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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

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Summary

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.

Introduction

Dengue infection is the most common mosquito-borne viral disease worldwide. In 2013, Bhatt and colleagues1 estimated that 390 million infections occur per year, with 96 million becoming symptomatic, and that 70% of cases occur in Asia. The number of infections is expected to rise with rapid urbanisation, international travel, and global warming.2 Infection with any one of the four antigenically distinct dengue virus serotypes (DENV1–4) leads to a range of problems, from self-limiting febrile illness to life-threatening severe dengue, which encompasses hypovolaemic shock from vascular leakage, internal haemorrhage, and organ dysfunction. Mild dengue is debilitating and contributes to substantial morbidity and loss of economic productivity.2, 3, 4, 5, 6, 7, 8

No antiviral drugs against dengue are available. The lifecycle of the virus offers many targets for drug development and much focus has been placed on the multifunctional enzyme NS3 (necessary for viral polyprotein processing) and NS5 (necessary for RNA replication).9, 10, 11, 12, 13, 14, 15 Clinical trials of chloroquine16 (a potential inhibitor of dengue virus entry into host cells) and balapiravir17 (a nucleoside inhibitor) did not show any efficacy. Vaccine development has also been challenging: the most advanced tetravalent dengue vaccine candidate has only 30% efficacy,18 and researchers have called for new approaches to vaccine development.19 Effective interventions that either reduce risk of severe dengue or halt transmission are urgently needed.

Celgosivir (or Bu-Cast) is a 6-O butanoyl prodrug of castanospermine, a naturally occurring iminosugar derived from the seeds of Castanospermum australe.20 It exerts antiviral activity by inhibiting the endoplasmic-reticulum-resident α-glucosidase I enzyme that, together with α-glucosidase II, is needed for the trimming of three terminal glucose residues attached to N-glycans of newly synthesised glycoproteins.21 Iminosugars, such as castanospermine and N-butyl deoxynojiramycin, can exert broad antiviral properties by interfering with virus morphogenesis through misfolding of glycosylated proteins, including those encoded by the dengue virus genome, such as E, prM, and NS1.21, 22, 23 In-vitro dengue infection assays have shown that celgosivir inhibits all four serotypes of the virus at submicromolar concentrations.23 In the case of DENV2, NS1 misfolds and accumulates in the endoplasmic reticulum of infected cells. A dose-dependent reduction of luciferase reporter activity in celgosivir-treated DENV2 replicon cells suggests that NS1 is necessary for viral RNA replication.23 In vivo, celgosivir has activity in mice even when treatment is delayed for 48 h after infection.23, 24, 25 A study25 has shown that the drug's effectiveness is dependent on dosing frequency—50 mg/kg twice daily yielded 100% survival in an otherwise lethal dengue infection model, but 100 mg/kg once a day conferred no protection.

Celgosivir has been tested in phase 1 and 2 trials as a possible treatment for infection with HIV and infection with hepatitis C virus,20, 26 which, like dengue, is a flavivirius. However, its efficacy was not superior to that of existing treatments, so testing was not continued. Nevertheless, no cardiovascular or neurological complications were reported; adverse events were typically osmotic diarrhoea and flatulence, as for acarbose—an approved α-glucosidase inhibitor used for treatment of type 2 diabetes.20 Unlike antiviral drug treatment of hepatitis C and HIV infections—chronic diseases that require long-term regimens of months to years—an acute disease like dengue would only need a short course. We aimed to assess the activity and safety of celgosivir as treatment for acute dengue.

Section snippets

Study design and participants

CELADEN was a phase 1b, randomised, double-blind, placebo-controlled, proof-of-concept trial done in one centre in Singapore, where dengue is endemic. Between July 30, 2012, and March 4, 2013, patients were referred for screening at the SingHealth Investigational Medicine Unit at Singapore General Hospital, Singapore, from private and public primary-care clinics and collaborating hospitals in Singapore. Patients aged 21–65 years were referred when they had had a fever (≥38°C) for less than 48

Results

69 patients were screened and 50 were randomly assigned to receive placebo or celgosivir (figure 1). One patient was inadvertently given two randomisation codes, and the second code was used. One patient in the placebo group was lost to follow-up on day 7 (patient 042; no samples from day 4 onwards). Except for one participant in the placebo group, all patients completed at least 80% of their schedule of doses.

The demographic and clinical characteristics (table 1) and baseline laboratory

Discussion

Celgosivir does not significantly reduce viral load or fever burden in patients with dengue (panel). The drug is generally safe and well tolerated. The adverse events reported were typical of dengue infection37, 41 or known side-effects of celgosivir.20 Despite the increased number of patients with mild-to-moderate diarrhoea in the celgosivir group, no severe cases of diarrhoea were reported.

Previous antiviral clinical trials in dengue16, 17 have shown large variation in viraemia and viraemia

References (45)

  • S Bhatt et al.

    The global distribution and burden of dengue

    Nature

    (2013)
  • V Racloz et al.

    Surveillance of dengue fever virus: a review of epidemiological models and early warning systems

    PLoS Negl Trop Dis

    (2012)
  • CP Simmons et al.

    Dengue

    N Engl J Med

    (2012)
  • DJ Gubler

    Dengue/dengue haemorrhagic fever: history and current status

    Novartis Found Symp

    (2006)
  • SB Halstead

    Antibodies determine virulence in dengue

    Ann N Y Acad Sci

    (2009)
  • A Wilder-Smith et al.

    Update on dengue: epidemiology, virus evolution, antiviral drugs, and vaccine development

    Curr Infect Dis Rep

    (2010)
  • MG Guzman et al.

    Dengue: a continuing global threat

    Nat Rev Microbiol

    (2010)
  • JA Suaya et al.

    Cost of dengue cases in eight countries in the Americas and Asia: a prospective study

    Am J Trop Med Hyg

    (2009)
  • TH Keller et al.

    Finding new medicines for flaviviral targets

    Novartis Found Symp

    (2006)
  • C Botting et al.

    Novel approaches to flavivirus drug discovery

    Expert Opin Drug Discov

    (2011)
  • OM Sessions et al.

    Discovery of insect and human dengue virus host factors

    Nature

    (2009)
  • J Fink et al.

    Host gene expression profiling of dengue virus infection in cell lines and patients

    PLoS Negl Trop Dis

    (2007)
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