Ciprofloxacin Versus an Aminoglycoside Followed by Ciprofloxacin for Bubonic Plague

NCT04110340 | Completed Phase 3 DMC

• 1 other identifier: 45-18
• Study Type: interventional
• Target: 222
• Locations: 1 country
• Sites: 1

Brief Summary

The primary objective of this trial is to test the hypothesis that ciprofloxacin monotherapy given (orally, intravenously, or combination) for 10 days is non-inferior to an aminoglycoside (given on days 1-3) followed by ciprofloxacin (given on days 4-10) in the treatment of bubonic plague. Secondary objectives are: \- to evaluate the level and kinetics of anti-Y. pestis antibodies of patients (bubonic and pneumonic plague) included in the study (anti-F1 ELISA techniques) at D1, D11, D21, M3 for patients who are positive at D21, and M12 for patients who are positive at M3. The tertiary objectives are: \- to evaluate the level and kinetics of the levels of anti-Y. pestis antibodies and circulating F1 antigen of the patients (bubonic and pneumonic plague) included in the study (Luminex MagPix techniques with a Multiplex containing anti-F1 and rLcrV antigens and an F1 antigen capture multiplex) at D1, D11, D21, M3 for patients positive at D21, and M12 for patients who are positive at M3. Observational non-comparative study of pneumonic plague

• The primary objective is to document the efficacy and safety of the currently recommended combination therapy treatment of pneumonic plague - an aminoglycoside (streptomycin or gentamicin) and ciprofloxacin combination therapy.
• The secondary and tertiary objectives of the bubonic plague trial also apply to the pneumonic plague cohort.

Conditions

Plague, Bubonic; Plague, Pneumonic

Outcome Measures

Primary Outcomes (1)

• Proportion of patients with bubonic plague with a therapeutic response (assessed on day 11).Therapeutic response is defined as follows for subjects with a visible bubo:

  * Alive * Absence of fever * Has not received alternative treatment for plague * No clinical decision to continue anti-plague antibiotics beyond day 10

  11 days

Secondary Outcomes (17)

• Bubonic plague

  4 days

• Bubonic plague

  4 days

• Bubonic plague

  11 days

• Bubonic plague

  4 days

• Bubonic plague

  11 days

Study Arms (2)

Ciprofloxacin Arm

ACTIVE COMPARATOR

Adults: Ciprofloxacin 500mg orally twice daily (or 400mg IV twice daily for those who cannot take oral medication) for 10 days; Children:Ciprofloxacin 15mg/kg twice daily (max 500mg per dose) orally (or 10mg/kg IV twice daily for those who cannot take oral - maximum dose 400mg) for 10 days.

Drug: Ciprofloxacin

Control arm

OTHER

Adults: streptomycin 1g twice daily for three days, followed by ciprofloxacin 500mg orally twice daily (or ciprofloxacin 400mg twice daily by IV for those who cannot take it orally) for an additional 7 days. OR 2.5mg/kg IV gentamicin twice daily for 3 days followed by ciprofloxacin 500 mg orally twice daily (or ciprofloxacin 400 mg twice daily IV for those who cannot take oral) for a further 7 days. Children: streptomycin 15mg/kg twice daily for three days followed by ciprofloxacin 15mg/kg twice daily (max 500mg per dose) orally (or 10mg/kg IV twice daily for those who cannot take oral - maximum dose 400mg) for 7 additional days. OR 2.5mg/kg IV gentamicin twice daily for 3 days, followed by ciprofloxacin 15mg/kg (max 500mg per dose) orally (or 10mg/kg IV twice daily for those who cannot take the oral route) for a further 7 days.

Drug: Ciprofloxacin; Drug: Streptomycin; Drug: Gentamicin

Interventions

Ciprofloxacin DRUG

Adults: Ciprofloxacin 500mg orally twice daily (or 400mg IV twice daily for those who cannot take oral medication) for 10 days; Children:Ciprofloxacin 15mg/kg twice daily (max 500mg per dose) orally (or 10mg/kg IV twice daily for those who cannot take oral - maximum dose 400mg) for 10 days. Patients who begin intravenous therapy may switch to oral administration once they are able to swallow or once deemed clinically appropriate by the treating physician.

Ciprofloxacin Arm; Control arm

Streptomycin DRUG

Adults: streptomycin 1g twice daily for three days, followed by ciprofloxacin 500mg orally twice daily (or ciprofloxacin 400mg twice daily by IV for those unable to take orally) for an additional 7 days. Children: streptomycin 15mg/kg twice daily for three days followed by ciprofloxacin 15mg/kg twice daily (max 500mg per dose) orally (or 10mg/kg IV twice daily for those who cannot take oral - maximum dose 400mg) for 7 additional days. Patients who begin intravenous therapy may switch to oral administration once they are able to swallow or once deemed clinically appropriate by the treating physician.

Control arm

Gentamicin DRUG

Adults: 2.5mg/kg IV gentamicin twice daily for 3 days followed by ciprofloxacin 500 mg orally twice daily (or ciprofloxacin 400 mg twice daily IV for those who cannot take oral) for a further 7 days. Children: 2.5mg/kg IV gentamicin twice daily for 3 days, followed by ciprofloxacin 15mg/kg (max 500mg per dose) orally (or 10mg/kg IV twice daily for those who cannot take the oral route) for a further 7 days.

Control arm

Eligibility Criteria

• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Bubonic plague
• Patients of any age AND
• Recent onset (\< 10 days) of fever (uncorrected axillary temperature ≥ 37.5C) or history of fever AND
• One or more buboes (tender lymph node swelling) AND
• Residence or travel to a plague endemic area in Madagascar within 14 days of the onset of symptoms AND
• Patients identified as clinically suspected of plague by health personnel (doctors or paramedics)

You may not qualify if:

• Known allergy to aminoglycosides or fluoroquinolones
• Tendinitis
• Myasthenia gravis
• Theophylline or warfarin use
• Already treated for bubonic or pneumonic plague in the preceeding 3 months
• Women who report being pregnant
• Suspected, probable and confirmed cases of pneumonic plague

Sponsors & Collaborators

• University of Oxford: lead
• Hôpital Universitaire Joseph Raseta Befelatanana CHU d'Antananarivo: collaborator
• Institut Pasteur de Madagascar: collaborator
• Foreign, Commonwealth and Development Office and Wellcome (216273.Z.19.Z): collaborator

Study Sites (1)

Professor Mamy Randria

Antananarivo, Madagascar

Location

Related Publications (3)

• Randremanana RV, Raberahona M, Bourner J, Rajerison M, Edwards T, Randriamparany R, Fehizoro Razafindratsinana T, Razananaivo LH, Zadonirina G, Mayouya-Gamana T, Salam APA, Mangahasimbola RT, Andrianaivoarimanana V, Pesonel E, Rakotoarivelo RA, Randria MJD, Horby P, Olliaro P; IMASOY Study Group. Ciprofloxacin versus Aminoglycoside-Ciprofloxacin for Bubonic Plague. N Engl J Med. 2025 Aug 7;393(6):544-555. doi: 10.1056/NEJMoa2413772.

  PMID: 40768716 DERIVED

• Randremanana RV, Raberahona M, de Dieu Randria MJ, Bourner J, Zadonirina G, Razananaivo H, Mayouya-Gamana T, Mangahasimbola R, Pesonel E, Gillesen A, Rajerison M, Andrianaivoarimanana V, Edwards T, Horby P, Olliaro P. An open-label, randomized, non-inferiority trial of the efficacy and safety of ciprofloxacin versus an aminoglycoside + ciprofloxacin in the treatment of bubonic plague (IMASOY): study protocol for a randomized control trial-an update to the published protocol. Trials. 2024 Jul 5;25(1):457. doi: 10.1186/s13063-024-08302-7.

  PMID: 38970065 DERIVED

• Randremanana RV, Raberahona M, Randria MJD, Rajerison M, Andrianaivoarimanana V, Legrand A, Rasoanaivo TF, Randriamparany R, Mayouya-Gamana T, Mangahasimbola R, Bourner J, Salam A, Gillesen A, Edwards T, Schoenhals M, Baril L, Horby P, Olliaro P. 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. Trials. 2020 Aug 17;21(1):722. doi: 10.1186/s13063-020-04642-2.

  PMID: 32807214 DERIVED

MeSH Terms

Conditions

Plague

Interventions

Ciprofloxacin; Streptomycin; Gentamicins

Condition Hierarchy (Ancestors)

Yersinia Infections; Enterobacteriaceae Infections; Gram-Negative Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections; Vector Borne Diseases

Intervention Hierarchy (Ancestors)

Fluoroquinolones; 4-Quinolones; Quinolones; Quinolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Aminoglycosides; Glycosides; Carbohydrates

Study Officials

• Peter W Horby, MD

  University of Oxford

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: An open label, randomised, non-inferiority trial of the efficacy and safety of ciprofloxacin versus an aminoglycoside + ciprofloxacin in treatment of bubonic plague. We are using a non-inferiority design since the overall cure rate for bubonic plague without septicaemia with streptomycin is approximately 95%. As a result, demonstrating superiority would be unnecessary and impractical given the sample size that would be required. Our aim is therefore to demonstrate that ciprofloxacin alone is not more than 15% inferior to an aminoglycoside followed by ciprofloxacin.

Study Record Dates

• First Submitted: January 28, 2019
• First Posted: October 1, 2019
• Study Start: February 15, 2020
• Primary Completion: April 30, 2024
• Study Completion: February 5, 2025
• Last Updated: March 6, 2025

Record last verified: 2025-02

Data Sharing

• IPD Sharing: Will share
• Time Frame: Anticipated release date: May 2025
• Access Criteria: To be confirmed

Locations

MA (1)