Administrative information
Title {1} | An open-label, randomized, non-inferiority trial of the efficacy and safety of ciprofloxacin versus streptomycin + ciprofloxacin in the treatment of bubonic plague (IMASOY) |
Trial registration {2a and 2b}. | ClinicalTrials.gov, NCT04110340, registered 01-Oct-2019, https://clinicaltrials.gov/ct2/show/NCT04110340 |
Protocol version {3} | v2.8 27-Sep-2019 |
Funding {4} | Wellcome Trust/Department for International Development (WT/DFID) |
Author details {5a} | Rindra Vatosoa Randremanana – Institut Pasteur de Madagascar Mihaja Raberahona – Infectious Diseases Department, University Hospital Joseph Raseta Befelatanana Antananarivo – Centre d’Infectiologie Charles Mérieux, University of Antananarivo Mamy Jean de Dieu Randria – Infectious Diseases Department, University Hospital Joseph Raseta Befelatanana Antananarivo Minoarisoa Rajerison - Institut Pasteur de Madagascar Voahangy Andrianaivoarimanana- Institut Pasteur de Madagascar Agathe Legrand – Institut Pasteur de Madagascar Tsinjo Fehizoro Rasoanaivo – Institut Pasteur de Madagascar Ravaka Randriamparany – Institut Pasteur de Madagascar Théodora Mayouya-Gamana – Institut Pasteur de Madagascar Reziky Mangahasimbola – Institut Pasteur de Madagascar Josie Bourner – University of Oxford Alex Salam – University of Oxford Annelies Gillesen – University of Oxford Tansy Edwards – London School of Hygiene and Tropical Medicine Matthieu Schoenhals- Institut Pasteur de Madagascar Laurence Baril- Institut Pasteur de Madagascar Peter Horby – University of Oxford Piero Olliaro – University of Oxford |
Name and contact information for the trial sponsor {5b} | University of Oxford Joint Research Office 1st floor, Boundary Brook House Churchill Drive, Headington Oxford OX3 7GB, UK Trial Manager email address: josephine.bourner@ndm.ox.ac.uk |
Role of sponsor {5c} | In collaboration, the University of Oxford, Institut Pasteur de Madagascar (IPM), University Hospital Joseph Raseta Befelatanana Antananarivo, Centre Infectiologie Charles Mérieux Madagascar are responsible for the design and management of the IMASOY trial. The University of Oxford and IPM are jointly responsible for data collection and management. All collaborators will be responsible for writing and publishing the final report. The London School of Hygiene and Tropical Medicine is primarily responsible for the statistical analysis, alongside IPM de Madagascar and the University of Oxford. Any further publications that arise following the dissemination of the final report will be reviewed by the University of Oxford before their release. All publications will be open-access. Laboratory data analysis will be the responsibility of IPM. |
Introduction
Background and rationale {6a}
Plague
Current treatment options
Study rationale
Objectives {7}
Trial design {8}
Study schematics
Box 1—Case definitions
Probable and confirmed cases are defined as: | |
Probable case: rapid diagnostic test (RDT) or qPCR or serology (anti-F1 IgG ELISA) is positive but without evidence of seroconversion or a fourfold increase in antibody titre. | |
Confirmed case: RDT and qPCR are positive, or culture is positive, or there has been a seroconversion or a fourfold increase in antibody titre on two separate serological samples (either between D1 and D11, between D11 and D21 or between D1 and D21). |
Study timelines
Study population
Methods: participants, interventions and outcomes
Study setting {9}
Study setting
Study sites
Eligibility criteria {10}
Inclusion criteria
-
Patients of any age
-
Recent onset (< 10 days) of fever (uncorrected axillary temperature ≥ 37.5 °C) or history of fever
-
One or more buboes (tender lymph node swelling)
-
Residence or travel to a plague endemic or outbreak area in Madagascar within 14 days of the onset of symptoms
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Patients identified as clinically suspected of plague by health personnel (doctors or paramedics)
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Patients of any age
-
Recent onset (< 7 days) of fever (uncorrected axillary temperature ≥ 37.5 °C) or history of fever
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Cough
-
Tachypnoea (respiratory rate > 24 in adults and age-specific in children)
-
Epidemiological link with a confirmed or probable case of primary or secondary pneumonic plague within 7 days of onset of symptoms
Exclusion criteria
-
Known allergy to aminoglycosides or fluoroquinolones
-
Tendinitis
-
Myasthenia gravis
-
Theophylline or warfarin use
-
Already treated for bubonic or pneumonic plague in the preceding 3 months
-
Women who report being pregnant
Who will take informed consent? {26a}
Additional consent provisions for collection and use of participant data and biological specimens {26b}
Interventions
Explanation for the choice of comparators {6b}
Intervention description {11a}
Dosing schedule in bubonic plague
-
Adults: 500 mg orally twice daily (or 400 mg IV twice daily for those who cannot take oral medication) for 10 days.
-
Children: 15 mg/kg twice daily (max 500 mg per dose) orally (or 10 mg/kg IV twice daily for those who cannot take oral—maximum dose 400 mg) 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.
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Adults: streptomycin 1 g twice daily for 3 days, followed by ciprofloxacin 500 mg orally twice daily (or ciprofloxacin 400 mg twice daily by IV for those who cannot take it orally) for an additional 7 days.
-
Children: streptomycin 15 mg/kg twice daily for three days followed by ciprofloxacin 15 mg/kg twice daily (max 500 mg per dose) orally (or 10 mg/kg IV twice daily for those who cannot take oral—maximum dose 400 mg) 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.
Dosing schedule in pneumonic plague
-
Adults: 500 mg orally twice daily (or 400 mg IV twice daily for those who cannot take oral medication) for 10 days.
-
Children: 15 mg/kg twice daily (max 500 mg per dose) orally (or 10 mg/kg IV twice daily for those who cannot take oral—maximum dose 400 mg) 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.
-
Adults: streptomycin 1 g twice daily for 5 days with ciprofloxacin 500 mg orally twice daily (or ciprofloxacin 400 mg twice daily IV for those who cannot take it orally) for 10 days.
-
Children: streptomycin 15 mg/kg twice daily for 5 days with ciprofloxacin 15 mg/kg twice daily (max 500 mg per dose) orally (or 10 mg/kg IV twice daily for those who cannot take it orally—maximum dose 400 mg) for 10 days. This is the alternative treatment proposed by the Ministry of Public Health since the 2018–2019 plague season.
-
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.
Route of administration
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Vomiting
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Unable to swallow
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Unconscious
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Systolic blood pressure < 90 mmHg
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Any other conditions or situations for which the physician decides that intravenous treatment is indicated
Timing of dosing
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Ciprofloxacin: doses will be administered morning and evening.
-
Streptomycin: doses will be administered morning and evening.
Duration of therapy
Dosing duration justification
Prohibited drugs
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Theophylline
-
Warfarin
Criteria for discontinuing or modifying allocated interventions {11b}
Strategies to improve adherence to interventions {11c}
Relevant concomitant care permitted or prohibited during the trial {11d}
Provisions for post-trial care {30}
Post-trial care
Insurance
Outcomes {12}
Primary endpoint
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Alive
-
Resolution of fever (uncorrected axillary temperature < 37.5 °C)
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A ≥ 25% decrease in bubo size (in the case of multiple buboes, the largest bubo)
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Has not received alternative treatment for plague
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No clinical decision to continue anti-plague antibiotics beyond day 10
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Alive
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Absence of fever (uncorrected axillary temperature < 37.5 °C)
-
Bubo has not enlarged
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Has not received alternative treatment for plague
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No clinical decision to continue anti-plague antibiotics beyond day 10
Secondary endpoints
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Proportion of patients without fever (uncorrected axillary temperature < 37.5 °C) at D4
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Proportion of patients with a pain score < 3 at D4
-
Proportion of patients with a pain score < 3 at D11
-
Mean % change in bubo size at D4
-
Mean % change in bubo size at D11
-
Proportion of patients experiencing a serious adverse event on or before D4
-
Proportion of patients experiencing a serious adverse event on or before D11
-
Proportion of patients experiencing a serious adverse event on or before D21
-
Proportion of patients who are fully adherent to the study treatment schedule
-
Proportion of patients with a therapeutic response at D11. Therapeutic response is defined as follows:
-
◦ Alive
-
◦ Resolution of fever (uncorrected axillary temperature < 37.5 °C)
-
◦ Resolution of tachypnoea (RR < 24 in adults, but age-specific in children)
-
-
Proportion of patients without fever (uncorrected axillary temperature < 37.5 °C) at D4
-
Proportion of patients with tachnypnoea resolution (RR < 24 in adults, but age-specific in children) at D4
-
Proportion of patients experiencing a serious adverse event on or before D4
-
Proportion of patients experiencing a serious adverse event on or before D11
-
Proportion of patients experiencing a serious adverse event on or before D21
-
Proportion of patients who fully adhere to the study treatment schedule
Participant timeline {13}
Variables | Timings (day) | ||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 | 11 | 21+/−2 | M3 | |
Informed consent | X | ||||||||||||
Demographics | X | ||||||||||||
Medical history | X | ||||||||||||
Signs and symptoms | X | X | X | X am | X | X | |||||||
Vital signs | X | X | X | X | X | X | |||||||
Doses administered at CSB (am and pm) | XX | XX | XX | X am | |||||||||
Doses administered at home (am and pm) | X pm | XX | XX | XX | XX | XX | XX | ||||||
Adverse events | X | X | X | X | X | X | |||||||
Bubo size and pain score | X | X | X | X |
Variables | Timing (days) | ||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 | 11 | 21+/−2 | M3 | |
RDT Bubo/sputum | X | ||||||||||||
PCR Bubo/sputum | X | ||||||||||||
Bubo/sputum culture | X | ||||||||||||
Plague serology | X | X | X | X* | |||||||||
Malaria Ag | X |
Sample size {14}
Therapeutic response* | Margin (%), unilateral confidence interval of 2.5%, loss of 10%, power 90% | ||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|
5 | 6 | 7 | 8 | 9 | 10 | 11 | 12 | 13 | 14 | 15 | |
0.95 | 890 | 618 | 454 | 348 | 276 | 224 | 186 | 156 | 134 | 114 | 100 |
0.90 | 1684 | 1170 | 858 | 658 | 520 | 424 | 350 | 294 | 250 | 216 | 190 |
0.85 | 2384 | 1656 | 1216 | 932 | 736 | 596 | 494 | 416 | 354 | 306 | 268 |
0.80 | 2990 | 2076 | 1528 | 1170 | 926 | 750 | 618 | 520 | 444 | 384 | 334 |
0.75 | 3506 | 2434 | 1790 | 1370 | 1084 | 878 | 726 | 610 | 520 | 450 | 392 |
Recruitment {15}
Community engagement and outreach
Assignment of interventions: allocation
Sequence generation {16a}
Concealment mechanism {16b}
Implementation {16c}
Assignment of interventions: blinding
Who will be blinded {17a}
Procedure for unblinding if needed {17b}
Data collection and management
Plans for assessment and collection of outcomes {18a}
Plans to promote participant retention and complete follow-up {18b}
Data management {19}
Confidentiality {27}
Participant confidentiality
Plans for collection, laboratory evaluation and storage of biological specimens for genetic or molecular analysis in this trial/future use {33}
Rapid diagnostic test (RDT) for plague at admission
At the central plague laboratory (CPL) level
Malaria
Serology
Statistical methods
Statistical methods for primary and secondary outcomes {20a}
Primary endpoint analysis
Analysis of secondary endpoints
Interim analyses {21b}
Methods for additional analyses (e.g. subgroup analyses) {20b}
Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c}
Missing data handling: primary endpoint
Protocol deviations
Plans to give access to the full protocol, participant-level data and statistical code {31c}
Oversight and monitoring
Composition of the coordinating centre and trial steering committee {5d}
Composition of the data monitoring committee, its role and reporting structure {21a}
-
Paul Mead, Chief of the Bacterial Diseases Branch (BDB), Division of Vector-Borne Diseases (DVBD), National Center for Emerging and Zoonotic Infectious Diseases (NCEZID), Centres for Disease Control and Prevention
-
Professor David Lalloo, Director Liverpool School of Tropical Medicine and Professor of Tropical Medicine, Liverpool School of Tropical Medicine, Pembroke Place Liverpool, L3 5QA, UK
-
Professor Julie A Simpson, Head of Biostatistics Unit/Deputy Head of School, Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Victoria 3010, Australia
Adverse event reporting and harms {22}
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Respiratory symptoms (cough, tachypnea, haemotysis)
-
Intestinal symptoms (diarrhoea, vomiting)
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Fever
-
Bubo
-
Pain at bubo’s site
-
Routine examination
-
Medical/surgical/hospital procedure planned before inclusion
-
A condition present before inclusion or discovered at inclusion (e.g. malaria discovered at inclusion and requiring hospitalization)