Jenny G Low1, Cynthia Sung1, Limin Wijaya2, Yuan Wei3, Abhay P S Rathore1, Satoru Watanabe1, Boon Hian Tan1, Liying Toh1, Lian Tee Chua1, Yan'an Hou1, Angelia Chow1, Shiqin Howe1, Wing Ki Chan1, Kah Hin Tan1, Jasmine S Chung2, Benjamin P Cherng2, David C Lye4, Paul A Tambayah5, Lee Ching Ng6, John Connolly7, Martin L Hibberd8, Yee Sin Leo4, Yin Bun Cheung9, Eng Eong Ooi1, Subhash G Vasudevan10. 1. Program in Emerging Infectious Diseases, Duke-NUS Graduate Medical School, Singapore, Singapore. 2. Department of Infectious Diseases, Singapore General Hospital, Singapore, Singapore. 3. Singapore Clinical Research Institute, Singapore, Singapore. 4. Communicable Disease Centre, Tan Tock Seng Hospital, Singapore, Singapore. 5. National University Hospital of Singapore, Singapore, Singapore. 6. Environmental Health Institute, National Environment Agency, Singapore, Singapore. 7. Program in Translational Immunology, Singapore Immunology Network, Singapore, Singapore. 8. Genome Institute of Singapore, Singapore, Singapore. 9. Center for Quantitative Medicine, Duke-NUS Graduate Medical School, Singapore, Singapore; Department of International Health, University of Tampere, Tampere, Finland. 10. Program in Emerging Infectious Diseases, Duke-NUS Graduate Medical School, Singapore, Singapore. Electronic address: subhash.vasudevan@duke-nus.edu.sg.
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. FINDINGS: We screened 69 patients and randomly assigned 50 (24 to celgosivir, 26 toplacebo). 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.
RCT Entities:
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. 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.
Authors: Hongjie Xia; Xuping Xie; Jing Zou; Christian G Noble; William K Russell; Luis Marcelo F Holthauzen; Kyung H Choi; Mark A White; Pei-Yong Shi Journal: Proc Natl Acad Sci U S A Date: 2020-07-15 Impact factor: 11.205