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Clinical Trial Results:
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

Summary
EudraCT number	2014-004163-21
Trial protocol	Outside EU/EEA
Global end of trial date	07 Sep 2010

Results information
Results version number	v1(current)
This version publication date	27 Apr 2016
First version publication date	08 Jul 2015
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

A0661157

ISRCTN number

US NCT number

NCT00677833

WHO universal trial number (UTN)

Sponsor organisation name

Pfizer Inc.

Sponsor organisation address

235 E 42nd Street, New York, United States, NY 10017

Public contact

Pfizer Clinical Trials.gov Call Center, Pfizer Inc , 001 8007181021, ClinicalTrials.govCallCenter@pfizer.com

Scientific contact

Pfizer Clinical Trials.gov Call Center, Pfizer Inc , 001 8007181021, ClinicalTrials.govCallCenter@pfizer.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Yes

Analysis stage

Final

Date of interim/final analysis

04 Aug 2011

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

07 Sep 2010

Was the trial ended prematurely?

Main objective of the trial

To confirm the hypothesis that azithromycin used in combination with chloroquine was non-inferior to artemether- Lumefantrine for the treatment of symptomatic, uncomplicated malaria due to Plasmodium Falciparum (P. Falciparum) in children in Africa.

Protection of trial subjects

The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were followed.

Background therapy

Evidence for comparator

Actual start date of recruitment

05 Jun 2008

Long term follow-up planned

Yes

Long term follow-up rationale

Safety, Efficacy

Long term follow-up duration

2 Months

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Ghana: 99

Country: Number of subjects enrolled

Côte d’Ivoire: 30

Country: Number of subjects enrolled

Mali: 80

Country: Number of subjects enrolled

Burkina Faso: 90

Country: Number of subjects enrolled

Kenya: 62

Worldwide total number of subjects

361

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

309

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Subjects were recruited in 2 age-based Cohorts. Cohort 1= Subjects 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, subjects between >=6 months of age to <=59 months of age were enrolled in Cohort 2.

Screening details

Subjects were enrolled in 2 cohorts based on different age criteria. All Subjects in Cohort 1 met the age criteria whereas 3 Subjects enrolled in Cohort 2 were slightly older than 5 years (by less than 2 months).

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Cohort 1: Azithromycin + Chloroquine

Arm description

Azithromycin/Chloroquine administered orally once daily for 3 days as a combination tablet on Days 0, 1, 2. The combination tablets were administered on the basis of body weight approximately 30 milligram per kilogram (mg/kg) Azithromycin + approximately 10 mg base/kg Chloroquine base. Cohort 1 included subjects between greater than or equal to (>=) 5 years of age and less than or equal to (<=) 12 years of age.

Arm type

Experimental

Investigational medicinal product name

Azithromycin/Chloroquine combination tablet

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Azithromycin/Chloroquine administered orally once daily for 3 days as a combination tablet (300 mg Azithromycin and 100 mg Chloroquine or 150 mg Azithromycin and 50 mg Chloroquine) on Days 0, 1, 2.

Cohort 1: Artemether + Lumefantrine

Arm description

Artemether/Lumefantrine administered orally once daily for 3 days as a combination tablet on Days 0, 1, 2. Cohort 1 included subjects between >=5 years of age and <=12 years of age.

Arm type

Active comparator

Investigational medicinal product name

Artemether/Lumefantrine combination tablet

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

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: Azithromycin + Chloroquine

Arm description

Azithromycin/Chloroquine administered orally once daily for 3 days as a combination tablet 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 subjects between >=6 months of age to <=59 months of age.

Arm type

Experimental

Investigational medicinal product name

Azithromycin/Chloroquine combination tablet

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Azithromycin/Chloroquine administered orally once daily for 3 days as a combination tablet (300 mg Azithromycin and 100 mg Chloroquine or 150 mg Azithromycin and 50 mg Chloroquine) on Days 0, 1, 2.

Cohort 2: Artemether + Lumefantrine

Arm description

Artemether/Lumefantrine administered orally once daily for 3 days as a combination tablet on Days 0, 1, 2. Cohort 2 included subjects between >=6 months of age to <=59 months of age.

Arm type

Active comparator

Investigational medicinal product name

Artemether/Lumefantrine combination tablet

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

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.

Number of subjects in period 1	Cohort 1: Azithromycin + Chloroquine	Cohort 1: Artemether + Lumefantrine	Cohort 2: Azithromycin + Chloroquine	Cohort 2: Artemether + Lumefantrine
Started	55	51	124	131
Completed	51	51	122	128
Not completed	4	0	2	3
Consent withdrawn by subject	4	-	1	3
Lost to follow-up	-	-	1	-

Baseline characteristics

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Reporting group title

Cohort 1: Azithromycin + Chloroquine

Reporting group description

Reporting group title

Cohort 1: Artemether + Lumefantrine

Reporting group description

Artemether/Lumefantrine administered orally once daily for 3 days as a combination tablet on Days 0, 1, 2. Cohort 1 included subjects between >=5 years of age and <=12 years of age.

Reporting group title

Cohort 2: Azithromycin + Chloroquine

Reporting group description

Azithromycin/Chloroquine administered orally once daily for 3 days as a combination tablet 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 subjects between >=6 months of age to <=59 months of age.

Reporting group title

Cohort 2: Artemether + Lumefantrine

Reporting group description

Artemether/Lumefantrine administered orally once daily for 3 days as a combination tablet on Days 0, 1, 2. Cohort 2 included subjects between >=6 months of age to <=59 months of age.

Reporting group values	Cohort 1: Azithromycin + Chloroquine	Cohort 1: Artemether + Lumefantrine	Cohort 2: Azithromycin + Chloroquine	Cohort 2: Artemether + Lumefantrine	Total
Number of subjects	55	51	124	131	361
Age categorical
Units: Subjects
6 months – less than 5 years	0	0	123	129	252
5 years – 12 years	55	51	1	2	109
Gender categorical
Units: Subjects
Female	28	21	50	65	164
Male	27	30	74	66	197

End points

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Reporting group title

Cohort 1: Azithromycin + Chloroquine

Reporting group description

Reporting group title

Cohort 1: Artemether + Lumefantrine

Reporting group description

Artemether/Lumefantrine administered orally once daily for 3 days as a combination tablet on Days 0, 1, 2. Cohort 1 included subjects between >=5 years of age and <=12 years of age.

Reporting group title

Cohort 2: Azithromycin + Chloroquine

Reporting group description

Azithromycin/Chloroquine administered orally once daily for 3 days as a combination tablet 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 subjects between >=6 months of age to <=59 months of age.

Reporting group title

Cohort 2: Artemether + Lumefantrine

Reporting group description

Artemether/Lumefantrine administered orally once daily for 3 days as a combination tablet on Days 0, 1, 2. Cohort 2 included subjects between >=6 months of age to <=59 months of age.

Primary: Percentage of Subjects With Polymerase Chain Reaction (PCR)-Corrected Adequate Clinical and Parasitologic Response (ACPR) at Day 28 in the Modified Intent-to-treat (mITT) Population

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End point title

Percentage of Subjects With Polymerase Chain Reaction (PCR)-Corrected Adequate Clinical and Parasitologic Response (ACPR) at Day 28 in the Modified Intent-to-treat (mITT) Population ^[1]

End point description

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 Early Treatment Failure(ETF) 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. mITT:treated subjects 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).Subjects in Ivory Coast center excluded from analysis.

End point type

Primary

End point timeframe

Day 28

Notes
[1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Cohort 1 was a screening cohort, meant for safety evaluation, but not included in the efficacy assessments.

End point values	Cohort 2: Azithromycin + Chloroquine	Cohort 2: Artemether + Lumefantrine
Number of subjects analysed	120	126
Units: Percentage of Subjects
number (confidence interval 95%)	89.27 (82.77 to 95.77)	98.37 (95.59 to 100)

ACPR (PCR-corrected) at Day 28 For mITT population

Statistical analysis description

A two-sided 95 percent (%) confidence interval (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 (PCR-corrected) proportions from the Kaplan-Meier curves and their standard errors estimated by the greenwood formula. The drug (AZ-CQ) was considered non-inferior with respect to this primary endpoint if the lower bound of this 95% CI was >= -10% points.

Comparison groups

Cohort 2: Artemether + Lumefantrine v Cohort 2: Azithromycin + Chloroquine

Number of subjects included in analysis

246

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[2]

Method

Kaplan-Meier curves

Parameter type

ACPR percent difference

Point estimate

-9.1

Confidence interval

level

95%

sides

2-sided

lower limit

-16.02

upper limit

-2.18

Notes
[2] - Null hypothesis: proportion of subjects with ACPR (PCR-corrected) of Azithromycin/Chloroquine (AZ-CQ) at Day 28 is less than that of Artemether/Lumefantrine (AL); Alternative hypothesis: proportion of subjects 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.

Primary: Percentage of Subjects With PCR-corrected ACPR at Day 28 in Per-Protocol (PP) Population

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End point title

Percentage of Subjects With PCR-corrected ACPR at Day 28 in Per-Protocol (PP) Population ^[3]

End point description

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. 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, subjects in Ivory Coast center excluded from PP population.

End point type

Primary

End point timeframe

Day 28

Notes
[3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Cohort 1 was a screening cohort, meant for safety evaluation, but not included in the efficacy assessments.

End point values	Cohort 2: Azithromycin + Chloroquine	Cohort 2: Artemether + Lumefantrine
Number of subjects analysed	114	124
Units: Percentage of Subjects
number (confidence interval 95%)	93.08 (87.32 to 98.84)	99.16 (96.97 to 100)

ACPR (PCR-corrected) at Day 28 For PP population

Statistical analysis description

Comparison groups

Cohort 2: Azithromycin + Chloroquine v Cohort 2: Artemether + Lumefantrine

Number of subjects included in analysis

238

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[4]

Method

Kaplan-Meier curves

Parameter type

ACPR percent difference

Point estimate

-6.08

Confidence interval

level

95%

sides

2-sided

lower limit

-12.1

upper limit

-0.05

Notes
[4] - Null hypothesis: proportion of subjects with ACPR (PCR-corrected) of AZ-CQ at Day 28 is less than that of AL; Alternative hypothesis: proportion of Subjects 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.

Secondary: Percentage of Subjects With PCR-corrected ACPR in the mITT Population

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End point title

Percentage of Subjects With PCR-corrected ACPR in the mITT Population ^[5]

End point description

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. mITT population. For ACPR efficacy endpoints, subjects in Ivory Coast center excluded from mITT population.

End point type

Secondary

End point timeframe

Days 7, 14, 21, 35, 42

Notes
[5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Cohort 1 was a screening cohort, meant for safety evaluation, but not included in the efficacy assessments.

End point values	Cohort 2: Azithromycin + Chloroquine	Cohort 2: Artemether + Lumefantrine
Number of subjects analysed	120	126
Units: Percentage of Subjects
number (confidence interval 95%)
Day 7	94.17 (89.55 to 98.78)	99.21 (97.25 to 100)
Day 14	92.47 (87.3 to 97.64)	99.21 (97.24 to 100)
Day 21	91.59 (86.04 to 97.14)	98.37 (95.65 to 100)
Day 35	89.27 (82.68 to 95.86)	96.19 (91.85 to 100)
Day 42	87.55 (80.08 to 95.03)	96.19 (91.79 to 100)

Estimates for Day 7

Statistical analysis description

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.

Comparison groups

Cohort 2: Artemether + Lumefantrine v Cohort 2: Azithromycin + Chloroquine

Number of subjects included in analysis

246

Analysis specification

Pre-specified

Analysis type

superiority

Method

Kaplan-Meier curves

Parameter type

ACPR percent difference

Point estimate

-5.04

Confidence interval

level

95%

sides

2-sided

lower limit

-9.93

upper limit

-0.15

Estimates for Day 14

Statistical analysis description

Comparison groups

Cohort 2: Azithromycin + Chloroquine v Cohort 2: Artemether + Lumefantrine

Number of subjects included in analysis

246

Analysis specification

Pre-specified

Analysis type

superiority

Method

Kaplan-Meier curves

Parameter type

ACPR percent difference

Point estimate

-6.74

Confidence interval

level

95%

sides

2-sided

lower limit

-12.15

upper limit

-1.32

Estimates for Day 21

Statistical analysis description

Comparison groups

Cohort 2: Azithromycin + Chloroquine v Cohort 2: Artemether + Lumefantrine

Number of subjects included in analysis

246

Analysis specification

Pre-specified

Analysis type

superiority

Method

Kaplan-Meier curves

Parameter type

ACPR percent difference

Point estimate

-6.78

Confidence interval

level

95%

sides

2-sided

lower limit

-12.82

upper limit

-0.75

Estimates for Day 35

Statistical analysis description

Comparison groups

Cohort 2: Azithromycin + Chloroquine v Cohort 2: Artemether + Lumefantrine

Number of subjects included in analysis

246

Analysis specification

Pre-specified

Analysis type

superiority

Method

Kaplan-Meier curves

Parameter type

ACPR percent difference

Point estimate

-6.92

Confidence interval

level

95%

sides

2-sided

lower limit

-14.59

upper limit

0.76

Estimates for Day 42

Statistical analysis description

Comparison groups

Cohort 2: Azithromycin + Chloroquine v Cohort 2: Artemether + Lumefantrine

Number of subjects included in analysis

246

Analysis specification

Pre-specified

Analysis type

superiority

Method

Kaplan-Meier curves

Parameter type

ACPR percent difference

Point estimate

-8.63

Confidence interval

level

95%

sides

2-sided

lower limit

-17.08

upper limit

-0.18

Secondary: Percentage of Subjects With PCR-corrected ACPR in PP Population

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End point title

Percentage of Subjects With PCR-corrected ACPR in PP Population ^[6]

End point description

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. PP population. For ACPR efficacy endpoints, subjects in Ivory Coast center were excluded from the PP population. Here "99999" in the CI signifies not available (NA). CI was not calculable as standard error for 100% rate could not be estimated from Kaplan-Meier method.

End point type

Secondary

End point timeframe

Days 7, 14, 21, 35, 42

Notes
[6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Cohort 1 was a screening cohort, meant for safety evaluation, but not included in the efficacy assessments.

End point values	Cohort 2: Azithromycin + Chloroquine	Cohort 2: Artemether + Lumefantrine
Number of subjects analysed	114	124
Units: Percentage of Subjects
number (confidence interval 95%)
Day 7	98.25 (95.39 to 100)	100 (-99999 to 99999)
Day 14	96.46 (92.59 to 100)	100 (-99999 to 99999)
Day 21	95.53 (91.1 to 99.96)	99.16 (97.03 to 100)
Day 35	93.08 (87.22 to 98.95)	96.96 (92.9 to 100)
Day 42	91.29 (84.31 to 98.28)	96.96 (92.84 to 100)

Estimates for Day 21

Statistical analysis description

Comparison groups

Cohort 2: Azithromycin + Chloroquine v Cohort 2: Artemether + Lumefantrine

Number of subjects included in analysis

238

Analysis specification

Pre-specified

Analysis type

superiority

Method

Kaplan-Meier curves

Parameter type

ACPR percent difference

Point estimate

-3.63

Confidence interval

level

95%

sides

2-sided

lower limit

-8.4

upper limit

1.14

Estimates for Day 35

Statistical analysis description

Comparison groups

Cohort 2: Azithromycin + Chloroquine v Cohort 2: Artemether + Lumefantrine

Number of subjects included in analysis

238

Analysis specification

Pre-specified

Analysis type

superiority

Method

Kaplan-Meier curves

Parameter type

ACPR percent difference

Point estimate

-3.87

Confidence interval

level

95%

sides

2-sided

lower limit

-10.79

upper limit

3.04

Estimates for Day 42

Statistical analysis description

Comparison groups

Cohort 2: Azithromycin + Chloroquine v Cohort 2: Artemether + Lumefantrine

Number of subjects included in analysis

238

Analysis specification

Pre-specified

Analysis type

superiority

Method

Kaplan-Meier curves

Parameter type

ACPR percent difference

Point estimate

-5.66

Confidence interval

level

95%

sides

2-sided

lower limit

-13.55

upper limit

2.22

Secondary: Percentage of Subjects With PCR-uncorrected ACPR in the mITT Population

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End point title

Percentage of Subjects With PCR-uncorrected ACPR in the mITT Population ^[7]

End point description

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. mITT population. For ACPR efficacy endpoints, subjects in Ivory Coast center were excluded from mITT population.

End point type

Secondary

End point timeframe

Days 7, 14, 21, 28, 35, 42

Notes
[7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Cohort 1 was a screening cohort, meant for safety evaluation, but not included in the efficacy assessments.

End point values	Cohort 2: Azithromycin + Chloroquine	Cohort 2: Artemether + Lumefantrine
Number of subjects analysed	120	126
Units: Percentage of Subjects
number (confidence interval 95%)
Day 7	94.17 (89.55 to 98.78)	99.21 (97.25 to 100)
Day 14	89.08 (83.05 to 95.11)	96.79 (93.28 to 100)
Day 21	67.87 (59.02 to 76.72)	82.96 (75.91 to 90.01)
Day 28	51.55 (42.07 to 61.02)	73.31 (65.1 to 81.52)
Day 35	44.67 (35.24 to 54.11)	62.91 (54 to 71.82)
Day 42	37.8 (28.58 to 47.02)	56.29 (47.12 to 65.46)

Estimates for Day 7

Statistical analysis description

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.

Comparison groups

Cohort 2: Azithromycin + Chloroquine v Cohort 2: Artemether + Lumefantrine

Number of subjects included in analysis

246

Analysis specification

Pre-specified

Analysis type

superiority

Method

Kaplan-Meier curves

Parameter type

ACPR percent difference

Point estimate

-5.04

Confidence interval

level

95%

sides

2-sided

lower limit

-9.93

upper limit

-0.15

Estimates for Day 14

Statistical analysis description

Comparison groups

Cohort 2: Azithromycin + Chloroquine v Cohort 2: Artemether + Lumefantrine

Number of subjects included in analysis

246

Analysis specification

Pre-specified

Analysis type

superiority

Method

Kaplan-Meier curves

Parameter type

ACPR percent difference

Point estimate

-7.71

Confidence interval

level

95%

sides

2-sided

lower limit

-14.54

upper limit

-0.88

Estimates for Day 21

Statistical analysis description

Comparison groups

Cohort 2: Azithromycin + Chloroquine v Cohort 2: Artemether + Lumefantrine

Number of subjects included in analysis

246

Analysis specification

Pre-specified

Analysis type

superiority

Method

Kaplan-Meier curves

Parameter type

ACPR percent difference

Point estimate

-15.09

Confidence interval

level

95%

sides

2-sided

lower limit

-26.24

upper limit

-3.94

Estimates for Day 28

Statistical analysis description

Comparison groups

Cohort 2: Azithromycin + Chloroquine v Cohort 2: Artemether + Lumefantrine

Number of subjects included in analysis

246

Analysis specification

Pre-specified

Analysis type

superiority

Method

Kaplan-Meier curves

Parameter type

ACPR percent difference

Point estimate

-21.76

Confidence interval

level

95%

sides

2-sided

lower limit

-34.14

upper limit

-9.39

Estimates for Day 35

Statistical analysis description

Comparison groups

Cohort 2: Azithromycin + Chloroquine v Cohort 2: Artemether + Lumefantrine

Number of subjects included in analysis

246

Analysis specification

Pre-specified

Analysis type

superiority

Method

Kaplan-Meier curves

Parameter type

ACPR percent difference

Point estimate

-18.24

Confidence interval

level

95%

sides

2-sided

lower limit

-31.05

upper limit

-5.43

Estimates for Day 42

Statistical analysis description

Comparison groups

Cohort 2: Azithromycin + Chloroquine v Cohort 2: Artemether + Lumefantrine

Number of subjects included in analysis

246

Analysis specification

Pre-specified

Analysis type

superiority

Method

Kaplan-Meier curves

Parameter type

ACPR percent difference

Point estimate

-18.49

Confidence interval

level

95%

sides

2-sided

lower limit

-31.33

upper limit

-5.65

Secondary: Percentage of Subjects With PCR-uncorrected ACPR in PP Population

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End point title

Percentage of Subjects With PCR-uncorrected ACPR in PP Population ^[8]

End point description

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. PP population. For ACPR efficacy endpoints, subjects in Ivory Coast center were excluded from the PP population. Here "99999" in the CI signifies not available (NA). CI is not calculable when rate is 100%.

End point type

Secondary

End point timeframe

Days 7, 14, 21, 28, 35, 42

Notes
[8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Cohort 1 was a screening cohort, meant for safety evaluation, but not included in the efficacy assessments.

End point values	Cohort 2: Azithromycin + Chloroquine	Cohort 2: Artemether + Lumefantrine
Number of subjects analysed	114	124
Units: Percentage of Subjects
number (confidence interval 95%)
Day 7	98.25 (95.39 to 100)	100 (-99999 to 99999)
Day 14	92.89 (87.69 to 98.08)	97.56 (94.42 to 100)
Day 21	70.56 (61.67 to 79.45)	83.62 (76.65 to 90.6)
Day 28	54.28 (44.57 to 63.98)	73.9 (65.71 to 82.08)
Day 35	47.04 (37.31 to 56.77)	63.41 (54.49 to 72.34)
Day 42	39.8 (30.24 to 49.36)	56.74 (47.54 to 65.94)

Estimates for Day 14

Statistical analysis description

Comparison groups

Cohort 2: Azithromycin + Chloroquine v Cohort 2: Artemether + Lumefantrine

Number of subjects included in analysis

238

Analysis specification

Pre-specified

Analysis type

superiority

Method

Kaplan-Meier curves

Parameter type

ACPR percent difference

Point estimate

-4.67

Confidence interval

level

95%

sides

2-sided

lower limit

-10.6

upper limit

1.25

Estimates for Day 21

Statistical analysis description

Comparison groups

Cohort 2: Azithromycin + Chloroquine v Cohort 2: Artemether + Lumefantrine

Number of subjects included in analysis

238

Analysis specification

Pre-specified

Analysis type

superiority

Method

Kaplan-Meier curves

Parameter type

ACPR percent difference

Point estimate

-13.07

Confidence interval

level

95%

sides

2-sided

lower limit

-24.21

upper limit

-1.92

Estimates for Day 28

Statistical analysis description

Comparison groups

Cohort 2: Azithromycin + Chloroquine v Cohort 2: Artemether + Lumefantrine

Number of subjects included in analysis

238

Analysis specification

Pre-specified

Analysis type

superiority

Method

Kaplan-Meier curves

Parameter type

ACPR percent difference

Point estimate

-19.62

Confidence interval

level

95%

sides

2-sided

lower limit

-32.16

upper limit

-7.08

Estimates for Day 35

Statistical analysis description

Comparison groups

Cohort 2: Azithromycin + Chloroquine v Cohort 2: Artemether + Lumefantrine

Number of subjects included in analysis

238

Analysis specification

Pre-specified

Analysis type

superiority

Method

Kaplan-Meier curves

Parameter type

ACPR percent difference

Point estimate

-16.38

Confidence interval

level

95%

sides

2-sided

lower limit

-29.42

upper limit

-3.33

Estimates for Day 42

Statistical analysis description

Comparison groups

Cohort 2: Azithromycin + Chloroquine v Cohort 2: Artemether + Lumefantrine

Number of subjects included in analysis

238

Analysis specification

Pre-specified

Analysis type

superiority

Method

Kaplan-Meier curves

Parameter type

ACPR percent difference

Point estimate

-16.94

Confidence interval

level

95%

sides

2-sided

lower limit

-30.04

upper limit

-3.83

Secondary: Percentage of Subjects With Early Treatment Failure (ETF) in the mITT Population (PCR-corrected)

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End point title

Percentage of Subjects With Early Treatment Failure (ETF) in the mITT Population (PCR-corrected) ^[9]

End point description

ETF defined as subjects 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. mITT population, subjects in Ivory Coast center were excluded from mITT population.

End point type

Secondary

End point timeframe

Day 0 up to Day 3

Notes
[9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Cohort 1 was a screening cohort, meant for safety evaluation, but not included in the efficacy assessments.

End point values	Cohort 2: Azithromycin + Chloroquine	Cohort 2: Artemether + Lumefantrine
Number of subjects analysed	120	126
Units: Percentage of Subjects
number (not applicable)	5.83	0.79

No statistical analyses for this end point

Secondary: Percentage of Subjects With ETF in PP Population (PCR-corrected)

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End point title

Percentage of Subjects With ETF in PP Population (PCR-corrected) ^[10]

End point description

ETF defined as subjects 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. PP population, subjects in Ivory Coast center were excluded from the PP population.

End point type

Secondary

End point timeframe

Day 0 up to Day 3

Notes
[10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Cohort 1 was a screening cohort, meant for safety evaluation, but not included in the efficacy assessments.

End point values	Cohort 2: Azithromycin + Chloroquine	Cohort 2: Artemether + Lumefantrine
Number of subjects analysed	114	124
Units: Percentage of Subjects
number (not applicable)	1.75	0

No statistical analyses for this end point

Secondary: Percentage of Subjects With Late Clinical Failure (LCF) in the mITT Population (PCR-corrected)

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End point title

Percentage of Subjects With Late Clinical Failure (LCF) in the mITT Population (PCR-corrected) ^[11]

End point description

LCF included subjects 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 5 and 6) 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 5 and 6). PCR-corrected refers to the use of molecular testing to differentiate recrudescence from reinfection in the context of an efficacy evaluation. mITT population, subjects in Ivory Coast center were excluded from mITT population.

End point type

Secondary

End point timeframe

Days 7, 14, 21, 28, 35, 42

Notes
[11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Cohort 1 was a screening cohort, meant for safety evaluation, but not included in the efficacy assessments.

End point values	Cohort 2: Azithromycin + Chloroquine	Cohort 2: Artemether + Lumefantrine
Number of subjects analysed	120	126
Units: Percentage of Subjects
number (not applicable)
Day 7	0	0
Day 14	0	0
Day 21	0	0
Day 28	0	0
Day 35	0	0
Day 42	0	0

No statistical analyses for this end point

Secondary: Percentage of Subjects With LCF in PP Population (PCR-corrected)

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End point title

Percentage of Subjects With LCF in PP Population (PCR-corrected) ^[12]

End point description

LCF included subjects 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 5 and 6) 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 5 and 6). PCR-corrected refers to the use of molecular testing to differentiate recrudescence from reinfection in the context of an efficacy evaluation. PP population, subjects in Ivory Coast center were excluded from the PP population.

End point type

Secondary

End point timeframe

Days 7, 14, 21, 28, 35, 42

Notes
[12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Cohort 1 was a screening cohort, meant for safety evaluation, but not included in the efficacy assessments.

End point values	Cohort 2: Azithromycin + Chloroquine	Cohort 2: Artemether + Lumefantrine
Number of subjects analysed	114	124
Units: Percentage of Subjects
number (not applicable)
Day 7	0	0
Day 14	0	0
Day 21	0	0
Day 28	0	0
Day 35	0	0
Day 42	0	0

No statistical analyses for this end point

Secondary: Percentage of Subjects With Late Parasitologic Failure (LPF) in the mITT Population (PCR-corrected)

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End point title

Percentage of Subjects With Late Parasitologic Failure (LPF) in the mITT Population (PCR-corrected) ^[13]

End point description

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 5 and 6) or LCF (see measure description in secondary outcome measure 7 and 8). PCR-corrected refers to the use of molecular testing to differentiate recrudescence from reinfection in the context of an efficacy evaluation. mITT population, subjects in Ivory Coast center were excluded from mITT population.

End point type

Secondary

End point timeframe

Days 7, 14, 21, 28, 35, 42

Notes
[13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Cohort 1 was a screening cohort, meant for safety evaluation, but not included in the efficacy assessments.

End point values	Cohort 2: Azithromycin + Chloroquine	Cohort 2: Artemether + Lumefantrine
Number of subjects analysed	120	126
Units: Percentage of subjects
number (not applicable)
Day 7	0	0
Day 14	1.67	0
Day 21	2.5	0.79
Day 28	4.17	0.79
Day 35	4.17	2.38
Day 42	5	2.38

No statistical analyses for this end point

Secondary: Percentage of Subjects With LPF in PP Population (PCR-corrected)

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End point title

Percentage of Subjects With LPF in PP Population (PCR-corrected) ^[14]

End point description

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 5 and 6) or LCF (see measure description in secondary outcome measure 7 and 8). PCR-corrected refers to the use of molecular testing to differentiate recrudescence from reinfection in the context of an efficacy evaluation. PP population, subjects in Ivory Coast center were excluded from the PP population.

End point type

Secondary

End point timeframe

Days 7, 14, 21, 28, 35, 42

Notes
[14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Cohort 1 was a screening cohort, meant for safety evaluation, but not included in the efficacy assessments.

End point values	Cohort 2: Azithromycin + Chloroquine	Cohort 2: Artemether + Lumefantrine
Number of subjects analysed	114	124
Units: Percentage of subjects
number (not applicable)
Day 7	0	0
Day 14	1.75	0
Day 21	2.63	0.81
Day 28	4.39	0.81
Day 35	4.39	2.42
Day 42	5.26	2.42

No statistical analyses for this end point

Secondary: Percentage of Subjects With Asexual Parasitologic Response (PCR-corrected)

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End point title

Percentage of Subjects With Asexual Parasitologic Response (PCR-corrected) ^[15]

End point description

Percentage of Subjects 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. mITT population. "n"=Subjects who were evaluable at specified time points for each arm, respectively.

End point type

Secondary

End point timeframe

Days 7, 14, 21, 28, 35, 42

Notes
[15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Cohort 1 was a screening cohort, meant for safety evaluation, but not included in the efficacy assessments.

End point values	Cohort 2: Azithromycin + Chloroquine	Cohort 2: Artemether + Lumefantrine
Number of subjects analysed	120 ^[16]	128 ^[17]
Units: Percentage of Subjects
number (not applicable)
Day 7 (n=120, 128)	93.33	99.22
Day 14 (n=120, 127)	91.67	99.21
Day 21 (n=120, 128)	90.83	98.44
Day 28 (n=120, 127)	89.17	98.43
Day 35 (n=120, 128)	89.17	96.88
Day 42 (n=120, 127)	88.33	96.85

Notes
[16] - Subjects with evaluable data, including subjects in Ivory Coast center.
[17] - Subjects with evaluable data, including subjects in Ivory Coast center.

Asexual Parasitologic Response for Day 7

Statistical analysis description

Day 7.

Comparison groups

Cohort 2: Azithromycin + Chloroquine v Cohort 2: Artemether + Lumefantrine

Number of subjects included in analysis

248

Analysis specification

Pre-specified

Analysis type

superiority

Method

large sample approximation to binomial

Parameter type

Percent difference

Point estimate

-5.89

Confidence interval

level

95%

sides

2-sided

lower limit

-11.02

upper limit

-0.75

Asexual Parasitologic Response for Day 14

Statistical analysis description

Day 14.

Comparison groups

Cohort 2: Azithromycin + Chloroquine v Cohort 2: Artemether + Lumefantrine

Number of subjects included in analysis

248

Analysis specification

Pre-specified

Analysis type

superiority

Method

large sample approximation to binomial

Parameter type

Percent difference

Point estimate

-7.55

Confidence interval

level

95%

sides

2-sided

lower limit

-13.14

upper limit

-1.95

Asexual Parasitologic Response for Day 21

Statistical analysis description

Day 21.

Comparison groups

Cohort 2: Artemether + Lumefantrine v Cohort 2: Azithromycin + Chloroquine

Number of subjects included in analysis

248

Analysis specification

Pre-specified

Analysis type

superiority

Method

large sample approximation to binomial

Parameter type

Percent difference

Point estimate

-7.6

Confidence interval

level

95%

sides

2-sided

lower limit

-13.61

upper limit

-1.6

Asexual Parasitologic Response for Day 28

Statistical analysis description

Day 28.

Comparison groups

Cohort 2: Azithromycin + Chloroquine v Cohort 2: Artemether + Lumefantrine

Number of subjects included in analysis

248

Analysis specification

Pre-specified

Analysis type

superiority

Method

large sample approximation to binomial

Parameter type

Percent difference

Point estimate

-9.26

Confidence interval

level

95%

sides

2-sided

lower limit

-15.64

upper limit

-2.87

Asexual Parasitologic Response for Day 35

Statistical analysis description

Day 35.

Comparison groups

Cohort 2: Azithromycin + Chloroquine v Cohort 2: Artemether + Lumefantrine

Number of subjects included in analysis

248

Analysis specification

Pre-specified

Analysis type

superiority

Method

large sample approximation to binomial

Parameter type

Percent difference

Point estimate

-7.71

Confidence interval

level

95%

sides

2-sided

lower limit

-14.45

upper limit

-0.97

Asexual Parasitologic Response for Day 42

Statistical analysis description

Day 42.

Comparison groups

Cohort 2: Azithromycin + Chloroquine v Cohort 2: Artemether + Lumefantrine

Number of subjects included in analysis

248

Analysis specification

Pre-specified

Analysis type

superiority

Method

large sample approximation to binomial

Parameter type

Percent difference

Point estimate

-8.52

Confidence interval

level

95%

sides

2-sided

lower limit

-15.43

upper limit

-1.6

Secondary: Percentage of Subjects With Gametocytologic Response

Top of page

End point title

Percentage of Subjects With Gametocytologic Response ^[18]

End point description

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. mITT population. "n"=subjects who were evaluable at specified time points for each arm, respectively.

End point type

Secondary

End point timeframe

Days 7, 14, 21, 28, 35, 42

Notes
[18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Cohort 1 was a screening cohort, meant for safety evaluation, but not included in the efficacy assessments.

End point values	Cohort 2: Azithromycin + Chloroquine	Cohort 2: Artemether + Lumefantrine
Number of subjects analysed	122 ^[19]	130 ^[20]
Units: Percentage of Subjects
number (not applicable)
Day 7 (n=122, 129)	81.97	91.47
Day 14 (n=122, 130)	81.15	91.54
Day 21 (n=122, 130)	80.33	93.08
Day 28 (n=122, 130)	81.97	93.08
Day 35 (n=122, 130)	81.97	92.31
Day 42 (n=122, 130)	80.33	91.54

Notes
[19] - Subjects with evaluable data, including subjects in the Ivory Coast center.
[20] - Subjects with evaluable data, including subjects in the Ivory Coast center.

Gametocytologic Response for Day 7

Statistical analysis description

Day 7.

Comparison groups

Cohort 2: Azithromycin + Chloroquine v Cohort 2: Artemether + Lumefantrine

Number of subjects included in analysis

252

Analysis specification

Pre-specified

Analysis type

superiority

Method

large sample approximation to binomial

Parameter type

Percent difference

Point estimate

-9.51

Confidence interval

level

95%

sides

2-sided

lower limit

-18.27

upper limit

-0.74

Gametocytologic Response for Day 14

Statistical analysis description

Day 14.

Comparison groups

Cohort 2: Azithromycin + Chloroquine v Cohort 2: Artemether + Lumefantrine

Number of subjects included in analysis

252

Analysis specification

Pre-specified

Analysis type

superiority

Method

large sample approximation to binomial

Parameter type

Percent difference

Point estimate

-10.39

Confidence interval

level

95%

sides

2-sided

lower limit

-19.23

upper limit

-1.55

Gametocytologic Response for Day 21

Statistical analysis description

Day 21.

Comparison groups

Cohort 2: Azithromycin + Chloroquine v Cohort 2: Artemether + Lumefantrine

Number of subjects included in analysis

252

Analysis specification

Pre-specified

Analysis type

superiority

Method

large sample approximation to binomial

Parameter type

Percent difference

Point estimate

-12.75

Confidence interval

level

95%

sides

2-sided

lower limit

-21.45

upper limit

-4.04

Gametocytologic Response for Day 28

Statistical analysis description

Day 28.

Comparison groups

Cohort 2: Azithromycin + Chloroquine v Cohort 2: Artemether + Lumefantrine

Number of subjects included in analysis

252

Analysis specification

Pre-specified

Analysis type

superiority

Method

large sample approximation to binomial

Parameter type

Percent difference

Point estimate

-11.11

Confidence interval

level

95%

sides

2-sided

lower limit

-19.62

upper limit

-2.6

Gametocytologic Response for Day 35

Statistical analysis description

Day 35.

Comparison groups

Cohort 2: Azithromycin + Chloroquine v Cohort 2: Artemether + Lumefantrine

Number of subjects included in analysis

252

Analysis specification

Pre-specified

Analysis type

superiority

Method

large sample approximation to binomial

Parameter type

Percent difference

Point estimate

-10.34

Confidence interval

level

95%

sides

2-sided

lower limit

-18.97

upper limit

-1.71

Gametocytologic Response for Day 42

Statistical analysis description

Day 42.

Comparison groups

Cohort 2: Azithromycin + Chloroquine v Cohort 2: Artemether + Lumefantrine

Number of subjects included in analysis

252

Analysis specification

Pre-specified

Analysis type

superiority

Method

large sample approximation to binomial

Parameter type

Percent difference

Point estimate

-11.21

Confidence interval

level

95%

sides

2-sided

lower limit

-20.14

upper limit

-2.28

Secondary: Fever Clearance Time

Top of page

End point title

Fever Clearance Time ^[21]

End point description

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). mITT population, including subjects in the Ivory Coast center.

End point type

Secondary

End point timeframe

Baseline to Day 42

Notes
[21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Cohort 1 was a screening cohort, meant for safety evaluation, but not included in the efficacy assessments.

End point values	Cohort 2: Azithromycin + Chloroquine	Cohort 2: Artemether + Lumefantrine
Number of subjects analysed	124	131
Units: Hours
median (full range (min-max))	24 (1 to 504)	24 (1 to 336)

Fever Clearance Time

Statistical analysis description

Time to event data was analyzed using the Kaplan-Meier curve.

Comparison groups

Cohort 2: Azithromycin + Chloroquine v Cohort 2: Artemether + Lumefantrine

Number of subjects included in analysis

255

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2564

Method

Kaplan-Meier, log rank

Confidence interval

Secondary: Asexual Plasmodium Falciparum Parasite Clearance Time

Top of page

End point title

Asexual Plasmodium Falciparum Parasite Clearance Time ^[22]

End point description

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. mITT population, including subjects in the Ivory Coast center.

End point type

Secondary

End point timeframe

Baseline to Day 42

Notes
[22] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Cohort 1 was a screening cohort, meant for safety evaluation, but not included in the efficacy assessments.

End point values	Cohort 2: Azithromycin + Chloroquine	Cohort 2: Artemether + Lumefantrine
Number of subjects analysed	124	131
Units: Hours
median (full range (min-max))	48 (24 to 504)	24 (1 to 48)

Asexual P Falciparum Parasite Clearance Time

Statistical analysis description

Time to event data was analyzed using the Kaplan-Meier curve.

Comparison groups

Cohort 2: Azithromycin + Chloroquine v Cohort 2: Artemether + Lumefantrine

Number of subjects included in analysis

255

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Kaplan-Meier, log rank

Confidence interval

Secondary: Nadir Hemoglobin Level

Top of page

End point title

Nadir Hemoglobin Level ^[23]

End point description

Nadir hemoglobin for each Subject was defined as the minimum hemoglobin values obtained from Day 0 through Day 3. mITT population, including Subjects in the Ivory Coast center.

End point type

Secondary

End point timeframe

Day 0 through Day 3

Notes
[23] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Cohort 1 was a screening cohort, meant for safety evaluation, but not included in the efficacy assessments.

End point values	Cohort 2: Azithromycin + Chloroquine	Cohort 2: Artemether + Lumefantrine
Number of subjects analysed	124	131
Units: grams per deciliter (g/dL)
arithmetic mean (standard deviation)	9.63 ± 1.53	9.82 ± 1.61

No statistical analyses for this end point

Secondary: Change From Nadir Hemoglobin Level at Days 14, 28, and 42

Top of page

End point title

Change From Nadir Hemoglobin Level at Days 14, 28, and 42 ^[24]

End point description

Change from nadir= observation minus nadir. Nadir defined as the minimum value for each subject on Days 0-3. mITT population. "n"=subjects who were evaluable at specified time points for each arm, respectively.

End point type

Secondary

End point timeframe

Day 14, 28, 42

Notes
[24] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Cohort 1 was a screening cohort, meant for safety evaluation, but not included in the efficacy assessments.

End point values	Cohort 2: Azithromycin + Chloroquine	Cohort 2: Artemether + Lumefantrine
Number of subjects analysed	122 ^[25]	128 ^[26]
Units: g/dL
arithmetic mean (standard error)
Change at Day 14 (n=122, 127)	0.52 ± 0.11	0.44 ± 0.13
Change at Day 28 (n=122, 127)	1.15 ± 0.11	0.96 ± 0.13
Change at Day 42 (n=122, 128)	1.29 ± 0.12	1.14 ± 0.14

Notes
[25] - Subjects with evaluable data, including subjects in the Ivory Coast center.
[26] - Subjects with evaluable data, including subjects in the Ivory Coast center.

No statistical analyses for this end point

Secondary: Time to Recurrence of Parasitemia

Top of page

End point title

Time to Recurrence of Parasitemia ^[27]

End point description

Time from the day of clearance to the time of recurrence of asexual P.falciparum parasitemia (PCR-uncorrected). mITT population, including subjects in the Ivory Coast center. Here "9.9999" indicates median as median time to recurrence could not be calculated for subjects in the Artemether-Lumefantrine treatment groups since fewer than 50% of the subjects experienced recurrent parasitemia during the study.

End point type

Secondary

End point timeframe

Baseline (Day 0) to Day 42

Notes
[27] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Cohort 1 was a screening cohort, meant for safety evaluation, but not included in the efficacy assessments.

End point values	Cohort 2: Azithromycin + Chloroquine	Cohort 2: Artemether + Lumefantrine
Number of subjects analysed	124	131
Units: Days
median (full range (min-max))	34 (2 to 42)	9.9999 (7 to 43)

Time to Recurrence of Parasitemia

Statistical analysis description

Time to event data was analyzed using the Kaplan-Meier curve.

Comparison groups

Cohort 2: Azithromycin + Chloroquine v Cohort 2: Artemether + Lumefantrine

Number of subjects included in analysis

255

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0006

Method

Kaplan-Meier, log rank

Confidence interval

Secondary: Number of Subjects With Recurrent Parasitemia Versus Baseline Plasmodium Falciparum Chloroquine Resistance Transporter (PfCRT) Status

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End point title

Number of Subjects With Recurrent Parasitemia Versus Baseline Plasmodium Falciparum Chloroquine Resistance Transporter (PfCRT) Status ^[28]

End point description

End point type

Secondary

End point timeframe

Baseline to Day 42

Notes
[28] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Cohort 1 was a screening cohort, meant for safety evaluation, but not included in the efficacy assessments.

End point values	Cohort 2: Azithromycin + Chloroquine	Cohort 2: Artemether + Lumefantrine
Number of subjects analysed	0 ^[29]	0 ^[30]
Units: Subjects

Notes
[29] - Data for this outcome measure was not analyzed as per change in planned analysis.
[30] - Data for this outcome measure was not analyzed as per change in planned analysis.

No statistical analyses for this end point

Secondary: Percentage of Subjects With PfCRT in True Failures

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End point title

Percentage of Subjects With PfCRT in True Failures ^[31]

End point description

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 subject experienced from Day 0 through the Day 42 visit: ETF (see measure description in secondary outcome measures 5 and 6), LCF (PCR corrected) (see measure description in secondary outcome measure 7 and 8), or LPF (PCR corrected) (see measure description in secondary outcome measure 9 and 10). Recrudescence of asexual P.falciparum parasites was considered treatment failure. Data for this outcome measure was not analyzed as per change in planned analysis.

End point type

Secondary

End point timeframe

Baseline to Day 42

Notes
[31] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Cohort 1 was a screening cohort, meant for safety evaluation, but not included in the efficacy assessments.

End point values	Cohort 2: Azithromycin + Chloroquine	Cohort 2: Artemether + Lumefantrine
Number of subjects analysed	0 ^[32]	0 ^[33]
Units: Percentage of subjects
number (not applicable)

Notes
[32] - Data for this outcome measure was not analyzed as per change in planned analysis.
[33] - Data for this outcome measure was not analyzed as per change in planned analysis.

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Baseline up to 35 days after last dose of study drug

Adverse event reporting additional description

The same event may appear as both an AE and a SAE.However, what is presented are distinct events.An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study. EU BR specific AE tables were generated separately using latest coding.

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

17.1

Reporting group title

COHORT1- AZITHROMYCIN/CHLOROQUINE

Reporting group description

Reporting group title

COHORT1- ARTEMETHER/LUMEFANTRINE

Reporting group description

Artemether/Lumefantrine administered orally once daily for 3 days as a combination tablet on Days 0, 1, 2. Cohort 1 included subjects between >=5 years of age and <=12 years of age.

Reporting group title

COHORT2- AZITHROMYCIN/CHLOROQUINE

Reporting group description

Azithromycin/Chloroquine administered orally once daily for 3 days as a combination tablet 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 subjects between >=6 months of age to <=59 months of age.

Reporting group title

COHORT2- ARTEMETHER/LUMEFANTRINE

Reporting group description

Artemether/Lumefantrine administered orally once daily for 3 days as a combination tablet on Days 0, 1, 2. Cohort 2 included subjects between >=6 months of age to <=59 months of age.

Serious adverse events	COHORT1- AZITHROMYCIN/CHLOROQUINE	COHORT1- ARTEMETHER/LUMEFANTRINE	COHORT2- AZITHROMYCIN/CHLOROQUINE	COHORT2- ARTEMETHER/LUMEFANTRINE
Total subjects affected by serious adverse events
subjects affected / exposed	1 / 55 (1.82%)	2 / 51 (3.92%)	0 / 124 (0.00%)	1 / 131 (0.76%)
number of deaths (all causes)	0	0	0	0
number of deaths resulting from adverse events
Nervous system disorders
Convulsion
subjects affected / exposed	0 / 55 (0.00%)	0 / 51 (0.00%)	0 / 124 (0.00%)	1 / 131 (0.76%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Hepatitis B
subjects affected / exposed	0 / 55 (0.00%)	1 / 51 (1.96%)	0 / 124 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Malaria
subjects affected / exposed	1 / 55 (1.82%)	0 / 51 (0.00%)	0 / 124 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	0 / 55 (0.00%)	1 / 51 (1.96%)	0 / 124 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 0%

Non-serious adverse events	COHORT1- AZITHROMYCIN/CHLOROQUINE	COHORT1- ARTEMETHER/LUMEFANTRINE	COHORT2- AZITHROMYCIN/CHLOROQUINE	COHORT2- ARTEMETHER/LUMEFANTRINE
Total subjects affected by non serious adverse events
subjects affected / exposed	40 / 55 (72.73%)	36 / 51 (70.59%)	103 / 124 (83.06%)	99 / 131 (75.57%)
Vascular disorders
Pallor
subjects affected / exposed	1 / 55 (1.82%)	0 / 51 (0.00%)	0 / 124 (0.00%)	0 / 131 (0.00%)
occurrences all number	1	0	0	0
General disorders and administration site conditions
Chest pain
subjects affected / exposed	0 / 55 (0.00%)	0 / 51 (0.00%)	1 / 124 (0.81%)	3 / 131 (2.29%)
occurrences all number	0	0	1	3
Chills
subjects affected / exposed	2 / 55 (3.64%)	2 / 51 (3.92%)	3 / 124 (2.42%)	5 / 131 (3.82%)
occurrences all number	2	2	3	5
Fatigue
subjects affected / exposed	1 / 55 (1.82%)	2 / 51 (3.92%)	0 / 124 (0.00%)	3 / 131 (2.29%)
occurrences all number	1	2	0	3
Feeling hot
subjects affected / exposed	1 / 55 (1.82%)	0 / 51 (0.00%)	0 / 124 (0.00%)	0 / 131 (0.00%)
occurrences all number	1	0	0	0
Inflammation
subjects affected / exposed	0 / 55 (0.00%)	0 / 51 (0.00%)	0 / 124 (0.00%)	1 / 131 (0.76%)
occurrences all number	0	0	0	1
Malaise
subjects affected / exposed	0 / 55 (0.00%)	1 / 51 (1.96%)	3 / 124 (2.42%)	2 / 131 (1.53%)
occurrences all number	0	1	3	2
Product taste abnormal
subjects affected / exposed	0 / 55 (0.00%)	0 / 51 (0.00%)	1 / 124 (0.81%)	0 / 131 (0.00%)
occurrences all number	0	0	1	0
Pyrexia
subjects affected / exposed	4 / 55 (7.27%)	3 / 51 (5.88%)	17 / 124 (13.71%)	27 / 131 (20.61%)
occurrences all number	4	3	20	31
Reproductive system and breast disorders
Balanoposthitis
subjects affected / exposed	1 / 55 (1.82%)	0 / 51 (0.00%)	0 / 124 (0.00%)	0 / 131 (0.00%)
occurrences all number	1	0	0	0
Vaginal inflammation
subjects affected / exposed	0 / 55 (0.00%)	0 / 51 (0.00%)	1 / 124 (0.81%)	0 / 131 (0.00%)
occurrences all number	0	0	1	0
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	3 / 55 (5.45%)	6 / 51 (11.76%)	15 / 124 (12.10%)	13 / 131 (9.92%)
occurrences all number	4	7	16	14
Dyspnoea
subjects affected / exposed	0 / 55 (0.00%)	0 / 51 (0.00%)	1 / 124 (0.81%)	0 / 131 (0.00%)
occurrences all number	0	0	1	0
Epistaxis
subjects affected / exposed	3 / 55 (5.45%)	0 / 51 (0.00%)	1 / 124 (0.81%)	0 / 131 (0.00%)
occurrences all number	4	0	1	0
Nasal congestion
subjects affected / exposed	0 / 55 (0.00%)	0 / 51 (0.00%)	0 / 124 (0.00%)	1 / 131 (0.76%)
occurrences all number	0	0	0	1
Oropharyngeal pain
subjects affected / exposed	1 / 55 (1.82%)	0 / 51 (0.00%)	0 / 124 (0.00%)	0 / 131 (0.00%)
occurrences all number	1	0	0	0
Rhinorrhoea
subjects affected / exposed	0 / 55 (0.00%)	1 / 51 (1.96%)	4 / 124 (3.23%)	2 / 131 (1.53%)
occurrences all number	0	1	4	2
Tachypnoea
subjects affected / exposed	0 / 55 (0.00%)	0 / 51 (0.00%)	1 / 124 (0.81%)	1 / 131 (0.76%)
occurrences all number	0	0	1	1
Psychiatric disorders
Irritability
subjects affected / exposed	0 / 55 (0.00%)	0 / 51 (0.00%)	0 / 124 (0.00%)	1 / 131 (0.76%)
occurrences all number	0	0	0	1
Restlessness
subjects affected / exposed	0 / 55 (0.00%)	0 / 51 (0.00%)	0 / 124 (0.00%)	1 / 131 (0.76%)
occurrences all number	0	0	0	1
Investigations
Electrocardiogram QT prolonged
subjects affected / exposed	0 / 55 (0.00%)	1 / 51 (1.96%)	0 / 124 (0.00%)	0 / 131 (0.00%)
occurrences all number	0	1	0	0
Injury, poisoning and procedural complications
Scratch
subjects affected / exposed	0 / 55 (0.00%)	1 / 51 (1.96%)	0 / 124 (0.00%)	0 / 131 (0.00%)
occurrences all number	0	1	0	0
Thermal burn
subjects affected / exposed	0 / 55 (0.00%)	0 / 51 (0.00%)	0 / 124 (0.00%)	1 / 131 (0.76%)
occurrences all number	0	0	0	1
Wound
subjects affected / exposed	0 / 55 (0.00%)	2 / 51 (3.92%)	2 / 124 (1.61%)	1 / 131 (0.76%)
occurrences all number	0	3	2	1
Congenital, familial and genetic disorders
Phimosis
subjects affected / exposed	1 / 55 (1.82%)	0 / 51 (0.00%)	0 / 124 (0.00%)	0 / 131 (0.00%)
occurrences all number	1	0	0	0
Cardiac disorders
Atrioventricular block first degree
subjects affected / exposed	1 / 55 (1.82%)	0 / 51 (0.00%)	0 / 124 (0.00%)	0 / 131 (0.00%)
occurrences all number	1	0	0	0
Tachycardia
subjects affected / exposed	0 / 55 (0.00%)	1 / 51 (1.96%)	1 / 124 (0.81%)	1 / 131 (0.76%)
occurrences all number	0	1	1	2
Nervous system disorders
Dizziness
subjects affected / exposed	1 / 55 (1.82%)	0 / 51 (0.00%)	0 / 124 (0.00%)	0 / 131 (0.00%)
occurrences all number	1	0	0	0
Headache
subjects affected / exposed	8 / 55 (14.55%)	5 / 51 (9.80%)	4 / 124 (3.23%)	4 / 131 (3.05%)
occurrences all number	9	7	4	4
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 55 (0.00%)	1 / 51 (1.96%)	2 / 124 (1.61%)	4 / 131 (3.05%)
occurrences all number	0	1	2	4
Lymphadenopathy
subjects affected / exposed	0 / 55 (0.00%)	1 / 51 (1.96%)	1 / 124 (0.81%)	0 / 131 (0.00%)
occurrences all number	0	1	1	0
Splenomegaly
subjects affected / exposed	0 / 55 (0.00%)	3 / 51 (5.88%)	1 / 124 (0.81%)	0 / 131 (0.00%)
occurrences all number	0	3	1	0
Thrombocytopenia
subjects affected / exposed	1 / 55 (1.82%)	0 / 51 (0.00%)	0 / 124 (0.00%)	0 / 131 (0.00%)
occurrences all number	1	0	0	0
Ear and labyrinth disorders
Ear pain
subjects affected / exposed	1 / 55 (1.82%)	2 / 51 (3.92%)	0 / 124 (0.00%)	0 / 131 (0.00%)
occurrences all number	1	2	0	0
Eye disorders
Conjunctival pallor
subjects affected / exposed	0 / 55 (0.00%)	1 / 51 (1.96%)	0 / 124 (0.00%)	0 / 131 (0.00%)
occurrences all number	0	1	0	0
Eye swelling
subjects affected / exposed	0 / 55 (0.00%)	0 / 51 (0.00%)	0 / 124 (0.00%)	1 / 131 (0.76%)
occurrences all number	0	0	0	1
Periorbital oedema
subjects affected / exposed	0 / 55 (0.00%)	0 / 51 (0.00%)	0 / 124 (0.00%)	1 / 131 (0.76%)
occurrences all number	0	0	0	1
Gastrointestinal disorders
Abdominal distension
subjects affected / exposed	0 / 55 (0.00%)	1 / 51 (1.96%)	0 / 124 (0.00%)	0 / 131 (0.00%)
occurrences all number	0	1	0	0
Abdominal pain
subjects affected / exposed	10 / 55 (18.18%)	5 / 51 (9.80%)	4 / 124 (3.23%)	14 / 131 (10.69%)
occurrences all number	11	5	6	16
Abdominal pain upper
subjects affected / exposed	0 / 55 (0.00%)	1 / 51 (1.96%)	0 / 124 (0.00%)	0 / 131 (0.00%)
occurrences all number	0	1	0	0
Anal pruritus
subjects affected / exposed	0 / 55 (0.00%)	0 / 51 (0.00%)	1 / 124 (0.81%)	1 / 131 (0.76%)
occurrences all number	0	0	1	1
Colitis
subjects affected / exposed	0 / 55 (0.00%)	0 / 51 (0.00%)	0 / 124 (0.00%)	1 / 131 (0.76%)
occurrences all number	0	0	0	1
Diarrhoea
subjects affected / exposed	2 / 55 (3.64%)	1 / 51 (1.96%)	4 / 124 (3.23%)	8 / 131 (6.11%)
occurrences all number	2	2	4	8
Enteritis
subjects affected / exposed	0 / 55 (0.00%)	0 / 51 (0.00%)	1 / 124 (0.81%)	2 / 131 (1.53%)
occurrences all number	0	0	1	2
Gastrointestinal sounds abnormal
subjects affected / exposed	0 / 55 (0.00%)	0 / 51 (0.00%)	1 / 124 (0.81%)	0 / 131 (0.00%)
occurrences all number	0	0	1	0
Mucous stools
subjects affected / exposed	0 / 55 (0.00%)	0 / 51 (0.00%)	1 / 124 (0.81%)	1 / 131 (0.76%)
occurrences all number	0	0	1	1
Nausea
subjects affected / exposed	3 / 55 (5.45%)	2 / 51 (3.92%)	0 / 124 (0.00%)	1 / 131 (0.76%)
occurrences all number	3	2	0	1
Stomatitis
subjects affected / exposed	0 / 55 (0.00%)	0 / 51 (0.00%)	0 / 124 (0.00%)	1 / 131 (0.76%)
occurrences all number	0	0	0	1
Vomiting
subjects affected / exposed	11 / 55 (20.00%)	5 / 51 (9.80%)	38 / 124 (30.65%)	13 / 131 (9.92%)
occurrences all number	12	6	44	14
Skin and subcutaneous tissue disorders
Blister
subjects affected / exposed	0 / 55 (0.00%)	1 / 51 (1.96%)	0 / 124 (0.00%)	0 / 131 (0.00%)
occurrences all number	0	1	0	0
Dermatitis atopic
subjects affected / exposed	0 / 55 (0.00%)	0 / 51 (0.00%)	0 / 124 (0.00%)	1 / 131 (0.76%)
occurrences all number	0	0	0	1
Pruritus
subjects affected / exposed	9 / 55 (16.36%)	1 / 51 (1.96%)	8 / 124 (6.45%)	2 / 131 (1.53%)
occurrences all number	9	1	8	2
Pruritus generalised
subjects affected / exposed	2 / 55 (3.64%)	0 / 51 (0.00%)	0 / 124 (0.00%)	0 / 131 (0.00%)
occurrences all number	2	0	0	0
Rash
subjects affected / exposed	0 / 55 (0.00%)	0 / 51 (0.00%)	2 / 124 (1.61%)	2 / 131 (1.53%)
occurrences all number	0	0	2	2
Rash generalised
subjects affected / exposed	0 / 55 (0.00%)	0 / 51 (0.00%)	2 / 124 (1.61%)	0 / 131 (0.00%)
occurrences all number	0	0	2	0
Rash papular
subjects affected / exposed	0 / 55 (0.00%)	0 / 51 (0.00%)	0 / 124 (0.00%)	1 / 131 (0.76%)
occurrences all number	0	0	0	1
Skin ulcer
subjects affected / exposed	0 / 55 (0.00%)	0 / 51 (0.00%)	0 / 124 (0.00%)	1 / 131 (0.76%)
occurrences all number	0	0	0	1
Swelling face
subjects affected / exposed	1 / 55 (1.82%)	1 / 51 (1.96%)	1 / 124 (0.81%)	0 / 131 (0.00%)
occurrences all number	1	1	1	0
Urticaria
subjects affected / exposed	1 / 55 (1.82%)	0 / 51 (0.00%)	1 / 124 (0.81%)	0 / 131 (0.00%)
occurrences all number	1	0	1	0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 55 (0.00%)	1 / 51 (1.96%)	0 / 124 (0.00%)	0 / 131 (0.00%)
occurrences all number	0	1	0	0
Musculoskeletal pain
subjects affected / exposed	0 / 55 (0.00%)	1 / 51 (1.96%)	0 / 124 (0.00%)	0 / 131 (0.00%)
occurrences all number	0	1	0	0
Myalgia
subjects affected / exposed	1 / 55 (1.82%)	1 / 51 (1.96%)	0 / 124 (0.00%)	1 / 131 (0.76%)
occurrences all number	1	2	0	1
Pain in extremity
subjects affected / exposed	0 / 55 (0.00%)	0 / 51 (0.00%)	0 / 124 (0.00%)	1 / 131 (0.76%)
occurrences all number	0	0	0	1
Infections and infestations
Abscess limb
subjects affected / exposed	0 / 55 (0.00%)	1 / 51 (1.96%)	0 / 124 (0.00%)	1 / 131 (0.76%)
occurrences all number	0	1	0	1
Amoebiasis
subjects affected / exposed	0 / 55 (0.00%)	0 / 51 (0.00%)	0 / 124 (0.00%)	1 / 131 (0.76%)
occurrences all number	0	0	0	1
Bacterial infection
subjects affected / exposed	0 / 55 (0.00%)	0 / 51 (0.00%)	1 / 124 (0.81%)	1 / 131 (0.76%)
occurrences all number	0	0	1	1
Blister infected
subjects affected / exposed	0 / 55 (0.00%)	0 / 51 (0.00%)	0 / 124 (0.00%)	1 / 131 (0.76%)
occurrences all number	0	0	0	1
Body tinea
subjects affected / exposed	0 / 55 (0.00%)	1 / 51 (1.96%)	0 / 124 (0.00%)	1 / 131 (0.76%)
occurrences all number	0	1	0	1
Bronchitis
subjects affected / exposed	1 / 55 (1.82%)	0 / 51 (0.00%)	4 / 124 (3.23%)	9 / 131 (6.87%)
occurrences all number	1	0	4	9
Bronchopneumonia
subjects affected / exposed	0 / 55 (0.00%)	0 / 51 (0.00%)	0 / 124 (0.00%)	2 / 131 (1.53%)
occurrences all number	0	0	0	2
Conjunctivitis
subjects affected / exposed	0 / 55 (0.00%)	3 / 51 (5.88%)	3 / 124 (2.42%)	2 / 131 (1.53%)
occurrences all number	0	3	3	2
Dysentery
subjects affected / exposed	0 / 55 (0.00%)	1 / 51 (1.96%)	1 / 124 (0.81%)	1 / 131 (0.76%)
occurrences all number	0	1	1	1
Ear infection
subjects affected / exposed	0 / 55 (0.00%)	0 / 51 (0.00%)	1 / 124 (0.81%)	1 / 131 (0.76%)
occurrences all number	0	0	1	1
Fungal skin infection
subjects affected / exposed	0 / 55 (0.00%)	0 / 51 (0.00%)	0 / 124 (0.00%)	2 / 131 (1.53%)
occurrences all number	0	0	0	2
Furuncle
subjects affected / exposed	0 / 55 (0.00%)	0 / 51 (0.00%)	1 / 124 (0.81%)	5 / 131 (3.82%)
occurrences all number	0	0	1	6
Gastroenteritis
subjects affected / exposed	0 / 55 (0.00%)	0 / 51 (0.00%)	2 / 124 (1.61%)	5 / 131 (3.82%)
occurrences all number	0	0	2	6
Giardiasis
subjects affected / exposed	0 / 55 (0.00%)	1 / 51 (1.96%)	0 / 124 (0.00%)	0 / 131 (0.00%)
occurrences all number	0	1	0	0
Helminthic infection
subjects affected / exposed	0 / 55 (0.00%)	0 / 51 (0.00%)	0 / 124 (0.00%)	1 / 131 (0.76%)
occurrences all number	0	0	0	1
Hepatitis A
subjects affected / exposed	0 / 55 (0.00%)	0 / 51 (0.00%)	0 / 124 (0.00%)	1 / 131 (0.76%)
occurrences all number	0	0	0	1
Infection parasitic
subjects affected / exposed	14 / 55 (25.45%)	11 / 51 (21.57%)	37 / 124 (29.84%)	31 / 131 (23.66%)
occurrences all number	14	11	39	33
Malaria
subjects affected / exposed	5 / 55 (9.09%)	4 / 51 (7.84%)	26 / 124 (20.97%)	19 / 131 (14.50%)
occurrences all number	5	4	26	19
Mumps
subjects affected / exposed	0 / 55 (0.00%)	0 / 51 (0.00%)	1 / 124 (0.81%)	1 / 131 (0.76%)
occurrences all number	0	0	1	1
Oral herpes
subjects affected / exposed	1 / 55 (1.82%)	0 / 51 (0.00%)	0 / 124 (0.00%)	1 / 131 (0.76%)
occurrences all number	1	0	0	1
Otitis media
subjects affected / exposed	0 / 55 (0.00%)	0 / 51 (0.00%)	1 / 124 (0.81%)	1 / 131 (0.76%)
occurrences all number	0	0	1	1
Otitis media acute
subjects affected / exposed	0 / 55 (0.00%)	1 / 51 (1.96%)	0 / 124 (0.00%)	1 / 131 (0.76%)
occurrences all number	0	1	0	1
Pneumonia
subjects affected / exposed	0 / 55 (0.00%)	0 / 51 (0.00%)	2 / 124 (1.61%)	0 / 131 (0.00%)
occurrences all number	0	0	2	0
Respiratory tract infection
subjects affected / exposed	0 / 55 (0.00%)	0 / 51 (0.00%)	2 / 124 (1.61%)	8 / 131 (6.11%)
occurrences all number	0	0	3	8
Rhinitis
subjects affected / exposed	2 / 55 (3.64%)	1 / 51 (1.96%)	2 / 124 (1.61%)	1 / 131 (0.76%)
occurrences all number	2	1	2	1
Septic rash
subjects affected / exposed	0 / 55 (0.00%)	0 / 51 (0.00%)	0 / 124 (0.00%)	1 / 131 (0.76%)
occurrences all number	0	0	0	1
Skin infection
subjects affected / exposed	0 / 55 (0.00%)	1 / 51 (1.96%)	0 / 124 (0.00%)	0 / 131 (0.00%)
occurrences all number	0	1	0	0
Staphylococcal skin infection
subjects affected / exposed	0 / 55 (0.00%)	0 / 51 (0.00%)	0 / 124 (0.00%)	1 / 131 (0.76%)
occurrences all number	0	0	0	1
Subcutaneous abscess
subjects affected / exposed	0 / 55 (0.00%)	0 / 51 (0.00%)	0 / 124 (0.00%)	1 / 131 (0.76%)
occurrences all number	0	0	0	1
Tinea capitis
subjects affected / exposed	5 / 55 (9.09%)	2 / 51 (3.92%)	2 / 124 (1.61%)	2 / 131 (1.53%)
occurrences all number	5	2	2	2
Tonsillitis
subjects affected / exposed	0 / 55 (0.00%)	1 / 51 (1.96%)	0 / 124 (0.00%)	0 / 131 (0.00%)
occurrences all number	0	1	0	0
Upper respiratory tract infection
subjects affected / exposed	6 / 55 (10.91%)	4 / 51 (7.84%)	9 / 124 (7.26%)	12 / 131 (9.16%)
occurrences all number	6	4	13	14
Urinary tract infection
subjects affected / exposed	1 / 55 (1.82%)	0 / 51 (0.00%)	0 / 124 (0.00%)	1 / 131 (0.76%)
occurrences all number	1	0	0	1
Viral rash
subjects affected / exposed	0 / 55 (0.00%)	0 / 51 (0.00%)	1 / 124 (0.81%)	0 / 131 (0.00%)
occurrences all number	0	0	1	0
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	3 / 55 (5.45%)	3 / 51 (5.88%)	9 / 124 (7.26%)	5 / 131 (3.82%)
occurrences all number	3	3	10	5

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Were there any global substantial amendments to the protocol? Yes

18 Dec 2007

1. The primary endpoint was changed from asexual P. falciparum parasite clearance rate at Day 28 to adequate clinical and parasitological response (ACPR) at Day 28 2. The primary endpoint (ACPR) was also changed to be based on PCR-corrected data rather than using uncorrected data. 3. Secondary endpoint changed from % Late treatment failure (LTF) to % Late Clinical Failures (LCF)

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

Cohort 1 was a screening cohort, meant for safety evaluation, but not included in the efficacy assessments.

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Clinical trials

Clinical Trial Results: 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

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Percentage of Subjects With Polymerase Chain Reaction (PCR)-Corrected Adequate Clinical and Parasitologic Response (ACPR) at Day 28 in the Modified Intent-to-treat (mITT) Population

Primary: Percentage of Subjects With Polymerase Chain Reaction (PCR)-Corrected Adequate Clinical and Parasitologic Response (ACPR) at Day 28 in the Modified Intent-to-treat (mITT) Population

Primary: Percentage of Subjects With PCR-corrected ACPR at Day 28 in Per-Protocol (PP) Population

Primary: Percentage of Subjects With PCR-corrected ACPR at Day 28 in Per-Protocol (PP) Population

Secondary: Percentage of Subjects With PCR-corrected ACPR in the mITT Population

Secondary: Percentage of Subjects With PCR-corrected ACPR in the mITT Population

Secondary: Percentage of Subjects With PCR-corrected ACPR in PP Population

Secondary: Percentage of Subjects With PCR-corrected ACPR in PP Population

Secondary: Percentage of Subjects With PCR-uncorrected ACPR in the mITT Population

Secondary: Percentage of Subjects With PCR-uncorrected ACPR in the mITT Population

Secondary: Percentage of Subjects With PCR-uncorrected ACPR in PP Population

Secondary: Percentage of Subjects With PCR-uncorrected ACPR in PP Population

Secondary: Percentage of Subjects With Early Treatment Failure (ETF) in the mITT Population (PCR-corrected)

Secondary: Percentage of Subjects With Early Treatment Failure (ETF) in the mITT Population (PCR-corrected)

Secondary: Percentage of Subjects With ETF in PP Population (PCR-corrected)

Secondary: Percentage of Subjects With ETF in PP Population (PCR-corrected)

Secondary: Percentage of Subjects With Late Clinical Failure (LCF) in the mITT Population (PCR-corrected)

Secondary: Percentage of Subjects With Late Clinical Failure (LCF) in the mITT Population (PCR-corrected)

Secondary: Percentage of Subjects With LCF in PP Population (PCR-corrected)

Secondary: Percentage of Subjects With LCF in PP Population (PCR-corrected)

Secondary: Percentage of Subjects With Late Parasitologic Failure (LPF) in the mITT Population (PCR-corrected)

Secondary: Percentage of Subjects With Late Parasitologic Failure (LPF) in the mITT Population (PCR-corrected)

Secondary: Percentage of Subjects With LPF in PP Population (PCR-corrected)

Secondary: Percentage of Subjects With LPF in PP Population (PCR-corrected)

Secondary: Percentage of Subjects With Asexual Parasitologic Response (PCR-corrected)

Secondary: Percentage of Subjects With Asexual Parasitologic Response (PCR-corrected)

Secondary: Percentage of Subjects With Gametocytologic Response

Secondary: Percentage of Subjects With Gametocytologic Response

Secondary: Fever Clearance Time

Secondary: Fever Clearance Time

Secondary: Asexual Plasmodium Falciparum Parasite Clearance Time

Secondary: Asexual Plasmodium Falciparum Parasite Clearance Time

Secondary: Nadir Hemoglobin Level

Secondary: Nadir Hemoglobin Level

Secondary: Change From Nadir Hemoglobin Level at Days 14, 28, and 42

Secondary: Change From Nadir Hemoglobin Level at Days 14, 28, and 42

Secondary: Time to Recurrence of Parasitemia

Secondary: Time to Recurrence of Parasitemia

Secondary: Number of Subjects With Recurrent Parasitemia Versus Baseline Plasmodium Falciparum Chloroquine Resistance Transporter (PfCRT) Status

Secondary: Number of Subjects With Recurrent Parasitemia Versus Baseline Plasmodium Falciparum Chloroquine Resistance Transporter (PfCRT) Status

Secondary: Percentage of Subjects With PfCRT in True Failures

Secondary: Percentage of Subjects With PfCRT in True Failures

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical Trial Results:
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