"Prolonging the Therapeutic Life Span of Artemisinin-based Combination Therapies (ACT) in Bagamoyo District, Tanzania"

Malaria,Falciparum Clinical Trial

— ALU-PQ  

Official title:

"Aiming at Prolonging the Therapeutic Life Span of Artemisinin-based Combination Therapies (ACT) in an Era of Imminent Plasmodium Falciparum Resistance in Bagamoyo District, Tanzania - New Strategies With Old Tools"

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03241901
• Other study ID #: No. 01.05.2017
• Status: Completed
• Phase: Phase 4
• First received: July 5, 2017
• Last updated: March 24, 2018
• Start date: July 27, 2017
• Est. completion date: February 17, 2018

Study information

• Verified date: March 2018
• Source: Muhimbili University of Health and Allied Sciences
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Description:

Despite documented high cure rates of ACT in Tanzania, and Africa elsewhere, clinical trials conducted in Tanzania with Swedish International Development cooperation Agency (SIDA) and Swedish Research Council support, provide evidence for in vivo selection of lumefantrine tolerant/resistant parasites among recurrent infections. Similarly, molecular epidemiology studies from Bagamoyo District, Tanzania, have shown temporal selection of lumefantrine associated genetic tolerance/resistance markers in the parasite population following wide scale use of Artemether-lumefantrine, but without signs of compromised treatment efficacy.

During the last decade, and despite the documented rapid microscopy determined parasite clearance of artemether-lumefantrine in Bagamoyo District, interest has developed in understanding the observation of high residual polymerase chain reaction (PCR) determined positivity rate on day 3 after supervised artemether-lumefantrine treatment in the magnitude of almost 30% in previous assessments from 2015. Using deep sequencing approaches studies have recently detected PCR determined delayed parasite clearance curves in P. falciparum sub-populations in Bagamoyo District. The clearance times by PCR of these sub-populations were similar to artemisinin resistant parasites in Myanmar as assessed by microscopy, but the former did, importantly, not harbor any of the described mutations in Kelch13 propeller associated with artemisinin resistance. However, these Tanzanian parasite sub-populations need to be further studied and characterized since they may provide important clues to the understanding of artemisinin survival strategies among the East African P. falciparum parasite population.

Taken together, longitudinal clinical and molecular data described above from Tanzania, East Africa, extending from pre-ACT implementation, (before 2006), to a decade of wide scale artemether-lumefantrine use in Bagamoyo district, provide evidence for declining susceptibility to ACT, both to artemether and lumefantrine, among the P. falciparum population. These parasites ("last man standing") that survived 10 years of ACT exposure have indeed shown excellent survival instincts and may thus be particularly resistant prone. However, if P. falciparum resistance to ACT develops in Africa, this will have devastating effects on malaria morbidity and mortality and may swiftly ruin the improvements the global malaria community achieved during the past decade with ACT as a key component for success.

Based on the above the investigators suggest prolonged treatment with ACT and addition of transmission blocking treatment using a single low dose of primaquine administered on the last day of ACT treatment.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 280
• Est. completion date: February 17, 2018
• Est. primary completion date: December 28, 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 1 Year to 65 Years

Eligibility

Inclusion Criteria:

1. Age more than 1 year and less than 65 years.

2. Weight 10 kg and above;

3. Body temperature =37.5°C or history of fever in the last 24 hours;

4. Microscopy determined asexual P. falciparum mono-infection regardless of parasitemia

5. Normal - corrected QT Interval in Baseline ECG of less than 440ms in male and 460ms in females

Exclusion Criteria:

1. Symptoms/signs of severe malaria or danger signs;

2. Pregnancy, Breastfeeding or unwilling to practice birth control during participation in the study.

3. Known allergy to study medications;

4. Hb <8 g/dl;

5. Reported antimalarial intake within last 2 weeks;

6. On regular medication, which may interfere with antimalarial pharmacokinetics and

7. Blood transfusion within last 90 days.

Related Conditions & MeSH terms

• Malaria, Falciparum
• Malaria,Falciparum

Intervention

Drug:
• Artemether-Lumefantrine Tab 20-120mg
Artemether-Lumefantrine Tablet 20-120mg
• Primaquine Phosphate 0.25 mg/kg
Primaquine Phosphate 0.25 mg/kg

Other:
• Placebo
Aqueous solution prepared to mimic the taste of the intervention drug.

Locations

Country	Name	City	State
Tanzania	Fukayosi Dispensary	Bagamoyo	Pwani
Tanzania	Yombo Dispensary	Bagamoyo	Yombo

Sponsors (4)

Lead Sponsor	Collaborator
Muhimbili University of Health and Allied Sciences	Karolinska Institutet, The University of Western Australia, Uppsala University

Country where clinical trial is conducted

Tanzania, 

References & Publications (22)

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, Ménard 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, Ménard 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. — View Citation

Aydin-Schmidt B, Morris U, Ding XC, Jovel I, Msellem MI, Bergman D, Islam A, Ali AS, Polley S, Gonzalez IJ, Mårtensson A, Björkman 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. — View Citation

Aydin-Schmidt B, Xu W, González IJ, Polley SD, Bell D, Shakely D, Msellem MI, Björkman A, Mårtensson 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. — View Citation

Cook J, Aydin-Schmidt B, González IJ, Bell D, Edlund E, Nassor MH, Msellem M, Ali A, Abass AK, Mårtensson A, Björkman 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. — View Citation

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. Erratum in: N Engl J Med. 2009 Oct 22;361(17):1714. — View Citation

Fröberg G, Jörnhagen L, Morris U, Shakely D, Msellem MI, Gil JP, Björkman A, Mårtensson 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. — View Citation

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. Erratum in: PLoS Negl Trop Dis. 2008;2(10):10.1371/annotation/1f73ee39-9e3c-4ce4-9c35-2a6ab393de7d.. — View Citation

Lundin M, Szymas J, Linder E, Beck H, de Wilde P, van Krieken H, García 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. — View Citation

Malmberg M, Ferreira PE, Tarning J, Ursing J, Ngasala B, Björkman A, Mårtensson 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. — View Citation

Malmberg M, Ngasala B, Ferreira PE, Larsson E, Jovel I, Hjalmarsson A, Petzold M, Premji Z, Gil JP, Björkman A, Mårtensson 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. — View Citation

Mårtensson A, Strömberg J, Sisowath C, Msellem MI, Gil JP, Montgomery SM, Olliaro P, Ali AS, Björkman 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. Epub 2005 Sep 13. — View Citation

Mideo N, Bailey JA, Hathaway NJ, Ngasala B, Saunders DL, Lon C, Kharabora O, Jamnik A, Balasubramanian S, Björkman A, Mårtensson 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. — View Citation

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. — View Citation

Mwaiswelo R, Ngasala BE, Jovel I, Gosling R, Premji Z, Poirot E, Mmbando BP, Björkman A, Mårtensson 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. — View Citation

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. — View Citation

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

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. — View Citation

Sisowath C, Strömberg J, Mårtensson A, Msellem M, Obondo C, Björkman 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. Epub 2005 Feb 8. — View Citation

Straimer J, Gnädig 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, Ménard 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. — View Citation

Veiga MI, Ferreira PE, Björkman 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. Epub 2006 Feb 7. — View Citation

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. — View Citation

Xu W, Morris U, Aydin-Schmidt B, Msellem MI, Shakely D, Petzold M, Björkman A, Mårtensson 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. — View Citation

* Note: There are 22 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Fever Clearance Time	This will assess the rate of clearance of fever after initiation of treatment	7 Days
Other	Incidence of Treatment-Emergent Adverse Events (Safety and tolerability)	Incidence of prolonged Corrected QT interval in ECG measures at day 7	Baseline and day 7
Other	Incidence of Severe anemia	Proportion of Severe anemia as measured by hemoglobin baseline to day 7, 14, 28, 42	baseline to day 7, 14, 28, 42
Other	Incidence of Biochemistry parameters derangements	Proportions of biochemistry parameters (ALAT, ASAT, Bilirubin and Creatinine) outside the normal range .	Baseline and day 7
Primary	Parasite Clearance Times	Proportion of PCR detectable parasitemia on Day 5	5 Days
Primary	Parasite Clearance Times	Proportion of PCR detectable parasitemia on Day 7	7 Days
Secondary	Gametocyte Clearance	PCR determined gametocyte carriage/clearance times	42 Days
Secondary	Cure Rate	Crude and PCR corrected cure rates by day 28	28 Days
Secondary	Genetic Markers of Drug Resistance	Selection of genetic drug resistance markers during the early treatment phase	6 Days
Secondary	Pharmacokinetics	Area under the plasma concentration versus time curve (AUC) of Artemether-lumefantrine	7 Days
Secondary	Peak Plasma Concentration (Cmax)	Peak Plasma Concentration (Cmax) of Lumefantrine measured for 28 days	At hours, -1, 0 ,2 ,4 ,12, 24, 36, 40, 48, 52, 60, 72, 84, 88, 96, 100, 108,120, 132, 134, 136 ,144, 168, 192, 240, 336, 504 and 672
Secondary	Day 7 plasma lumefantrine	Day 7 plasma lumefantrine concentrations in the respective arms	7 Days

External Links

•   "WHO World Malaria Report 2015," Geneva, Switzerland, 2015
•   BAGAMOYO DISTRICT HEALTH PROFILE
•   PRESIDENT'S MALARIA INITIATIVE Tanzania Malaria Operational Plan FY 2015
•   WHO guidelines for the treatment of malaria 2015, 3rd Edition. Geneva, Switzerland, 2015