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

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

Population: African \<=5 years PP28: participants with parasitologically confirmed Plasmodium falciparum malaria at screening/baseline, received the single administration of OZ439/FQ, without major protocol violations impacting efficacy, evaluable for crude ACPR at Day 28, excluding those who received rescue treatment due to vomiting during drug administration.

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)

Population: Analysis was performed on African \>5 years PP population participants with fever and did not receive paracetamol within 96 hours of study drug administration. Here, overall number of participants analyzed=participants who were included in the analysis of below reported results which consisted of both, who had event, plus those who were censored.

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)

Population: Analysis was performed on Asian PP population participants with fever and did not receive paracetamol within 96 hours of study drug administration. Here, '0' in overall number of participants analyzed=no participants were evaluable since they had paracetamol within 96 hours of study drug administration.

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)

Population: Analyzed performed on African \<=5 years PP population participants with fever and did not receive paracetamol within 96 hours of study drug administration. Here, overall number of participants analyzed=participants who were included in the analysis of below reported results which consisted of both, who had event, plus those who were censored.

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

Population: Analyzed on safety population which included all randomized participants who received at least 1 dose or part of a dose of the study medication.

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)

Population: African \>5years PP population participants with parasitologically confirmed P.falciparum malaria at screening/baseline, received the single administration of OZ439/FQ, without major protocol violation impacting efficacy, evaluable for crude ACPR at pre-defined time point, excluding who had rescue treatment due to vomiting during drug administration

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)

Population: Asian PP population: participants with parasitologically confirmed P.falciparum malaria at screening/baseline, received the single administration of OZ439/FQ, without major protocol violations impacting efficacy, evaluable for crude ACPR at pre-defined time point, excluding who had rescue treatment due to vomiting during drug administration.

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)

Population: African\<=5years PP population participants with parasitologically confirmed P.falciparum malaria at screening/baseline, received the single administration of OZ439/FQ, without major protocol violation impacting efficacy, evaluable for crude ACPR at pre-defined time point, excluding who had rescue treatment due to vomiting during drug administration

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

Population: Analysis was performed on African \>5 years PP population. Here, overall number of participants analyzed=participants evaluable for this outcome measure.

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

Population: Analysis was performed on Asian PP population. Here, overall number of participants analyzed=participants evaluable for this outcome measure.

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

Population: Analysis was performed on African \<=5 years PP population. Here, overall number of participants analyzed=participants evaluable for this outcome measure.

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

Population: Analysis was performed on African \<=5 years PP28 population. Here, overall number of participants analyzed=participants evaluable for this outcome measure.

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

Population: Analysis was performed on African \<=5 years PP42 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

Population: Analysis was performed on African \<=5 years PP63 population.

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

Population: African \>5 years PP28: participants with parasitologically confirmed Plasmodium falciparum malaria at screening/baseline, received the single administration of OZ439/FQ, without major protocol violations impacting efficacy, evaluable for crude ACPR at Day 28, excluding those who received rescue treatment due to vomiting during drug administration.

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

Population: Asian PP28 population: participants with parasitologically confirmed Plasmodium falciparum malaria at screening/baseline, received the single administration of OZ439/FQ, without major protocol violations impacting efficacy, evaluable for crude ACPR at Day 28, excluding those who received rescue treatment due to vomiting during drug administration.

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

Population: African \<=5 years PP42: participants with parasitologically confirmed Plasmodium falciparum malaria at screening/baseline, received the single administration of OZ439/FQ, without major protocol violations impacting efficacy, evaluable for crude ACPR at Day 42, excluding those who received rescue treatment due to vomiting during drug administration.

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

Population: African \<=5 years PP63: participants with parasitologically confirmed Plasmodium falciparum malaria at screening/baseline, received the single administration of OZ439/FQ, without major protocol violations impacting efficacy, evaluable for crude ACPR at Day 63, excluding those who received rescue treatment due to vomiting during drug administration.

Clearance is defined as a quantitative measure of the rate at which a drug substance is removed from the body.

Time frame: 2, 4, 6, 12, 24, 48, 72 and 672 hours post dose

Population: Focus of PK assessment was to support the analysis of exposure versus efficacy relationship (PK and PD). Since clearance was considered irrelevant to the objective of the PK and exposure-response analyses, therefore data for this outcome measure were not collected and reported.

Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug.

Time frame: 2, 4, 6, 12, 24, 48, 72 and 672 hours post dose

Population: Focus of PK assessment was to support the analysis of exposure versus efficacy relationship (PK and PD). Since volume of distribution was considered irrelevant to the objective of the PK and exposure-response analyses, therefore data for this outcome measure were not collected and reported.

Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug.

Time frame: 2, 4, 6, 12, 24, 48, 72 and 672 hours post dose

Population: Focus of PK assessment was to support the analysis of exposure versus efficacy relationship (PK and PD). Since volume of distribution was considered irrelevant to the objective of the PK and exposure-response analyses, therefore data for this outcome measure were not collected and reported.

Area under the plasma concentration versus time curve from time 0 to Day 28 (i.e. 672 hours).

Time frame: 2, 4, 6, 8, 12, 24, 48, 168, 336 and 672 hours postdose

Population: Analysis was performed on PK population for FQ. Here, overall number of participants analyzed=participants evaluable for this outcome measure.

Area under the plasma concentration versus time curve from time zero to infinity.

Time frame: 2, 4, 6, 12, 24, 48, 72 and 672 hours post dose

Population: Analysis was performed on PK population for OZ439.

Time frame: 2, 4, 6, 12, 24, 48, 72 and 672 hours post dose

Population: Focus of PK assessment was to support the analysis of exposure versus efficacy relationship (PK and PD). Since blood plasma ratio of active drug and metabolite was considered irrelevant to the objective of the PK and exposure-response analyses, therefore data for this outcome measure were not collected and reported.

Cmax is the maximum observed plasma concentration of Ferroquine.

Time frame: 2, 4, 6, 12, 24, 48, 72 and 672 hours post dose

Population: Analysis was performed on the PK population for FQ which included all participants who received FQ and had at least one evaluable blood sample for PK and with adequate documentation of dosing date and sampling date. Here, overall number of participants analyzed=participants evaluable for this outcome measure.

Clearance is defined as a quantitative measure of the rate at which a drug substance is removed from the body.

Time frame: 2, 4, 6, 12, 24, 48, 72 and 672 hours post dose

Population: Focus of PK assessment was to support the analysis of exposure versus efficacy relationship (PK and pharmacodynamic \[PD\]). Since clearance was considered irrelevant to the objective of the PK and exposure-response analyses, therefore data for this outcome measure were not collected and reported.

Cmax is the maximum observed plasma concentration of artefenomel.

Time frame: 2, 4, 6, 12, 24, 48, 72 and 672 hours post dose

Population: Analysis was performed on the PK population for OZ439 which included all participants who received OZ439 and had at least one evaluable blood sample for PK and with adequate documentation of dosing date and sampling date.

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

Population: Analysis was performed on African \<=5 years mITT population. 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 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

Population: African \<=5 years modified Intent-To-Treat (mITT) population: all randomized African participants \<=5 years with parasitological confirmed Plasmodium falciparum (P. falciparum) malaria at baseline, who received the single administration of OZ439/FQ and excluding participants who required rescue treatment due to vomiting during drug administration.

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

Population: Analysis was performed on African \<=5 years mITT population. 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.