title: DSM265 for Plasmodium falciparum chemoprophylaxis: a randomised, double blinded, phase 1 trial with controlled human malaria infection.
abstract: A drug for causal (ie, pre-erythrocytic) prophylaxis of Plasmodium falciparum malaria with prolonged activity would substantially advance malaria control. DSM265 is an experimental antimalarial that selectively inhibits the parasite dihydroorotate dehydrogenase. DSM265 shows in vitro activity against liver and blood stages of P falciparum. We assessed the prophylactic activity of DSM265 against controlled human malaria infection (CHMI).
  
  
  
  At the Institute of Tropical Medicine, Eberhard Karls University (Tübingen, Germany), healthy, malaria-naive adults were allocated to receive 400 mg DSM265 or placebo either 1 day (cohort 1A) or 7 days (cohort 2) before CHMI by direct venous inoculation (DVI) of 3200 aseptic, purified, cryopreserved P falciparum sporozoites (PfSPZ Challenge; Sanaria Inc, Rockville, MD, USA). An additional group received daily atovaquone-proguanil (250-100 mg) for 9 days, starting 1 day before CHMI (cohort 1B). Allocation to DSM265, atovaquone-proguanil, or placebo was randomised by an interactive web response system. Allocation to cohort 1A and 1B was open-label, within cohorts 1A and 2, allocation to DSM265 and placebo was double-blinded. All treatments were given orally. Volunteers were treated with an antimalarial on day 28, or when parasitaemic, as detected by thick blood smear (TBS) microscopy. The primary efficacy endpoint was time-to-parasitaemia, assessed by TBS. All participants receiving at least one dose of chemoprophylaxis or placebo were considered for safety, those receiving PfSPZ Challenge for efficacy analyses. Log-rank test was used to compare time-to-parasitemia between interventions. The trial was registered with ClinicalTrials.gov, number NCT02450578.
  
  
  
  22 participants were enrolled between Oct 23, 2015, and Jan 18, 2016. Five participants received 400 mg DSM265 and two participants received placebo 1 day before CHMI (cohort 1A), six participants received daily atovaquone-proguanil 1 day before CHMI (cohort 1B), and six participants received 400 mg DSM265 and two participants received placebo 7 days before CHMI (cohort 2). Five of five participants receiving DSM265 1 day before CHMI and six of six in the atovaquone-proguanil cohort were protected, whereas placebo recipients (two of two) developed malaria on days 11 and 14. When given 7 days before CHMI, three of six volunteers receiving DSM265 became TBS positive on days 11, 13, and 24. The remaining three DSM265-treated, TBS-negative participants of cohort 2 developed transient submicroscopic parasitaemia. Both participants receiving placebo 7 days before CHMI became TBS positive on day 11. The only possible DSM265-related adverse event was a moderate transient elevation in serum bilirubin in one participant.
  
  
  
  A single dose of 400 mg DSM265 was well tolerated and had causal prophylactic activity when given 1 day before CHMI. Future trials are needed to investigate further the use of DSM265 for the prophylaxis of malaria.
  
  
  
  Global Health Innovative Technology Fund, Wellcome Trust, Bill & Melinda Gates Foundation through Medicines for Malaria Venture, and the German Center for Infection Research.
authors.affiliation: Institute of Tropical Medicine, and German Center for Infection Research, partner site Tübingen, Eberhard Karls University, Tübingen, Germany. Electronic address: mihaly.sulyok@klinikum.uni-tuebingen.de.
authors.forename: Mihály
authors.initials: M
authors.lastname: Sulyok
authors.affiliation: Medicines for Malaria Venture, Geneva, Switzerland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Rückle
authors.affiliation: Institute of Tropical Medicine, and German Center for Infection Research, partner site Tübingen, Eberhard Karls University, Tübingen, Germany.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Roth
authors.affiliation: Institute of Tropical Medicine, and German Center for Infection Research, partner site Tübingen, Eberhard Karls University, Tübingen, Germany.
authors.forename: Raymund E
authors.initials: RE
authors.lastname: Mürbeth
authors.affiliation: Medicines for Malaria Venture, Geneva, Switzerland.
authors.forename: Stephan
authors.initials: S
authors.lastname: Chalon
authors.affiliation: Medicines for Malaria Venture, Geneva, Switzerland.
authors.forename: Nicola
authors.initials: N
authors.lastname: Kerr
authors.affiliation: Medicines for Malaria Venture, Geneva, Switzerland.
authors.forename: Sonia Schnieper
authors.initials: SS
authors.lastname: Samec
authors.affiliation: Medicines for Malaria Venture, Geneva, Switzerland.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Gobeau
authors.affiliation: Institute of Tropical Medicine, and German Center for Infection Research, partner site Tübingen, Eberhard Karls University, Tübingen, Germany.
authors.forename: Carlos Lamsfus
authors.initials: CL
authors.lastname: Calle
authors.affiliation: Institute of Tropical Medicine, and German Center for Infection Research, partner site Tübingen, Eberhard Karls University, Tübingen, Germany.
authors.forename: Javier
authors.initials: J
authors.lastname: Ibáñez
authors.affiliation: Institute of Tropical Medicine, and German Center for Infection Research, partner site Tübingen, Eberhard Karls University, Tübingen, Germany.
authors.forename: Zita
authors.initials: Z
authors.lastname: Sulyok
authors.affiliation: Institute of Tropical Medicine, and German Center for Infection Research, partner site Tübingen, Eberhard Karls University, Tübingen, Germany.
authors.forename: Jana
authors.initials: J
authors.lastname: Held
authors.affiliation: Institute of Tropical Medicine, and German Center for Infection Research, partner site Tübingen, Eberhard Karls University, Tübingen, Germany.
authors.forename: Tamirat
authors.initials: T
authors.lastname: Gebru
authors.affiliation: Institute of Tropical Medicine, and German Center for Infection Research, partner site Tübingen, Eberhard Karls University, Tübingen, Germany.
authors.forename: Patricia
authors.initials: P
authors.lastname: Granados
authors.affiliation: Institute of Tropical Medicine, and German Center for Infection Research, partner site Tübingen, Eberhard Karls University, Tübingen, Germany.
authors.forename: Sina
authors.initials: S
authors.lastname: Brückner
authors.affiliation: Institute of Tropical Medicine, and German Center for Infection Research, partner site Tübingen, Eberhard Karls University, Tübingen, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Nguetse
authors.affiliation: Institute of Tropical Medicine, and German Center for Infection Research, partner site Tübingen, Eberhard Karls University, Tübingen, Germany.
authors.forename: Juliana
authors.initials: J
authors.lastname: Mengue
authors.affiliation: Institute of Tropical Medicine, and German Center for Infection Research, partner site Tübingen, Eberhard Karls University, Tübingen, Germany.
authors.forename: Albert
authors.initials: A
authors.lastname: Lalremruata
authors.affiliation: Sanaria Inc, Rockville, MD, USA.
authors.forename: B Kim Lee
authors.initials: BKL
authors.lastname: Sim
authors.affiliation: Sanaria Inc, Rockville, MD, USA.
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Hoffman
authors.affiliation: Medicines for Malaria Venture, Geneva, Switzerland.
authors.forename: Jörg J
authors.initials: JJ
authors.lastname: Möhrle
authors.affiliation: Institute of Tropical Medicine, and German Center for Infection Research, partner site Tübingen, Eberhard Karls University, Tübingen, Germany.
authors.forename: Peter G
authors.initials: PG
authors.lastname: Kremsner
authors.affiliation: Institute of Tropical Medicine, and German Center for Infection Research, partner site Tübingen, Eberhard Karls University, Tübingen, Germany.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Mordmüller
mesh_terms: D061605:Administration, Intravenous; D000293:Adolescent; D000328:Adult; D000962:Antimalarials / Q000008:administration & dosage* / Q000627:therapeutic use; D018890:Chemoprevention; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000276:immunology / Q000469:parasitology; D008297:Male; D008875:Middle Aged; D018512:Parasitemia / Q000276:immunology / Q000469:parasitology; D010963:Plasmodium falciparum / Q000276:immunology*; D011743:Pyrimidines / Q000008:administration & dosage* / Q000627:therapeutic use; D034101:Sporozoites / Q000276:immunology; D014230:Triazoles / Q000008:administration & dosage* / Q000627:therapeutic use; D014838:Volunteers
chemical_list: D000962:Antimalarials; D011743:Pyrimidines; D014230:Triazoles; C000606979:DSM265