Azithromycin Plus Chloroquine Versus Artemether-Lumefantrine For The Treatment Of Uncomplicated P. Falciparum Malaria In Children In Africa

Study Overview
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Brief Summary
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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.

Official Title
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Phase 2/3, Open-Label, Comparative Trial Of Azithromycin Plus Chloroquine Versus Artemether-Lumefantrine For The Treatment Of Uncomplicated Plasmodium Falciparum Malaria In Children In Africa

Conditions
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Malaria, Falciparum

Intervention / Treatment
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* Drug: Azithromycin plus Chloroquine
* Drug: Artemether-lumefantrine


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 6 Months
Maximum Age: 12 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br> | Drug: Azithromycin plus Chloroquine<br>* 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)<br>|
| Experimental: 2<br> | Drug: Artemether-lumefantrine<br>* Artemether-lumefantrine tablet(s) based on weight and labeling for 3 days (Days 0, 1, 2)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Day 28 | 
| 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. | Day 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Days 7, 14, 21, 35, 42 | 
| 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. | Days 7, 14, 21, 35, 42 | 
| 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. | Days 7, 14, 21, 28, 35, 42 | 
| 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. | Days 7, 14, 21, 28, 35, 42 | 
| Percentage of Participants With Early Treatment Failure (ETF) in the mITT Population (PCR-corrected) | ETF defined as participants who met the following criteria: 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 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. Parasitemia (P. falciparum) on Day 3 with fever or 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. | Day 0 up to Day 3 | 
| Percentage of Participants With ETF in PP Population (PCR-corrected) | ETF defined as participants who met the following criteria: 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 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. Parasitemia (P.falciparum) on Day 3 with fever or 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. | Day 0 up to Day 3 | 
| Percentage of Participants With Late Clinical Failure (LCF) in the mITT Population (PCR-corrected) | LCF included participants who met any of the following criteria: 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) 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. | Days 7, 14, 21, 28, 35, 42 | 
| Percentage of Participants With LCF in PP Population (PCR-corrected) | LCF included participants who met any of the following criteria: 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) 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. | Days 7, 14, 21, 28, 35, 42 | 
| 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. | Days 7, 14, 21, 28, 35, 42 | 
| 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. | Days 7, 14, 21, 28, 35, 42 | 
| 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. | Day 7, 14, 21, 28, 35, 42 | 
| 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. | Days 7, 14, 21, 28, 35, 42 | 
| 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). | Baseline to Day 42 | 
| 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. | Baseline to Day 42 | 
| Nadir Hemoglobin Level | Nadir hemoglobin for each participant was defined as the minimum hemoglobin values obtained from Day 0 through Day 3. | Day 0 through Day 3 | 
| 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. | Day 14, 28, 42 | 
| Time to Recurrence of Parasitemia | Time from the day of clearance to the time of recurrence of asexual P.falciparum parasitemia (PCR-uncorrected). | Baseline (Day 0) to Day 42 | 
| 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 | 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. | Baseline to Day 42 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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P. Falciparum Malaria, drug treatment, clinical trial