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Ciprofloxacin Versus an Aminoglycoside Followed by Ciprofloxacin for Bubonic Plague (IMASOY)

Primary Purpose

Plague, Bubonic, Plague, Pneumonic

Status
Recruiting
Phase
Phase 3
Locations
Madagascar
Study Type
Interventional
Intervention
Ciprofloxacin
Streptomycin
Gentamicin
Sponsored by
University of Oxford
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Plague, Bubonic

Eligibility Criteria

undefined - undefined (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Professor Mamy RandriaRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Other

Arm Label

Ciprofloxacin Arm

Control arm

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

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 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

Bubonic plague
• Proportion of patients without fever (uncorrected axillary temperature <37.5C) at Day 4
Bubonic plague
• Proportion of patients with a pain score < 3 at Day 4 (using pain scale questionnaires)
Bubonic plague
• Proportion of patients with a pain score < 3 at Day 11 (using pain scale questionnaires)
Bubonic plague
• Mean % change in bubo size at Day 4 (measured by use of calipers and/or ultrasound)
Bubonic plague
• Mean % change in bubo size at Day11 (measured by use of calipers and/or ultrasound)
Bubonic plague
• Proportion of patients experiencing a serious adverse event on or before Day 4
Bubonic plague
• Proportion of patients experiencing a serious adverse event on or before Day 11
Bubonic plague
• Proportion of patients experiencing a serious adverse event on or before Day 21
Bubonic plague
• Proportion of patients who are fully adherent to the study treatment schedule.
Pneumonic plague
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)
Pneumonic plague
• Proportion of patients without fever (uncorrected axillary temperature <37.5C) at Day 4
Pneumonic plague
• Proportion of patients with tachypnoea resolution (RR< 24 in adults, but age-specific in children) at Day 4
Pneumonic plague
• Proportion of patients experiencing a serious adverse event on or before Day 4
Pneumonic plague
• Proportion of patients experiencing a serious adverse event on or before Day 11
Pneumonic plague
• Proportion of patients experiencing a serious adverse event on or before Day 21
Pneumonic plague
• Proportion of patients who are fully adherent to the study treatment schedule.

Full Information

First Posted
January 28, 2019
Last Updated
November 1, 2022
Sponsor
University of Oxford
Collaborators
Hôpital Universitaire Joseph Raseta Befelatanana CHU d'Antananarivo, Institut Pasteur de Madagascar, Foreign, Commonwealth and Development Office and Wellcome (216273.Z.19.Z)
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1. Study Identification

Unique Protocol Identification Number
NCT04110340
Brief Title
Ciprofloxacin Versus an Aminoglycoside Followed by Ciprofloxacin for Bubonic Plague
Acronym
IMASOY
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

2. Study Status

Record Verification Date
October 2022
Overall Recruitment Status
Recruiting
Study Start Date
February 15, 2020 (Actual)
Primary Completion Date
March 31, 2023 (Anticipated)
Study Completion Date
March 31, 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of Oxford
Collaborators
Hôpital Universitaire Joseph Raseta Befelatanana CHU d'Antananarivo, Institut Pasteur de Madagascar, Foreign, Commonwealth and Development Office and Wellcome (216273.Z.19.Z)

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Plague, Bubonic, Plague, Pneumonic

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
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.
Masking
None (Open Label)
Allocation
Randomized
Enrollment
600 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Ciprofloxacin Arm
Arm Type
Active Comparator
Arm Description
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.
Arm Title
Control arm
Arm Type
Other
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Ciprofloxacin
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Streptomycin
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Gentamicin
Intervention Description
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.
Primary Outcome Measure Information:
Title
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:
Description
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
Time Frame
11 days
Secondary Outcome Measure Information:
Title
Bubonic plague
Description
• Proportion of patients without fever (uncorrected axillary temperature <37.5C) at Day 4
Time Frame
4 days
Title
Bubonic plague
Description
• Proportion of patients with a pain score < 3 at Day 4 (using pain scale questionnaires)
Time Frame
4 days
Title
Bubonic plague
Description
• Proportion of patients with a pain score < 3 at Day 11 (using pain scale questionnaires)
Time Frame
11 days
Title
Bubonic plague
Description
• Mean % change in bubo size at Day 4 (measured by use of calipers and/or ultrasound)
Time Frame
4 days
Title
Bubonic plague
Description
• Mean % change in bubo size at Day11 (measured by use of calipers and/or ultrasound)
Time Frame
11 days
Title
Bubonic plague
Description
• Proportion of patients experiencing a serious adverse event on or before Day 4
Time Frame
4 days
Title
Bubonic plague
Description
• Proportion of patients experiencing a serious adverse event on or before Day 11
Time Frame
11 days
Title
Bubonic plague
Description
• Proportion of patients experiencing a serious adverse event on or before Day 21
Time Frame
21 days
Title
Bubonic plague
Description
• Proportion of patients who are fully adherent to the study treatment schedule.
Time Frame
21 days
Title
Pneumonic plague
Description
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)
Time Frame
11 days
Title
Pneumonic plague
Description
• Proportion of patients without fever (uncorrected axillary temperature <37.5C) at Day 4
Time Frame
4 days
Title
Pneumonic plague
Description
• Proportion of patients with tachypnoea resolution (RR< 24 in adults, but age-specific in children) at Day 4
Time Frame
4 days
Title
Pneumonic plague
Description
• Proportion of patients experiencing a serious adverse event on or before Day 4
Time Frame
4 days
Title
Pneumonic plague
Description
• Proportion of patients experiencing a serious adverse event on or before Day 11
Time Frame
11 days
Title
Pneumonic plague
Description
• Proportion of patients experiencing a serious adverse event on or before Day 21
Time Frame
21 days
Title
Pneumonic plague
Description
• Proportion of patients who are fully adherent to the study treatment schedule.
Time Frame
21 days

10. Eligibility

Sex
All
Accepts Healthy Volunteers
No
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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Josephine Bourner
Phone
+447385933832
Email
josephine.bourner@ndm.ox.ac.uk
First Name & Middle Initial & Last Name or Official Title & Degree
Alex Salam, MD
Phone
+441865 612959
Email
alex.salam@ndm.ox.ac.uk
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Peter W Horby, MD
Organizational Affiliation
University of Oxford
Official's Role
Principal Investigator
Facility Information:
Facility Name
Professor Mamy Randria
City
Antananarivo
Country
Madagascar
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Mamy Randria, Prof
Email
rmamyjeandedieu@yahoo.fr
First Name & Middle Initial & Last Name & Degree
Mihaja Raberahona Raberahona, MD
Email
raberahona@gmail.com

12. IPD Sharing Statement

Plan to Share IPD
Undecided
Citations:
PubMed Identifier
32807214
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.
Results Reference
derived

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Ciprofloxacin Versus an Aminoglycoside Followed by Ciprofloxacin for Bubonic Plague

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