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Efficacy and safety of celgosivir in patients with dengue fever (CELADEN): a phase 1b, randomised, double-blind, placebo-controlled, proof-of-concept trial.

AbstractBACKGROUND:
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.
FINDINGS:
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.
INTERPRETATION:
Although generally safe and well tolerated, celgosivir does not seem to reduce viral load or fever burden in patients with dengue.
FUNDING:
STOP Dengue Translational Clinical Research.
AuthorsJenny G Low, Cynthia Sung, Limin Wijaya, Yuan Wei, Abhay P S Rathore, Satoru Watanabe, Boon Hian Tan, Liying Toh, Lian Tee Chua, Yan'an Hou, Angelia Chow, Shiqin Howe, Wing Ki Chan, Kah Hin Tan, Jasmine S Chung, Benjamin P Cherng, David C Lye, Paul A Tambayah, Lee Ching Ng, John Connolly, Martin L Hibberd, Yee Sin Leo, Yin Bun Cheung, Eng Eong Ooi, Subhash G Vasudevan
JournalThe Lancet. Infectious diseases (Lancet Infect Dis) Vol. 14 Issue 8 Pg. 706-715 (Aug 2014) ISSN: 1474-4457 [Electronic] United States
PMID24877997 (Publication Type: Clinical Trial, Phase I, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2014 Elsevier Ltd. All rights reserved.
Chemical References
  • Antiviral Agents
  • Indolizines
  • Placebos
  • celgosivir
Topics
  • Adult
  • Aged
  • Antiviral Agents (adverse effects, therapeutic use)
  • Dengue (drug therapy)
  • Double-Blind Method
  • Drug-Related Side Effects and Adverse Reactions (epidemiology, pathology)
  • Female
  • Fever
  • Humans
  • Indolizines (adverse effects, therapeutic use)
  • Male
  • Middle Aged
  • Placebos (administration & dosage)
  • Singapore
  • Treatment Outcome
  • Viral Load
  • Young Adult

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