Working…
COVID-19 is an emerging, rapidly evolving situation.
Get the latest public health information from CDC: https://www.coronavirus.gov.

Get the latest research information from NIH: https://www.nih.gov/coronavirus.
ClinicalTrials.gov
ClinicalTrials.gov Menu

Ciprofloxacin Versus Streptomycin and Ciprofloxacin for Bubonic Plague (IMASOY)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04110340
Recruitment Status : Recruiting
First Posted : October 1, 2019
Last Update Posted : March 31, 2020
Sponsor:
Collaborators:
Hôpital Universitaire Joseph Raseta Befelatanana CHU d'Antananarivo
Institut Pasteur de Madagascar
Information provided by (Responsible Party):
University of Oxford

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 streptomycin (given on days 1-3) followed by ciprofloxacin (given on days 4-10) in the treatment of bubonic plague.

Secondary objectives are:

-to collect data on the effectiveness of ciprofloxacin in the treatment of pneumonic plague, although the trial is not able to formally assess the non-inferiority of ciprofloxacin monotherapy compared to streptomycin and ciprofloxacin combination therapy in pneumonic plague.

--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 and M3 for patients who are positive at D21.

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 and M3 for patients positive at D21.
  • to evaluate the extent to which qPCR is positive in the blood of confirmed patients on D1.
  • to evaluate the performance of new rapid tests that may be made available to the Plague Unit of the Institut Pasteur de Madagascar.

Condition or disease Intervention/treatment Phase
Plague, Bubonic Plague, Pneumonic Drug: Ciprofloxacin Drug: Streptomycin Phase 3

Detailed Description:

An individually randomised, open label, non-inferiority trial of ciprofloxacin versus streptomycin 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 streptomycin followed by ciprofloxacin. (15% is the non-inferiority margin in our study). The trial is powered for bubonic plague, although we will recruit pneumonic plague patients as well. 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 third 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.

Whilst we will also recruit and collect data on patients with pneumonic plague, it is highly unlikely that we will have the power to complete a non-inferiority trial for pneumonic plague patients. For example, with a case fatality rate of 20-25%, we would need a sample size of approximately 400 patients with probable/confirmed pneumonic plague for a non-inferiority margin of 15%, which is unrealistic.

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 600 participants
Allocation: Randomized
Intervention Model: Factorial Assignment
Intervention Model Description: An open label, randomised, non-inferiority trial of the efficacy and safety of ciprofloxacin versus streptomycin + 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 streptomycin followed by ciprofloxacin.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: An Open-label, Randomised, Non-inferiority Trial of the Efficacy and Safety of Ciprofloxacin Versus Streptomycin + Ciprofloxacin in the Treatment of Bubonic Plague
Actual Study Start Date : February 15, 2020
Estimated Primary Completion Date : March 31, 2021
Estimated Study Completion Date : March 31, 2021


Arm Intervention/treatment
Active Comparator: Ciprofloxacin Arm

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.

Drug: Ciprofloxacin

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.


Control arm

Control arm 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.

Control arm 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 start taking intravenous ciprofloxacin may switch to oral administration once they are able to swallow or once deemed clinically appropriate by the treating physician.

Drug: Ciprofloxacin

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.


Drug: Streptomycin

Control arm 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.

Control arm 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.





Primary Outcome Measures :
  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: [ Time Frame: 11 days ]
    • Alive
    • Resolution of fever (uncorrected axillary temperature <37.5C))
    • ≥ 25% decrease in bubo size (in the case of multiple buboes, the largest bubo) (measured by calipers and/or ultrasound)
    • Has not received alternative treatment for plague
    • No clinical decision to continue anti-plague antibiotics beyond day 10

    For patients with small buboes that are palpable but not measurable:

    • Alive
    • Absence of fever (uncorrected axillary temperature <37.5C)
    • Bubo has not enlarged (measured by use of calipers and/or ultrasound)
    • Has not received alternative treatment for plague
    • No clinical decision to continue anti-plague antibiotics beyond day 10


Secondary Outcome Measures :
  1. Bubonic plague [ Time Frame: 4 days ]
    • Proportion of patients without fever (uncorrected axillary temperature <37.5C) at Day 4

  2. Bubonic plague [ Time Frame: 4 days ]
    • Proportion of patients with a pain score < 3 at Day 4 (using pain scale questionnaires)

  3. Bubonic plague [ Time Frame: 11 days ]
    • Proportion of patients with a pain score < 3 at Day 11 (using pain scale questionnaires)

  4. Bubonic plague [ Time Frame: 4 days ]
    • Mean % change in bubo size at Day 4 (measured by use of calipers and/or ultrasound)

  5. Bubonic plague [ Time Frame: 11 days ]
    • Mean % change in bubo size at Day11 (measured by use of calipers and/or ultrasound)

  6. Bubonic plague [ Time Frame: 4 days ]
    • Proportion of patients experiencing a serious adverse event on or before Day 4

  7. Bubonic plague [ Time Frame: 11 days ]
    • Proportion of patients experiencing a serious adverse event on or before Day 11

  8. Bubonic plague [ Time Frame: 21 days ]
    • Proportion of patients experiencing a serious adverse event on or before Day 21

  9. Bubonic plague [ Time Frame: 21 days ]
    • Proportion of patients who are fully adherent to the study treatment schedule.

  10. Pneumonic plague [ Time Frame: 11 days ]

    Proportion of patients with a therapeutic response at Day 11. Therapeutic response is defined as follows:

    • Alive
    • Resolution of fever (uncorrected axillary temperature <37.5C)
    • Resolution of tachypnoea (RR< 24 in adults, but age-specific in children)

  11. Pneumonic plague [ Time Frame: 4 days ]
    • Proportion of patients without fever (uncorrected axillary temperature <37.5C) at Day 4

  12. Pneumonic plague [ Time Frame: 4 days ]
    • Proportion of patients with tachypnoea resolution (RR< 24 in adults, but age-specific in children) at Day 4

  13. Pneumonic plague [ Time Frame: 4 days ]
    • Proportion of patients experiencing a serious adverse event on or before Day 4

  14. Pneumonic plague [ Time Frame: 11 days ]
    • Proportion of patients experiencing a serious adverse event on or before Day 11

  15. Pneumonic plague [ Time Frame: 21 days ]
    • Proportion of patients experiencing a serious adverse event on or before Day 21

  16. Pneumonic plague [ Time Frame: 21 days ]
    • Proportion of patients who are fully adherent to the study treatment schedule.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   Child, Adult, Older Adult
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

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)

Pneumonic plague

  • Patients of any age AND
  • Recent onset (< 7 days) of fever (uncorrected axillary temperature ≥ 37.5C) or history of fever AND
  • Cough AND
  • Tachypnoea (respiratory rate > 24 in adults and age specific in children) AND
  • Epidemiological link to a confirmed or probable case of primary or secondary pneumonic plague within 7 days of symptom onset

Exclusion Criteria:

  • 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04110340


Contacts
Layout table for location contacts
Contact: Annelies Gillesen, RGN +441865 612959 annelies.gillesen@ndm.ox.ac.uk
Contact: Alex Salam, MD +441865 612959 alex.salam@ndm.ox.ac.uk

Locations
Layout table for location information
Madagascar
Professor Mamy Randria Recruiting
Antananarivo, Madagascar
Contact: Mamy Randria, Prof       rmamyjeandedieu@yahoo.fr   
Contact: Mihaja Raberahona Raberahona, MD       raberahona@gmail.com   
Sponsors and Collaborators
University of Oxford
Hôpital Universitaire Joseph Raseta Befelatanana CHU d'Antananarivo
Institut Pasteur de Madagascar
Investigators
Layout table for investigator information
Principal Investigator: Peter W Horby, MD University of Oxford
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Layout table for additonal information
Responsible Party: University of Oxford
ClinicalTrials.gov Identifier: NCT04110340    
Other Study ID Numbers: 45-18
First Posted: October 1, 2019    Key Record Dates
Last Update Posted: March 31, 2020
Last Verified: February 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Layout table for additional information
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
Layout table for MeSH terms
Plague
Yersinia Infections
Enterobacteriaceae Infections
Gram-Negative Bacterial Infections
Bacterial Infections
Ciprofloxacin
Streptomycin
Anti-Bacterial Agents
Anti-Infective Agents
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Cytochrome P-450 CYP1A2 Inhibitors
Cytochrome P-450 Enzyme Inhibitors
Protein Synthesis Inhibitors