Clinical trial NCT04211649: 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)
Official title: 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)
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE4
Conditions: Mild Leptospirosis
Keywords: neglected infectious
tropical diseases
emerging diseases
mild leptospirosis
insular context
antibiotics
short treatment period
non-inferiority trial
Lead sponsor: University Hospital Center of Martinique
Sponsor class: OTHER
Collaborators: name: University Hospital of Guadeloupe
name: Centre Hospitalier de Cayenne
name: Centre Hospitalier Universitaire de la Réunion
name: Hôpital de Mayotte
First posted: 2019-12-26
Enrollment: 220
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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

Eligibility criteria: 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

Primary outcomes:
measure: Treatment failure
timeFrame: 7 days from the beginning of antibiotic therapy
measure: Treatment failure
timeFrame: 7 days from the beginning of antibiotic therapy
measure: Treatment failure
timeFrame: 7 days from the beginning of antibiotic therapy
Secondary outcomes:
measure: Evolution of clinical characteristics according to 3-day versus 7-day treatment duration
timeFrame: 21 days
measure: Evolution functional signs according to 3-day versus 7-day treatment duration
timeFrame: 21 days
measure: No evolution of infection at 21 days from start of antibiotic therapy according to 3-day versus 7-day treatment duration
timeFrame: 21 days
measure: Evolution of Quality of life according to 3-day versus 7-day treatment duration
timeFrame: 21 days
measure: Evolution of bilirubinemia values according to 3-day versus 7-day treatment duration
timeFrame: 21 days
measure: Evolution of serum creatinine values according to 3-day versus 7-day treatment duration
timeFrame: 21 days
measure: Evolution of hemoglobin values according to 3-day versus 7-day treatment duration
timeFrame: 21 days
measure: Length of hospital stay according to 3-day versus 7-day treatment duration
timeFrame: 21 days
measure: Factors associated with treatment failure : Serogroup of leptospira
timeFrame: 7 days
measure: Factors associated with treatment failure : Genovar of leptospira
timeFrame: 7 days
measure: Factors associated with treatment failure : quantitative leptospiremia (blood) before antibiotic treatment
timeFrame: 7 days
measure: Factors associated with treatment failure : quantitative leptospiremia (blood) Day+3 of antibiotic treatment
timeFrame: 3 days
measure: Factors associated with treatment failure : Delay between symptom onset and beginning of treatment
timeFrame: From day of frist symptoms until enrollment (with a maximum of 7 days between first symptom and date of enrollement)
measure: Factors associated with treatment failure : Presence of co-morbidities
timeFrame: From the enrollment, until followup visit 1 (Day 0+7days)
measure: Tolerance to treatment
timeFrame: 21 days
Other outcomes:
Locations:
city: Cayenne
country: French Guiana
facility: Centre Hospitalier Andrée Rosemond (CH de Cayenne)
city: Pointe-à-Pitre
country: Guadeloupe
facility: University Hospital of Guadeloupe
city: Fort-de-France
country: Martinique
facility: Centre Hospitalier Universitaire de Martinique
city: Mamoudzou
country: Mayotte
facility: Centre Hospitalier de Mayotte
city: Saint-Pierre
country: Réunion
facility: Centre Hospitalier Universitaire Sud Réunion
Study officials:
affiliation: University Hospital of Martinique
name: André CABIE, Professor
role: STUDY_DIRECTOR
References: