kharabora O, Jamnik A, Balasubramanian S, Bjorkman A, Martensson A, Meshnick SR, Read AF, Juliano JJ. A deep sequencing tool for partitioning clearance rates following antimalarial treatment in polyclonal infections. Evol Med Public Health. 2016 Jan 27;2016(1):21-36. doi: 10.1093/emph/eov036.
- Background Mwaiswelo R, Ngasala BE, Jovel I, Gosling R, Premji Z, Poirot E, Mmbando BP, Bjorkman A, Martensson A. Safety of a single low-dose of primaquine in addition to standard artemether-lumefantrine regimen for treatment of acute uncomplicated Plasmodium falciparum malaria in Tanzania. Malar J. 2016 Jun 10;15:316. doi: 10.1186/s12936-016-1341-3.
- Background R. Mwaiswelo, B. Ngasala, I. Jovel, W. Xu, and M. Malmberg, "Occurrence of day 3 submicroscopic Plasmodium falciparum parasitemia before and after implementation of artemether-lumefantrine treatment policy in Tanzania .," Dar Es Salaam, 2016
- Background Dondorp AM, Nosten F, Yi P, Das D, Phyo AP, Tarning J, Lwin KM, Ariey F, Hanpithakpong W, Lee SJ, Ringwald P, Silamut K, Imwong M, Chotivanich K, Lim P, Herdman T, An SS, Yeung S, Singhasivanon P, Day NP, Lindegardh N, Socheat D, White NJ. Artemisinin resistance in Plasmodium falciparum malaria. N Engl J Med. 2009 Jul 30;361(5):455-67. doi: 10.1056/NEJMoa0808859.
- Background Ariey F, Witkowski B, Amaratunga C, Beghain J, Langlois AC, Khim N, Kim S, Duru V, Bouchier C, Ma L, Lim P, Leang R, Duong S, Sreng S, Suon S, Chuor CM, Bout DM, Menard S, Rogers WO, Genton B, Fandeur T, Miotto O, Ringwald P, Le Bras J, Berry A, Barale JC, Fairhurst RM, Benoit-Vical F, Mercereau-Puijalon O, Menard D. A molecular marker of artemisinin-resistant Plasmodium falciparum malaria. Nature. 2014 Jan 2;505(7481):50-5. doi: 10.1038/nature12876. Epub 2013 Dec 18.
- Background Witkowski B, Amaratunga C, Khim N, Sreng S, Chim P, Kim S, Lim P, Mao S, Sopha C, Sam B, Anderson JM, Duong S, Chuor CM, Taylor WR, Suon S, Mercereau-Puijalon O, Fairhurst RM, Menard D. Novel phenotypic assays for the detection of artemisinin-resistant Plasmodium falciparum malaria in Cambodia: in-vitro and ex-vivo drug-response studies. Lancet Infect Dis. 2013 Dec;13(12):1043-9. doi: 10.1016/S1473-3099(13)70252-4. Epub 2013 Sep 11.
- Background Straimer J, Gnadig NF, Witkowski B, Amaratunga C, Duru V, Ramadani AP, Dacheux M, Khim N, Zhang L, Lam S, Gregory PD, Urnov FD, Mercereau-Puijalon O, Benoit-Vical F, Fairhurst RM, Menard D, Fidock DA. Drug resistance. K13-propeller mutations confer artemisinin resistance in Plasmodium falciparum clinical isolates. Science. 2015 Jan 23;347(6220):428-31. doi: 10.1126/science.1260867. Epub 2014 Dec 11.
- Background Malmberg M, Ferreira PE, Tarning J, Ursing J, Ngasala B, Bjorkman A, Martensson A, Gil JP. Plasmodium falciparum drug resistance phenotype as assessed by patient antimalarial drug levels and its association with pfmdr1 polymorphisms. J Infect Dis. 2013 Mar 1;207(5):842-7. doi: 10.1093/infdis/jis747. Epub 2012 Dec 5.
- Background Linder E, Lundin M, Thors C, Lebbad M, Winiecka-Krusnell J, Helin H, Leiva B, Isola J, Lundin J. Web-based virtual microscopy for parasitology: a novel tool for education and quality assurance. PLoS Negl Trop Dis. 2008;2(10):e315. doi: 10.1371/journal.pntd.0000315. Epub 2008 Oct 22.
- Background Lundin M, Szymas J, Linder E, Beck H, de Wilde P, van Krieken H, Garcia Rojo M, Moreno I, Ariza A, Tuzlali S, Dervisoglu S, Helin H, Lehto VP, Lundin J. A European network for virtual microscopy--design, implementation and evaluation of performance. Virchows Arch. 2009 Apr;454(4):421-9. doi: 10.1007/s00428-009-0749-3. Epub 2009 Mar 12.
- Background Aydin-Schmidt B, Xu W, Gonzalez IJ, Polley SD, Bell D, Shakely D, Msellem MI, Bjorkman A, Martensson A. Loop mediated isothermal amplification (LAMP) accurately detects malaria DNA from filter paper blood samples of low density parasitaemias. PLoS One. 2014 Aug 8;9(8):e103905. doi: 10.1371/journal.pone.0103905. eCollection 2014.
- Background Cook J, Aydin-Schmidt B, Gonzalez IJ, Bell D, Edlund E, Nassor MH, Msellem M, Ali A, Abass AK, Martensson A, Bjorkman A. Loop-mediated isothermal amplification (LAMP) for point-of-care detection of asymptomatic low-density malaria parasite carriers in Zanzibar. Malar J. 2015 Jan 28;14:43. doi: 10.1186/s12936-015-0573-y.
- Background Aydin-Schmidt B, Morris U, Ding XC, Jovel I, Msellem MI, Bergman D, Islam A, Ali AS, Polley S, Gonzalez IJ, Martensson A, Bjorkman A. Field Evaluation of a High Throughput Loop Mediated Isothermal Amplification Test for the Detection of Asymptomatic Plasmodium Infections in Zanzibar. PLoS One. 2017 Jan 17;12(1):e0169037. doi: 10.1371/journal.pone.0169037. eCollection 2017.
- Background Xu W, Morris U, Aydin-Schmidt B, Msellem MI, Shakely D, Petzold M, Bjorkman A, Martensson A. SYBR Green real-time PCR-RFLP assay targeting the plasmodium cytochrome B gene--a highly sensitive molecular tool for malaria parasite detection and species determination. PLoS One. 2015 Mar 16;10(3):e0120210. doi: 10.1371/journal.pone.0120210. eCollection 2015.
- Background Mlambo G, Vasquez Y, LeBlanc R, Sullivan D, Kumar N. A filter paper method for the detection of Plasmodium falciparum gametocytes by reverse transcription polymerase chain reaction. Am J Trop Med Hyg. 2008 Jan;78(1):114-6.
- Background Schneider P, Reece SE, van Schaijk BC, Bousema T, Lanke KH, Meaden CS, Gadalla A, Ranford-Cartwright LC, Babiker HA. Quantification of female and male Plasmodium falciparum gametocytes by reverse transcriptase quantitative PCR. Mol Biochem Parasitol. 2015 Jan-Feb;199(1-2):29-33. doi: 10.1016/j.molbiopara.2015.03.006. Epub 2015 Mar 28.
- Background Froberg G, Jornhagen L, Morris U, Shakely D, Msellem MI, Gil JP, Bjorkman A, Martensson A. Decreased prevalence of Plasmodium falciparum resistance markers to amodiaquine despite its wide scale use as ACT partner drug in Zanzibar. Malar J. 2012 Sep 11;11:321. doi: 10.1186/1475-2875-11-321.
- Background Veiga MI, Ferreira PE, Bjorkman A, Gil JP. Multiplex PCR-RFLP methods for pfcrt, pfmdr1 and pfdhfr mutations in Plasmodium falciparum. Mol Cell Probes. 2006 Apr;20(2):100-4. doi: 10.1016/j.mcp.2005.10.003. Epub 2006 Feb 7.
- Background Price RN, Uhlemann AC, Brockman A, McGready R, Ashley E, Phaipun L, Patel R, Laing K, Looareesuwan S, White NJ, Nosten F, Krishna S. Mefloquine resistance in Plasmodium falciparum and increased pfmdr1 gene copy number. Lancet. 2004 Jul 31-Aug 6;364(9432):438-447. doi: 10.1016/S0140-6736(04)16767-6.
- Mhamilawa LE, Wikstrom S, Mmbando BP, Ngasala B, Martensson A. Electrocardiographic safety evaluation of extended artemether-lumefantrine treatment in patients with uncomplicated Plasmodium falciparum malaria in Bagamoyo District, Tanzania. Malar J. 2020 Jul 14;19(1):250. doi: 10.1186/s12936-020-03309-2.
- Mhamilawa LE, Ngasala B, Morris U, Kitabi EN, Barnes R, Soe AP, Mmbando BP, Bjorkman A, Martensson A. Parasite clearance, cure rate, post-treatment prophylaxis and safety of standard 3-day versus an extended 6-day treatment of artemether-lumefantrine and a single low-dose primaquine for uncomplicated Plasmodium falciparum malaria in Bagamoyo district, Tanzania: a randomized controlled trial. Malar J. 2020 Jun 23;19(1):216. doi: 10.1186/s12936-020-03287-5.
Drugs
| Evaluation | Drug | Modality | Dose | Route |
|---|---|---|---|---|
| Subject | Artemether | Small molecule | 20 mg | Oral |
| Subject | Artemether | Small molecule | 40 mg | Oral |
| Subject | Artemether | Small molecule | 60 mg | Oral |
| Subject | Artemether | Small molecule | 80 mg | Oral |
| Subject | Primaquine | Small molecule | 0.25 mg/kg | — |
| Subject | lumefantrine | Small molecule | 120 mg | Oral |
| Subject | lumefantrine | Small molecule | 240 mg | Oral |
| Subject | lumefantrine | Small molecule | 360 mg | Oral |
| Subject | lumefantrine | Small molecule | 480 mg | Oral |