title: Randomized trial of primaquine hypnozoitocidal efficacy when administered with artemisinin-combined blood schizontocides for radical cure of Plasmodium vivax in Indonesia.
abstract: BACKGROUND
  Safety and efficacy of primaquine against repeated attacks of Plasmodium vivax depends upon co-administered blood schizontocidal therapy in radical cure. We assessed primaquine (PQ) as hypnozoitocide when administered with dihydroartemisinin-piperaquine (Eurartesim®, DHA-PP) or artesunate-pyronaridine (Pyramax®, AS-PYR) to affirm its good tolerability and efficacy. A third arm, artesunate followed by primaquine, was not intended as therapy for practice, but addressed a hypothesis concerning primaquine efficacy without co-administration of blood schizontocide.
  
  
  METHODS
  During March to July 2013, an open-label, randomized trial enrolled Indonesian soldiers with vivax malaria at Sragen, Central Java, after six months duty in malarious Papua, Indonesia. No malaria transmission occurred at the study site and P. vivax recurrences in the 12 months following therapy were classified as relapses. A historic relapse control derived from a cohort of soldiers who served in the same area of Papua was applied to estimate risk of relapse among randomized treatment groups. Those were: 1) AS followed 2d later by PQ (0.5 mg/kg daily for 14d); 2) co-formulated AS-PYR concurrent with the same regimen of PQ; or 3) co-formulated DHA-PP concurrent with the same regimen of PQ.
  
  
  RESULTS
  Among 532 soldiers, 219 had vivax malaria during the four months following repatriation to Java; 180 of these were otherwise healthy and G6PD-normal and enrolled in the trial. Subjects in all treatment groups tolerated the therapies well without untoward events and cleared parasitemia within three days. First relapse appeared at day 39 post-enrollment, and the last at day 270. Therapeutic efficacy of PQ against relapse by incidence density analysis was 92 % (95 %CI = 83-97 %), 94 %(95 %CI = 86-97 %), and 95 %(95 %CI = 88-98 %) when combined with AS, AS-PYR, or DHA-PP, respectively.
  
  
  CONCLUSIONS
  This trial offers evidence of good tolerability and efficacy of PQ against P. vivax relapse when administered concurrently with DHA-PP or AS-PYR. These offer alternative partner drugs for radical cure with primaquine. The AS arm demonstrated efficacy with a total dose of 7 mg/kg PQ without concurrently administered blood schizontocide, another option when primaquine therapy is removed in time from the treatment of the acute malaria or applied presumptively without an attack.
  
  
  BACKGROUND
  Current Controlled Trials ISRCTN82366390, assigned 20 March 2013.
authors.affiliation: Faculty of Medicine, University of Indonesia, Jalan Salemba Raya No. 6, Jakarta, 10430, Indonesia. ejnelwan@yahoo.com.
authors.forename: Erni J
authors.initials: EJ
authors.lastname: Nelwan
authors.affiliation: Eijkman-Oxford Clinical Research Unit, Jalan Diponegoro No. 69, Jakarta, 10430, Indonesia. lekawati@eocru.org.
authors.forename: Lenny L
authors.initials: LL
authors.lastname: Ekawati
authors.affiliation: Health Services, Army of the Republic of Indonesia, Jalan Letjen Soetoyo, Jakarta, 13640, Indonesia. bagustjahjono@yahoo.com.
authors.forename: Bagus
authors.initials: B
authors.lastname: Tjahjono
authors.affiliation: Faculty of Medicine, University of Indonesia, Jalan Salemba Raya No. 6, Jakarta, 10430, Indonesia. rianto_set@yahoo.com.
authors.forename: Rianto
authors.initials: R
authors.lastname: Setiabudy
authors.affiliation: Faculty of Medicine, University of Indonesia, Jalan Salemba Raya No. 6, Jakarta, 10430, Indonesia. sutanto.inge@yahoo.com.
authors.forename: Inge
authors.initials: I
authors.lastname: Sutanto
authors.affiliation: Eijkman-Oxford Clinical Research Unit, Jalan Diponegoro No. 69, Jakarta, 10430, Indonesia. sanariliskris@yahoo.com.
authors.forename: Krisin
authors.initials: K
authors.lastname: Chand
authors.affiliation: Eijkman-Oxford Clinical Research Unit, Jalan Diponegoro No. 69, Jakarta, 10430, Indonesia. yeisha_42@yahoo.co.id.
authors.forename: Tyas
authors.initials: T
authors.lastname: Ekasari
authors.affiliation: Health Services, Army of the Republic of Indonesia, Jalan Letjen Soetoyo, Jakarta, 13640, Indonesia. dwidjoko33@gmail.com.
authors.forename: Dwi
authors.initials: D
authors.lastname: Djoko
authors.affiliation: Eijkman-Oxford Clinical Research Unit, Jalan Diponegoro No. 69, Jakarta, 10430, Indonesia. hbasri@eocru.org.
authors.forename: Hasan
authors.initials: H
authors.lastname: Basri
authors.affiliation: Eijkman-Oxford Clinical Research Unit, Jalan Diponegoro No. 69, Jakarta, 10430, Indonesia. bob@tropmedres.ac.
authors.forename: W Robert
authors.initials: WR
authors.lastname: Taylor
authors.affiliation: Medicines for Malaria Venture, Route de Pré-Bois 20, 1215, Meyrin, Switzerland. duparcs@mmv.org.
authors.forename: Stephan
authors.initials: S
authors.lastname: Duparc
authors.affiliation: Eijkman-Oxford Clinical Research Unit, Jalan Diponegoro No. 69, Jakarta, 10430, Indonesia. dsubekti@eocru.org.
authors.forename: Decy
authors.initials: D
authors.lastname: Subekti
authors.affiliation: Eijkman-Oxford Clinical Research Unit, Jalan Diponegoro No. 69, Jakarta, 10430, Indonesia. iqbal.elyazar@gmail.com.
authors.forename: Iqbal
authors.initials: I
authors.lastname: Elyazar
authors.affiliation: Eijkman Institute for Molecular Biology, Jalan Diponegoro No. 69, Jakarta, 10430, Indonesia. rintis@eijkman.go.id.
authors.forename: Rintis
authors.initials: R
authors.lastname: Noviyanti
authors.affiliation: Eijkman Institute for Molecular Biology, Jalan Diponegoro No. 69, Jakarta, 10430, Indonesia. herawati@eijkman.go.id.
authors.forename: Herawati
authors.initials: H
authors.lastname: Sudoyo
authors.affiliation: Eijkman-Oxford Clinical Research Unit, Jalan Diponegoro No. 69, Jakarta, 10430, Indonesia. kevin.baird@ndm.ox.ac.uk.|The Centre for Tropical Medicine, Nuffield Department of Medicine, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford, OX3 7FZ, UK. kevin.baird@ndm.ox.ac.uk.
authors.forename: J Kevin
authors.initials: JK
authors.lastname: Baird
mesh_terms: D000328:Adult; D000962:Antimalarials / Q000008:administration & dosage* / Q000009:adverse effects; D037621:Artemisinins / Q000008:administration & dosage* / Q000009:adverse effects; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007214:Indonesia; D016780:Malaria, Vivax / Q000188:drug therapy*; D008297:Male; D008889:Military Personnel; D010966:Plasmodium vivax; D011319:Primaquine / Q000008:administration & dosage* / Q000009:adverse effects; D012008:Recurrence
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D011319:Primaquine