Prospective, randomised, parallel-group, open-label study to evaluate the effectiveness and safety of IMU-838, in combination with oseltamivir, in adults with COVID-19: the IONIC trial protocol

Kavi Sharma, Lisa Berry, Evangelos Vryonis, Asad Ali, Beatriz Lara, Angela Noufaily, Nicholas Parsons, Christopher Bradley, Becky Haley, Maria Tabuso, Ramesh P Arasaradnam, Kavi Sharma, Lisa Berry, Evangelos Vryonis, Asad Ali, Beatriz Lara, Angela Noufaily, Nicholas Parsons, Christopher Bradley, Becky Haley, Maria Tabuso, Ramesh P Arasaradnam

Abstract

Background: Globally, there is a scarcity of effective treatments for SARS-CoV-2 infections (causing COVID-19). Repurposing existing medications may offer the best hope for treating patients with COVID-19 to curb the pandemic. IMU-838 is a dihydroorotate dehydrogenase inhibitor, which is an effective mechanism for antiviral effects against respiratory viruses. When used synergistically with oseltamivir, therapeutic effects have been observed against influenza and SARS-CoV-2 in rodents. The IMU-838 and Oseltamivir in the Treatment of COVID-19 (IONIC) trial is a randomised controlled trial that will investigate whether time to clinical improvement in patients with COVID-19 is improved following a 14-day course of IMU-838+oseltamivir versus oseltamivir alone.

Methods: IONIC trial is an open-label study in which participants will be randomised 1:1 in two parallel arms: the intervention arm (IMU-838+oseltamivir) and the control arm (oseltamivir only). The primary outcome is time to clinical improvement; defined as the time from randomisation to a two-point improvement on WHO ordinal scale; discharge from hospital, or death (whichever occurs first). The study is sponsored by the University Hospitals Coventry and Warwickshire NHS Trust and funded by LifeArc.

Discussion: The IONIC protocol describes an overarching trial design to provide reliable evidence on the effectiveness of IMU-838 (vidofludimus calcium) when delivered in combination with an antiviral therapy (oseltamivir) (IONIC intervention) for confirmed or suspected COVID-19 infection in adult patients receiving usual standard of care.

Ethics and dissemination: This study has been independently reviewed and approved by Wales Research Ethics Committee. In addition, required regulatory approvals were received from Medicines and Healthcare products Regulatory Agency.

Trial registration number: EudraCT 2020-001805-21, ISRCTN53038326, NCT04516915.

Keywords: COVID-19; immunology; infectious diseases; public health.

Conflict of interest statement

Competing interests: None declared.

© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1
Figure 1
Flow of participants in trial. IONIC, IMU-838 and Oseltamivir in the Treatment of COVID-19.
Figure 2
Figure 2
Pharmacokinetic (PK) profile for 22.5 mg two times per day of IMU-838 over a 14-day treatment period.

References

    1. Li L-Q, Huang T, Wang Y-Q, et al. . COVID-19 patients' clinical characteristics, discharge rate, and fatality rate of meta-analysis. J Med Virol 2020;92:577–83. 10.1002/jmv.25757
    1. Sun P, Qie S, Liu Z, et al. . Clinical characteristics of hospitalized patients with SARS-CoV-2 infection: a single arm meta-analysis. J Med Virol 2020;92:612–7. 10.1002/jmv.25735
    1. Meyerowitz-Katz G, Merone L. A systematic review and meta-analysis of published research data on COVID-19 infection fatality rates. Int J Infect Dis 2020;101:138–48. 10.1016/j.ijid.2020.09.1464
    1. Cooper I, Mondal A, Antonopoulos CG. A Sir model assumption for the spread of COVID-19 in different communities. Chaos Solitons Fractals 2020;139:110057. 10.1016/j.chaos.2020.110057
    1. Cheung NN, Lai KK, Dai J, et al. . Broad-Spectrum inhibition of common respiratory RNA viruses by a pyrimidine synthesis inhibitor with involvement of the host antiviral response. J Gen Virol 2017;98:946–54. 10.1099/jgv.0.000758
    1. Lucas-Hourani M, Dauzonne D, Jorda P, et al. . Inhibition of pyrimidine biosynthesis pathway suppresses viral growth through innate immunity. PLoS Pathog 2013;9:e1003678. 10.1371/journal.ppat.1003678
    1. Luthra P, Naidoo J, Pietzsch CA, et al. . Inhibiting pyrimidine biosynthesis impairs Ebola virus replication through depletion of nucleoside pools and activation of innate immune responses. Antiviral Res 2018;158:288–302. 10.1016/j.antiviral.2018.08.012
    1. Xiong R, Zhang L, Li S, et al. . Novel and potent inhibitors targeting DHODH are broad-spectrum antivirals against RNA viruses including newly-emerged coronavirus SARS-CoV-2. Protein Cell 2020;11:723–39. 10.1007/s13238-020-00768-w
    1. Ding Q, Lu P, Fan Y, et al. . The clinical characteristics of pneumonia patients coinfected with 2019 novel coronavirus and influenza virus in Wuhan, China. J Med Virol 2020;92:1549–55. 10.1002/jmv.25781
    1. Khodamoradi Z, Moghadami M, Lotfi M. Co-Infection of coronavirus disease 2019 and influenza A: a report from Iran. Arch Iran Med 2020;23:239–43. 10.34172/aim.2020.04
    1. Cai Q, Yang M, Liu D, et al. . Experimental treatment with Favipiravir for COVID-19: an open-label control study. Engineering 2020;6:1192–8. 10.1016/j.eng.2020.03.007
    1. Costanzo M, De Giglio MAR, Roviello GN. SARS-CoV-2: recent reports on antiviral therapies based on Lopinavir/Ritonavir, Darunavir/Umifenovir, hydroxychloroquine, Remdesivir, Favipiravir and other drugs for the treatment of the new coronavirus. Curr Med Chem 2020;27:4536–41. 10.2174/0929867327666200416131117
    1. Lin L, Jiang X, Zhang Z, et al. . Gastrointestinal symptoms of 95 cases with SARS-CoV-2 infection. Gut 2020;69:997–1001. 10.1136/gutjnl-2020-321013
    1. Jefferson T, Jones M, Doshi P, et al. . Oseltamivir for influenza in adults and children: systematic review of clinical study reports and summary of regulatory comments. BMJ 2014;348:g2545. 10.1136/bmj.g2545
    1. Mahase E. Covid-19: What do we know about "long covid"? BMJ 2020;370:m2815. 10.1136/bmj.m2815
    1. Nasserie T, Hittle M, Goodman SN. Assessment of the frequency and variety of persistent symptoms among patients with COVID-19: a systematic review. JAMA Netw Open 2021;4:e2111417. 10.1001/jamanetworkopen.2021.11417
    1. Taquet M, Dercon Q, Luciano S, et al. . Incidence, co-occurrence, and evolution of long-COVID features: a 6-month retrospective cohort study of 273,618 survivors of COVID-19. PLoS Med 2021;18:e1003773. 10.1371/journal.pmed.1003773
    1. Poudel AN, Zhu S, Cooper N, et al. . Impact of Covid-19 on health-related quality of life of patients: a structured review. PLoS One 2021;16:e0259164. 10.1371/journal.pone.0259164
    1. Lam CLK, Tse ETY, Wong CKH, et al. . A pilot study on the validity and psychometric properties of the electronic EQ-5D-5L in routine clinical practice. Health Qual Life Outcomes 2021;19:266. 10.1186/s12955-021-01898-3
    1. Van Houwelingen H. Modelling Survival Data in Medical Research. D. Collett, Chapman & Hall, London, 1994. No of pages: XVII + 347. Price: E19.99. ISBN 0-41 2-44890-4. Stat Med 1995;14:1147–8. 10.1002/sim.4780140936

Source: PubMed

スポンサーと協力者

医学的状態

薬物療法

3
購読する