Clinical Trials Register

Summary
EudraCT Number:	2019-004037-17
Sponsor's Protocol Code Number:	19_RIPH1_07
National Competent Authority:	France - ANSM
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2020-12-10
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

France - ANSM

A.2

EudraCT number

2019-004037-17

A.3

Full title of the trial

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)

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

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)

A.3.2

Name or abbreviated title of the trial where available

LEPTO3

A.4.1

Sponsor's protocol code number

19_RIPH1_07

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT04211649

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Centre Hospitalier Universitaire de Martinique
B.1.3.4	Country	Martinique
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	French Ministry of Health
B.4.2	Country	France
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Centre Hospitalier Universitaire de Martinique
B.5.2	Functional name of contact point	Attaché de recherche clinique
B.5.3	Address:
B.5.3.1	Street Address	CS90632
B.5.3.2	Town/ city	Fort-de-France
B.5.3.3	Post code	97261
B.5.3.4	Country	Martinique
B.5.4	Telephone number	+5960596592697
B.5.5	Fax number	+5960596757652
B.5.6	E-mail	janick.jean-marie@chu-martinique.fr

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.2	Country which granted the Marketing Authorisation	France
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.4	Pharmaceutical form	Cachet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	AMOXICILLIN
D.3.9.1	CAS number	26787-78-0
D.3.9.4	EV Substance Code	SUB05481MIG
D.3.10	Strength
D.3.10.1	Concentration unit	g gram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	1
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.2	Country which granted the Marketing Authorisation	France
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.4	Pharmaceutical form	Cachet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	DOXYCYCLINE
D.3.9.1	CAS number	564-25-0
D.3.9.4	EV Substance Code	SUB06393MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	100
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 3
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.2	Country which granted the Marketing Authorisation	France
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.4	Pharmaceutical form	Powder and solvent for solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	CEFTRIAXONE
D.3.9.1	CAS number	73384-59-5
D.3.9.4	EV Substance Code	SUB07431MIG
D.3.10	Strength
D.3.10.1	Concentration unit	g gram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	1
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Mild Leptospirosis : defined as Leptospirosis without the following severity criteria :
a. Hemodynamic failure* with onset of septic shock
b. Hematologic failure* with hemoglobin requiring red blood cell transfusion or platelets* requiring platelet transfusion
c. Ventilatory failure* or resort to mechanical ventilation
d. Renal failure* or resort to renal dialysis
e. Hepatic failure*
*condition defined and discribed in the protocol

E.1.1.1

Medical condition in easily understood language

Mild Leptospirosis : Defined as Leptospirosis without severity criteria

E.1.1.2

Therapeutic area

Diseases [C] - Bacterial Infections and Mycoses [C01]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	PT
E.1.2	Classification code	10024238
E.1.2	Term	Leptospirosis
E.1.2	System Organ Class	10021881 - Infections and infestations

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10024241
E.1.2	Term	Leptospirosis, unspecified
E.1.2	System Organ Class	10021881 - Infections and infestations

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

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)

E.2.2

Secondary objectives of the trial

- 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

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Patient aged 18 years and above at the time of study inclusion
- Patient consulting at a recruiting hospital center
- Clinical and biological suspicion of leptospirosis, confirmed by PCR at most 72 hours after start of antibiotic treatment
- Affiliate or beneficiary of a social security scheme.
- Acceptance of participation in the clinical trial and in the follow-up process at 7 and 21 days (from start of antibiotic therapy),
- Provision of a signed consent form from the study participant

E.4

Principal exclusion criteria

- 1. Presence of severity criteria appearing between the time of first patient care at the hospital and study inclusion:
a. 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
b. Hematologic failure with hemoglobin <7 g / L requiring red blood cell transfusion or platelets <20 G / L requiring platelet transfusion
c. Ventilatory failure defined by PaO2 / Fi O2 ratio <300 mmHg or resort to mechanical ventilation
d. Renal failure defined by serum creatinine > 301 μmol / L or resort to renal dialysis
e. Hepatic failure defined by total bilirubinemia> 101 μmol / L
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 after the 7th day from symptom onset or after the 3rd day from beginning of treatment
5. Pregnant or lactating woman, or woman of childbearing age without effective contraception
6. Allergy to amoxicillin and doxycycline or contraindication to the latter’s use

E.5 End points

E.5.1

Primary end point(s)

Treatment failure at 7 days from the beginning of antibiotic therapy, as defined by one of the following conditions:
- occurrence of a complication:
o 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
o hematologic failure with hemoglobin <7 g / L requiring red blood cell transfusion or platelets < 20 G / L requiring platelet transfusion
o Ventilatory failure defined by PaO2 / Fi O2 ratio <300 mmHg or resort to mechanical ventilation
o Renal failure defined by serum creatinine > 301 μmol / L or resort to renal dialysis
o Hepatic failure defined by total bilirubinemia> 101 μmol / L
or
- 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
- death

E.5.1.1

Timepoint(s) of evaluation of this end point

At :
- Visit 1 (4 days after enrollment)
- Visit 2 (11 days after enrollment)
- Visit 3 (18 days +/- 3 days after enrollment)

E.5.2

Secondary end point(s)

1. 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)
o Absence of clinical symptoms (jaundice, nausea, abdominal pain, myalgia, and arthlagia)
o Normalization of biological parameters (creatinine, bilirubin, platelets, hemoglobin)
- Quality of life criteria evaluated by the EQ5D questionnaire

2. Evolution of biological characteristics according to 3-day versus 7-day treatment duration (regression of biological inflammatory syndrome, improved renal, hepato-biliary and hematologic functions)

3. Length of hospital stay according to 3-day versus 7-day treatment duration

4. Factors associated with treatment failure (serogroup, quantitative leptospiremia at start of antibiotic therapy, quantitative leptospiremia at 3 days from start of antibiotic therapy, delay between symptom onset and beginning of treatment, presence of co-morbidities)

5. - Tolerance to treatment assessed by the occurrence of Jarisch-Herzheimer reactions, as well as adverse event reporting based on a standardized and internationally recognized toxicity table for adults (adult toxicity table made by the Division of Microbiology and Infectious Diseases (DMID), of the National Institute of Allergies and Infectious Diseases)

E.5.2.1

Timepoint(s) of evaluation of this end point

At :
- Visit 1 (4 days after enrollment)
- Visit 2 (11 days after enrollment)
- Vistt 3 (18 days +/- 3 days after enrollment)

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

Yes

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

Reduce at 3 days (reduce of duration) of antibiotherapy for the treatment of Mild Leptospirosis

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

220

F.1.3

Elderly (>=65 years)

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

220

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

None

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2021-03-04

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2021-07-28

P. End of Trial
P.	End of Trial Status	Ongoing

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