title: Efficacy and safety of celgosivir in patients with dengue fever (CELADEN): a phase 1b, randomised, double-blind, placebo-controlled, proof-of-concept trial.
abstract: BACKGROUND
  Dengue infection is the most common mosquito-borne viral disease worldwide, but no suitable antiviral drugs are available. We tested the α-glucosidase inhibitor celgosivir as a treatment for acute dengue fever.
  
  
  METHODS
  To establish eligibility for inclusion in a phase 1b, randomised, double-blind, placebo-controlled, proof-of-concept trial, individuals aged 21-65 years who had had a fever (≥38°C) for less than 48 h, met at least two criteria indicating probable dengue infection, and had a positive result on a dengue point-of-care test kit or PCR assay were referred for screening at a centre in Singapore between July 30, 2012, and March 4, 2013. Using a web-based system, we randomly assigned patients who met full inclusion criteria after screening (1:1; random permuted block length four) to celgosivir (initial 400 mg loading dose within 6 h of randomisation, followed by 200 mg every 12 h for a total of nine doses) or matched placebo. Patients and the entire study team were masked to group assignment. The primary endpoints were mean virological log reduction (VLR) from baseline for days 2, 3, and 4, and area under the fever curve (AUC) for a temperature above 37°C from 0 h to 96 h. Efficacy analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01619969.
  
  
  RESULTS
  We screened 69 patients and randomly assigned 50 (24 to celgosivir, 26 to placebo). Mean VLR was greater in the celgosivir group (-1·86, SD 1·07) than in the placebo group (-1·64, 0·75), but the difference was non-significant (-0·22, 90% CI -0·65 to 0·22; one-sided p=0·203). The mean AUC was also higher in the celgosivir group (54·92, SD 31·04) than in the placebo group (40·72, 18·69), but again the difference was non-significant (14·20, 90% CI 2·16-26·25; one-sided p=0·973). We noted similar incidences of adverse events between groups.
  
  
  CONCLUSIONS
  Although generally safe and well tolerated, celgosivir does not seem to reduce viral load or fever burden in patients with dengue.
  
  
  BACKGROUND
  STOP Dengue Translational Clinical Research.
authors.affiliation: Program in Emerging Infectious Diseases, Duke-NUS Graduate Medical School, Singapore, Singapore.
authors.forename: Jenny G
authors.initials: JG
authors.lastname: Low
authors.affiliation: Program in Emerging Infectious Diseases, Duke-NUS Graduate Medical School, Singapore, Singapore.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Sung
authors.affiliation: Department of Infectious Diseases, Singapore General Hospital, Singapore, Singapore.
authors.forename: Limin
authors.initials: L
authors.lastname: Wijaya
authors.affiliation: Singapore Clinical Research Institute, Singapore, Singapore.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Wei
authors.affiliation: Program in Emerging Infectious Diseases, Duke-NUS Graduate Medical School, Singapore, Singapore.
authors.forename: Abhay P S
authors.initials: APS
authors.lastname: Rathore
authors.affiliation: Program in Emerging Infectious Diseases, Duke-NUS Graduate Medical School, Singapore, Singapore.
authors.forename: Satoru
authors.initials: S
authors.lastname: Watanabe
authors.affiliation: Program in Emerging Infectious Diseases, Duke-NUS Graduate Medical School, Singapore, Singapore.
authors.forename: Boon Hian
authors.initials: BH
authors.lastname: Tan
authors.affiliation: Program in Emerging Infectious Diseases, Duke-NUS Graduate Medical School, Singapore, Singapore.
authors.forename: Liying
authors.initials: L
authors.lastname: Toh
authors.affiliation: Program in Emerging Infectious Diseases, Duke-NUS Graduate Medical School, Singapore, Singapore.
authors.forename: Lian Tee
authors.initials: LT
authors.lastname: Chua
authors.affiliation: Program in Emerging Infectious Diseases, Duke-NUS Graduate Medical School, Singapore, Singapore.
authors.forename: Yan'an
authors.initials: Y
authors.lastname: Hou
authors.affiliation: Program in Emerging Infectious Diseases, Duke-NUS Graduate Medical School, Singapore, Singapore.
authors.forename: Angelia
authors.initials: A
authors.lastname: Chow
authors.affiliation: Program in Emerging Infectious Diseases, Duke-NUS Graduate Medical School, Singapore, Singapore.
authors.forename: Shiqin
authors.initials: S
authors.lastname: Howe
authors.affiliation: Program in Emerging Infectious Diseases, Duke-NUS Graduate Medical School, Singapore, Singapore.
authors.forename: Wing Ki
authors.initials: WK
authors.lastname: Chan
authors.affiliation: Program in Emerging Infectious Diseases, Duke-NUS Graduate Medical School, Singapore, Singapore.
authors.forename: Kah Hin
authors.initials: KH
authors.lastname: Tan
authors.affiliation: Department of Infectious Diseases, Singapore General Hospital, Singapore, Singapore.
authors.forename: Jasmine S
authors.initials: JS
authors.lastname: Chung
authors.affiliation: Department of Infectious Diseases, Singapore General Hospital, Singapore, Singapore.
authors.forename: Benjamin P
authors.initials: BP
authors.lastname: Cherng
authors.affiliation: Communicable Disease Centre, Tan Tock Seng Hospital, Singapore, Singapore.
authors.forename: David C
authors.initials: DC
authors.lastname: Lye
authors.affiliation: National University Hospital of Singapore, Singapore, Singapore.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Tambayah
authors.affiliation: Environmental Health Institute, National Environment Agency, Singapore, Singapore.
authors.forename: Lee Ching
authors.initials: LC
authors.lastname: Ng
authors.affiliation: Program in Translational Immunology, Singapore Immunology Network, Singapore, Singapore.
authors.forename: John
authors.initials: J
authors.lastname: Connolly
authors.affiliation: Genome Institute of Singapore, Singapore, Singapore.
authors.forename: Martin L
authors.initials: ML
authors.lastname: Hibberd
authors.affiliation: Communicable Disease Centre, Tan Tock Seng Hospital, Singapore, Singapore.
authors.forename: Yee Sin
authors.initials: YS
authors.lastname: Leo
authors.affiliation: Center for Quantitative Medicine, Duke-NUS Graduate Medical School, Singapore, Singapore; Department of International Health, University of Tampere, Tampere, Finland.
authors.forename: Yin Bun
authors.initials: YB
authors.lastname: Cheung
authors.affiliation: Program in Emerging Infectious Diseases, Duke-NUS Graduate Medical School, Singapore, Singapore.
authors.forename: Eng Eong
authors.initials: EE
authors.lastname: Ooi
authors.affiliation: Program in Emerging Infectious Diseases, Duke-NUS Graduate Medical School, Singapore, Singapore. Electronic address: subhash.vasudevan@duke-nus.edu.sg.
authors.forename: Subhash G
authors.initials: SG
authors.lastname: Vasudevan
mesh_terms: D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000009:adverse effects* / Q000627:therapeutic use*; D003715:Dengue / Q000188:drug therapy*; D004311:Double-Blind Method; D064420:Drug-Related Side Effects and Adverse Reactions / Q000453:epidemiology / Q000473:pathology; D005260:Female; D005334:Fever; D006801:Humans; D007212:Indolizines / Q000009:adverse effects* / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D010919:Placebos / Q000008:administration & dosage; D012846:Singapore; D016896:Treatment Outcome; D019562:Viral Load; D055815:Young Adult; D054836:Indolizidines
chemical_list: D000998:Antiviral Agents; D007212:Indolizines; D010919:Placebos; C070715:celgosivir; D054836:Indolizidines