Outcome
| Type |
Measure |
Description |
Time frame |
Safety issue |
| Primary |
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. |
Day 28 |
|
| Secondary |
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. |
Day 28 |
|
| Secondary |
Percentage of Participants With Polymerase Chain Reaction-adjusted Adequate Clinical and Parasitological Response at Day 28: Asian PP Population at Day 28 (APP28) |
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. |
Day 28 |
|
| Secondary |
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. |
Day 42 |
|
| Secondary |
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. |
Day 63 |
|
| Secondary |
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. |
Day 28 |
|
| Secondary |
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. |
Day 42 |
|
| Secondary |
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. |
Day 63 |
|
| Secondary |
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. |
Up to Day 63 |
|
| Secondary |
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. |
Up to Day 63 |
|
| Secondary |
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. |
Up to Day 63 |
|
| Secondary |
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. |
From the start of study drug administration up to the time of the first negative film (up to Day 63) |
|
| Secondary |
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. |
From the start of study drug administration up to the time of the first negative film (up to Day 63) |
|
| Secondary |
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. |
From the start of study drug administration up to the time of the first negative film (up to Day 63) |
|
| Secondary |
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. |
From the start of study drug administration up to the time of the first temperature measurement <37.5°C (up to Day 63) |
|
| Secondary |
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. |
From the start of study drug administration up to the time of the first temperature measurement <37.5°C (up to Day 63) |
|
| Secondary |
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. |
From the start of study drug administration up to the time of the first temperature measurement <37.5°C (up to Day 63) |
|
| Secondary |
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. |
24 and 48 hours post dose |
|
| Secondary |
Parasite Reduction Ratio 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. |
24 and 48 hours post dose |
|
| Secondary |
Parasite Reduction Ratio at 24 Hours and 48 Hours: Asian 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. |
24 and 48 hours post dose |
|
| Secondary |
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. |
From Baseline up to Day 63 |
|
| Secondary |
Pharmacokinetics (PK): Maximum Observed Plasma Concentration (Cmax) of Artefenomel |
Cmax is the maximum observed plasma concentration of artefenomel. |
2, 4, 6, 12, 24, 48, 72 and 672 hours post dose |
|
| Secondary |
Pharmacokinetics: Area Under the Curve From Time 0 to Infinity (AUC0-inf) of Artefenomel |
Area under the plasma concentration versus time curve from time zero to infinity. |
2, 4, 6, 12, 24, 48, 72 and 672 hours post dose |
|
| Secondary |
Pharmacokinetics (PK): Apparent Total Clearance of Artefenomel From Plasma After Oral Administration |
Clearance is defined as a quantitative measure of the rate at which a drug substance is removed from the body. |
2, 4, 6, 12, 24, 48, 72 and 672 hours post dose |
|
| Secondary |
Pharmacokinetics: Apparent Volume of Distribution at Steady State After Non-intravenous Administration (Vss/F) of Artefenomel |
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. |
2, 4, 6, 12, 24, 48, 72 and 672 hours post dose |
|
| Secondary |
Pharmacokinetics: Maximum Observed Plasma Concentration of Ferroquine (Cmax) |
Cmax is the maximum observed plasma concentration of Ferroquine. |
2, 4, 6, 12, 24, 48, 72 and 672 hours post dose |
|
| Secondary |
Pharmacokinetics: Area Under the Curve From Time 0 to Day 28 (AUC0-day28) of Ferroquine |
Area under the plasma concentration versus time curve from time 0 to Day 28 (i.e. 672 hours). |
2, 4, 6, 8, 12, 24, 48, 168, 336 and 672 hours postdose |
|
| Secondary |
Pharmacokinetics: Apparent Total Clearance of Ferroquine From Plasma After Oral Administration |
Clearance is defined as a quantitative measure of the rate at which a drug substance is removed from the body. |
2, 4, 6, 12, 24, 48, 72 and 672 hours post dose |
|
| Secondary |
Pharmacokinetics: Apparent Volume of Distribution at Steady State After Non-intravenous Administration of Ferroquine |
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. |
2, 4, 6, 12, 24, 48, 72 and 672 hours post dose |
|
| Secondary |
Pharmacokinetics: Blood/Plasma Ratio for Ferroquine and Its Active Metabolite SSR97213 |
|
2, 4, 6, 12, 24, 48, 72 and 672 hours post dose |
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