Clinical trial NCT04110340: Ciprofloxacin Versus an Aminoglycoside Followed by Ciprofloxacin for Bubonic Plague
Official title: An Open-label, Randomised, Non-inferiority Trial of the Efficacy and Safety of Ciprofloxacin Versus an Aminoglycoside Followed by Ciprofloxacin in the Treatment of Bubonic Plague
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Plague, Bubonic
Plague, Pneumonic
Lead sponsor: University of Oxford
Sponsor class: OTHER
Collaborators: name: Hôpital Universitaire Joseph Raseta Befelatanana CHU d'Antananarivo
name: Institut Pasteur de Madagascar
name: Foreign, Commonwealth and Development Office and Wellcome (216273.Z.19.Z)
First posted: 2019-10-01
Enrollment: 222
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: PARALLEL
Intervention model description: 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.
Primary purpose: TREATMENT

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.

Detailed description: An individually randomised, open label, non-inferiority trial of ciprofloxacin versus an aminoglycoside and ciprofloxacin in patients with 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. (15% is the non-inferiority margin in our study). We will recruit patients with a clinical suspicion of bubonic plague, but the size of our sample is powered based on an intention to treat infected patients sample size of 190, where infected is defined as a confirmed or probable case of bubonic plague. As a result the total number of patients to be enrolled will be higher than 190. We estimate that we will need to recruit approximately 600 patients with bubonic plague to achieve a sample size of 190 confirmed/probable bubonic plague patients. However, to mitigate risks of being under-powered we will propose to recruit for three full seasons with a minimum target of 190 confirmed/probable cases. Should we achieve the target of 190 confirmed/probable bubonic plague cases before the end of the final transmission season, we will nevertheless continue to recruit until the end of the season to retain power in the event of different treatment success percentages and to allow us to increase precision.

We will also recruit and collect data on patients with pneumonic plague, who will be enrolled in to a parallel observational cohort.

Eligibility criteria: Inclusion Criteria for randomisation to the bubonic plague treatment trial:

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)

Exclusion Criteria to the bubonic plague treatment trial:

* 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

Inclusion of patients to the pneumonic plague observational cohort:

• Suspected, probable and confirmed cases of pneumonic plague

Primary outcomes:
measure: 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:
timeFrame: 11 days
Secondary outcomes:
measure: Bubonic plague
timeFrame: 4 days
measure: Bubonic plague
timeFrame: 4 days
measure: Bubonic plague
timeFrame: 11 days
measure: Bubonic plague
timeFrame: 4 days
measure: Bubonic plague
timeFrame: 11 days
measure: Bubonic plague
timeFrame: 4 days
measure: Bubonic plague
timeFrame: 11 days
measure: Bubonic plague
timeFrame: 21 days
measure: Bubonic plague
timeFrame: 21 days
measure: Pneumonic plague
timeFrame: 11 days
measure: Pneumonic plague
timeFrame: 4 days
measure: Pneumonic plague
timeFrame: 4 days
measure: Pneumonic plague
timeFrame: 4 days
measure: Pneumonic plague
timeFrame: 11 days
measure: Pneumonic plague
timeFrame: 21 days
measure: Pneumonic plague
timeFrame: 21 days
measure: Therapeutic response is defined as follows for subjects with a visible bubo:
timeFrame: 11 days
Other outcomes:
Locations:
city: Antananarivo
country: Madagascar
facility: Professor Mamy Randria
Study officials:
affiliation: University of Oxford
name: Peter W Horby, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.