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 (FALCI)

Sanofi

Status and phase: Terminated; Phase 2

Conditions: Plasmodium Falciparum Infection

Treatments: Other: Placebo; Drug: Ferroquine SSR97193; Drug: Artefenomel

Study type: Interventional

Funder types: Other; Industry

Identifiers

NCT02497612

DRI12805

U1111-1155-7960 (Other Identifier)

Details and patient eligibility

About

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.

Full description

Total duration was 63 days for each participant.

Enrollment: 377 patients

Sex: All

Ages: 6 months to 69 years old

Volunteers: No Healthy Volunteers

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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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377 participants in 4 patient groups

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

Experimental group

Description:

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.

Treatment:

Drug: Ferroquine SSR97193

Other: Placebo

Drug: Artefenomel

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

Experimental group

Description:

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.

Treatment:

Drug: Ferroquine SSR97193

Other: Placebo

Drug: Artefenomel

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

Experimental group

Description:

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.

Treatment:

Drug: Ferroquine SSR97193

Other: Placebo

Drug: Artefenomel

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

Experimental group

Description:

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.

Treatment:

Drug: Ferroquine SSR97193

Other: Placebo

Drug: Artefenomel