Malaria, Falciparum
Conditions
Keywords
P. Falciparum Malaria, drug treatment, clinical trial
Brief summary
The primary objective is to confirm the hypothesis that azithromycin used in combination with chloroquine is non-inferior to artemether- Lumefantrine for the treatment of symptomatic, uncomplicated malaria due to P. falciparum in children in African countries.
Interventions
Combination of Azithromycin plus Chloroquine Azithromycin (\ 30 mg/kg) + chloroquine (\ 10mg base /kg) combination tablet(s) on weight basis, once daily for 3 days (Days 0,1,2) or Artemether-lumefantrine tablet(s) based on weight and labeling for 3 days (Days 0, 1, 2)
DRUGArtemether-lumefantrine
Artemether-lumefantrine tablet(s) based on weight and labeling for 3 days (Days 0, 1, 2)
Sponsors
Pfizer
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
6 Months to 12 Years
Healthy volunteers
No
Inclusion criteria
* Girls and boys ≥5 years to ≤12 years (Cohort 1); and ≥6 to ≤59 months of age (Cohort 2) with uncomplicated, symptomatic malaria as indicated by the presence of the following: * Blood smears positive for monoinfection with P. falciparum and asexual parasitemia between 1000 -100,000 parasites/µL; * Documented fever (38.0°C/100.4°F rectal or tympanic; 37.2°C/99.0°F axillary or 37.5°C/99.5°F oral) or history of fever (as reported by the legally acceptable representative) within the prior 24 hours; * Appropriate for outpatient treatment; * Blood glucose ≥60 mg/dL; * Hemoglobin ≥6 g/dl or hematocrit ≥18% without signs of anemia-induced Congestive Heart Failure (CHF); * Negative urine pregnancy test for females ≥10 years of age (and of child bearing potential)
Exclusion criteria
* Peripheral blood smear positive for mixed infection with multiple Plasmodium spp. * Severe or complicated malaria including subjects with any of the following: * Impaired consciousness (eg, obtundation, unarousable coma), seizures or abnormal neurologic exam suggestive of severe or complicated malaria; * Known hemoglobinuria; * Jaundice; * Respiratory distress; * Persistent vomiting; * Gross hematuria, as reported by the subject's legally acceptable representative; * Recent history of convulsions; * Inability to drink or breastfeed; * Unable to sit or stand as appropriate for age; * Known pregnancy or breast-feeding or positive urine pregnancy test (females ≥10 years of age and of child bearing potential); * History of allergy to or hypersensitivity to azithromycin, any macrolide, chloroquine, artemether, any artemisinin derivative, lumefantrine; * Any contraindication to any study drug including AZ, CQ and AL; * History of treatment with any antimalarial drug (such as halofantrine, chloroquine, quinine, mefloquine, Malarone, SP, artemisinin compounds) or antibacterial with known antimalarial activity (macrolides, doxycycline, clindamycin) within 2 weeks prior to enrollment of a subject (and/or of the mother of a subject who is being breastfed) into the study; * Known or suspected cardiovascular, hepatic or renal abnormality that in the opinion of the investigator would place the subject at increased risk to participate in the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Polymerase Chain Reaction (PCR)-Corrected Adequate Clinical and Parasitologic Response (ACPR) at Day 28 in the Modified Intent-to-treat (mITT) Population | Day 28 | ACPR (PCR-corrected) was defined as asexual Plasmodium falciparum (P.falciparum) parasitologic clearance at Day 28 irrespective of axillary, oral, rectal, or tympanic temperature, without previously meeting the criteria of Early Treatment Failure (ETF) (see measure description in secondary outcome measures 7 and 8) or PCR-corrected Late Treatment Failure (LTF) (which includes PCR-corrected Late Clinical Failures \[LCF\] - see measure description in secondary outcome measure 9 and 10, and PCR-corrected Late Parasitologic Failures (LPF)- see measure description in secondary outcome measure 11 and 12). PCR-corrected refers to the use of molecular testing to differentiate recrudescence from reinfection in the context of an efficacy evaluation. |
| Percentage of Participants With PCR-corrected ACPR at Day 28 in Per-Protocol (PP) Population | Day 28 | ACPR (PCR-corrected) was defined as asexual P.falciparum parasitologic clearance at Day 28 irrespective of axillary, oral, rectal, or tympanic temperature, without previously meeting the criteria of ETF (see measure description in secondary outcome measures 7 and 8) or PCR-corrected LTF (which includes PCR-corrected LCF - see measure description in secondary outcome measure 9 and 10, and PCR-corrected LPF - see measure description in secondary outcome measure 11 and 12). PCR-corrected refers to the use of molecular testing to differentiate recrudescence from reinfection in the context of an efficacy evaluation. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Gametocytologic Response | Days 7, 14, 21, 28, 35, 42 | Gametocyte response/absence/clearance: Clearance of P.falciparum gametocytemia (PCR-uncorrected) (attainment of 2 consecutive zero gametocyte counts) without subsequent recurrence through the day of consideration. PCR-uncorrected: not adjusted for molecular testing which determined recrudescence or true failures from reinfection. |
| Percentage of Participants With PCR-uncorrected ACPR in the mITT Population | Days 7, 14, 21, 28, 35, 42 | ACPR (PCR-uncorrected) was defined as asexual P.falciparum parasitologic clearance on Days 7, 14, 21, 28, 35, 42 irrespective of axillary, oral, rectal, or tympanic temperature, without previously meeting the criteria of ETF (see measure description in secondary outcome measures 7 and 8) or PCR-uncorrected LTF (which includes PCR-uncorrected LCF - see measure description in secondary outcome measure 9 and 10, and PCR-uncorrected LPF - see measure description in secondary outcome measure 11 and 12). PCR-uncorrected: not adjusted for molecular testing which determined recrudescence or true failures from reinfection. |
| Percentage of Participants With PCR-uncorrected ACPR in PP Population | Days 7, 14, 21, 28, 35, 42 | ACPR (PCR-uncorrected) was defined as asexual P.falciparum parasitologic clearance on Days 7, 14, 21, 28, 35, 42 irrespective of axillary, oral, rectal, or tympanic temperature, without previously meeting the criteria of ETF (see measure description in secondary outcome measures 7 and 8) or PCR-uncorrected LTF (which includes PCR-uncorrected LCF - see measure description in secondary outcome measure 9 and 10, and PCR-uncorrected LPF - see measure description in secondary outcome measure 11 and 12). PCR-uncorrected: not adjusted for molecular testing which determined recrudescence or true failures from reinfection. |
| Percentage of Participants With Early Treatment Failure (ETF) in the mITT Population (PCR-corrected) | Day 0 up to Day 3 | ETF defined as participants who met the following criteria: 1. Developed signs of severe malaria or clinical deterioration that required rescue medication on Days 0, 1, 2 or 3, in the presence of P. falciparum parasitemia 2. Last available asexual P. falciparum parasite count on Day 2 greater than the first available parasite count on Day 0 (Baseline), irrespective of axillary, oral or rectal temperature. 3. Parasitemia (P. falciparum) on Day 3 with fever or 4. Last available P. falciparum parasite count on Day 3 \>=25% of the first available parasite count on Day 0 (Baseline). PCR-corrected refers to the use of molecular testing to differentiate recrudescence from reinfection in the context of an efficacy evaluation. |
| Percentage of Participants With ETF in PP Population (PCR-corrected) | Day 0 up to Day 3 | ETF defined as participants who met the following criteria: 1. Developed signs of severe malaria or clinical deterioration that required rescue medication on Days 0, 1, 2 or 3, in the presence of P.falciparum parasitemia 2. Last available asexual P.falciparum parasite count on Day 2 greater than the first available parasite count on Day 0 (Baseline), irrespective of axillary, oral or rectal temperature. 3. Parasitemia (P.falciparum) on Day 3 with fever or 4. Last available P.falciparum parasite count on Day 3 \>=25% of the first available parasite count on Day 0 (Baseline). PCR-corrected refers to the use of molecular testing to differentiate recrudescence from reinfection in the context of an efficacy evaluation. |
| Percentage of Participants With Late Clinical Failure (LCF) in the mITT Population (PCR-corrected) | Days 7, 14, 21, 28, 35, 42 | LCF included participants who met any of the following criteria: 1. Development of signs of severe malaria or clinical deterioration requiring rescue medication after Day 3 in the presence of P.falciparum parasitemia, without previously meeting any of the criteria of ETF (see measure description in secondary outcome measures 7 and 8) 2. Presence of P.falciparum parasitemia and fever on any day from Day 4 onward, without previously meeting any of the criteria of ETF (see measure description in secondary outcome measures 7 and 8). PCR-corrected refers to the use of molecular testing to differentiate recrudescence from reinfection in the context of an efficacy evaluation. |
| Percentage of Participants With LCF in PP Population (PCR-corrected) | Days 7, 14, 21, 28, 35, 42 | LCF included participants who met any of the following criteria: 1. Development of signs of severe malaria or clinical deterioration requiring rescue medication after Day 3 in the presence of P.falciparum parasitemia, without previously meeting any of the criteria of ETF (see measure description in secondary outcome measures 7 and 8) 2. Presence of P.falciparum parasitemia and fever on any day from Day 4 onward, without previously meeting any of the criteria of ETF (see measure description in secondary outcome measures 7 and 8). PCR-corrected refers to the use of molecular testing to differentiate recrudescence from reinfection in the context of an efficacy evaluation. |
| Percentage of Participants With Late Parasitologic Failure (LPF) in the mITT Population (PCR-corrected) | Days 7, 14, 21, 28, 35, 42 | LPF: Presence of P. falciparum parasitemia in the mITT population on any day from Day 7 onward and the absence of fever without previously meeting any of the criteria of ETF (see measure description in secondary outcome measures 7 and 8) or LCF (see measure description in secondary outcome measure 9 and 10). PCR-corrected refers to the use of molecular testing to differentiate recrudescence from reinfection in the context of an efficacy evaluation. |
| Percentage of Participants With PCR-corrected ACPR in the mITT Population | Days 7, 14, 21, 35, 42 | ACPR (PCR-corrected) was defined as asexual P.falciparum parasitologic clearance on Days 7, 14, 21, 35, 42 irrespective of axillary, oral, rectal, or tympanic temperature, without previously meeting the criteria of ETF (see measure description in secondary outcome measures 7 and 8) or PCR-corrected LTF (which includes PCR-Corrected LCF- see measure description in secondary outcome measure 9 and 10, and PCR-corrected LPF - see measure description in secondary outcome measure 11 and 12). PCR-corrected refers to the use of molecular testing to differentiate recrudescence from reinfection in the context of an efficacy evaluation. |
| Percentage of Participants With Asexual Parasitologic Response (PCR-corrected) | Day 7, 14, 21, 28, 35, 42 | Percentage of participants who were cleared of asexual parasites. Asexual parasite clearance - clearance of asexual P.falciparum parasitemia within 7 days of initiation of treatment without subsequent recurrence (PCR-corrected) through the day of consideration. PCR-corrected refers to the use of molecular testing to differentiate recrudescence from reinfection in the context of an efficacy evaluation. |
| Fever Clearance Time | Baseline to Day 42 | Calculated as time of first occurrence of two consecutive time points with temperature less than (\<) 38.0 degrees C/100.4 degrees Fahrenheit (F) (rectal), 37.2 degrees C/99.0 degrees F (axillary), or \<37.5 degrees C/99.5 degrees F (oral). |
| Asexual Plasmodium Falciparum Parasite Clearance Time | Baseline to Day 42 | Defined as time to first of two consecutive zero asexual P. falciparum parasite (PCR-corrected) counts, regardless of recurrence of parasitemia later. PCR-corrected refers to the use of molecular testing to differentiate recrudescence from reinfection in the context of an efficacy evaluation. |
| Nadir Hemoglobin Level | Day 0 through Day 3 | Nadir hemoglobin for each participant was defined as the minimum hemoglobin values obtained from Day 0 through Day 3. |
| Change From Nadir Hemoglobin Level at Days 14, 28, and 42 | Day 14, 28, 42 | Change from nadir = observation minus nadir. Nadir defined as the minimum value for each participant on Days 0-3. |
| Time to Recurrence of Parasitemia | Baseline (Day 0) to Day 42 | Time from the day of clearance to the time of recurrence of asexual P.falciparum parasitemia (PCR-uncorrected). |
| Number of Participants With Recurrent Parasitemia Versus Baseline Plasmodium Falciparum Chloroquine Resistance Transporter (PfCRT) Status | Baseline to Day 42 | — |
| Percentage of Participants With PfCRT in True Failures | Baseline to Day 42 | A genetic marker, P.falciparum chloroquine resistance transporter (PfCRT), indicative of P.falciparum chloroquine resistance was to be determined from blood blots obtained on Day 0 and at the time of treatment failure. Treatment failure was defined as any of the following events that a participant experienced from Day 0 through the Day 42 visit: ETF (see measure description in secondary outcome measures 7 and 8), LCF (PCR corrected) (see measure description in secondary outcome measure 9 and 10), or LPF (PCR corrected) (see measure description in secondary outcome measure 11 and 12). Recrudescence of asexual P.falciparum parasites was considered treatment failure. |
| Percentage of Participants With LPF in PP Population (PCR-corrected) | Days 7, 14, 21, 28, 35, 42 | LPF: Presence of P.falciparum parasitemia in the PP population on any day from Day 7 onward and the absence of fever without previously meeting any of the criteria of ETF (see measure description in secondary outcome measures 7 and 8) or LCF (see measure description in secondary outcome measure 9 and 10). PCR-corrected refers to the use of molecular testing to differentiate recrudescence from reinfection in the context of an efficacy evaluation. |
| Percentage of Participants With PCR-corrected ACPR in PP Population | Days 7, 14, 21, 35, 42 | ACPR (PCR-corrected) was defined as asexual P.falciparum parasitologic clearance on Days 7, 14, 21, 35, 42 irrespective of axillary, oral, rectal, or tympanic temperature, without previously meeting the criteria of ETF (see measure description in secondary outcome measures 7 and 8) or PCR-corrected LTF (which includes PCR-corrected LCF - see measure description in secondary outcome measure 9 and 10, and PCR-corrected LPF - see measure description in secondary outcome measure 11 and 12). PCR-corrected refers to the use of molecular testing to differentiate recrudescence from reinfection in the context of an efficacy evaluation. |
Countries
Burkina Faso, Côte d’Ivoire, Ghana, Kenya, Mali
Participant flow
Recruitment details
Participants were recruited in 2 age-based Cohorts. Cohort 1=participants between 5-12 years of age, assumed to have some degree of immunity and at less risk for untoward outcome. After demonstration of successful treatment, safety and tolerability in Cohort 1, participants between \>=6 months of age to \<=59 months of age were enrolled in Cohort 2.
Pre-assignment details
Participants were enrolled in 2 cohorts based on different age criteria. All participants in Cohort 1 met the age criteria where as 3 participants enrolled in Cohort 2 were slightly older than 5 years (by less than 2 months).
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1: Azithromycin + Chloroquine Azithromycin/Chloroquine administered orally once daily for 3 days as a combination tablet (300 milligrams \[mg\] Azithromycin and 100 mg Chloroquine or 150 mg Azithromycin and 50 mg Chloroquine) on Days 0, 1, 2. The combination tablets were administered on the basis of body weight approximately 30 milligram/kilogram (mg/kg) Azithromycin + approximately 10 mg base/kg Chloroquine base. Cohort 1 included participants between \>=5 years of age and \<=12 years of age. | 55 |
| Cohort 1: Artemether + Lumefantrine Artemether/Lumefantrine administered orally once daily for 3 days as a combination tablet (20 mg Artemether and 120 mg Lumefantrine) on Days 0, 1, 2.
Cohort 1 included participants between \>=5 years of age and \<=12 years of age. | 51 |
| Cohort 2: Azithromycin + Chloroquine Azithromycin/Chloroquine administered orally once daily for 3 days as a combination tablet (300 milligrams \[mg\] Azithromycin and 100 mg Chloroquine or 150 mg Azithromycin and 50 mg Chloroquine) on Days 0, 1, 2. The combination tablets were administered on the basis of body weight approximately 30 milligram/kilogram (mg/kg) Azithromycin + approximately 10 mg base/kg Chloroquine base. Cohort 2 included participants between \>=6 months of age to \<=59 months of age. | 124 |
| Cohort 2: Artemether + Lumefantrine Artemether/Lumefantrine administered orally once daily for 3 days as a combination tablet (20 mg Artemether and 120 mg Lumefantrine) on Days 0, 1, 2. Cohort 2 included participants between \>=6 months of age to \<=59 months of age. | 131 |
| Total | 361 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 0 | 0 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 4 | 0 | 1 | 3 |
Baseline characteristics
| Characteristic | Total | Cohort 1: Azithromycin + Chloroquine | Cohort 1: Artemether + Lumefantrine | Cohort 2: Azithromycin + Chloroquine | Cohort 2: Artemether + Lumefantrine |
|---|---|---|---|---|---|
| Age, Customized 5 years - 12 years | 109 Participants | 55 Participants | 51 Participants | 1 Participants | 2 Participants |
| Age, Customized 6 months - less than 5 years | 252 Participants | 0 Participants | 0 Participants | 123 Participants | 129 Participants |
| Sex: Female, Male Female | 164 Participants | 28 Participants | 21 Participants | 50 Participants | 65 Participants |
| Sex: Female, Male Male | 197 Participants | 27 Participants | 30 Participants | 74 Participants | 66 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 40 / 55 | 36 / 51 | 103 / 124 | 99 / 131 |
| serious Total, serious adverse events | 1 / 55 | 2 / 51 | 0 / 124 | 1 / 131 |
Outcome results
Primary
Percentage of Participants With PCR-corrected ACPR at Day 28 in Per-Protocol (PP) Population
ACPR (PCR-corrected) was defined as asexual P.falciparum parasitologic clearance at Day 28 irrespective of axillary, oral, rectal, or tympanic temperature, without previously meeting the criteria of ETF (see measure description in secondary outcome measures 7 and 8) or PCR-corrected LTF (which includes PCR-corrected LCF - see measure description in secondary outcome measure 9 and 10, and PCR-corrected LPF - see measure description in secondary outcome measure 11 and 12). PCR-corrected refers to the use of molecular testing to differentiate recrudescence from reinfection in the context of an efficacy evaluation.
Time frame: Day 28
Population: Per-Protocol (PP) population was a subset of the mITT population, who received all 3 days of study medication to which they were assigned. For ACPR efficacy endpoints, participants in Ivory Coast center excluded from PP population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 2: Azithromycin + Chloroquine | Percentage of Participants With PCR-corrected ACPR at Day 28 in Per-Protocol (PP) Population | 93.08 Percentage of participants |
| Cohort 2: Artemether + Lumefantrine | Percentage of Participants With PCR-corrected ACPR at Day 28 in Per-Protocol (PP) Population | 99.16 Percentage of participants |
Comparison: Null hypothesis: proportion of participants with ACPR (PCR-corrected) of AZ-CQ at Day 28 is less than that of AL; Alternative hypothesis: proportion of participants with ACPR (PCR-corrected) of AZ-CQ at Day 28 is greater than or equal (non-inferior) to that of AL by a non-inferiority margin of -0.1.95% CI: [-12.1, -0.05]Kaplan-Meier curves
Primary
Percentage of Participants With Polymerase Chain Reaction (PCR)-Corrected Adequate Clinical and Parasitologic Response (ACPR) at Day 28 in the Modified Intent-to-treat (mITT) Population
ACPR (PCR-corrected) was defined as asexual Plasmodium falciparum (P.falciparum) parasitologic clearance at Day 28 irrespective of axillary, oral, rectal, or tympanic temperature, without previously meeting the criteria of Early Treatment Failure (ETF) (see measure description in secondary outcome measures 7 and 8) or PCR-corrected Late Treatment Failure (LTF) (which includes PCR-corrected Late Clinical Failures \[LCF\] - see measure description in secondary outcome measure 9 and 10, and PCR-corrected Late Parasitologic Failures (LPF)- see measure description in secondary outcome measure 11 and 12). PCR-corrected refers to the use of molecular testing to differentiate recrudescence from reinfection in the context of an efficacy evaluation.
Time frame: Day 28
Population: mITT:treated participants who met disease criteria(blood smears positive for P.falciparum monoinfection;asexual parasitemia=1000-100,000 parasites/microliter \[mcL\];fever/history of fever \>=38 degree Celsius\[C\] \[rectal\],37.2 degree C \[axillary\] or \>=37.5 degree C \[oral\] within last 24 hours).Participants in Ivory Coast center excluded from analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 2: Azithromycin + Chloroquine | Percentage of Participants With Polymerase Chain Reaction (PCR)-Corrected Adequate Clinical and Parasitologic Response (ACPR) at Day 28 in the Modified Intent-to-treat (mITT) Population | 89.27 Percentage of participants |
| Cohort 2: Artemether + Lumefantrine | Percentage of Participants With Polymerase Chain Reaction (PCR)-Corrected Adequate Clinical and Parasitologic Response (ACPR) at Day 28 in the Modified Intent-to-treat (mITT) Population | 98.37 Percentage of participants |
Comparison: Null hypothesis: proportion of participants with ACPR (PCR-corrected) of Azithromycin/Chloroquine (AZ-CQ) at Day 28 is less than that of Artemether/Lumefantrine (AL); Alternative hypothesis: proportion of participants with ACPR (PCR-corrected) of AZ-CQ at Day 28 is greater than or equal (non-inferior) to that of AL by a non-inferiority margin of -0.1.95% CI: [-16.02, -2.18]Kaplan-Meier curves
Secondary
Asexual Plasmodium Falciparum Parasite Clearance Time
Defined as time to first of two consecutive zero asexual P. falciparum parasite (PCR-corrected) counts, regardless of recurrence of parasitemia later. PCR-corrected refers to the use of molecular testing to differentiate recrudescence from reinfection in the context of an efficacy evaluation.
Time frame: Baseline to Day 42
Population: mITT population, including participants in the Ivory Coast center.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 2: Azithromycin + Chloroquine | Asexual Plasmodium Falciparum Parasite Clearance Time | 48.000 Hours |
| Cohort 2: Artemether + Lumefantrine | Asexual Plasmodium Falciparum Parasite Clearance Time | 24.000 Hours |
Comparison: Time to event data was analyzed using the Kaplan-Meier curve.p-value: <0.0001Kaplan-Meier, log rank
Secondary
Change From Nadir Hemoglobin Level at Days 14, 28, and 42
Change from nadir = observation minus nadir. Nadir defined as the minimum value for each participant on Days 0-3.
Time frame: Day 14, 28, 42
Population: mITT population. N = number of participants with evaluable data, including participants in the Ivory Coast center. n=participants who were evaluable at specified time points for each arm, respectively.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 2: Azithromycin + Chloroquine | Change From Nadir Hemoglobin Level at Days 14, 28, and 42 | Change at Day 14 (n=122, 127) | 0.52 g/dL | Standard Error 0.11 |
| Cohort 2: Azithromycin + Chloroquine | Change From Nadir Hemoglobin Level at Days 14, 28, and 42 | Change at Day 28 (n=122, 127) | 1.15 g/dL | Standard Error 0.11 |
| Cohort 2: Azithromycin + Chloroquine | Change From Nadir Hemoglobin Level at Days 14, 28, and 42 | Change at Day 42 (n=122, 128) | 1.29 g/dL | Standard Error 0.12 |
| Cohort 2: Artemether + Lumefantrine | Change From Nadir Hemoglobin Level at Days 14, 28, and 42 | Change at Day 14 (n=122, 127) | 0.44 g/dL | Standard Error 0.13 |
| Cohort 2: Artemether + Lumefantrine | Change From Nadir Hemoglobin Level at Days 14, 28, and 42 | Change at Day 28 (n=122, 127) | 0.96 g/dL | Standard Error 0.13 |
| Cohort 2: Artemether + Lumefantrine | Change From Nadir Hemoglobin Level at Days 14, 28, and 42 | Change at Day 42 (n=122, 128) | 1.14 g/dL | Standard Error 0.14 |
Secondary
Fever Clearance Time
Calculated as time of first occurrence of two consecutive time points with temperature less than (\<) 38.0 degrees C/100.4 degrees Fahrenheit (F) (rectal), 37.2 degrees C/99.0 degrees F (axillary), or \<37.5 degrees C/99.5 degrees F (oral).
Time frame: Baseline to Day 42
Population: mITT population, including participants in the Ivory Coast center.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 2: Azithromycin + Chloroquine | Fever Clearance Time | 24.000 Hours |
| Cohort 2: Artemether + Lumefantrine | Fever Clearance Time | 24.000 Hours |
Comparison: Time to event data was analyzed using the Kaplan-Meier curve.p-value: 0.2564Kaplan-Meier, log rank
Secondary
Nadir Hemoglobin Level
Nadir hemoglobin for each participant was defined as the minimum hemoglobin values obtained from Day 0 through Day 3.
Time frame: Day 0 through Day 3
Population: mITT population, including participants in the Ivory Coast center.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 2: Azithromycin + Chloroquine | Nadir Hemoglobin Level | 9.63 grams per deciliter (g/dL) | Standard Deviation 1.53 |
| Cohort 2: Artemether + Lumefantrine | Nadir Hemoglobin Level | 9.82 grams per deciliter (g/dL) | Standard Deviation 1.61 |
Secondary
Number of Participants With Recurrent Parasitemia Versus Baseline Plasmodium Falciparum Chloroquine Resistance Transporter (PfCRT) Status
Time frame: Baseline to Day 42
Population: Data for this outcome measure was not analyzed as per change in planned analysis.
Secondary
Percentage of Participants With Asexual Parasitologic Response (PCR-corrected)
Percentage of participants who were cleared of asexual parasites. Asexual parasite clearance - clearance of asexual P.falciparum parasitemia within 7 days of initiation of treatment without subsequent recurrence (PCR-corrected) through the day of consideration. PCR-corrected refers to the use of molecular testing to differentiate recrudescence from reinfection in the context of an efficacy evaluation.
Time frame: Day 7, 14, 21, 28, 35, 42
Population: mITT population. Number of participants analyzed (N)=participants with evaluable data, including participants in the Ivory Coast center. n=participants who were evaluable at specified time points for each arm, respectively.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 2: Azithromycin + Chloroquine | Percentage of Participants With Asexual Parasitologic Response (PCR-corrected) | Day 7 (n=120, 128) | 93.33 Percentage of participants |
| Cohort 2: Azithromycin + Chloroquine | Percentage of Participants With Asexual Parasitologic Response (PCR-corrected) | Day 14 (n=120, 127) | 91.67 Percentage of participants |
| Cohort 2: Azithromycin + Chloroquine | Percentage of Participants With Asexual Parasitologic Response (PCR-corrected) | Day 21 (n=120, 128) | 90.83 Percentage of participants |
| Cohort 2: Azithromycin + Chloroquine | Percentage of Participants With Asexual Parasitologic Response (PCR-corrected) | Day 28 (n=120, 127) | 89.17 Percentage of participants |
| Cohort 2: Azithromycin + Chloroquine | Percentage of Participants With Asexual Parasitologic Response (PCR-corrected) | Day 35 (n=120, 128) | 89.17 Percentage of participants |
| Cohort 2: Azithromycin + Chloroquine | Percentage of Participants With Asexual Parasitologic Response (PCR-corrected) | Day 42 (n=120, 127) | 88.33 Percentage of participants |
| Cohort 2: Artemether + Lumefantrine | Percentage of Participants With Asexual Parasitologic Response (PCR-corrected) | Day 35 (n=120, 128) | 96.88 Percentage of participants |
| Cohort 2: Artemether + Lumefantrine | Percentage of Participants With Asexual Parasitologic Response (PCR-corrected) | Day 7 (n=120, 128) | 99.22 Percentage of participants |
| Cohort 2: Artemether + Lumefantrine | Percentage of Participants With Asexual Parasitologic Response (PCR-corrected) | Day 28 (n=120, 127) | 98.43 Percentage of participants |
| Cohort 2: Artemether + Lumefantrine | Percentage of Participants With Asexual Parasitologic Response (PCR-corrected) | Day 14 (n=120, 127) | 99.21 Percentage of participants |
| Cohort 2: Artemether + Lumefantrine | Percentage of Participants With Asexual Parasitologic Response (PCR-corrected) | Day 42 (n=120, 127) | 96.85 Percentage of participants |
| Cohort 2: Artemether + Lumefantrine | Percentage of Participants With Asexual Parasitologic Response (PCR-corrected) | Day 21 (n=120, 128) | 98.44 Percentage of participants |
Comparison: Day 795% CI: [-11.02, -0.75]large sample approximation to binomial
Comparison: Day 1495% CI: [-13.14, -1.95]large sample approximation to binomial
Comparison: Day 2195% CI: [-13.61, -1.6]large sample approximation to binomial
Comparison: Day 2895% CI: [-15.64, -2.87]Large sample approximation to binomial
Comparison: Day 3595% CI: [-14.45, -0.97]Large sample approximation to binomial
Comparison: Day 4295% CI: [-15.43, -1.6]Large sample approximation to binomial
Secondary
Percentage of Participants With Early Treatment Failure (ETF) in the mITT Population (PCR-corrected)
ETF defined as participants who met the following criteria: 1. Developed signs of severe malaria or clinical deterioration that required rescue medication on Days 0, 1, 2 or 3, in the presence of P. falciparum parasitemia 2. Last available asexual P. falciparum parasite count on Day 2 greater than the first available parasite count on Day 0 (Baseline), irrespective of axillary, oral or rectal temperature. 3. Parasitemia (P. falciparum) on Day 3 with fever or 4. Last available P. falciparum parasite count on Day 3 \>=25% of the first available parasite count on Day 0 (Baseline). PCR-corrected refers to the use of molecular testing to differentiate recrudescence from reinfection in the context of an efficacy evaluation.
Time frame: Day 0 up to Day 3
Population: mITT population, participants in Ivory Coast center were excluded from mITT population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 2: Azithromycin + Chloroquine | Percentage of Participants With Early Treatment Failure (ETF) in the mITT Population (PCR-corrected) | 5.83 Percentage of participants |
| Cohort 2: Artemether + Lumefantrine | Percentage of Participants With Early Treatment Failure (ETF) in the mITT Population (PCR-corrected) | 0.79 Percentage of participants |
Secondary
Percentage of Participants With ETF in PP Population (PCR-corrected)
ETF defined as participants who met the following criteria: 1. Developed signs of severe malaria or clinical deterioration that required rescue medication on Days 0, 1, 2 or 3, in the presence of P.falciparum parasitemia 2. Last available asexual P.falciparum parasite count on Day 2 greater than the first available parasite count on Day 0 (Baseline), irrespective of axillary, oral or rectal temperature. 3. Parasitemia (P.falciparum) on Day 3 with fever or 4. Last available P.falciparum parasite count on Day 3 \>=25% of the first available parasite count on Day 0 (Baseline). PCR-corrected refers to the use of molecular testing to differentiate recrudescence from reinfection in the context of an efficacy evaluation.
Time frame: Day 0 up to Day 3
Population: PP population, participants in Ivory Coast center were excluded from the PP population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 2: Azithromycin + Chloroquine | Percentage of Participants With ETF in PP Population (PCR-corrected) | 1.75 Percentage of participants |
| Cohort 2: Artemether + Lumefantrine | Percentage of Participants With ETF in PP Population (PCR-corrected) | 0 Percentage of participants |
Secondary
Percentage of Participants With Gametocytologic Response
Gametocyte response/absence/clearance: Clearance of P.falciparum gametocytemia (PCR-uncorrected) (attainment of 2 consecutive zero gametocyte counts) without subsequent recurrence through the day of consideration. PCR-uncorrected: not adjusted for molecular testing which determined recrudescence or true failures from reinfection.
Time frame: Days 7, 14, 21, 28, 35, 42
Population: mITT population. N= participants with evaluable data, including participants in the Ivory Coast center. n=participants who were evaluable at specified time points for each arm, respectively.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 2: Azithromycin + Chloroquine | Percentage of Participants With Gametocytologic Response | Day 7 (n=122, 129) | 81.97 Percentage of participants |
| Cohort 2: Azithromycin + Chloroquine | Percentage of Participants With Gametocytologic Response | Day 14 (n=122, 130) | 81.15 Percentage of participants |
| Cohort 2: Azithromycin + Chloroquine | Percentage of Participants With Gametocytologic Response | Day 21 (n=122, 130) | 80.33 Percentage of participants |
| Cohort 2: Azithromycin + Chloroquine | Percentage of Participants With Gametocytologic Response | Day 28 (n=122, 130) | 81.97 Percentage of participants |
| Cohort 2: Azithromycin + Chloroquine | Percentage of Participants With Gametocytologic Response | Day 35 (n=122, 130) | 81.97 Percentage of participants |
| Cohort 2: Azithromycin + Chloroquine | Percentage of Participants With Gametocytologic Response | Day 42 (n=122, 130) | 80.33 Percentage of participants |
| Cohort 2: Artemether + Lumefantrine | Percentage of Participants With Gametocytologic Response | Day 35 (n=122, 130) | 92.31 Percentage of participants |
| Cohort 2: Artemether + Lumefantrine | Percentage of Participants With Gametocytologic Response | Day 7 (n=122, 129) | 91.47 Percentage of participants |
| Cohort 2: Artemether + Lumefantrine | Percentage of Participants With Gametocytologic Response | Day 28 (n=122, 130) | 93.08 Percentage of participants |
| Cohort 2: Artemether + Lumefantrine | Percentage of Participants With Gametocytologic Response | Day 14 (n=122, 130) | 91.54 Percentage of participants |
| Cohort 2: Artemether + Lumefantrine | Percentage of Participants With Gametocytologic Response | Day 42 (n=122, 130) | 91.54 Percentage of participants |
| Cohort 2: Artemether + Lumefantrine | Percentage of Participants With Gametocytologic Response | Day 21 (n=122, 130) | 93.08 Percentage of participants |
Comparison: Day 795% CI: [-18.27, -0.74]Large sample approximation to binomial
Comparison: Day 1495% CI: [-19.23, -1.55]Large sample approximation to binomial
Comparison: Day 2195% CI: [-21.45, -4.04]Large sample approximation to binomial
Comparison: Day 2895% CI: [-19.62, -2.6]Large sample approximation to binomial
Comparison: Day 3595% CI: [-18.97, -1.71]Large sample approximation to binomial
Comparison: Day 4295% CI: [-20.14, -2.28]Large sample approximation to binomial
Secondary
Percentage of Participants With Late Clinical Failure (LCF) in the mITT Population (PCR-corrected)
LCF included participants who met any of the following criteria: 1. Development of signs of severe malaria or clinical deterioration requiring rescue medication after Day 3 in the presence of P.falciparum parasitemia, without previously meeting any of the criteria of ETF (see measure description in secondary outcome measures 7 and 8) 2. Presence of P.falciparum parasitemia and fever on any day from Day 4 onward, without previously meeting any of the criteria of ETF (see measure description in secondary outcome measures 7 and 8). PCR-corrected refers to the use of molecular testing to differentiate recrudescence from reinfection in the context of an efficacy evaluation.
Time frame: Days 7, 14, 21, 28, 35, 42
Population: mITT population, participants in Ivory Coast center were excluded from mITT population.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 2: Azithromycin + Chloroquine | Percentage of Participants With Late Clinical Failure (LCF) in the mITT Population (PCR-corrected) | Day 7 | 0 Percentage of participants |
| Cohort 2: Azithromycin + Chloroquine | Percentage of Participants With Late Clinical Failure (LCF) in the mITT Population (PCR-corrected) | Day 14 | 0 Percentage of participants |
| Cohort 2: Azithromycin + Chloroquine | Percentage of Participants With Late Clinical Failure (LCF) in the mITT Population (PCR-corrected) | Day 21 | 0 Percentage of participants |
| Cohort 2: Azithromycin + Chloroquine | Percentage of Participants With Late Clinical Failure (LCF) in the mITT Population (PCR-corrected) | Day 28 | 0 Percentage of participants |
| Cohort 2: Azithromycin + Chloroquine | Percentage of Participants With Late Clinical Failure (LCF) in the mITT Population (PCR-corrected) | Day 35 | 0 Percentage of participants |
| Cohort 2: Azithromycin + Chloroquine | Percentage of Participants With Late Clinical Failure (LCF) in the mITT Population (PCR-corrected) | Day 42 | 0 Percentage of participants |
| Cohort 2: Artemether + Lumefantrine | Percentage of Participants With Late Clinical Failure (LCF) in the mITT Population (PCR-corrected) | Day 35 | 0 Percentage of participants |
| Cohort 2: Artemether + Lumefantrine | Percentage of Participants With Late Clinical Failure (LCF) in the mITT Population (PCR-corrected) | Day 7 | 0 Percentage of participants |
| Cohort 2: Artemether + Lumefantrine | Percentage of Participants With Late Clinical Failure (LCF) in the mITT Population (PCR-corrected) | Day 28 | 0 Percentage of participants |
| Cohort 2: Artemether + Lumefantrine | Percentage of Participants With Late Clinical Failure (LCF) in the mITT Population (PCR-corrected) | Day 14 | 0 Percentage of participants |
| Cohort 2: Artemether + Lumefantrine | Percentage of Participants With Late Clinical Failure (LCF) in the mITT Population (PCR-corrected) | Day 42 | 0 Percentage of participants |
| Cohort 2: Artemether + Lumefantrine | Percentage of Participants With Late Clinical Failure (LCF) in the mITT Population (PCR-corrected) | Day 21 | 0 Percentage of participants |
Secondary
Percentage of Participants With Late Parasitologic Failure (LPF) in the mITT Population (PCR-corrected)
LPF: Presence of P. falciparum parasitemia in the mITT population on any day from Day 7 onward and the absence of fever without previously meeting any of the criteria of ETF (see measure description in secondary outcome measures 7 and 8) or LCF (see measure description in secondary outcome measure 9 and 10). PCR-corrected refers to the use of molecular testing to differentiate recrudescence from reinfection in the context of an efficacy evaluation.
Time frame: Days 7, 14, 21, 28, 35, 42
Population: mITT population, participants in Ivory Coast center were excluded from mITT population.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 2: Azithromycin + Chloroquine | Percentage of Participants With Late Parasitologic Failure (LPF) in the mITT Population (PCR-corrected) | Day 7 | 0 Percentage of participants |
| Cohort 2: Azithromycin + Chloroquine | Percentage of Participants With Late Parasitologic Failure (LPF) in the mITT Population (PCR-corrected) | Day 14 | 1.67 Percentage of participants |
| Cohort 2: Azithromycin + Chloroquine | Percentage of Participants With Late Parasitologic Failure (LPF) in the mITT Population (PCR-corrected) | Day 21 | 2.50 Percentage of participants |
| Cohort 2: Azithromycin + Chloroquine | Percentage of Participants With Late Parasitologic Failure (LPF) in the mITT Population (PCR-corrected) | Day 28 | 4.17 Percentage of participants |
| Cohort 2: Azithromycin + Chloroquine | Percentage of Participants With Late Parasitologic Failure (LPF) in the mITT Population (PCR-corrected) | Day 35 | 4.17 Percentage of participants |
| Cohort 2: Azithromycin + Chloroquine | Percentage of Participants With Late Parasitologic Failure (LPF) in the mITT Population (PCR-corrected) | Day 42 | 5.00 Percentage of participants |
| Cohort 2: Artemether + Lumefantrine | Percentage of Participants With Late Parasitologic Failure (LPF) in the mITT Population (PCR-corrected) | Day 35 | 2.38 Percentage of participants |
| Cohort 2: Artemether + Lumefantrine | Percentage of Participants With Late Parasitologic Failure (LPF) in the mITT Population (PCR-corrected) | Day 7 | 0 Percentage of participants |
| Cohort 2: Artemether + Lumefantrine | Percentage of Participants With Late Parasitologic Failure (LPF) in the mITT Population (PCR-corrected) | Day 28 | 0.79 Percentage of participants |
| Cohort 2: Artemether + Lumefantrine | Percentage of Participants With Late Parasitologic Failure (LPF) in the mITT Population (PCR-corrected) | Day 14 | 0 Percentage of participants |
| Cohort 2: Artemether + Lumefantrine | Percentage of Participants With Late Parasitologic Failure (LPF) in the mITT Population (PCR-corrected) | Day 42 | 2.38 Percentage of participants |
| Cohort 2: Artemether + Lumefantrine | Percentage of Participants With Late Parasitologic Failure (LPF) in the mITT Population (PCR-corrected) | Day 21 | 0.79 Percentage of participants |
Secondary
Percentage of Participants With LCF in PP Population (PCR-corrected)
LCF included participants who met any of the following criteria: 1. Development of signs of severe malaria or clinical deterioration requiring rescue medication after Day 3 in the presence of P.falciparum parasitemia, without previously meeting any of the criteria of ETF (see measure description in secondary outcome measures 7 and 8) 2. Presence of P.falciparum parasitemia and fever on any day from Day 4 onward, without previously meeting any of the criteria of ETF (see measure description in secondary outcome measures 7 and 8). PCR-corrected refers to the use of molecular testing to differentiate recrudescence from reinfection in the context of an efficacy evaluation.
Time frame: Days 7, 14, 21, 28, 35, 42
Population: PP population, participants in Ivory Coast center were excluded from the PP population.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 2: Azithromycin + Chloroquine | Percentage of Participants With LCF in PP Population (PCR-corrected) | Day 7 | 0 Percentage of participants |
| Cohort 2: Azithromycin + Chloroquine | Percentage of Participants With LCF in PP Population (PCR-corrected) | Day 14 | 0 Percentage of participants |
| Cohort 2: Azithromycin + Chloroquine | Percentage of Participants With LCF in PP Population (PCR-corrected) | Day 21 | 0 Percentage of participants |
| Cohort 2: Azithromycin + Chloroquine | Percentage of Participants With LCF in PP Population (PCR-corrected) | Day 28 | 0 Percentage of participants |
| Cohort 2: Azithromycin + Chloroquine | Percentage of Participants With LCF in PP Population (PCR-corrected) | Day 35 | 0 Percentage of participants |
| Cohort 2: Azithromycin + Chloroquine | Percentage of Participants With LCF in PP Population (PCR-corrected) | Day 42 | 0 Percentage of participants |
| Cohort 2: Artemether + Lumefantrine | Percentage of Participants With LCF in PP Population (PCR-corrected) | Day 35 | 0 Percentage of participants |
| Cohort 2: Artemether + Lumefantrine | Percentage of Participants With LCF in PP Population (PCR-corrected) | Day 7 | 0 Percentage of participants |
| Cohort 2: Artemether + Lumefantrine | Percentage of Participants With LCF in PP Population (PCR-corrected) | Day 28 | 0 Percentage of participants |
| Cohort 2: Artemether + Lumefantrine | Percentage of Participants With LCF in PP Population (PCR-corrected) | Day 14 | 0 Percentage of participants |
| Cohort 2: Artemether + Lumefantrine | Percentage of Participants With LCF in PP Population (PCR-corrected) | Day 42 | 0 Percentage of participants |
| Cohort 2: Artemether + Lumefantrine | Percentage of Participants With LCF in PP Population (PCR-corrected) | Day 21 | 0 Percentage of participants |
Secondary
Percentage of Participants With LPF in PP Population (PCR-corrected)
LPF: Presence of P.falciparum parasitemia in the PP population on any day from Day 7 onward and the absence of fever without previously meeting any of the criteria of ETF (see measure description in secondary outcome measures 7 and 8) or LCF (see measure description in secondary outcome measure 9 and 10). PCR-corrected refers to the use of molecular testing to differentiate recrudescence from reinfection in the context of an efficacy evaluation.
Time frame: Days 7, 14, 21, 28, 35, 42
Population: PP population, participants in Ivory Coast center were excluded from the PP population.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 2: Azithromycin + Chloroquine | Percentage of Participants With LPF in PP Population (PCR-corrected) | Day 7 | 0 Percentage of participants |
| Cohort 2: Azithromycin + Chloroquine | Percentage of Participants With LPF in PP Population (PCR-corrected) | Day 14 | 1.75 Percentage of participants |
| Cohort 2: Azithromycin + Chloroquine | Percentage of Participants With LPF in PP Population (PCR-corrected) | Day 21 | 2.63 Percentage of participants |
| Cohort 2: Azithromycin + Chloroquine | Percentage of Participants With LPF in PP Population (PCR-corrected) | Day 28 | 4.39 Percentage of participants |
| Cohort 2: Azithromycin + Chloroquine | Percentage of Participants With LPF in PP Population (PCR-corrected) | Day 35 | 4.39 Percentage of participants |
| Cohort 2: Azithromycin + Chloroquine | Percentage of Participants With LPF in PP Population (PCR-corrected) | Day 42 | 5.26 Percentage of participants |
| Cohort 2: Artemether + Lumefantrine | Percentage of Participants With LPF in PP Population (PCR-corrected) | Day 35 | 2.42 Percentage of participants |
| Cohort 2: Artemether + Lumefantrine | Percentage of Participants With LPF in PP Population (PCR-corrected) | Day 7 | 0 Percentage of participants |
| Cohort 2: Artemether + Lumefantrine | Percentage of Participants With LPF in PP Population (PCR-corrected) | Day 28 | 0.81 Percentage of participants |
| Cohort 2: Artemether + Lumefantrine | Percentage of Participants With LPF in PP Population (PCR-corrected) | Day 14 | 0 Percentage of participants |
| Cohort 2: Artemether + Lumefantrine | Percentage of Participants With LPF in PP Population (PCR-corrected) | Day 42 | 2.42 Percentage of participants |
| Cohort 2: Artemether + Lumefantrine | Percentage of Participants With LPF in PP Population (PCR-corrected) | Day 21 | 0.81 Percentage of participants |
Secondary
Percentage of Participants With PCR-corrected ACPR in PP Population
ACPR (PCR-corrected) was defined as asexual P.falciparum parasitologic clearance on Days 7, 14, 21, 35, 42 irrespective of axillary, oral, rectal, or tympanic temperature, without previously meeting the criteria of ETF (see measure description in secondary outcome measures 7 and 8) or PCR-corrected LTF (which includes PCR-corrected LCF - see measure description in secondary outcome measure 9 and 10, and PCR-corrected LPF - see measure description in secondary outcome measure 11 and 12). PCR-corrected refers to the use of molecular testing to differentiate recrudescence from reinfection in the context of an efficacy evaluation.
Time frame: Days 7, 14, 21, 35, 42
Population: PP population. For ACPR efficacy endpoints, participants in Ivory Coast center were excluded from the PP population.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 2: Azithromycin + Chloroquine | Percentage of Participants With PCR-corrected ACPR in PP Population | Day 14 | 96.46 Percentage of participants |
| Cohort 2: Azithromycin + Chloroquine | Percentage of Participants With PCR-corrected ACPR in PP Population | Day 35 | 93.08 Percentage of participants |
| Cohort 2: Azithromycin + Chloroquine | Percentage of Participants With PCR-corrected ACPR in PP Population | Day 21 | 95.53 Percentage of participants |
| Cohort 2: Azithromycin + Chloroquine | Percentage of Participants With PCR-corrected ACPR in PP Population | Day 42 | 91.29 Percentage of participants |
| Cohort 2: Azithromycin + Chloroquine | Percentage of Participants With PCR-corrected ACPR in PP Population | Day 7 | 98.25 Percentage of participants |
| Cohort 2: Artemether + Lumefantrine | Percentage of Participants With PCR-corrected ACPR in PP Population | Day 42 | 96.96 Percentage of participants |
| Cohort 2: Artemether + Lumefantrine | Percentage of Participants With PCR-corrected ACPR in PP Population | Day 7 | 100.00 Percentage of participants |
| Cohort 2: Artemether + Lumefantrine | Percentage of Participants With PCR-corrected ACPR in PP Population | Day 14 | 100.00 Percentage of participants |
| Cohort 2: Artemether + Lumefantrine | Percentage of Participants With PCR-corrected ACPR in PP Population | Day 21 | 99.16 Percentage of participants |
| Cohort 2: Artemether + Lumefantrine | Percentage of Participants With PCR-corrected ACPR in PP Population | Day 35 | 96.96 Percentage of participants |
Comparison: A two-sided 95% CI for the difference in ACPR (PCR-corrected) proportions \[(AZ-CQ)-(AL)\] using the normal approximation to the binomial with continuity correction was constructed based on the estimated ACPR proportions from the Kaplan-Meier curves and their standard errors estimated by the greenwood formula. Estimates for Day 21.95% CI: [-8.4, 1.14]Kaplan-Meier, curves
Comparison: A two-sided 95% CI for the difference in ACPR (PCR-corrected) proportions \[(AZ-CQ)-(AL)\] using the normal approximation to the binomial with continuity correction was constructed based on the estimated ACPR proportions from the Kaplan-Meier curves and their standard errors estimated by the greenwood formula. Estimates for Day 35.95% CI: [-10.79, 3.04]Kaplan-Meier, curves
Comparison: A two-sided 95% CI for the difference in ACPR (PCR-corrected) proportions \[(AZ-CQ)-(AL)\] using the normal approximation to the binomial with continuity correction was constructed based on the estimated ACPR proportions from the Kaplan-Meier curves and their standard errors estimated by the greenwood formula. Estimates for Day 42.95% CI: [-13.55, 2.22]Kaplan-Meier, curves
Secondary
Percentage of Participants With PCR-corrected ACPR in the mITT Population
ACPR (PCR-corrected) was defined as asexual P.falciparum parasitologic clearance on Days 7, 14, 21, 35, 42 irrespective of axillary, oral, rectal, or tympanic temperature, without previously meeting the criteria of ETF (see measure description in secondary outcome measures 7 and 8) or PCR-corrected LTF (which includes PCR-Corrected LCF- see measure description in secondary outcome measure 9 and 10, and PCR-corrected LPF - see measure description in secondary outcome measure 11 and 12). PCR-corrected refers to the use of molecular testing to differentiate recrudescence from reinfection in the context of an efficacy evaluation.
Time frame: Days 7, 14, 21, 35, 42
Population: mITT population. For ACPR efficacy endpoints, participants in Ivory Coast center excluded from mITT population.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 2: Azithromycin + Chloroquine | Percentage of Participants With PCR-corrected ACPR in the mITT Population | Day 14 | 92.47 Percentage of participants |
| Cohort 2: Azithromycin + Chloroquine | Percentage of Participants With PCR-corrected ACPR in the mITT Population | Day 35 | 89.27 Percentage of participants |
| Cohort 2: Azithromycin + Chloroquine | Percentage of Participants With PCR-corrected ACPR in the mITT Population | Day 21 | 91.59 Percentage of participants |
| Cohort 2: Azithromycin + Chloroquine | Percentage of Participants With PCR-corrected ACPR in the mITT Population | Day 42 | 87.55 Percentage of participants |
| Cohort 2: Azithromycin + Chloroquine | Percentage of Participants With PCR-corrected ACPR in the mITT Population | Day 7 | 94.17 Percentage of participants |
| Cohort 2: Artemether + Lumefantrine | Percentage of Participants With PCR-corrected ACPR in the mITT Population | Day 42 | 96.19 Percentage of participants |
| Cohort 2: Artemether + Lumefantrine | Percentage of Participants With PCR-corrected ACPR in the mITT Population | Day 7 | 99.21 Percentage of participants |
| Cohort 2: Artemether + Lumefantrine | Percentage of Participants With PCR-corrected ACPR in the mITT Population | Day 14 | 99.21 Percentage of participants |
| Cohort 2: Artemether + Lumefantrine | Percentage of Participants With PCR-corrected ACPR in the mITT Population | Day 21 | 98.37 Percentage of participants |
| Cohort 2: Artemether + Lumefantrine | Percentage of Participants With PCR-corrected ACPR in the mITT Population | Day 35 | 96.19 Percentage of participants |
Comparison: A two-sided 95% CI for the difference in ACPR (PCR-corrected) proportions \[(AZ-CQ)-(AL)\] using the normal approximation to the binomial with continuity correction was constructed based on the estimated ACPR proportions from the Kaplan-Meier curves and their standard errors estimated by the greenwood formula. Estimates for Day 7.95% CI: [-9.93, -0.15]Kaplan-Meier curves
Comparison: A two-sided 95% CI for the difference in ACPR (PCR-corrected) proportions \[(AZ-CQ)-(AL)\] using the normal approximation to the binomial with continuity correction was constructed based on the estimated ACPR proportions from the Kaplan-Meier curves and their standard errors estimated by the greenwood formula. Estimates for Day 14.95% CI: [-12.15, -1.32]Kaplan-Meier curves
Comparison: A two-sided 95% CI for the difference in ACPR (PCR-corrected) proportions \[(AZ-CQ)-(AL)\] using the normal approximation to the binomial with continuity correction was constructed based on the estimated ACPR proportions from the Kaplan-Meier curves and their standard errors estimated by the greenwood formula. Estimates for Day 21.95% CI: [-12.82, -0.75]Kaplan-Meier curves
Comparison: A two-sided 95% CI for the difference in ACPR (PCR-corrected) proportions \[(AZ-CQ)-(AL)\] using the normal approximation to the binomial with continuity correction was constructed based on the estimated ACPR proportions from the Kaplan-Meier curves and their standard errors estimated by the greenwood formula. Estimates for Day 35.95% CI: [-14.59, 0.76]Kaplan-Meier curves
Comparison: A two-sided 95% CI for the difference in ACPR (PCR-corrected) proportions \[(AZ-CQ)-(AL)\] using the normal approximation to the binomial with continuity correction was constructed based on the estimated ACPR proportions from the Kaplan-Meier curves and their standard errors estimated by the greenwood formula. Estimates for Day 42.95% CI: [-17.08, -0.18]Kaplan-Meier curves
Secondary
Percentage of Participants With PCR-uncorrected ACPR in PP Population
ACPR (PCR-uncorrected) was defined as asexual P.falciparum parasitologic clearance on Days 7, 14, 21, 28, 35, 42 irrespective of axillary, oral, rectal, or tympanic temperature, without previously meeting the criteria of ETF (see measure description in secondary outcome measures 7 and 8) or PCR-uncorrected LTF (which includes PCR-uncorrected LCF - see measure description in secondary outcome measure 9 and 10, and PCR-uncorrected LPF - see measure description in secondary outcome measure 11 and 12). PCR-uncorrected: not adjusted for molecular testing which determined recrudescence or true failures from reinfection.
Time frame: Days 7, 14, 21, 28, 35, 42
Population: PP population. For ACPR efficacy endpoints, participants in Ivory Coast center were excluded from the PP population.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 2: Azithromycin + Chloroquine | Percentage of Participants With PCR-uncorrected ACPR in PP Population | Day 7 | 98.25 Percentage of participants |
| Cohort 2: Azithromycin + Chloroquine | Percentage of Participants With PCR-uncorrected ACPR in PP Population | Day 14 | 92.89 Percentage of participants |
| Cohort 2: Azithromycin + Chloroquine | Percentage of Participants With PCR-uncorrected ACPR in PP Population | Day 21 | 70.56 Percentage of participants |
| Cohort 2: Azithromycin + Chloroquine | Percentage of Participants With PCR-uncorrected ACPR in PP Population | Day 28 | 54.28 Percentage of participants |
| Cohort 2: Azithromycin + Chloroquine | Percentage of Participants With PCR-uncorrected ACPR in PP Population | Day 35 | 47.04 Percentage of participants |
| Cohort 2: Azithromycin + Chloroquine | Percentage of Participants With PCR-uncorrected ACPR in PP Population | Day 42 | 39.80 Percentage of participants |
| Cohort 2: Artemether + Lumefantrine | Percentage of Participants With PCR-uncorrected ACPR in PP Population | Day 35 | 63.41 Percentage of participants |
| Cohort 2: Artemether + Lumefantrine | Percentage of Participants With PCR-uncorrected ACPR in PP Population | Day 7 | 100.00 Percentage of participants |
| Cohort 2: Artemether + Lumefantrine | Percentage of Participants With PCR-uncorrected ACPR in PP Population | Day 28 | 73.90 Percentage of participants |
| Cohort 2: Artemether + Lumefantrine | Percentage of Participants With PCR-uncorrected ACPR in PP Population | Day 14 | 97.56 Percentage of participants |
| Cohort 2: Artemether + Lumefantrine | Percentage of Participants With PCR-uncorrected ACPR in PP Population | Day 42 | 56.74 Percentage of participants |
| Cohort 2: Artemether + Lumefantrine | Percentage of Participants With PCR-uncorrected ACPR in PP Population | Day 21 | 83.62 Percentage of participants |
Comparison: A two-sided 95% CI for the difference in ACPR (PCR-uncorrected) proportions \[(AZ-CQ)-(AL)\] using the normal approximation to the binomial with continuity correction was constructed based on the estimated ACPR proportions from the Kaplan-Meier curves and their standard errors estimated by the greenwood formula. Estimates for Day 14.95% CI: [-10.6, 1.25]Kaplan-Meier curves
Comparison: A two-sided 95% CI for the difference in ACPR (PCR-uncorrected) proportions \[(AZ-CQ)-(AL)\] using the normal approximation to the binomial with continuity correction was constructed based on the estimated ACPR proportions from the Kaplan-Meier curves and their standard errors estimated by the greenwood formula. Estimates for Day 21.95% CI: [-24.21, -1.92]Kaplan-Meier curves
Comparison: A two-sided 95% CI for the difference in ACPR (PCR-uncorrected) proportions \[(AZ-CQ)-(AL)\] using the normal approximation to the binomial with continuity correction was constructed based on the estimated ACPR proportions from the Kaplan-Meier curves and their standard errors estimated by the greenwood formula. Estimates for Day 28.95% CI: [-32.16, -7.08]Kaplan-Meier curves
Comparison: A two-sided 95% CI for the difference in ACPR (PCR-uncorrected) proportions \[(AZ-CQ)-(AL)\] using the normal approximation to the binomial with continuity correction was constructed based on the estimated ACPR proportions from the Kaplan-Meier curves and their standard errors estimated by the greenwood formula. Estimates for Day 35.95% CI: [-29.42, -3.33]Kaplan-Meier curves
Comparison: A two-sided 95% CI for the difference in ACPR (PCR-uncorrected) proportions \[(AZ-CQ)- (AL)\] using the normal approximation to the binomial with continuity correction was constructed based on the estimated ACPR proportions from the Kaplan-Meier curves and their standard errors estimated by the Greenwood formula. Estimates for Day 42.95% CI: [-30.04, -3.83]Kaplan-Meier curves
Secondary
Percentage of Participants With PCR-uncorrected ACPR in the mITT Population
ACPR (PCR-uncorrected) was defined as asexual P.falciparum parasitologic clearance on Days 7, 14, 21, 28, 35, 42 irrespective of axillary, oral, rectal, or tympanic temperature, without previously meeting the criteria of ETF (see measure description in secondary outcome measures 7 and 8) or PCR-uncorrected LTF (which includes PCR-uncorrected LCF - see measure description in secondary outcome measure 9 and 10, and PCR-uncorrected LPF - see measure description in secondary outcome measure 11 and 12). PCR-uncorrected: not adjusted for molecular testing which determined recrudescence or true failures from reinfection.
Time frame: Days 7, 14, 21, 28, 35, 42
Population: mITT population. For ACPR efficacy endpoints, participants in Ivory Coast center were excluded from mITT population.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 2: Azithromycin + Chloroquine | Percentage of Participants With PCR-uncorrected ACPR in the mITT Population | Day 7 | 94.17 Percentage of participants |
| Cohort 2: Azithromycin + Chloroquine | Percentage of Participants With PCR-uncorrected ACPR in the mITT Population | Day 14 | 89.08 Percentage of participants |
| Cohort 2: Azithromycin + Chloroquine | Percentage of Participants With PCR-uncorrected ACPR in the mITT Population | Day 21 | 67.87 Percentage of participants |
| Cohort 2: Azithromycin + Chloroquine | Percentage of Participants With PCR-uncorrected ACPR in the mITT Population | Day 28 | 51.55 Percentage of participants |
| Cohort 2: Azithromycin + Chloroquine | Percentage of Participants With PCR-uncorrected ACPR in the mITT Population | Day 35 | 44.67 Percentage of participants |
| Cohort 2: Azithromycin + Chloroquine | Percentage of Participants With PCR-uncorrected ACPR in the mITT Population | Day 42 | 37.80 Percentage of participants |
| Cohort 2: Artemether + Lumefantrine | Percentage of Participants With PCR-uncorrected ACPR in the mITT Population | Day 35 | 62.91 Percentage of participants |
| Cohort 2: Artemether + Lumefantrine | Percentage of Participants With PCR-uncorrected ACPR in the mITT Population | Day 7 | 99.21 Percentage of participants |
| Cohort 2: Artemether + Lumefantrine | Percentage of Participants With PCR-uncorrected ACPR in the mITT Population | Day 28 | 73.31 Percentage of participants |
| Cohort 2: Artemether + Lumefantrine | Percentage of Participants With PCR-uncorrected ACPR in the mITT Population | Day 14 | 96.79 Percentage of participants |
| Cohort 2: Artemether + Lumefantrine | Percentage of Participants With PCR-uncorrected ACPR in the mITT Population | Day 42 | 56.29 Percentage of participants |
| Cohort 2: Artemether + Lumefantrine | Percentage of Participants With PCR-uncorrected ACPR in the mITT Population | Day 21 | 82.96 Percentage of participants |
Comparison: A two-sided 95% CI for the difference in ACPR (PCR-uncorrected) proportions \[(AZ-CQ)-(AL)\] using the normal approximation to the binomial with continuity correction was constructed based on the estimated ACPR proportions from the Kaplan-Meier curves and their standard errors estimated by the greenwood formula. Estimates for Day 7.95% CI: [-9.93, -0.15]Kaplan-Meier curves
Comparison: A two-sided 95% CI for the difference in ACPR (PCR-uncorrected) proportions \[(AZ-CQ)-(AL)\] using the normal approximation to the binomial with continuity correction was constructed based on the estimated ACPR proportions from the Kaplan-Meier curves and their standard errors estimated by the greenwood formula. Estimates for Day 14.95% CI: [-14.54, -0.88]Kaplan-Meier curves
Comparison: A two-sided 95% CI for the difference in ACPR (PCR-uncorrected) proportions \[(AZ-CQ)-(AL)\] using the normal approximation to the binomial with continuity correction was constructed based on the estimated ACPR proportions from the Kaplan-Meier curves and their standard errors estimated by the greenwood formula. Estimates for Day 21.95% CI: [-26.24, -3.94]Kaplan-Meier curves
Comparison: A two-sided 95% CI for the difference in ACPR (PCR-uncorrected) proportions \[(AZ-CQ)-(AL)\] using the normal approximation to the binomial with continuity correction was constructed based on the estimated ACPR proportions from the Kaplan-Meier curves and their standard errors estimated by the greenwood formula. Estimates for Day 28.95% CI: [-34.14, -9.39]Kaplan-Meier curves
Comparison: A two-sided 95% CI for the difference in ACPR (PCR-uncorrected) proportions \[(AZ-CQ)-(AL)\] using the normal approximation to the binomial with continuity correction was constructed based on the estimated ACPR proportions from the Kaplan-Meier curves and their standard errors estimated by the greenwood formula. Estimates for Day 35.95% CI: [-31.05, -5.43]Kaplan-Meier curves
Comparison: A two-sided 95% CI for the difference in ACPR (PCR-uncorrected) proportions \[(AZ-CQ)-(AL)\] using the normal approximation to the binomial with continuity correction was constructed based on the estimated ACPR proportions from the Kaplan-Meier curves and their standard errors estimated by the greenwood formula. Estimates for Day 42.95% CI: [-31.33, -5.65]Kaplan-Meier curves
Secondary
Percentage of Participants With PfCRT in True Failures
A genetic marker, P.falciparum chloroquine resistance transporter (PfCRT), indicative of P.falciparum chloroquine resistance was to be determined from blood blots obtained on Day 0 and at the time of treatment failure. Treatment failure was defined as any of the following events that a participant experienced from Day 0 through the Day 42 visit: ETF (see measure description in secondary outcome measures 7 and 8), LCF (PCR corrected) (see measure description in secondary outcome measure 9 and 10), or LPF (PCR corrected) (see measure description in secondary outcome measure 11 and 12). Recrudescence of asexual P.falciparum parasites was considered treatment failure.
Time frame: Baseline to Day 42
Population: Data for this outcome measure was not analyzed as per change in planned analysis.
Secondary
Time to Recurrence of Parasitemia
Time from the day of clearance to the time of recurrence of asexual P.falciparum parasitemia (PCR-uncorrected).
Time frame: Baseline (Day 0) to Day 42
Population: mITT population, including participants in the Ivory Coast center.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 2: Azithromycin + Chloroquine | Time to Recurrence of Parasitemia | 34 Days |
| Cohort 2: Artemether + Lumefantrine | Time to Recurrence of Parasitemia | NA Days |
Comparison: Time to event data was analyzed using the Kaplan-Meier curve.p-value: 0.0006Kaplan-Meier, log rank