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

Phase 2TerminatedNCT02497612

Sanofi377 enrolled

Overview

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.

Total duration was 63 days for each participant.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

377

Conditions

Plasmodium Falciparum Infection

Interventions

Eligibility

Sex: ALLMin age: 6 MonthsMax age: 69 Years

Medical Language ↔ Plain English

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.

Locations (12)

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

...and 2 more locations

Outcomes

Primary Outcomes

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)

ACPR: negative parasitemia at Day 28, irrespective of axillary temperature(AT), in participants not meeting any criteria of early therapy failure (ETF):Danger signs (DS)/severe malaria (SM) at Day 1, 2 or 3 in presence of parasitemia; or Day 2 parasite count \>Day 0 irrespective of AT; or parasitemia at Day 3 with AT \>=37.5 degree Celsius (°C); or parasite count on Day 3\>=25 percent (%) on Day 0, or late clinical failure(LCF):DS/ SM in presence of parasitemia between Day 4 and 28; or presence of parasitemia and AT\>=37.5°C between Day 4 and 28, or late parasitological failure (LPF):presence of parasitemia between Day 7 and 28 and AT\<37.5°C or having rescue therapy for malaria. PCR-adjusted ACPR applied to recrudescence (appearance of asexual parasites after clearance of initial infection with genotype identical to that present at Baseline), excluding participants with re-infection. In data table, "overall number of participants analyzed"=participants evaluable for this outcome measure.

Time frame: Day 28

Secondary Outcomes

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)

ACPR: negative parasitemia at Day 28, irrespective of AT, in participants not meeting any criteria of ETF: DS or SM at Day 1, 2 or 3 in presence of parasitemia; or Day 2 parasite count \> Day 0 irrespective of AT; or parasitemia at Day 3 with AT \>=37.5°C; or parasite count on Day 3 \>=25% on Day 0, or LCF: DS/ SM in presence of parasitemia between Day 4 and 28; or presence of parasitemia and AT \>=37.5°C between Day 4 and 28, or LPF: presence of parasitemia between Day 7 and 28 and AT \<37.5°C or having rescue therapy for malaria. PCR-adjusted ACPR was applied to recrudescence (appearance of asexual parasites after clearance of initial infection with a genotype identical to that of parasites present at Baseline), excluding participants with re-infection. Here, in the data table, "overall number of participants analyzed"=participants evaluable for this outcome measure.

Time frame: Day 28

Percentage of Participants With Polymerase Chain Reaction-adjusted Adequate Clinical and Parasitological Response at Day 28: Asian PP Population at Day 28 (APP28)

Time frame: Day 28

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)

ACPR: negative parasitemia at Day 42, irrespective of AT, in participants not meeting any criteria of ETF: DS or SM at Day 1, 2 or 3 in presence of parasitemia; or Day 2 parasite count \> Day 0 irrespective of AT; or parasitemia at Day 3 with AT \>=37.5°C; or parasite count on Day 3 \>=25% on Day 0, or LCF: DS/ SM in presence of parasitemia between Day 4 and 42; or presence of parasitemia and AT \>=37.5°C between Day 4 and 42, or LPF: presence of parasitemia between Day 7 and 42 and AT \<37.5°C or having rescue therapy for malaria. PCR-adjusted ACPR was applied to recrudescence (appearance of asexual parasites after clearance of initial infection with a genotype identical to that of parasites present at Baseline), excluding participants with re-infection. Here, in the data table, "overall number of participants analyzed"=participants evaluable for this outcome measure.

Time frame: Day 42

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)

ACPR: negative parasitemia at Day 63, irrespective of AT, in participants not meeting any criteria of ETF: DS or SM at Day 1, 2 or 3 in presence of parasitemia; or Day 2 parasite count \> Day 0 irrespective of AT; or parasitemia at Day 3 with AT \>=37.5°C; or parasite count on Day 3 \>=25% on Day 0, or LCF: DS/ SM in presence of parasitemia between Day 4 and 63; or presence of parasitemia and AT \>=37.5°C between Day 4 and 63, or LPF: presence of parasitemia between Day 7 and 63 and AT \<37.5°C or having rescue therapy for malaria. PCR-adjusted ACPR was applied to recrudescence (appearance of asexual parasites after clearance of initial infection with a genotype identical to that of parasites present at Baseline), excluding participants with re-infection. Here, in the data table, "overall number of participants analyzed"=participants evaluable for this outcome measure.

Time frame: Day 63

Percentage of Participants With Crude Adequate Clinical and Parasitological Response at Day 28: African <=5 Years PP28 Population

ACPR was defined as negative parasitemia at Day 28, irrespective of AT, in participants not meeting any criteria of ETF: DS or SM at Day 1, 2 or 3 in presence of parasitemia; or Day 2 parasite count \> Day 0 irrespective of AT; or parasitemia at Day 3 with AT \>=37.5°C; or parasite count on Day 3 \>=25% on Day 0, or LCF: DS/ SM in presence of parasitemia between Day 4 and 28; or presence of parasitemia and AT \>=37.5°C between Day 4 and 28 or, LPF: presence of parasitemia between Day 7 and 28 and AT \<37.5°C or having rescue therapy for malaria. PCR-adjusted ACPR applied to recrudescence (appearance of asexual parasites after clearance of initial infection with a genotype identical to that of parasites present at Baseline), excluding participants with re-infection, whereas crude ACPR does not distinguish re-infection (new clone of parasite) or recrudescence.

Time frame: Day 28

Percentage of Participants With Crude Adequate Clinical and Parasitological Response at Day 42: African <=5 Years PP42 Population

ACPR was defined as negative parasitemia at Day 42, irrespective of AT, in participants not meeting any criteria of ETF: DS or SM at Day 1, 2 or 3 in presence of parasitemia; or Day 2 parasite count \> Day 0 irrespective of AT; or parasitemia at Day 3 with AT \>=37.5°C; or parasite count on Day 3 \>=25% on Day 0, or LCF: DS/ SM in presence of parasitemia between Day 4 and 42; or presence of parasitemia and AT \>=37.5°C between Day 4 and 42 or, LPF: presence of parasitemia between Day 7 and 42 and AT \<37.5°C or having rescue therapy for malaria PCR-adjusted ACPR applied to recrudescence (appearance of asexual parasites after clearance of initial infection with a genotype identical to that of parasites present at Baseline), excluding participants with re-infection, whereas crude ACPR did not distinguish re-infection (new clone of parasite) or recrudescence.

Time frame: Day 42

Percentage of Participants With Crude Adequate Clinical and Parasitological Response at Day 63: African <=5 Years PP63 Population

Crude ACPR was defined as negative parasitemia at Day 63, irrespective of AT, in participants not meeting any criteria of ETF: DS or SM at Day 1, 2 or 3 in presence of parasitemia; or Day 2 parasite count \> Day 0 irrespective of AT; or parasitemia at Day 3 with AT \>=37.5°C; or parasite count on Day 3 \>=25% on Day 0, or LCF: DS/ SM in presence of parasitemia between Day 4 and 63; or presence of parasitemia and AT \>=37.5°C between Day 4 and 63 or, LPF: presence of parasitemia between Day 7 and 63 and AT \<37.5°C or having rescue therapy for malaria. PCR-adjusted ACPR applied to recrudescence (appearance of asexual parasites after clearance of initial infection with a genotype identical to that of parasites present at Baseline), excluding participants with re-infection, whereas crude ACPR did not distinguish re-infection (new clone of parasite) or recrudescence.

Time frame: Day 63

Time to Re-emergence

Time to re-emergence (in days) was defined as the time to appearance of asexual parasites after clearance of initial infection irrespective of genotype. Participants with no event were censored at the time of study completion, premature study discontinuation, including switch to established anti-malarial treatment or start of any other treatment with anti-malarial activity, whichever was earliest. Re-emergence was confirmed by microscopy (positive blood smear). Kaplan-Maier method was used for estimation. Here, "overall number of participants analyzed"=participants who were included in the analysis of below reported results which consisted of both, who had the event, plus those who were censored.

Time frame: Up to Day 63

Time to Recrudescence

Time to recrudescence (in days) was defined as the time to appearance of asexual parasites after clearance of initial infection with a genotype identical to that of parasites present at Baseline. Recrudescence was confirmed by PCR analysis. Kaplan-Maier method was used for estimation.

Time frame: Up to Day 63

Time to Re-infection

Time to re-infection (in days) was defined as the time to appearance of asexual parasites after clearance of initial infection with a genotype that differs from that of parasites present at Baseline. Re-infection was confirmed by PCR analysis. Kaplan-Maier method was used for estimation.

Time frame: Up to Day 63

Parasite Clearance Time (PCT): African <=5 Years PP Population

PCT was defined as the time (in hours) from the start of study drug administration until the time of first negative blood film (no asexual parasites). This first negative film was confirmed by a second negative film which was taken \>=6 to \<=12 hours of the first film. Kaplan-Meier method was used for the estimation. Here, in the data table "overall number of participants analyzed"=participants who were included in the analysis of below reported results which consisted of both, who had the event, plus those who were censored.

Time frame: From the start of study drug administration up to the time of the first negative film (up to Day 63)

Parasite Clearance Time: African >5 Years PP Population

PCT was defined as the time (in hours) from the start of study drug administration until the time of first negative blood film (no asexual parasites). This first negative film was confirmed by a second negative film which was taken \>=6 to \<=12 hours of the first film. Kaplan-Meier method was used for the estimation. Here, "overall number of participants analyzed"=participants who were included in the analysis of below reported results which consisted of both, who had the event, plus those who were censored.

Time frame: From the start of study drug administration up to the time of the first negative film (up to Day 63)

Parasite Clearance Time: Asian PP Population

PCT was defined as the time (in hours) from the start of study drug administration until the time of first negative blood film (no asexual parasites). This first negative film was confirmed by a second negative film which was taken \>=6 to \<=12 hours of the first film. Kaplan-Meier method was used for the estimation. Here, "overall number of participants analyzed"=participants who were included in the analysis of below reported results which consisted of both, who had the event, plus those who were censored.

Time frame: From the start of study drug administration up to the time of the first negative film (up to Day 63)

Fever Clearance Time (FCT): African <=5 Years PP Population

FCT was defined as the time (in hours) from start of study drug administration to the first assessment of adjusted body temperature \<37.5°C, confirmed by second assessment, taken within \>=6 to \<=12 hours of the first assessment. Only participants with fever (adjusted body temperature \>=37.5°C present at Baseline) and did not receive paracetamol on day of study drug administration until 96 hours after study drug administration were included in FCT analysis. Participants with no event were censored at the time of study completion, premature study discontinuation, including switch to established anti-malarial treatment or start of any other treatment with anti-malarial activity, whichever was earliest. Kaplan-Meier method was used for the estimation.

Time frame: From the start of study drug administration up to the time of the first temperature measurement <37.5°C (up to Day 63)

Fever Clearance Time: African >5 Years PP Population

FCT was defined as the time (in hours) from start of study drug administration to the first assessment of adjusted body temperature \<37.5°C, confirmed by second assessment, taken within \>=6 to \<=12 hours of the first. Only participants with fever (adjusted body temperature \>=37.5°C present at Baseline) and did not receive paracetamol on day of study drug administration until 96 hours after study drug administration were included in FCT analysis. Participants with no event were censored at the time of study completion, premature study discontinuation, including switch to established anti-malarial treatment or start of any other treatment with anti-malarial activity, whichever was earliest. Kaplan-Meier method was used for the estimation.

Time frame: From the start of study drug administration up to the time of the first temperature measurement <37.5°C (up to Day 63)

Fever Clearance Time: Asian PP Population

FCT was defined as the time (in hours) from start of study drug administration to the first assessment of adjusted body temperature \<37.5°C, confirmed by second assessment, taken within \>=6 to \<=12 hours of the first. Only participants with fever (adjusted body temperature \>=37.5°C present at Baseline) and did not receive paracetamol on day of study drug administration until 96 hours after study drug administration were included in FCT analysis. Participants with no event were censored at the time of study completion, premature study discontinuation, including switch to established anti-malarial treatment or start of any other treatment with anti-malarial activity, whichever was earliest. Kaplan-Meier method was used for the estimation. Here, "overall number of participants analyzed"=participants who were included in the analysis of below reported results which consisted of both, who had the event, plus those who were censored.

Time frame: From the start of study drug administration up to the time of the first temperature measurement <37.5°C (up to Day 63)

Parasite Reduction Ratio (PRRlog10) at 24 Hours and 48 Hours: African <=5 Years PP Population

The PRR was calculated as the slope of the linear portion of the regression fit of logarithm parasitemia (per milliliter) versus time (in hours). The PRR24 and PRR48 was the drop-in log units over 24 and 48 hours, respectively.

Time frame: 24 and 48 hours post dose

Parasite Reduction Ratio at 24 Hours and 48 Hours: African >5 Years PP Population

Time frame: 24 and 48 hours post dose

Parasite Reduction Ratio at 24 Hours and 48 Hours: Asian PP Population

Time frame: 24 and 48 hours post dose

Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs) and Adverse Event of Special Interest (AESI)

An AE was defined as any untoward medical occurrence in a participant who received study drug and did not necessarily had to have a causal relationship with the treatment. SAEs were any untoward medical occurrence that resulted in any of the following outcomes: death, life-threatening, required initial or prolonged in-patient hospitalization, persistent or significant disability/incapacity, congenital anomaly/birth defect, or considered as medically important event. TEAEs were defined as AEs that developed or worsened or became serious during on-treatment phase that was defined as the time from the start of the first dose of double-blind drug administration up to the Day 63. AE of special interest (AESI) was an AE (serious or non-serious) of scientific and medical concern specific to the Sponsor's product or program, for which ongoing monitoring and immediate notification by the Investigator to the Sponsor was required.

Time frame: From Baseline up to Day 63

Pharmacokinetics (PK): Maximum Observed Plasma Concentration (Cmax) of Artefenomel

Cmax is the maximum observed plasma concentration of artefenomel.