To Evaluate the Efficacy, Safety, Tolerability and Pharmacokinetics of a Single Dose Regimen of Ferroquine and Artefenomel in Adults and Children With Uncomplicated Plasmodium Falciparum Malaria

NCT ID: NCT02497612

Last Updated: 2022-03-24

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE2
• Total Enrollment: 377 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-07-25
• Study Completion Date: 2019-09-23

Brief Summary

Primary Objective:

To determine whether a single dose combination of OZ439 (Artefenomel)/FQ (Ferroquine) was an efficacious treatment for uncomplicated Plasmodium falciparum malaria in adults and children.

Secondary Objectives:

• To evaluate the efficacy of OZ439/FQ:

• To determine the incidence of recrudescence and re-infection.
• To determine the time to relief of fever and parasite clearance.
• To evaluate the safety and tolerability of OZ439/FQ in adults and children.
• To characterize the pharmacokinetics of OZ439 in plasma, FQ and its active metabolite SSR97213 in blood.
• To determine the blood/plasma ratio for FQ and SSR97213 in some participants at limited time points in selected sites.

Detailed Description

Total duration was 63 days for each participant.

Conditions

Plasmodium Falciparum Infection

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Ferroquine (up to 400 mg) + Artefenomel (up to 800 mg)

On Day 0, based on the body weight (BW), participants received orally a single dose of ferroquine (FQ) capsules or oral suspension (along with matching placebo, as applicable to maintain blinding) and a single dose of artefenomel (OZ439) (maximum dose up to 800 milligrams \[mg\]) oral suspension as follows: BW greater than or equal to (\>=) 35 kilograms (kg): FQ 400 mg + OZ439 800 mg; BW \>=24 kg to less than (\<) 35 kg: FQ 300 mg + OZ439 600 mg; BW \>=15 kg to \<24 kg: FQ 200 mg + OZ439 400 mg; BW \>=10 kg to \<15 kg: FQ 150 mg + OZ439 300 mg; BW \>=7 kg to \<10 kg: FQ 100 mg + OZ439 200 mg; \>=5 kg to \<7kg: FQ 75 mg + OZ439 150 mg.

Group Type: EXPERIMENTAL

Ferroquine SSR97193

Intervention Type: DRUG

Pharmaceutical form:Capsules Route of administration: oral

Artefenomel

Intervention Type: DRUG

Pharmaceutical form:Granules for suspension Route of administration: oral

Placebo

Intervention Type: OTHER

Capsules. Placebo capsules were used to keep the same number of capsules in each weight band while keeping the ferroquine dose blinded. No participant received placebo only.

Ferroquine (up to 600 mg) + Artefenomel (up to 800 mg)

On Day 0, based on the BW, participants received orally a single dose of FQ capsules or oral suspension (along with matching placebo, as applicable to maintain blinding) and a single dose of OZ439 (maximum dose up to 800 mg) oral suspension as follows: BW \>= 35 kg: FQ 600 mg + OZ439 800 mg; BW \>=24 kg to \<35 kg: FQ 450 mg + OZ439 600 mg; BW \>=15 kg to \<24 kg: FQ 300 mg + OZ439 400 mg; BW \>=10 kg to \<15 kg: FQ 225 mg + OZ439 300 mg; BW \>=7 kg to \<10 kg: FQ 150 mg + OZ439 200 mg; \>=5 kg to \<7kg: FQ 115 mg + OZ439 150 mg.

Group Type: EXPERIMENTAL

Ferroquine SSR97193

Intervention Type: DRUG

Pharmaceutical form:Capsules Route of administration: oral

Artefenomel

Intervention Type: DRUG

Pharmaceutical form:Granules for suspension Route of administration: oral

Placebo

Intervention Type: OTHER

Capsules. Placebo capsules were used to keep the same number of capsules in each weight band while keeping the ferroquine dose blinded. No participant received placebo only.

Ferroquine (up to 900 mg) + Artefenomel (up to 800 mg)

On Day 0, based on the BW, participants received orally a single dose of FQ capsules or oral suspension (along with matching placebo, as applicable to maintain blinding) and a single dose of OZ439 (maximum dose up to 800 mg) oral suspension as follows: BW \>= 35 kg: FQ 900 mg + OZ439 800 mg; BW \>=24 kg to \<35 kg: FQ 675 mg + OZ439 600 mg; BW \>=15 kg to \<24 kg: FQ 450 mg + OZ439 400 mg; BW \>=10 kg to \<15 kg: FQ 335 mg + OZ439 300 mg; BW \>=7 kg to \<10 kg: FQ 225 mg + OZ439 200 mg; \>=5 kg to \<7kg: FQ 170 mg + OZ439 150 mg.

Group Type: EXPERIMENTAL

Ferroquine SSR97193

Intervention Type: DRUG

Pharmaceutical form:Capsules Route of administration: oral

Artefenomel

Intervention Type: DRUG

Pharmaceutical form:Granules for suspension Route of administration: oral

Placebo

Intervention Type: OTHER

Capsules. Placebo capsules were used to keep the same number of capsules in each weight band while keeping the ferroquine dose blinded. No participant received placebo only.

Ferroquine (up to 1200 mg) + Artefenomel (up to 800 mg)

On Day 0, based on the BW, participants received orally a single dose of FQ capsules or oral suspension (along with matching placebo, as applicable to maintain blinding) and a single dose of OZ439 (maximum dose up to 800 mg) oral suspension as follows: BW \>= 35 kg: FQ 1200 mg + OZ439 800 mg; BW \>=24 kg to \<35 kg: FQ 900 mg + OZ439 600 mg; BW \>=15 kg to \<24 kg: FQ 600 mg + OZ439 400 mg; BW \>=10 kg to \<15 kg: FQ 450 mg + OZ439 300 mg; BW \>=7 kg to \<10 kg: FQ 300 mg + OZ439 200 mg; \>=5 kg to \<7kg: FQ 225 mg + OZ439 150 mg.

Group Type: EXPERIMENTAL

Ferroquine SSR97193

Intervention Type: DRUG

Pharmaceutical form:Capsules Route of administration: oral

Artefenomel

Intervention Type: DRUG

Pharmaceutical form:Granules for suspension Route of administration: oral

Placebo

Intervention Type: OTHER

Capsules. Placebo capsules were used to keep the same number of capsules in each weight band while keeping the ferroquine dose blinded. No participant received placebo only.

Interventions

Ferroquine SSR97193

Pharmaceutical form:Capsules Route of administration: oral

Intervention Type: DRUG

Artefenomel

Pharmaceutical form:Granules for suspension Route of administration: oral

Intervention Type: DRUG

Placebo

Capsules. Placebo capsules were used to keep the same number of capsules in each weight band while keeping the ferroquine dose blinded. No participant received placebo only.

Intervention Type: OTHER

Eligibility Criteria

Inclusion Criteria

Male or female participant aged greater than (>) 6 months old and <70 years old:

• Cohort 1 = 14 years < age <70 years and body weight greater than or equal to (>=) 35 kilogram (kg).
• Cohort 2 = 5 years < age less than or equal to (<=) 14 years.
• Cohort 3 = 2 years < age <=5 years.
• Cohort 4 = 6 months < age <=2 years.

Body weight >=5 kg and <=90 kg.

Presence of mono-infection by Plasmodium falciparum with:

• Fever, as defined by axillary temperature >=37.5 degrees Celsius (°C) or oral/rectal/tympanic temperature >=38°C, or history of fever in the previous 24 hours (history of fever must be documented) and,
• Microscopically (blood smear) confirmed parasite infection, ranging from 1000 to 100 000 asexual parasites/microliter of blood.

Informed consent form signed by the participant or by the legally acceptable representative of the minor participant.

Exclusion Criteria

Presence of severe malaria.

Anti-malarial treatment:

• With piperaquine-based compound, mefloquine, naphthoquine or sulphadoxine/pyrimethamine (SP) within the previous 6 weeks (after their inhibition of new infections had fallen below 50%).
• With amodiaquine or chloroquine within the previous 4 weeks.
• With quinine, halofantrine, lumefantrine-based compounds and any other anti-malarial treatment or antibiotics with antimalarial activity (including cotrimoxazole, tetracyclines, quinolones and fluoroquinolones, and azithromycin) within the past 14 days.
• With any herbal products or traditional medicines, within the past 7 days.

Known history or evidence of clinically significant disorders.

Previous treatment within 5 times the half-life or within the last 14 days, whichever the longest which are: P-glycoprotein substrates, Cytochrome P450 (CYP) 2D6 main substrates and/or strong CYP2C or CYP3A inhibitors and/or moderate inhibitors but inhibiting both CYP2C and CYP3A and/or CYP inducers.

Mixed plasmodium infection.

Severe vomiting.

Severe malnutrition.

Laboratory parameters with clinically significant abnormalities and/or reaching critical values. For Liver Function Test. Aspartate aminotransferase (>2 [upper limit of normal] ULN), or alanine aminotransferase (>2 ULN) or total bilirubin >1.5 ULN.

Presence of Hepatitis A Immunoglobulin M, Hepatitis B surface antigen or Hepatitis C antibody.

Had received an investigational drug within the past 4 weeks.

Previous participation in any malaria vaccine study or received malaria vaccine in any other circumstance.

Measles and yellow fever vaccine injection within the last 15 days and or planned for the 28 days after randomization.

Female participant of child bearing potential not willing to use an effective contraceptive(s) method(s) for the duration of the study.

Positive serum or urine beta-human chorionic gonadotropin pregnancy test at study screening for female participants of childbearing potential.

Breastfeeding women.

Male participant having a partner of child bearing potential not willing to use an effective method of birth control during the study treatment period.

Splenectomized participants or presence of surgical scar on left hypochondrium. Participant unable to drink.

Known history of hypersensitivity, allergic or anaphylactoid reactions to ferroquine or other amino-quinolines or to OZ439 or OZ277 or to any of the excipients.

Family history of sudden death or of congenital prolongation of the Corrected QT (QTc) interval or known congenital prolongation of the QTc interval or any clinical condition known to prolong the QTc interval e.g., participants with a history of symptomatic cardiac arrhythmias or with clinically relevant bradycardia.

QTc using Fridericia's formula >450 millisecond at screening or pre-dose.

Hypokalemia (<3.5 millimoles per liter [mmol/L]), hypocalcemia (<2.0 mmol/L) or hypomagnesemia (<0.5 mmol/L) at screening or pre-dose.

Any treatment known to induce a lengthening of QT interval.

The above information is not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.

• Minimum Eligible Age: 6 Months
• Maximum Eligible Age: 69 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Medicines for Malaria Venture

OTHER

Sponsor Role: collaborator

Sanofi

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Clinical Sciences & Operations

Role: STUDY_DIRECTOR

Sanofi

Locations

Investigational Site Number 204001

Cotonou, , Benin

Investigational Site Number 854002

Comoé, , Burkina Faso

Investigational Site Number 854003

Niangoloko, , Burkina Faso

Investigational Site Number 854001

Ouagadougou, , Burkina Faso

Investigational Site Number 266002

Lambaréné, , Gabon

Investigational Site Number 266001

Libreville, , Gabon

Investigational Site Number 404003

Kisumu, , Kenya

Investigational Site Number 404002

Siaya, , Kenya

Investigational Site Number 508001

Chokwé, , Mozambique

Investigational Site Number 800002

Tororo, , Uganda

Investigational Site Number 704003

Bình Phước, , Vietnam

Investigational Site Number 704004

Pleiku, , Vietnam

Countries

Benin; Burkina Faso; Gabon; Kenya; Mozambique; Uganda; Vietnam

References

Adoke Y, Zoleko-Manego R, Ouoba S, Tiono AB, Kaguthi G, Bonzela JE, Duong TT, Nahum A, Bouyou-Akotet M, Ogutu B, Ouedraogo A, Macintyre F, Jessel A, Laurijssens B, Cherkaoui-Rbati MH, Cantalloube C, Marrast AC, Bejuit R, White D, Wells TNC, Wartha F, Leroy D, Kibuuka A, Mombo-Ngoma G, Ouattara D, Mugenya I, Phuc BQ, Bohissou F, Mawili-Mboumba DP, Olewe F, Soulama I, Tinto H; FALCI Study Group. A randomized, double-blind, phase 2b study to investigate the efficacy, safety, tolerability and pharmacokinetics of a single-dose regimen of ferroquine with artefenomel in adults and children with uncomplicated Plasmodium falciparum malaria. Malar J. 2021 May 19;20(1):222. doi: 10.1186/s12936-021-03749-4.

Reference Type: DERIVED

PMID: 34011358 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

U1111-1155-7960

Identifier Type: OTHER

Identifier Source: secondary_id

DRI12805

Identifier Type: -

Identifier Source: org_study_id