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

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.

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.

Study Overview

• Status: Terminated
• Conditions: Plasmodium Falciparum Infection
• Intervention / Treatment: Drug: Placebo; Drug: Ferroquine (SSR97193); Drug: artesunate

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.

• Study Type: Interventional
• Enrollment (Anticipated): 440
• Phase: Phase 2

Contacts and Locations

Study Locations

• Benin
  • Cotonou, Benin
    • Sanofi-Aventis Investigational Site Number 204001
• Burkina Faso
  • Bobo-Dioulasso 01, Burkina Faso
    • Sanofi-Aventis Investigational Site Number 854002
  • Nouna, Burkina Faso
    • Sanofi-Aventis Investigational Site Number 854003
  • Ouagadougou, Burkina Faso
    • Sanofi-Aventis Investigational Site Number 854001
• Cameroon
  • Yaounde, Cameroon
    • Sanofi-Aventis Investigational Site Number 120001
• Gabon
  • B.P. 118 Lambarene, Gabon
    • Sanofi-Aventis Investigational Site Number 266001
  • Libreville, Gabon
    • Sanofi-Aventis Investigational Site Number 266002
• Kenya
  • Kilifi, Kenya
    • Sanofi-Aventis Investigational Site Number 404001
  • Kisumu, Kenya
    • Sanofi-Aventis Investigational Site Number 404002
• Tanzania
  • Korogwe, Tanzania
    • Sanofi-Aventis Investigational Site Number 834001

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

4

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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	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

Collaborators and Investigators

• Sponsor: Sanofi

Publications and helpful links

General Publications

• Held J, Supan C, Salazar CL, Tinto H, Bonkian LN, Nahum A, Moulero B, Sie A, Coulibaly B, Sirima SB, Siribie M, Otsyula N, Otieno L, Abdallah AM, Kimutai R, Bouyou-Akotet M, Kombila M, Koiwai K, Cantalloube C, Din-Bell C, Djeriou E, Waitumbi J, Mordmuller B, Ter-Minassian D, Lell B, Kremsner PG. Ferroquine and artesunate in African adults and children with Plasmodium falciparum malaria: a phase 2, multicentre, randomised, double-blind, dose-ranging, non-inferiority study. Lancet Infect Dis. 2015 Dec;15(12):1409-19. doi: 10.1016/S1473-3099(15)00079-1. Epub 2015 Sep 3.

Study record dates

Study Major Dates

• Study Start: October 1, 2009
• Primary Completion (Actual): November 1, 2010
• Study Completion (Actual): November 1, 2010

Study Registration Dates

• First Submitted: October 1, 2009
• First Submitted That Met QC Criteria: October 1, 2009
• First Posted (Estimate): October 2, 2009

Study Record Updates

• Last Update Posted (Estimate): June 28, 2011
• Last Update Submitted That Met QC Criteria: June 27, 2011
• Last Verified: June 1, 2011

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Infections; Vector Borne Diseases; Parasitic Diseases; Protozoan Infections; Malaria; Anti-Infective Agents; Antiviral Agents; Antineoplastic Agents; Antiprotozoal Agents; Antiparasitic Agents; Antimalarials; Anthelmintics; Schistosomicides; Antiplatyhelmintic Agents; Artesunate; Ferroquine
• Other Study ID Numbers: DRI10382