Clinical trial NCT02497612: 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
Official title: A Randomized, Double-blind, Phase IIb Study to Investigate the Efficacy, Safety, Tolerability and Pharmacokinetics of a Single Dose Regimen of Ferroquine (FQ) With Artefenomel (OZ439) in Adults and Children With Uncomplicated Plasmodium Falciparum Malaria
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Plasmodium Falciparum Infection
Lead sponsor: Sanofi
Sponsor class: INDUSTRY
Collaborators: name: Medicines for Malaria Venture
First posted: 2015-07-14
Enrollment: 377
Sex: ALL
Minimum age (years): 6
Maximum age (years): 69
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Percentage of Participants With Polymerase Chain Reaction (PCR)-Adjusted Adequate Clinical and Parasitological Response (ACPR) at Day 28: African <=5 Years Per Protocol Population at Day 28 (PP28)
timeFrame: Day 28
Secondary outcomes:
measure: Percentage of Participants With Polymerase Chain Reaction-adjusted Adequate Clinical and Parasitological Response at Day 28: African >5 Years Per Protocol Population at Day 28 (A5PP28)
timeFrame: Day 28
measure: Percentage of Participants With Polymerase Chain Reaction-adjusted Adequate Clinical and Parasitological Response at Day 28: Asian PP Population at Day 28 (APP28)
timeFrame: Day 28
measure: Percentage of Participants With Polymerase Chain Reaction-adjusted Adequate Clinical and Parasitological Response at Day 42: African <=5 Years PP Population at Day 42 (PP42)
timeFrame: Day 42
measure: Percentage of Participants With Polymerase Chain Reaction-adjusted Adequate Clinical and Parasitological Response at Day 63: African <=5 Years PP Population at Day 63 (PP63)
timeFrame: Day 63
measure: Percentage of Participants With Crude Adequate Clinical and Parasitological Response at Day 28: African <=5 Years PP28 Population
timeFrame: Day 28
measure: Percentage of Participants With Crude Adequate Clinical and Parasitological Response at Day 42: African <=5 Years PP42 Population
timeFrame: Day 42
measure: Percentage of Participants With Crude Adequate Clinical and Parasitological Response at Day 63: African <=5 Years PP63 Population
timeFrame: Day 63
measure: Time to Re-emergence
timeFrame: Up to Day 63
measure: Time to Recrudescence
timeFrame: Up to Day 63
measure: Time to Re-infection
timeFrame: Up to Day 63
measure: Parasite Clearance Time (PCT): African <=5 Years PP Population
timeFrame: From the start of study drug administration up to the time of the first negative film (up to Day 63)
measure: Parasite Clearance Time: African >5 Years PP Population
timeFrame: From the start of study drug administration up to the time of the first negative film (up to Day 63)
measure: Parasite Clearance Time: Asian PP Population
timeFrame: From the start of study drug administration up to the time of the first negative film (up to Day 63)
measure: Fever Clearance Time (FCT): African <=5 Years PP Population
timeFrame: From the start of study drug administration up to the time of the first temperature measurement <37.5°C (up to Day 63)
measure: Fever Clearance Time: African >5 Years PP Population
timeFrame: From the start of study drug administration up to the time of the first temperature measurement <37.5°C (up to Day 63)
measure: Fever Clearance Time: Asian PP Population
timeFrame: From the start of study drug administration up to the time of the first temperature measurement <37.5°C (up to Day 63)
measure: Parasite Reduction Ratio (PRRlog10) at 24 Hours and 48 Hours: African <=5 Years PP Population
timeFrame: 24 and 48 hours post dose
measure: Parasite Reduction Ratio at 24 Hours and 48 Hours: African >5 Years PP Population
timeFrame: 24 and 48 hours post dose
measure: Parasite Reduction Ratio at 24 Hours and 48 Hours: Asian PP Population
timeFrame: 24 and 48 hours post dose
measure: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs) and Adverse Event of Special Interest (AESI)
timeFrame: From Baseline up to Day 63
measure: Pharmacokinetics (PK): Maximum Observed Plasma Concentration (Cmax) of Artefenomel
timeFrame: 2, 4, 6, 12, 24, 48, 72 and 672 hours post dose
measure: Pharmacokinetics: Area Under the Curve From Time 0 to Infinity (AUC0-inf) of Artefenomel
timeFrame: 2, 4, 6, 12, 24, 48, 72 and 672 hours post dose
measure: Pharmacokinetics (PK): Apparent Total Clearance of Artefenomel From Plasma After Oral Administration
timeFrame: 2, 4, 6, 12, 24, 48, 72 and 672 hours post dose
measure: Pharmacokinetics: Apparent Volume of Distribution at Steady State After Non-intravenous Administration (Vss/F) of Artefenomel
timeFrame: 2, 4, 6, 12, 24, 48, 72 and 672 hours post dose
measure: Pharmacokinetics: Maximum Observed Plasma Concentration of Ferroquine (Cmax)
timeFrame: 2, 4, 6, 12, 24, 48, 72 and 672 hours post dose
measure: Pharmacokinetics: Area Under the Curve From Time 0 to Day 28 (AUC0-day28) of Ferroquine
timeFrame: 2, 4, 6, 8, 12, 24, 48, 168, 336 and 672 hours postdose
measure: Pharmacokinetics: Apparent Total Clearance of Ferroquine From Plasma After Oral Administration
timeFrame: 2, 4, 6, 12, 24, 48, 72 and 672 hours post dose
measure: Pharmacokinetics: Apparent Volume of Distribution at Steady State After Non-intravenous Administration of Ferroquine
timeFrame: 2, 4, 6, 12, 24, 48, 72 and 672 hours post dose
measure: Pharmacokinetics: Blood/Plasma Ratio for Ferroquine and Its Active Metabolite SSR97213
timeFrame: 2, 4, 6, 12, 24, 48, 72 and 672 hours post dose
Other outcomes:
Locations:
city: Cotonou
country: Benin
facility: Investigational Site Number 204001
city: Comoé
country: Burkina Faso
facility: Investigational Site Number 854002
city: Niangoloko
country: Burkina Faso
facility: Investigational Site Number 854003
city: Ouagadougou
country: Burkina Faso
facility: Investigational Site Number 854001
city: Lambaréné
country: Gabon
facility: Investigational Site Number 266002
city: Libreville
country: Gabon
facility: Investigational Site Number 266001
city: Kisumu
country: Kenya
facility: Investigational Site Number 404003
city: Siaya
country: Kenya
facility: Investigational Site Number 404002
city: Chokwé
country: Mozambique
facility: Investigational Site Number 508001
city: Tororo
country: Uganda
facility: Investigational Site Number 800002
city: Binh Phuoc
country: Vietnam
facility: Investigational Site Number 704003
city: Gia Lai
country: Vietnam
facility: Investigational Site Number 704004
Study officials:
affiliation: Sanofi
name: Clinical Sciences & Operations
role: STUDY_DIRECTOR
References:
citation: 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.