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

NCT03241901 | Completed Phase 4 DMC

• 1 other identifier: No. 01.05.2017
• Study Type: interventional
• Target: 280
• Locations: 1 country
• Sites: 2

Brief 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.

Conditions

Malaria,Falciparum

Keywords

Artemether-Lumefantrine, Primaquine

Outcome Measures

Primary Outcomes (2)

• Parasite Clearance Times

  Proportion of PCR detectable parasitemia on Day 5

  5 Days

• Parasite Clearance Times

  Proportion of PCR detectable parasitemia on Day 7

  7 Days

Secondary Outcomes (6)

• Gametocyte Clearance

  42 Days

• Cure Rate

  28 Days

• Genetic Markers of Drug Resistance

  6 Days

• Pharmacokinetics

  7 Days

• Peak Plasma Concentration (Cmax)

  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

Other Outcomes (4)

• Fever Clearance Time

  7 Days

• Incidence of Treatment-Emergent Adverse Events (Safety and tolerability)

  Baseline and day 7

• Incidence of Severe anemia

  baseline to day 7, 14, 28, 42

Study Arms (2)

3 Days Artemether-Lumefantrine + Placebo

ACTIVE COMPARATOR

Oral tablets of artemether-lumefantrine (20-120mg): 1. tablet for 5-14kg; 2. tablets for 15-24 kg; 3. tables for 25 - 34kg and 4. tablets for above 35 Kg. The full course of treatment is 6-doses for 3 days given twice daily, at 0, 8, 24, 36, 48, 60 with the dose being given as directly observed therapy. Oral placebo after completion of the standard 3 days-six dose regimen. A fatty snack (biscuits) will be administered together with all artemether-lumefantrine doses to optimize absorption.

Drug: Artemether-Lumefantrine Tab 20-120mg; Other: Placebo

6Days Artemether/Lumefantrine+Primaquine

EXPERIMENTAL

Artemether-lumefantrine (20-120mg) twice daily for 6 days according to body weight as in the active comparator arm. And in addition to that, , a single 0.25 mg/kg primaquine dose (Primaquine phosphate) will be administered concomitantly with the last (i.e. twelfth) artemether-lumefantrine dose. Primaquine will be prepared and administered in an aqueous solution.

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

Interventions

Artemether-Lumefantrine Tab 20-120mg DRUG

Artemether-Lumefantrine Tablet 20-120mg

Also known as: ALU

3 Days Artemether-Lumefantrine + Placebo; 6Days Artemether/Lumefantrine+Primaquine

Primaquine Phosphate 0.25 mg/kg DRUG

Primaquine Phosphate 0.25 mg/kg

Also known as: PQ

6Days Artemether/Lumefantrine+Primaquine

Placebo OTHER

Aqueous solution prepared to mimic the taste of the intervention drug.

Also known as: Placebo for Artemether Lumefantrine + Primaquine Phosphate

3 Days Artemether-Lumefantrine + Placebo

Eligibility Criteria

• Age: 1 Year - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Age more than 1 year and less than 65 years.
• Weight 10 kg and above;
• Body temperature ≥37.5°C or history of fever in the last 24 hours;
• Microscopy determined asexual P. falciparum mono-infection regardless of parasitemia
• Normal - corrected QT Interval in Baseline ECG of less than 440ms in male and 460ms in females

You may not qualify if:

• Symptoms/signs of severe malaria or danger signs;
• Pregnancy, Breastfeeding or unwilling to practice birth control during participation in the study.
• Known allergy to study medications;
• Hb \<8 g/dl;
• Reported antimalarial intake within last 2 weeks;
• On regular medication, which may interfere with antimalarial pharmacokinetics and
• Blood transfusion within last 90 days.

Sponsors & Collaborators

• Muhimbili University of Health and Allied Sciences: lead
• Uppsala University: collaborator
• Karolinska Institutet: collaborator
• The University of Western Australia: collaborator

Study Sites (2)

Fukayosi Dispensary

Bagamoyo, Coast Region, +255, Tanzania

Location

Yombo Dispensary

Bagamoyo, Yombo, +255, Tanzania

Location

Related Publications (24)

• 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.

  PMID: 15717281 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.

  PMID: 16163624 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.

  PMID: 23506218 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.

  PMID: 26817485 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.

  PMID: 27287612 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.

  PMID: 19641202 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.

  PMID: 24352242 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.

  PMID: 24035558 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.

  PMID: 25502314 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.

  PMID: 23225895 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.

  PMID: 18941514 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.

  PMID: 19280223 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.

  PMID: 25105591 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.

  PMID: 25627037 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.

  PMID: 28095434 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.

  PMID: 25774805 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.

  PMID: 18187793 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.

  PMID: 25827756 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.

  PMID: 22966778 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.

  PMID: 16460912 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.

  PMID: 15288742 BACKGROUND

• 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.

  PMID: 32664948 DERIVED

• 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.

  PMID: 32576258 DERIVED

Related Links

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

MeSH Terms

Conditions

Malaria, Falciparum

Interventions

Artemether, Lumefantrine Drug Combination; Primaquine

Condition Hierarchy (Ancestors)

Malaria; Protozoan Infections; Parasitic Diseases; Infections; Mosquito-Borne Diseases; Vector Borne Diseases

Intervention Hierarchy (Ancestors)

Artemether; Artemisinins; Reactive Oxygen Species; Free Radicals; Inorganic Chemicals; Organic Chemicals; Lumefantrine; Fluorenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Sesquiterpenes; Terpenes; Polycyclic Compounds; Drug Combinations; Pharmaceutical Preparations; Aminoquinolines; Quinolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Lwidiko E Mhamilawa, MD

  Muhimbili University of Health and Allied Sciences

  PRINCIPAL INVESTIGATOR

• Andreas Martensson, PhD

  Uppsala University

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Masking Details: Due to the objectives of the study, the identity of test and control treatments will be known only to investigators, research staff, but NOT patients. The following study procedures will be in place to ensure single-blind administration of study treatments. 1. Access to the randomization code will be strictly controlled. 2. A taste-matching agent for the placebo. 3. Packaging and labeling of test and control treatments will be identical to maintain the blind. During the study, the blind may be broken only in emergencies when knowledge of the patient's treatment group is necessary for further patient management. When possible, the Investigator should discuss the emergency with the Medical Monitor prior to un-blinding
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Medical Doctor

Study Record Dates

• First Submitted: July 5, 2017
• First Posted: August 8, 2017
• Study Start: July 27, 2017
• Primary Completion: December 28, 2017
• Study Completion: February 17, 2018
• Last Updated: March 27, 2018

Record last verified: 2018-03

Data Sharing

• IPD Sharing: Will not share

Locations

TA (2)