Comparing Two Antibiotic Therapy Periods (3 Versus 7 Days) in Patients With Mild Leptospirosis and Seen at the Hospital in 5 French Overseas Departments (Martinique, Guadeloupe, French Guiana, Reunion, Mayotte) (LEPTO3)

Multicenter, Randomized, Open-label Non-inferiority Trial, Comparing Two Antibiotic Therapy Periods (3 Versus 7 Days) in Patients With Mild Leptospirosis and Seen at the Hospital in 5 French Overseas Departments (Martinique, Guadeloupe, French Guiana, Reunion, Mayotte)

Leptospirosis is a globally distributed neglected tropical disease affecting subtropical and tropical areas, such as the Caribbean and the Indian Ocean, with favorable climatic conditions for disease transmission. It shows a strong seasonality, with epidemic potential especially after heavy rainfall. A recent systematic review by Costa et al. (2015) places leptospirosis among the leading zoonotic causes of morbidity and mortality worldwide, with 1.03 million cases and 58,900 deaths each year.

Leptospirosis is an important public health problem, particularly within economically vulnerable populations. It is also emerging as a health threat in new settings due to globalization and climate change. Disasters and extreme weather events are recognized to precipitate epidemics.

Clinical manifestations are highly polymorphic, ranging from an anicteric, influenza-like form to severe forms with hepato-renal or pulmonary failures which are associated with high mortality.

Antibiotic therapy should be prescribed early, as soon as leptospirosis is suspected and preferably within the first 5 days, before leptospira spread to the tissues. In the treatment of mild forms, usual antibiotics are oral amoxicillin or doxycycline for a standard treatment duration of 7 days. In hospitalized cases of leptospirosis, parenteral antibiotic therapy with ceftriaxone is often favored as first-line therapy.

The most widely used antibiotics in the French Caribbean and Indian Ocean regions are amoxicillin, doxycyclin and third generation cephalosporins such as ceftriaxone.

Research hypothesis:

The effects of shorter antibiotic therapy periods for other infectious diseases have been explored by several authors. The efficacy of short ceftriaxone treatment has been highlighted for typhoid fever or meningococcal meningitis. In a retrospective series of 21 cases, the interest of short treatment periods (3-6 days) for mild and severe leptospirosis has also been described. A minimal 3-day therapy period would seem necessary in order to biologically confirm leptospirosis diagnosis and to rule out other community-acquired infections.

Our study proposal is the conduct of a non-inferiority trial comparing a shortened antibiotic therapy period of 3 days with the standard treatment period of 7 days in patients with mild leptospirosis and seen at the hospital in 5 French overseas departments (Martinique, Guadeloupe, French Guiana, Reunion, Mayotte).

Originality and innovative aspects:

To our knowledge, the efficacy of a 3-day antibiotic therapy for mild leptospirosis, as compared to the standard 7 day period, has not yet been explored.

In addition, the LEPTO3 study will be among the first clinical trials to focus on the endemic public health problem, which is leptospirosis, at a large geographical level (Caribbean and Indian Ocean regions) and to involve a high level of collaboration between medical and scientific teams of these territories.

Study Overview

• Status: Not yet recruiting
• Conditions: Mild Leptospirosis
• Intervention / Treatment: Drug: 3 days of antibiotherapy

Detailed Description

Leptospirosis is a globally distributed neglected tropical disease affecting subtropical and tropical areas, such as the Caribbean and the Indian Ocean, with favorable climatic conditions for disease transmission. It shows a strong seasonality, with epidemic potential especially after heavy rainfall. A recent systematic review by Costa et al. (2015) places leptospirosis among the leading zoonotic causes of morbidity and mortality worldwide, with 1.03 million cases and 58,900 deaths each year.

Leptospirosis is an important public health problem, particularly within economically vulnerable populations. It is also emerging as a health threat in new settings due to globalization and climate change. Disasters and extreme weather events are recognized to precipitate epidemics.

Clinical manifestations are highly polymorphic, ranging from an anicteric, influenza-like form to severe forms with hepato-renal or pulmonary failures which are associated with high mortality.

Antibiotic therapy should be prescribed early, as soon as leptospirosis is suspected and preferably within the first 5 days, before leptospira spread to the tissues. In the treatment of mild forms, usual antibiotics are oral amoxicillin or doxycycline for a standard treatment duration of 7 days. In hospitalized cases of leptospirosis, parenteral antibiotic therapy with ceftriaxone is often favored as first-line therapy.

The most widely used antibiotics in the French Caribbean and Indian Ocean regions are amoxicillin, doxycyclin and third generation cephalosporins such as ceftriaxone.

Research hypothesis:

The effects of shorter antibiotic therapy periods for other infectious diseases have been explored by several authors. The efficacy of short ceftriaxone treatment has been highlighted for typhoid fever or meningococcal meningitis. In a retrospective series of 21 cases, the interest of short treatment periods (3-6 days) for mild and severe leptospirosis has also been described. A minimal 3-day therapy period would seem necessary in order to biologically confirm leptospirosis diagnosis and to rule out other community-acquired infections.

Our study proposal is the conduct of a non-inferiority trial comparing a shortened antibiotic therapy period of 3 days with the standard treatment period of 7 days in patients with mild leptospirosis and seen at the hospital in 5 French overseas departments (Martinique, Guadeloupe, French Guiana, Reunion, Mayotte).

Originality and innovative aspects:

To our knowledge, the efficacy of a 3-day antibiotic therapy for mild leptospirosis, as compared to the standard 7 day period, has not yet been explored.

In addition, the LEPTO3 study will be among the first clinical trials to focus on the endemic public health problem, which is leptospirosis, at a large geographical level (Caribbean and Indian Ocean regions) and to involve a high level of collaboration between medical and scientific teams of these territories.

Main objective :

Compare the efficacy of a 3-day antibiotic therapy period with the standard period of 7 days in mild leptospirosis patients seen at the hospital in 5 French overseas departments (Martinique, Guadeloupe, French Guiana, Reunion, Mayotte)

Secondary objectives :

• Compare the evolution of clinical and biological characteristics in the 2 groups of patients (antibiotic therapy duration 3 days versus 7 days)
• Compare lengths of hospital stay in the 2 groups of patients (antibiotic therapy duration 3 days versus 7 days)
• Examine factors linked to a potential treatment failure in patients
• Assess patient tolerance to treatment

• Study Type: Interventional
• Enrollment (Estimated): 220
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Janick Jean-Marie, Master; Phone Number: +596 0596 59 26 97; Email: janick.jean-marie@chu-martinique.fr
• Study Contact Backup: Name: Isabelle CALMONT, Master; Phone Number: +596 0596 59 26 97; Email: isabelle.calmont@chu-martinique.fr

Study Locations

• French Guiana
  • Cayenne, French Guiana, 97300
    • Centre Hospitalier Andrée Rosemond (CH de Cayenne)
    • Contact: William Faurous, MD; Phone Number: +594 0594 39 77 99; Email: fanny.abad@ch-cayenne.fr
    • Principal Investigator: Félix Djossou, Pr
• Guadeloupe
  • Pointe-à-Pitre, Guadeloupe, 97159
    • University Hospital of Guadeloupe
    • Contact: Elvire Couchy, Master; Phone Number: +590 0590 91 19 30; Email: elvire.couchy@chu-gaudeloupe.fr
    • Principal Investigator: Elodie Curlier, MD
• Martinique
  • Fort-de-France, Martinique, 97200
    • Centre Hospitalier Universitaire de Martinique
    • Contact: Janick Jean-Marie, Master; Phone Number: +596 0596 59 26 97; Email: janick.jean-marie@chu-martinique.fr
    • Contact: Véronique PELONDE-ERIMME, Master; Phone Number: +596 0596 59 26 97; Email: veronique.pelonde-erimee@chu-martinique.fr
    • Principal Investigator: André CABIE, Pr
• Mayotte
  • Mamoudzou, Mayotte, 97600
    • Centre hospitalier de Mayotte
    • Contact: Mohamadou NIANG, MD; Phone Number: +262 02 69 61 80 00; Email: m.niang@chmayotte.fr
    • Principal Investigator: Mohamadou NIANG, MD
• Réunion
  • Saint-Pierre, Réunion, 97448
    • Centre Hospitalier Universitaire Sud Réunion
    • Contact: Antoine BERTOLOTTI, MD; Phone Number: +262 02 62 35 90 00; Email: antoine.bertolotti@chu-reunion.fr
    • Principal Investigator: Antoine BERTOLOTTI, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Patient aged 18 years and above at the time of study inclusion
2. Patient consulting at a recruiting hospital center
3. Clinical and biological suspicion of leptospirosis, confirmed by serological rapid testing or PCR at most 72 hours after start of antibiotic treatment
4. Affiliated or beneficiary of a social security scheme (For French Guiana, patients benefiting from State Medical Aid (AME) will be considered, in accordance with the provisions of article L1121-8-1 of the Public Health Code
5. Acceptance of participation in the clinical trial and in the follow-up process at 7 and 21 days (from start of antibiotic therapy)
6. Provision of a signed consent form from the study participant

Exclusion Criteria:

1. Presence of one of the severity criteria appearing between the time of first patient care at the hospital and study inclusion:

   1. Hemodynamic failure with onset of septic shock defined by persisting hypotension requiring vasopressor amines to maintain mean arterial pressure ≥65 mm Hg and blood lactates >2 mmol/L despite adequate volume resuscitation (73)
   2. Hematologic failure with hemoglobin <7 g / dL requiring red blood cell transfusion (74) or platelets <20 G / L requiring platelet transfusion (75)
   3. Ventilatory failure defined by PaO2 / Fi O2 ratio <300 mmHg (76) or resort to mechanical ventilation
   4. Renal failure defined by serum creatinine > 301 μmol / L 76) or resort to renal dialysis
   5. Hepatic failure defined by total bilirubinemia> 101 μmol / L (76)
   6. Heart failure (eg: ECG anomalies, myocarditis, cardiogenic shock)
   7. Neurologic affection such as meningitis, encephalitis, intracerebral hemorragia, stroke
   8. Ocular symptoms such as uveitis.
   9. Hemoptysis, lesional pulmonary oedema for pulmonary affection
   10. Hemorrhagic syndrome
2. Diagnosis of another bacterial infection documented during initial patient assessment (e.g. Gram-negative bacteremia, digestive tract infection, bacterial pneumonia)
3. Intake of antibiotics, active on leptospirosis, the week before clinical and biological suspicion of leptospirosis
4. Leptospirosis diagnosis by PCR or serological rapid testing after the 7th day from symptom onset
5. Pregnant or lactating woman, or woman of childbearing age without effective contraception
6. Previous hypersensitivity to β-lactams and doxycycline or contraindication to the latter's use
7. Ongoing treatment that is contraindicated with one of the study treatments

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 3 days of antibiotherapy; The patient viewed for the first time at the hospital and suspected of leptospirosis received a probabilistic antibiotherapy	Drug: 3 days of antibiotherapy; Reduce at 3 days of antibiotherapy for the treatment of mild leptospirosis
No Intervention: 7 days of antibiotherapy (Amoxycilline or Doxycycline); When the leptospirosis is confirmed ( PCR Leptospirosis positive) the pobabilistic antibiotherapy is switched to a prophylactic antibiotherapy with Amoxicillin or Doxycycline.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Treatment failure	- occurrence of a complication: Hemodynamic failure with onset of septic shock defined by persisting hypotension requiring vasopressor amines to maintain mean arterial pressure ≥65 mm Hg and blood lactates >2 mmol/L despite adequate volume resuscitation; hematologic failure with hemoglobin <7 g / L requiring red blood cell transfusion or platelets < 20 G / L requiring platelet transfusion; Ventilatory failure defined by PaO2 / Fi O2 ratio <300 mmHg or resort to mechanical ventilation; Renal failure defined by serum creatinine > 301 μmol / L or resort to renal dialysis; Hepatic failure defined by total bilirubinemia> 101 μmol / L; Heart failure (eg: ECG anomalies, myocarditis, cardiogenic shock); Neurologic affection such as meningitis, encephalitis, intracerebral hemorragia, stroke; Ocular symptoms such as uveitis.; Hemoptysis, lesional pulmonary oedema for pulmonary affection; Hemorrhagic syndrome , or	7 days from the beginning of antibiotic therapy
Treatment failure	continued fever (body temperature >38°C) 5 days after the start of antibiotic therapy, or fever reappearance (body temperature >38°C) observed 24 hours after initial apyrexia (body temperature <38°C). Both cases exclude fever due to a cause not attributable to leptospirosis infection. Or,	7 days from the beginning of antibiotic therapy
Treatment failure	death	7 days from the beginning of antibiotic therapy

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Evolution of clinical characteristics according to 3-day versus 7-day treatment duration	measure of body temperature; assessment of functional signs; no evolution of infection at 21 days from start of antibiotic therapy)Absence of clinical symptoms (jaundice, nausea, abdominal pain, myalgia, and arthlagia)Normalization of biological parameters (creatinine, bilirubin, platelets, hemoglobin); Quality of life criteria evaluated by the EQ5D questionnaire	21 days
Evolution functional signs according to 3-day versus 7-day treatment duration	Assessment of functional signs	21 days
Evolution of Quality of life according to 3-day versus 7-day treatment duration	Quality of life criteria evaluated by the EQ5D questionnaire (scale from 0 to 100 with 0 means worst imaginable health state; 100 means best imaginable health state	21 days
Evolution of bilirubinemia values according to 3-day versus 7-day treatment duration	μmol / L	21 days
Evolution of serum creatinine values according to 3-day versus 7-day treatment duration	μmol / L	21 days
Evolution of hemoglobin values according to 3-day versus 7-day treatment duration	G / L	21 days
Length of hospital stay according to 3-day versus 7-day treatment duration		21 days
Factors associated with treatment failure : Serogroup of leptospira		7 days
Factors associated with treatment failure : quantitative leptospiremia (blood) before antibiotic treatment	quantitative leptospiremia (blood) at start of antibiotic therapy	7 days
Factors associated with treatment failure : quantitative leptospiremia (blood) Day+3 of antibiotic treatment	quantitative leptospiremia (blood) at 3 days from start of antibiotic therapy	3 days
No evolution of infection at 21 days from start of antibiotic therapy according to 3-day versus 7-day treatment duration	Absence of clinical symptoms such as jaundice, nausea, abdominal pain, myalgia, and arthlagia Normalization of biological parameters (creatinine, bilirubin, platelets, hemoglobin)	21 days
Factors associated with treatment failure : Genovar of leptospira		7 days
Factors associated with treatment failure : Delay between symptom onset and beginning of treatment	day (unit)	From day of frist symptoms until enrollment (with a maximum of 7 days between first symptom and date of enrollement)
Factors associated with treatment failure : Presence of co-morbidities	day (unit)	From the enrollment, until followup visit 1 (Day 0+7days)
Tolerance to treatment	Tolerance to treatment assessed by the occurrence of Jarisch-Herxheimer reactions, as well as adverse event reporting based on a standardized and internationally recognized toxicity table for adults	21 days

Collaborators and Investigators

• Sponsor: University Hospital Center of Martinique
• Collaborators: Centre Hospitalier Universitaire de la Réunion; Centre Hospitalier de Cayenne; University Hospital of Guadeloupe; Hôpital de Mayotte
• Investigators: Study Director: André CABIE, Professor, University Hospital of Martinique

Study record dates

Study Major Dates

• Study Start (Estimated): October 1, 2024
• Primary Completion (Estimated): October 1, 2027
• Study Completion (Estimated): February 1, 2028

Study Registration Dates

• First Submitted: December 17, 2019
• First Submitted That Met QC Criteria: December 23, 2019
• First Posted (Actual): December 26, 2019

Study Record Updates

• Last Update Posted (Actual): July 18, 2024
• Last Update Submitted That Met QC Criteria: July 16, 2024
• Last Verified: July 1, 2024

More Information

Terms related to this study

• Keywords: antibiotics; neglected infectious; tropical diseases; emerging diseases; mild leptospirosis; insular context; short treatment period; non-inferiority trial
• Additional Relevant MeSH Terms: Infections; Gram-Negative Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Spirochaetales Infections; Leptospirosis; Weil Disease
• Other Study ID Numbers: 19_RIPH1_07; 2024-516533-13-00 (Ctis)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No