An open-label, randomized, non-inferiority trial of the efficacy and safety of ciprofloxacin versus streptomycin + ciprofloxacin in the treatment of bubonic plague (IMASOY): study protocol for a randomized control trial

Rindra Vatosoa Randremanana, Mihaja Raberahona, Mamy Jean de Dieu Randria, Minoarisoa Rajerison, Voahangy Andrianaivoarimanana, Agathe Legrand, Tsinjo Fehizoro Rasoanaivo, Ravaka Randriamparany, Théodora Mayouya-Gamana, Reziky Mangahasimbola, Josie Bourner, Alex Salam, Annelies Gillesen, Tansy Edwards, Matthieu Schoenhals, Laurence Baril, Peter Horby, Piero Olliaro, Rindra Vatosoa Randremanana, Mihaja Raberahona, Mamy Jean de Dieu Randria, Minoarisoa Rajerison, Voahangy Andrianaivoarimanana, Agathe Legrand, Tsinjo Fehizoro Rasoanaivo, Ravaka Randriamparany, Théodora Mayouya-Gamana, Reziky Mangahasimbola, Josie Bourner, Alex Salam, Annelies Gillesen, Tansy Edwards, Matthieu Schoenhals, Laurence Baril, Peter Horby, Piero Olliaro

Abstract

Background: Bubonic plague is the primary manifestation of infection with Yersinia pestis, accounting for 90% of all plague cases and with 75% of global cases reported in Madagascar. All drugs in use for treating plague are registered based on experimental data and anecdotal evidence, and no regimen currently recommended is supported by a randomized clinical trial. The IMASOY trial intends to fill this knowledge gap by comparing two 10-day regimens included in the national guidelines in Madagascar. The primary objective of the trial is to test the hypothesis that ciprofloxacin monotherapy is non-inferior to streptomycin followed by ciprofloxacin for the treatment of bubonic plague, thus avoiding the need for injectable, potentially toxic, aminoglycosides.

Methods: A two-arm parallel-group randomized control trial will be conducted across peripheral health centres in Madagascar in five districts. Males and non-pregnant females of all ages with suspected bubonic or pneumonic plague will be recruited over the course of three plague 'seasons'. The primary endpoint of the trial is to assess the proportion of patients with bubonic plague who have a therapeutic response to treatment (defined as alive, resolution of fever, 25% reduction in the size of measurable buboes, has not received an alternative treatment and no clinical decision to continue antibiotics) as assessed on day 11.

Discussion: If successful, the trial has the potential to inform the standard of care guidelines not just in Madagascar but in other countries afflicted by plague. The trial is currently ongoing and expected to complete recruitment in 2022.

Trial registration: ClinicalTrials.gov NCT04110340 . Registered on 1 October 2019.

Keywords: Bubonic plague; Ciprofloxacin; Plague; Pneumonic plague; Streptomycin.

Figures

Fig. 1
Fig. 1
Flow chart demonstrating the participant timeline
Fig. 2
Fig. 2
Conduct of the study

References

    1. Prentice MB, Rahalison L. Plague. Lancet. 2007;369:1196–1207. doi: 10.1016/S0140-6736(07)60566-2.
    1. Bertherat E. Plague around the world in 2019. Wkly Epidemiol Rec. 2019;94:289–292.
    1. Randremanana R, et al. Epidemiological characteristics of an urban plague epidemic in Madagascar, August-November, 2017: an outbreak report. Lancet Infect Dis. 2019;19(5):537–545. doi: 10.1016/S1473-3099(18)30730-8.
    1. Choksy NH. Report on the outbreak of bubonic plague: being a report based upon observations on 939 cases of bubonic plague treated at the Municipal Hospital for Infectious Diseases at Arthur Road, Bombay, from September 24th, 1896, to February 28th, 1897. Bombay: Times of India Steam Press; 1897.
    1. Mwengee W, et al. Treatment of plague with gentamicin or doxycycline in a randomized clinical trial in Tanzania. Clin Infect Dis. 2006;42:614–621. doi: 10.1086/500137.
    1. Apangu T, et al. Successful treatment of human plague with oral ciprofloxacin. Emerg Infect Dis. 2017;23(3):553–555. doi: 10.3201/eid2303.161212.
    1. Drugs@FDA: FDA Approved Drugs. . Accessed 2 Feb 2020.
    1. World Health Organization Plague around the world in 2019. Wkly Epidemiol Rec. 2019;25:289–292.
    1. Romanov VE, Vasil’ev NT, Shabalin BA, Mironin AV. Effect of antibacterial therapy on the epidemic threat of experimental pneumonic plague in monkeys. Antibiot Khimioter. 2001;46:16–18.
    1. Romanov VE, Evstigneev VI, Vasil’ev NT, Shabalin BA, Paramonov VE. Evaluation of the effectiveness of antibacterial substances in treating an experimental form of bubonic plague in monkeys. Antibiot Khimioter. 2001;46:6–8.
    1. World Health Organization Plague around the world, 2010-2015. Wkly Epidemiol Rec. 2016;91:89–104.

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe