Dose Ranging Study of Ferroquine With Artesunate in African Adults and Children With Uncomplicated Plasmodium Falciparum Malaria

Study Overview
=================
Brief Summary
-----------------
Primary objective: To assess the Day 28 efficacy defined as the percentage of patients with no parasitic recrudescence, of 3 treatment groups - 3 dose levels of ferroquine associated with artesunate - for a 3-day treatment. Secondary objectives: To assess the efficacy of ferroquine at one dose level alone for a 3-day treatment. To assess the clinical safety of 4 treatment groups - 3 dose levels of ferroquine associated with artesunate and one dose level of ferroquine alone. To assess pharmacokinetics parameters of ferroquine and its metabolites along sparse sampling schedules.

Detailed Description
-----------------
The overall study duration is 64 days, consisting of a screening period (less or equal 1 day), of a 3-day treatment period during which the patient is hospitalized for a maximum of 60 hours, and a follow-up period of 61 days.

Official Title
-----------------
Parallel Group, Double-blind, Randomized Study Assessing the Efficacy, Safety and Pharmacokinetic Profiles of Ferroquine Associated With Artesunate and a Single-blind Dose Level of Ferroquine Alone in a 3-day Treatment of Uncomplicated Malaria Due to Plasmodium Falciparum in an Immune Symptomatic African Adult and Pediatric Population.

Conditions
-----------------
Plasmodium Falciparum Infection

Intervention / Treatment
-----------------
* Drug: Ferroquine (SSR97193)
* Drug: Placebo
* Drug: artesunate


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: 3 cohorts enrolled in sequence with data interim review by Data Monitoring Committee (DMC) between cohort 1-2 and cohort 2-3 Cohort 1 : Adults > 50 kg or Adolescents >30 kg and age > or = 14 years Cohort 2 : Children with body weight [30 kg- 15 kg[ Cohort 3 : Children with body weight [15 kg-10 kg] Age related Body Mass Index (BMI)> or = 5 th percentile. Presence of body temperature > or = 37.5°C or history of fever in the last 24 hours. Monoinfection with Plasmodium falciparum with parasitemia from 1,000/microL to 200,000/microL. Signed Informed Consent Form by the patient (if the patient is > or = age defining majority) or by the parents or legal guardian of minor patients (<18 years of age or < other age locally defining majority). In addition, participants with capacity for writing will sign off on an Assent Form. Patients with no capacity for writing will have the Assent Form read. In that case, an impartial witness will certify the document was read to the child. Exclusion Criteria: Presence of HBs antigen and of anti-HCV antibodies Laboratory parameters with clinical significant abnormalities and/or reaching critical values : Hemoglobin (< 7g/dl), hematocrit, red blood cell count, white blood cell, reticulocytes, platelets, glucose, creatinine, aspartate transferase (AST), alanine transferase (ALT > 3 ULN), alkaline phosphatase, total bilirubine > 1.5 ULN. History or presence of any clinically significant disease or symptoms which might confound the interpretation of the safety and efficacy information. Splenectomized patients. Presence of criteria for complicated malaria Patients unable to drink Breastfeeding patients. Permanent vomiting. Female participants with child bearing potential not willing to use an effective contraceptive(s) method(s) for the duration of the study (e.g. implants, oral contraceptives, some intra-uterine devices or a double barrier method). The need for an efficient method will be reminded to the patient and the patient's legal guardian(s) by the investigator. Previous treatment within 5 times the elimination half-life or within the last 14 days, whichever the longest : with any anti-malaria agents i.e., quinine, chloroquine, amodiaquine, mefloquine, halofantrine, sufladoxine-pyrimethamine, doxycycline-pyrimethamine, primaquine, artemether, atovaquone, proguanil, lumefantrine, with an other investigational drug with 2D6 main substrates Past or concomitant participation in a study with an anti-malaria vaccine. Measles vaccine injection within the last 15 days.
Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ferroquine high dose + artesunate<br>Ferroquine at 6 mg/kg/d OD and artesunate 4mg/kg/d OD for 3 days + ferroquine placebo capsules to maintain the blind between treatment groups. | Drug: Ferroquine (SSR97193)<br>* Pharmaceutical form: capsule Route of administration: oral<br>Drug: Placebo<br>* Pharmaceutical form: capsule Route of administration: oral<br>Drug: artesunate<br>* Pharmaceutical form: tablets Route of administration: oral<br>|
| Experimental: Ferroquine medium dose + artesunate<br>Ferroquine at 4 mg/kg/d OD and artesunate 4mg/kg/d OD for 3 days + ferroquine placebo capsules to maintain the blind between treatment groups. | Drug: Ferroquine (SSR97193)<br>* Pharmaceutical form: capsule Route of administration: oral<br>Drug: Placebo<br>* Pharmaceutical form: capsule Route of administration: oral<br>Drug: artesunate<br>* Pharmaceutical form: tablets Route of administration: oral<br>|
| Experimental: Ferroquine low dose + artesunate<br>Ferroquine at 2 mg/kg/d OD and artesunate 4mg/kg/d OD for 3 days + ferroquine placebo capsules to maintain the blind between treatment groups. | Drug: Ferroquine (SSR97193)<br>* Pharmaceutical form: capsule Route of administration: oral<br>Drug: Placebo<br>* Pharmaceutical form: capsule Route of administration: oral<br>Drug: artesunate<br>* Pharmaceutical form: tablets Route of administration: oral<br>|
| Experimental: Ferroquine alone at medium dose<br>Ferroquine at 4 mg/kg/d OD alone for 3 days + ferroquine placebo capsules to maintain the blind between treatment groups. | Drug: Ferroquine (SSR97193)<br>* Pharmaceutical form: capsule Route of administration: oral<br>Drug: Placebo<br>* Pharmaceutical form: capsule Route of administration: oral<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recrudescent infections at D28 in the groups with ferroquine associated with artesunate. Recrudescence is defined as the recurrence of the same original strain of Plasmodium falciparum regardless of clinical symptoms |  | 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cure rate at Day 28 |  | 4 weeks | 
| Parasite Clearance Time (Median). |  | up to 63 days | 
| Fever Clearance Time (Median) |  | up to 63 days | 
| Recrudescent infections at Day 28 in the ferroquine group in monotherapy |  | 4 weeks | 
| Recrudescent infections at Day 63 |  | 9 weeks | 
| Adequate Clinical and Parasitological Response (ACPR) at D28 |  | 4 weeks |