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    Clinical Trial Results:
    A cluster randomized, single-centre, controlled, parallel,12-month prospective study and additional 12-month follow-up in Africa of malaria incidence in a community setting following systematic treatment of P. Falciparum asymptomatic carriers with artemether-lumefantrine (Coartem® / Coartem® Dispersible)

    Summary
    EudraCT number
    		 2015-004461-85
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    26 Jul 2012

    Results information
    Results version number
    		 v1(current)
    This version publication date
    27 Dec 2016
    First version publication date
    27 Dec 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CCOA566B2401/E1
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharmaceuticals AG
    Sponsor organisation address
    CH-4002, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharmaceuticals AG, +41 613241111,
    Scientific contact
    Clinical Disclosure Office, Novartis Pharmaceuticals AG, +41 613241111,
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    26 Jul 2012
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Jul 2012
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    • To evaluate at the community level whether treatment of AC of P falciparum is associated with a lower number of symptomatic malaria episodes RDT confirmed (SMRCs) per person-year over a 12 month follow-up in the infant and children population (i.e. <5 years of age) in the intervention clusters (villages) compared with the control clusters. • To evaluate whether treatment of AC of P. falciparum is associated with an improvement in hemoglobin levels after 28 days by comparing the change in hemoglobin levels from Day 1- of CSC 1 to Day 28 of CSC 1 for microscopy confirmed AC > 6 months of age in the intervention versus the control arms.
    Protection of trial subjects
    Development of danger signs or symptoms of severe malaria in the presence of parasitemia on Days 1, 2 or 3 or a clinical requirement for parenteral treatment warranted discontinuation of investigational treatment and the implementation of rescue medication. Rescue treatment involved therapy with an effective antimalarial available locally as per national treatment guidelines. Administration could be oral or parenteral depending on the subject’s clinical condition. Rescue treatment was not considered study medication. The MT is a mobile team of healthcare professionals from the central investigational site who will travel to each cluster as required to ensure that the same standard of care is provided in both study arms in order to decrease possible bias.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    22 Nov 2010
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Burkina Faso: 14075
    Worldwide total number of subjects
    14075
    EEA total number of subjects
    0
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    198
    Infants and toddlers (28 days-23 months)
    1126
    Children (2-11 years)
    4427
    Adolescents (12-17 years)
    2062
    Adults (18-64 years)
    5528
    From 65 to 84 years
    669
    85 years and over
    65

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Subjects were identified in a series of four community screening campaigns (CSCs).

    Period 1
    Period 1 title
    Period 1
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Intervention
    Arm description
    		 treatment is artemether-lumefantrine (tablets or dispersible tablets).
    Arm type
    		 Experimental

    Investigational medicinal product name
    artemether-lumefantrine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Each tablet or dispersible tablet contains 20 mg artemether and 120 mg lumefantrine and the treatment is given twice a day for 3 consecutive days.

    Arm title
    		 Control
    Arm description
    		 no study treatment was given except for the treatment of Symptomatic malaria episode, RDT-confirmed (SMRCs)
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		Intervention Control
    Started
    6817
    7258
    Completed
    5897
    6510
    Not completed
    920
    748
         Adverse event, serious fatal
    48
    44
         Consent withdrawn by subject
    35
    43
         Lost to follow-up
    837
    661
    Period 2
    Period 2 title
    Period 2 (follow-up)
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Intervention
    Arm description
    		 treatment is artemether-lumefantrine (tablets or dispersible tablets).
    Arm type
    		 Experimental

    Investigational medicinal product name
    artemether-lumefantrine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Each tablet or dispersible tablet contains 20 mg artemether and 120 mg lumefantrine and the treatment is given twice a day for 3 consecutive days.

    Arm title
    		 Control
    Arm description
    		 no study treatment was given except for the treatment of Symptomatic malaria episode, RDT-confirmed (SMRCs)
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 2 [1]
    		Intervention Control
    Started
    5854
    6372
    Completed
    0
    0
    Not completed
    5854
    6372
         Adverse event, serious fatal
    6
    8
         Study terminated by sponsor
    5777
    6287
         Lost to follow-up
    71
    77
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: A subject who emigrated was discontinued from the study, however, if later on during the study this subject immigrates to the cluster he/she was treated as an immigrant and was counted twice, once as a resident subject and once as an immigrant during the study.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Intervention
    Reporting group description
    		 treatment is artemether-lumefantrine (tablets or dispersible tablets).

    Reporting group title
    Control
    Reporting group description
    		 no study treatment was given except for the treatment of Symptomatic malaria episode, RDT-confirmed (SMRCs)

    Reporting group values
    		 Intervention Control Total
    Number of subjects
    		 6817 7258 14075
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 123 75 198
        Infants and toddlers (28 days-23 months)
    		 558 568 1126
        Children (2-11 years)
    		 2096 2331 4427
        Adolescents (12-17 years)
    		 1017 1045 2062
        Adults (18-64 years)
    		 2644 2884 5528
        From 65-84 years
    		 348 321 669
        85 years and over
    		 31 34 65
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 23.41 ( 21.026 ) 23.42 ( 20.371 ) -
    Gender categorical
    Units: Subjects
        Female
    		 3656 3816 7472
        Male
    		 3161 3442 6603

    End points

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    End points reporting groups
    Reporting group title
    Intervention
    Reporting group description
    		 treatment is artemether-lumefantrine (tablets or dispersible tablets).

    Reporting group title
    Control
    Reporting group description
    		 no study treatment was given except for the treatment of Symptomatic malaria episode, RDT-confirmed (SMRCs)
    Reporting group title
    Intervention
    Reporting group description
    		 treatment is artemether-lumefantrine (tablets or dispersible tablets).

    Reporting group title
    Control
    Reporting group description
    		 no study treatment was given except for the treatment of Symptomatic malaria episode, RDT-confirmed (SMRCs)

    Subject analysis set title
    Intervention
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Cluster level data, Eligible clusters set

    Subject analysis set title
    Control
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Cluster level data, Eligible clusters set

    Primary: Number of SMRC5000s per person-year in infants and children (<5 years) in post CSC follow-up at month 12

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    End point title
    		 Number of SMRC5000s per person-year in infants and children (<5 years) in post CSC follow-up at month 12
    End point description
    End point type
    Primary
    End point timeframe
    Month 12
    End point values
    		 Intervention Control
    Number of subjects analysed
    9
    9
    Units: Number of SMRC5000s
        arithmetic mean (standard deviation)
    1.69 ( 0.436 )
    1.6 ( 0.526 )
    Statistical analysis title
    		 Number of SMRC5000s per person
    Comparison groups
    Intervention v Control
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.3482
    Method
    		 t-test, 1-sided
    Confidence interval

    Primary: Change in hemoglobin level (g/dL) in asymptomatic carriers >6 months of age from CSC1/Day 1 to CSC1/Day 28 by study arm (Asymptomatic carriers at CSC1 analysis set)

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    End point title
    		 Change in hemoglobin level (g/dL) in asymptomatic carriers >6 months of age from CSC1/Day 1 to CSC1/Day 28 by study arm (Asymptomatic carriers at CSC1 analysis set)
    End point description
    End point type
    Primary
    End point timeframe
    Day 1 to Day 28
    End point values
    		 Intervention Control
    Number of subjects analysed
    9
    9 [1]
    Units: g/dL
    arithmetic mean (standard deviation)
        CSC1/Day 1
    11.81 ( 0.329 )
    12.06 ( 0.345 )
        CSC1/Day 28
    12.33 ( 0.318 )
    11.86 ( 0.373 )
        Change
    0.53 ( 0.256 )
    -0.21 ( 0.266 )
    Notes
    [1] - Applicable for about 40% randomly selected subjects of the control clusters.
    Statistical analysis title
    		 Change in hemoglobin level in asymptomatic carrier
    Comparison groups
    Intervention v Control
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 0.0001
    Method
    		 t-test, 1-sided
    Confidence interval

    Secondary: Microscopy confirmed gametocyte carriers CSC4 by study arm (Eligible clusters set)

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    End point title
    		 Microscopy confirmed gametocyte carriers CSC4 by study arm (Eligible clusters set)
    End point description
    End point type
    Secondary
    End point timeframe
    Day 1
    End point values
    		 Intervention Control
    Number of subjects analysed
    9
    9 [2]
    Units: prevalence of GCs
        least squares mean (confidence interval 90%)
    4.9 (4.16 to 5.58)
    5.1 (4.37 to 5.79)
    Notes
    [2] - Measured in about 40% randomly selected subjects of the control clusters.
    No statistical analyses for this end point

    Secondary: Microscopy confirmed asymptomatic carriers of P. falciparum at CSC4 by study arm (Eligible clusters set)

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    End point title
    		 Microscopy confirmed asymptomatic carriers of P. falciparum at CSC4 by study arm (Eligible clusters set)
    End point description
    End point type
    Secondary
    End point timeframe
    Day 1
    End point values
    		 Intervention Control
    Number of subjects analysed
    9
    9 [3]
    Units: prevalence of ACs
        least squares mean (confidence interval 90%)
    34.6 (31.36 to 37.9)
    37.6 (34.29 to 40.82)
    Notes
    [3] - Measured in about 40% randomly selected subjects of the control clusters.
    No statistical analyses for this end point

    Secondary: Change in hemoglobin level (g/dL) from CSC1/Day 1 to CSC4/Day 1 in infants and children (>6 months and <5 years) by study arm (Eligible clusters set Overall-C)

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    End point title
    		 Change in hemoglobin level (g/dL) from CSC1/Day 1 to CSC4/Day 1 in infants and children (>6 months and <5 years) by study arm (Eligible clusters set Overall-C)
    End point description
    End point type
    Secondary
    End point timeframe
    Day 1
    End point values
    		 Intervention Control
    Number of subjects analysed
    9
    9 [4]
    Units: g/dL
    arithmetic mean (standard deviation)
        CSC1/Day 1 - Overall-C
    10.24 ( 0.371 )
    10.04 ( 0.476 )
        CSC4/Day 1 - Overall-C
    10.99 ( 0.267 )
    11.13 ( 0.36 )
        Change - Overall-C
    0.76 ( 0.389 )
    1.08 ( 0.487 )
    Notes
    [4] - Applicable for about 40% randomly selected subjects of the control clusters.
    No statistical analyses for this end point

    Secondary: Change in hemoglobin level (g/dL) from CSC1/Day 1 to CSC4/Day 1 in infants and children (>6 months and <5 years) by study arm (Eligible clusters set Overall-I)

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    End point title
    		 Change in hemoglobin level (g/dL) from CSC1/Day 1 to CSC4/Day 1 in infants and children (>6 months and <5 years) by study arm (Eligible clusters set Overall-I)
    End point description
    End point type
    Secondary
    End point timeframe
    Day 1
    End point values
    		 Intervention Control
    Number of subjects analysed
    6817 [5]
    7258 [6]
    Units: g/dL
    arithmetic mean (standard deviation)
        CSC1/Day 1
    10.2 ( 1.777 )
    10.09 ( 1.762 )
        CSC4/Day 1
    10.98 ( 1.55 )
    11.17 ( 1.586 )
        Change
    0.74 ( 1.791 )
    1.03 ( 1.794 )
    Notes
    [5] - n = 819, 827, 745
    [6] - n = 348, 321, 308 Applicable for about 40% randomly selected subjects of the control clusters.
    No statistical analyses for this end point

    Secondary: Number of SMRC5000s per person-year in post CSC follow-up by study arm (Eligible clusters set)

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    End point title
    		 Number of SMRC5000s per person-year in post CSC follow-up by study arm (Eligible clusters set)
    End point description
    End point type
    Secondary
    End point timeframe
    365.25 days
    End point values
    		 Intervention Control
    Number of subjects analysed
    6817
    7258
    Units: days
    number (not applicable)
        Number of SMRC5000
    2217
    2091
        Person-year observed
    4945.7
    5405.2
        Number of SMRC5000 per person-year
    0.45
    0.39
    No statistical analyses for this end point

    Secondary: Number of participants with SAEs including death, severe malaria, hospitalizations post CSC follow-up period (Eligible clusters set)

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    End point title
    		 Number of participants with SAEs including death, severe malaria, hospitalizations post CSC follow-up period (Eligible clusters set)
    End point description
    End point type
    Secondary
    End point timeframe
    Adverse events are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV)
    End point values
    		 Intervention Control
    Number of subjects analysed
    9
    9
    Units: Number of participants
    arithmetic mean (standard deviation)
        Death
    0.4 ( 0.19 )
    0.4 ( 0.19 )
        Severe malaria
    0.1 ( 0.11 )
    0.1 ( 0.19 )
        Hospitalizations
    1.1 ( 0.46 )
    0.9 ( 0.64 )
    No statistical analyses for this end point

    Secondary: Number of participants with SAEs including death, severe malaria, hospitalizations post CSC follow-up period (Eligible clusters set)

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    End point title
    		 Number of participants with SAEs including death, severe malaria, hospitalizations post CSC follow-up period (Eligible clusters set)
    End point description
    End point type
    Secondary
    End point timeframe
    Adverse events are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV)
    End point values
    		 Intervention Control
    Number of subjects analysed
    6817
    7258
    Units: Percentage of participants
    number (not applicable)
        Death
    0.5
    0.4
        Severe malaria
    0.1
    0.1
        Hospitalizations
    1
    0.8
    No statistical analyses for this end point

    Secondary: Number of subjects in post CSC follow-up period with SAEs including death, severe malaria and hospitalizations in infants and children (> 6 months and < 5 years) Eligible clusters set

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    End point title
    		 Number of subjects in post CSC follow-up period with SAEs including death, severe malaria and hospitalizations in infants and children (> 6 months and < 5 years) Eligible clusters set
    End point description
    End point type
    Secondary
    End point timeframe
    Adverse events are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV)
    End point values
    		 Intervention Control
    Number of subjects analysed
    9
    9
    Units: Number of participants
    arithmetic mean (standard deviation)
        Death
    0.2 ( 0.39 )
    0.2 ( 0.44 )
        Severe malaria
    0.4 ( 0.52 )
    0.5 ( 0.71 )
        Hospitalizations
    2.2 ( 1.59 )
    2.1 ( 1.86 )
    No statistical analyses for this end point

    Secondary: Number of subjects in post CSC follow-up period with SAEs including death, severe malaria and hospitalizations in infants and children (> 6 months and < 5 years) Eligible clusters set

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    End point title
    		 Number of subjects in post CSC follow-up period with SAEs including death, severe malaria and hospitalizations in infants and children (> 6 months and < 5 years) Eligible clusters set
    End point description
    End point type
    Secondary
    End point timeframe
    Adverse events are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV)
    End point values
    		 Intervention Control
    Number of subjects analysed
    1023
    1040
    Units: Percentage of participants
    number (not applicable)
        Death
    0.2
    0.2
        Severe malaria
    0.04
    0.5
        Hospitalizations
    2
    2
    No statistical analyses for this end point

    Secondary: Mean of microscopy-confirmed asymptomatic carriers at day 1 of CSC1, CSC2, CSC3 and CSC4(Eligible clusters set

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    End point title
    		 Mean of microscopy-confirmed asymptomatic carriers at day 1 of CSC1, CSC2, CSC3 and CSC4(Eligible clusters set
    End point description
    End point type
    Secondary
    End point timeframe
    Day 1
    End point values
    		 Intervention Control
    Number of subjects analysed
    6817 [7]
    7258 [8]
    Units: percentages of cluster frequencies
    number (not applicable)
        CSC1/Day 1
    43.6
    46.6
        CSC2/Day 1
    4.2
    35.4
        CSC3/Day 1
    2.8
    30.6
        CSC4/Day 1
    34.8
    36.2
    Notes
    [7] - n = 5575, 5680, 6114, 5820
    [8] - n=2472, 2355, 2424, 2449 Applicable for about 40% randomly selected subjects of the control clusters
    No statistical analyses for this end point

    Secondary: Prevalence of microscopy-confirmed gametocyte carriers over time by study arm (Eligible clusters set)

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    End point title
    		 Prevalence of microscopy-confirmed gametocyte carriers over time by study arm (Eligible clusters set)
    End point description
    End point type
    Secondary
    End point timeframe
    Day 1
    End point values
    		 Intervention Control
    Number of subjects analysed
    9
    9 [9]
    Units: cluster frequencies
    arithmetic mean (standard deviation)
        CSC1/Day 1
    9.5 ( 2.95 )
    10.2 ( 4.54 )
        CSC2/Day 1
    0.6 ( 0.38 )
    5.5 ( 2.54 )
        CSC3/Day 1
    0.4 ( 0.4 )
    5.8 ( 1.77 )
        CSC4/Day 1
    4.8 ( 1.34 )
    5.1 ( 1.38 )
    Notes
    [9] - Applicable for about 40% randomly selected subjects of the control clusters.
    No statistical analyses for this end point

    Secondary: Prevalence of microscopy-confirmed gametocyte carriers over time by study arm (Eligible clusters set)

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    End point title
    		 Prevalence of microscopy-confirmed gametocyte carriers over time by study arm (Eligible clusters set)
    End point description
    End point type
    Secondary
    End point timeframe
    Day 1
    End point values
    		 Intervention Control
    Number of subjects analysed
    6817 [10]
    7258 [11]
    Units: percent
    number (not applicable)
        CSC1/Day1
    9.7
    10
        CSC2/Day1
    0.6
    5.5
        CSC3/Day1
    0.4
    5.9
        CSC4/Day1
    4.8
    5
    Notes
    [10] - n = 5575, 5680, 6114, 5820
    [11] - n=2472, 2355, 2424, 2249 Applicable for about 40% randomly selected subjects of the control clusters
    No statistical analyses for this end point

    Secondary: Prevalence of microscopy- and qRT-PCR-confirmed gametocyte carriers at CSC4/Day 1 by study arm (Eligible clusters set)

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    End point title
    		 Prevalence of microscopy- and qRT-PCR-confirmed gametocyte carriers at CSC4/Day 1 by study arm (Eligible clusters set)
    End point description
    End point type
    Secondary
    End point timeframe
    Day 1
    End point values
    		 Intervention Control
    Number of subjects analysed
    1023
    976 [12]
    Units: percent
    number (not applicable)
        Negative - Microscopy
    92.8
    93.8
        Negative - qRT-PCR
    50.2
    52.4
        Positive - Microscopy
    6
    5.4
        Positive - qRT-PCR
    49.7
    47.3
        Not evaluable - Microscopy
    1.3
    0.8
        Not evaluable - qRT-PCR
    0.1
    0.3
    Notes
    [12] - Applicable for about 40% randomly selected subjects of the control clusters.
    No statistical analyses for this end point

    Secondary: Overall summary and change in hemoglobin level from CSC1/Day 1 to CSC1/Day 28 in infants and children (>6 months and <5 years) by study arm (Asymptomatic carriers at CSC1 analysis set)

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    End point title
    		 Overall summary and change in hemoglobin level from CSC1/Day 1 to CSC1/Day 28 in infants and children (>6 months and <5 years) by study arm (Asymptomatic carriers at CSC1 analysis set)
    End point description
    End point type
    Secondary
    End point timeframe
    Day 1 to Day 28
    End point values
    		 Intervention Control Intervention Control
    Number of subjects analysed
    6817 [13]
    7258 [14]
    9
    9
    Units: (g/dL
    arithmetic mean (standard deviation)
        CSC1/Day 1
    9.83 ( 0.411 )
    9.68 ( 0.409 )
    9.78 ( 1.763 )
    9.67 ( 1.707 )
        CSC1/Day 28
    11.03 ( 0.321 )
    10.16 ( 0.394 )
    10.95 ( 1.543 )
    10.17 ( 1.748 )
        Change
    1.19 ( 0.282 )
    0.48 ( 0.356 )
    1.19 ( 1.52 )
    0.51 ( 1.308 )
    Notes
    [13] - n = 432, 406, 404
    [14] - n = 179, 174, 173
    No statistical analyses for this end point

    Secondary: Anemia status based on CSC1/Day 1 and CSC4/Day 1 in infants and children (>6 months and <5 years) by study arm (Eligible clusters set)

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    End point title
    		 Anemia status based on CSC1/Day 1 and CSC4/Day 1 in infants and children (>6 months and <5 years) by study arm (Eligible clusters set)
    End point description
    End point type
    Secondary
    End point timeframe
    Day 1
    End point values
    		 Intervention Control
    Number of subjects analysed
    9
    9
    Units: percentage of participants
    number (not applicable)
        CSC1/Day 1 - Severe
    0.4
    0.1
        CSC1/Day 1 - Moderate
    9.8
    3.5
        CSC1/Day 1 - Mild
    55.9
    42.2
        CSC1/Day 1 - No
    33.9
    54.2
        CSC1/Day 1 - Total
    100
    100
        CSC4/Day 1 - Severe
    0.3
    0.3
        CSC4/Day 1 - Moderate
    10.3
    2.8
        CSC4/Day 1 - Mild
    56
    36.4
        CSC4/Day 1 - No
    33.3
    60.4
        CSC4/Day 1 - Total
    100
    100
    No statistical analyses for this end point

    Secondary: Hemoglobin level in CSC1/Day1 and CSC4/Day1 by study arm and age group (Eligible clusters set)

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    End point title
    		 Hemoglobin level in CSC1/Day1 and CSC4/Day1 by study arm and age group (Eligible clusters set)
    End point description
    End point type
    Secondary
    End point timeframe
    Day 1
    End point values
    		 Intervention Control
    Number of subjects analysed
    9
    9 [15]
    Units: g/dL
    arithmetic mean (standard deviation)
        5 - 9 years CSC1/Day1
    11.63 ( 0.223 )
    11.59 ( 0.239 )
        5 - 9 years CSC4/Day1
    11.97 ( 0.224 )
    12.13 ( 0.324 )
        10 - 14 years CSC1/Day1
    12.32 ( 0.227 )
    12.71 ( 0.301 )
        10 - 14 years CSC4/Day1
    12.58 ( 0.161 )
    12.72 ( 0.487 )
        >= 15 years CSC1/Day1
    13.13 ( 0.304 )
    13.49 ( 0.355 )
        >= 15 years CSC4/Day1
    13.25 ( 0.167 )
    13.42 ( 0.266 )
    Notes
    [15] - Applicable for about 40% randomly selected subjects of the control clusters.
    No statistical analyses for this end point

    Secondary: Percentage of COA566-treated microscopy-confirmed asymptomatic carriers (AC) at any CSCs (1, 2 and 3) with parasitological cure rate at day 7

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    End point title
    		 Percentage of COA566-treated microscopy-confirmed asymptomatic carriers (AC) at any CSCs (1, 2 and 3) with parasitological cure rate at day 7 [16]
    End point description
    For AC any occasion: Subjects are counted multiple times if diagnosed and treated for AC more than once during the study.
    End point type
    Secondary
    End point timeframe
    Day 7
    Notes
    [16] - 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: The end point is reporting statistics for all the arms analysed in the baseline period.
    End point values
    		 Intervention
    Number of subjects analysed
    6817 [17]
    Units: Percentage of participants
    number (not applicable)
        CSC1 - Any
    99.5
        CSC1 - Tablet
    99.6
        CSC1 - Dispersible Tablet
    99.5
        CSC2 - Any
    100
        CSC2 - Tablet
    100
        CSC2 - Dispersible Tablet
    100
        CSC3 - Any
    96.7
        CSC3 - Tablet
    96.4
        CSC3 - Dispersible Tablet
    97
        AC any occasion - Any
    99.4
        AC any occasion - Tablet
    99.5
        AC any occasion - Dispersible Tablet
    99.4
    Notes
    [17] - CSC1 n=2161 CSC2 n=182 CSC3 n=121 AC any occasion n=2464
    No statistical analyses for this end point

    Secondary: Percentage of microscopy-confirmed gametocyte carriers treated with COA566 for asymptomatic carriers (Safety analyzable asymptomatic carriers set)

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    End point title
    		 Percentage of microscopy-confirmed gametocyte carriers treated with COA566 for asymptomatic carriers (Safety analyzable asymptomatic carriers set) [18]
    End point description
    End point type
    Secondary
    End point timeframe
    Day 1, Day 7 and Day 28 (Applicable to subjects with a positive RDT at Day 1 of the corresponding CSC)
    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: The end point is reporting statistics for all the arms analysed in the baseline period.
    End point values
    		 Intervention
    Number of subjects analysed
    6817 [19]
    Units: Percentage of carriers
    number (not applicable)
        CSC1 Day1: Any
    15.7
        CSC1 Day1: Tablet
    11.5
        CSC1 Day1: Dispersible Tablet
    20.9
        CSC1 Day7: Any
    1.4
        CSC1 Day7: Tablet
    0.5
        CSC1 Day7: Dispersible Tablet
    2.6
        CSC1 Day28: Any
    0.1
        CSC1 Day28: Tablet
    0.1
        CSC1 Day28: Dispersible Tablet
    0.2
        CSC2 Day1: Any
    2.6
        CSC2 Day1: Tablet
    2.3
        CSC2 Day1: Dispersible Tablet
    2.9
        CSC2 Day7: Any
    0.1
        CSC2 Day7: Tablet
    0
        CSC2 Day7: Dispersible Tablet
    0.2
        CSC3 Day1: Any
    4.7
        CSC3 Day1: Tablet
    2.1
        CSC3 Day1: Dispersible Tablet
    9.2
        CSC3 Day7: Any
    0
        CSC3 Day7: Tablet
    0
        CSC3 Day7: Dispersible Tablet
    0
        Immigrants after CSC3 Day1: Any
    4
        Immigrants after CSC3 Day1: Tablet
    2.1
        Immigrants after CSC3 Day1: Dispersible Tablet
    7.1
        Immigrants after CSC3 Day7: Any
    0
        Immigrants after CSC3 Day7: Tablet
    0
        Immigrants after CSC3 Day7: Dispersible Tablet
    0
    Notes
    [19] - CSC1 = 3045; CSC2 = 850; CSC3 = 363; Immigrants after CSC3 = 75
    No statistical analyses for this end point

    Secondary: Number of asymptomatic carriers with increase in hemoglobin levels by at least 0.5 g/dL from Day 1 to Day 28 of CSC1 in infants and children (>6 months and <5 years) by study arm (Asymptomatic carriers at CSC1 analysis set)

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    End point title
    		 Number of asymptomatic carriers with increase in hemoglobin levels by at least 0.5 g/dL from Day 1 to Day 28 of CSC1 in infants and children (>6 months and <5 years) by study arm (Asymptomatic carriers at CSC1 analysis set)
    End point description
    End point type
    Secondary
    End point timeframe
    Day 1 to Day 28
    End point values
    		 Intervention Control
    Number of subjects analysed
    9
    9 [20]
    Units: Percentages of cluster frequencies
        arithmetic mean (standard deviation)
    66.1 ( 9.17 )
    43.2 ( 12.45 )
    Notes
    [20] - Applicable for about 40% randomly selected subjects of the control clusters.
    No statistical analyses for this end point

    Secondary: Percentage of asymptomatic carriers with increase in hemoglobin levels by at least 0.5 g/dL from Day 1 to Day 28 of CSC1 in infants and children (>6 months and <5 years) by study arm (Asymptomatic carriers at CSC1 analysis set)

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    End point title
    		 Percentage of asymptomatic carriers with increase in hemoglobin levels by at least 0.5 g/dL from Day 1 to Day 28 of CSC1 in infants and children (>6 months and <5 years) by study arm (Asymptomatic carriers at CSC1 analysis set)
    End point description
    End point type
    Secondary
    End point timeframe
    Day 1 to Day 28
    End point values
    		 Intervention Control
    Number of subjects analysed
    434
    180 [21]
    Units: percent
        number (not applicable)
    66.4
    43.9
    Notes
    [21] - Applicable for about 40% randomly selected subjects of the control clusters.
    No statistical analyses for this end point

    Secondary: Number of SMRC5000 in asymptomatic carriers at any time of diagnosis

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    End point title
    		 Number of SMRC5000 in asymptomatic carriers at any time of diagnosis
    End point description
    End point type
    Secondary
    End point timeframe
    Day 1 to Day 28
    End point values
    		 Intervention Control
    Number of subjects analysed
    9
    9
    Units: Percentages of cluster frequencies
    arithmetic mean (standard deviation)
        1 SMRC5000
    15.25 ( 3.531 )
    9.49 ( 3.123 )
        2 SMRC5000
    3.56 ( 1.258 )
    2.78 ( 1.759 )
        3 SMRC5000
    1.28 ( 0.693 )
    97 ( 0.934 )
        >3 SMRC5000
    0.67 ( 0.664 )
    0.31 ( 0.417 )
    No statistical analyses for this end point

    Secondary: Number of SMRC5000 in asymptomatic carriers at any time of diagnosis

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    End point title
    		 Number of SMRC5000 in asymptomatic carriers at any time of diagnosis
    End point description
    End point type
    Secondary
    End point timeframe
    Day 1 to Day 28
    End point values
    		 Intervention Control
    Number of subjects analysed
    2740
    1381
    Units: percent
    number (not applicable)
        1 SMRC5000
    15.1
    9.8
        2 SMRC5000
    3.5
    2.8
        3 SMRC5000
    1.2
    0.9
        >3 SMRC5000
    0.6
    0.4
    No statistical analyses for this end point

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    Adverse events are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All adverse events reported in this record are from date of First Patient First Treatment until Last Patient Last Visit.
    Adverse event reporting additional description
    Consistent with EudraCT disclosure specifications, Novartis has reported under the Serious adverse events field “number of deaths resulting from adverse events” all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15.1
    Reporting groups
    Reporting group title
    Intervention core
    Reporting group description
    		 Intervention core

    Reporting group title
    Control core
    Reporting group description
    		 Control core

    Reporting group title
    Intervention Follow-up
    Reporting group description
    		 Intervention Follow-up

    Reporting group title
    Control Follow-up
    Reporting group description
    		 Control Follow-up

    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: AEs were collected within 7 days of initiation of treatment in subjects treated with artemether-lumefantrine for all SMRC episodes. All of them SAEs and included 14 deaths) were reported during the study.
    Serious adverse events
    		 Intervention core Control core Intervention Follow-up Control Follow-up
    Total subjects affected by serious adverse events
         subjects affected / exposed
    92 / 4826 (1.91%)
    67 / 2275 (2.95%)
    7 / 467 (1.50%)
    10 / 386 (2.59%)
         number of deaths (all causes)
    6
    2
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Pregnancy, puerperium and perinatal conditions
    ABORTION SPONTANEOUS
         subjects affected / exposed
    0 / 4826 (0.00%)
    1 / 2275 (0.04%)
    0 / 467 (0.00%)
    0 / 386 (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
    ABORTION THREATENED
         subjects affected / exposed
    1 / 4826 (0.02%)
    1 / 2275 (0.04%)
    0 / 467 (0.00%)
    0 / 386 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    COMPLICATION OF DELIVERY
         subjects affected / exposed
    2 / 4826 (0.04%)
    1 / 2275 (0.04%)
    0 / 467 (0.00%)
    1 / 386 (0.26%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    FOETAL DISTRESS SYNDROME
         subjects affected / exposed
    0 / 4826 (0.00%)
    1 / 2275 (0.04%)
    0 / 467 (0.00%)
    0 / 386 (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
    STILLBIRTH
         subjects affected / exposed
    1 / 4826 (0.02%)
    0 / 2275 (0.00%)
    0 / 467 (0.00%)
    0 / 386 (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
    UTERINE CERVICAL LACERATION DURING LABOUR
         subjects affected / exposed
    1 / 4826 (0.02%)
    0 / 2275 (0.00%)
    0 / 467 (0.00%)
    0 / 386 (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
    General disorders and administration site conditions
    DEATH
         subjects affected / exposed
    4 / 4826 (0.08%)
    2 / 2275 (0.09%)
    0 / 467 (0.00%)
    0 / 386 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    PYREXIA
         subjects affected / exposed
    4 / 4826 (0.08%)
    0 / 2275 (0.00%)
    0 / 467 (0.00%)
    0 / 386 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    TESTICULAR TORSION
         subjects affected / exposed
    1 / 4826 (0.02%)
    0 / 2275 (0.00%)
    0 / 467 (0.00%)
    0 / 386 (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
    Respiratory, thoracic and mediastinal disorders
    ASTHMATIC CRISIS
         subjects affected / exposed
    1 / 4826 (0.02%)
    1 / 2275 (0.04%)
    0 / 467 (0.00%)
    0 / 386 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    CHEMICAL POISONING
         subjects affected / exposed
    0 / 4826 (0.00%)
    2 / 2275 (0.09%)
    0 / 467 (0.00%)
    0 / 386 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    LOWER LIMB FRACTURE
         subjects affected / exposed
    1 / 4826 (0.02%)
    0 / 2275 (0.00%)
    0 / 467 (0.00%)
    0 / 386 (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
    PELVIC FRACTURE
         subjects affected / exposed
    1 / 4826 (0.02%)
    0 / 2275 (0.00%)
    0 / 467 (0.00%)
    0 / 386 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    SNAKE BITE
         subjects affected / exposed
    2 / 4826 (0.04%)
    0 / 2275 (0.00%)
    1 / 467 (0.21%)
    0 / 386 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    TOXICITY TO VARIOUS AGENTS
         subjects affected / exposed
    0 / 4826 (0.00%)
    1 / 2275 (0.04%)
    0 / 467 (0.00%)
    0 / 386 (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
    WOUND
         subjects affected / exposed
    1 / 4826 (0.02%)
    0 / 2275 (0.00%)
    0 / 467 (0.00%)
    0 / 386 (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
    Congenital, familial and genetic disorders
    SICKLE CELL ANAEMIA
         subjects affected / exposed
    0 / 4826 (0.00%)
    1 / 2275 (0.04%)
    0 / 467 (0.00%)
    0 / 386 (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
    Cardiac disorders
    CARDIAC FAILURE
         subjects affected / exposed
    0 / 4826 (0.00%)
    1 / 2275 (0.04%)
    0 / 467 (0.00%)
    0 / 386 (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
    Nervous system disorders
    DIZZINESS
         subjects affected / exposed
    1 / 4826 (0.02%)
    0 / 2275 (0.00%)
    0 / 467 (0.00%)
    0 / 386 (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
    HEADACHE
         subjects affected / exposed
    2 / 4826 (0.04%)
    0 / 2275 (0.00%)
    0 / 467 (0.00%)
    0 / 386 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SOMNOLENCE
         subjects affected / exposed
    0 / 4826 (0.00%)
    1 / 2275 (0.04%)
    0 / 467 (0.00%)
    0 / 386 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    EYELID OEDEMA
         subjects affected / exposed
    0 / 4826 (0.00%)
    1 / 2275 (0.04%)
    0 / 467 (0.00%)
    0 / 386 (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
    Gastrointestinal disorders
    ABDOMINAL PAIN
         subjects affected / exposed
    2 / 4826 (0.04%)
    0 / 2275 (0.00%)
    0 / 467 (0.00%)
    0 / 386 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    DIARRHOEA
         subjects affected / exposed
    1 / 4826 (0.02%)
    0 / 2275 (0.00%)
    0 / 467 (0.00%)
    0 / 386 (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
    FOOD POISONING
         subjects affected / exposed
    2 / 4826 (0.04%)
    1 / 2275 (0.04%)
    0 / 467 (0.00%)
    0 / 386 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    INGUINAL HERNIA STRANGULATED
         subjects affected / exposed
    1 / 4826 (0.02%)
    0 / 2275 (0.00%)
    0 / 467 (0.00%)
    0 / 386 (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
    INTESTINAL OBSTRUCTION
         subjects affected / exposed
    0 / 4826 (0.00%)
    1 / 2275 (0.04%)
    1 / 467 (0.21%)
    0 / 386 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    LIP OEDEMA
         subjects affected / exposed
    0 / 4826 (0.00%)
    1 / 2275 (0.04%)
    0 / 467 (0.00%)
    0 / 386 (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
    NAUSEA
         subjects affected / exposed
    1 / 4826 (0.02%)
    0 / 2275 (0.00%)
    0 / 467 (0.00%)
    0 / 386 (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
    PEPTIC ULCER
         subjects affected / exposed
    0 / 4826 (0.00%)
    0 / 2275 (0.00%)
    0 / 467 (0.00%)
    1 / 386 (0.26%)
         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
    VOMITING
         subjects affected / exposed
    14 / 4826 (0.29%)
    16 / 2275 (0.70%)
    1 / 467 (0.21%)
    0 / 386 (0.00%)
         occurrences causally related to treatment / all
    3 / 14
    9 / 17
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    NEPHROTIC SYNDROME
         subjects affected / exposed
    0 / 4826 (0.00%)
    1 / 2275 (0.04%)
    0 / 467 (0.00%)
    0 / 386 (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
    RENAL COLIC
         subjects affected / exposed
    1 / 4826 (0.02%)
    0 / 2275 (0.00%)
    0 / 467 (0.00%)
    0 / 386 (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
    RENAL FAILURE
         subjects affected / exposed
    1 / 4826 (0.02%)
    1 / 2275 (0.04%)
    0 / 467 (0.00%)
    0 / 386 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    APPENDICITIS
         subjects affected / exposed
    1 / 4826 (0.02%)
    0 / 2275 (0.00%)
    0 / 467 (0.00%)
    0 / 386 (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
    BACTERIAL INFECTION
         subjects affected / exposed
    2 / 4826 (0.04%)
    1 / 2275 (0.04%)
    0 / 467 (0.00%)
    0 / 386 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    BRONCHITIS
         subjects affected / exposed
    3 / 4826 (0.06%)
    1 / 2275 (0.04%)
    0 / 467 (0.00%)
    1 / 386 (0.26%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    GASTROENTERITIS
         subjects affected / exposed
    6 / 4826 (0.12%)
    4 / 2275 (0.18%)
    0 / 467 (0.00%)
    0 / 386 (0.00%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    HEPATIC AMOEBIASIS
         subjects affected / exposed
    0 / 4826 (0.00%)
    0 / 2275 (0.00%)
    0 / 467 (0.00%)
    1 / 386 (0.26%)
         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
    INFECTION
         subjects affected / exposed
    0 / 4826 (0.00%)
    0 / 2275 (0.00%)
    0 / 467 (0.00%)
    1 / 386 (0.26%)
         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
    MALARIA
         subjects affected / exposed
    34 / 4826 (0.70%)
    27 / 2275 (1.19%)
    5 / 467 (1.07%)
    5 / 386 (1.30%)
         occurrences causally related to treatment / all
    0 / 35
    0 / 27
    0 / 5
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    MENINGITIS
         subjects affected / exposed
    0 / 4826 (0.00%)
    2 / 2275 (0.09%)
    0 / 467 (0.00%)
    0 / 386 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ORCHITIS
         subjects affected / exposed
    1 / 4826 (0.02%)
    0 / 2275 (0.00%)
    0 / 467 (0.00%)
    0 / 386 (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
    PARASITIC GASTROENTERITIS
         subjects affected / exposed
    1 / 4826 (0.02%)
    1 / 2275 (0.04%)
    0 / 467 (0.00%)
    0 / 386 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PNEUMONIA
         subjects affected / exposed
    14 / 4826 (0.29%)
    12 / 2275 (0.53%)
    1 / 467 (0.21%)
    2 / 386 (0.52%)
         occurrences causally related to treatment / all
    0 / 14
    0 / 12
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    2 / 4826 (0.04%)
    0 / 2275 (0.00%)
    0 / 467 (0.00%)
    0 / 386 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    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 / 4826 (0.00%)
    1 / 2275 (0.04%)
    0 / 467 (0.00%)
    0 / 386 (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 / 1
    0 / 0
    0 / 0
    TYPHOID FEVER
         subjects affected / exposed
    2 / 4826 (0.04%)
    4 / 2275 (0.18%)
    0 / 467 (0.00%)
    0 / 386 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    MALNUTRITION
         subjects affected / exposed
    1 / 4826 (0.02%)
    0 / 2275 (0.00%)
    0 / 467 (0.00%)
    0 / 386 (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
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Intervention core Control core Intervention Follow-up Control Follow-up
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 4826 (0.00%)
    0 / 2275 (0.00%)
    0 / 467 (0.00%)
    0 / 386 (0.00%)

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    20 Dec 2010
    • To update the human sample collection description based on new information in the respective analysis technique validation process. • To clarify that, for the primary analyses and the analysis of similar secondary objectives assessed at community level, only the time period after completion of the series of community screenings 1 to 3 is considered. This period should cover the full transmission season. Even though only a negligible number of SMRCs is expected to occur during the dry season between CSC1 and CSC3, it is felt worthwhile to clarify that this period of time is excluded from the primary analysis variable and related analysis variables to prevent any potential bias introduced into this open-label trial. • To include in the protocol the information that a ±1 day window will be accepted for the study to account for public holidays at the local healthcare facilities or subject’s absence due to private/business reasons. This was previously not mentioned in the original protocol. Also, to clarify that the visits should be scheduled in full 24h periods days after Visit day 1. For example: visit Day 7 should occur 7 full days after visit Day 1, i.e. often on the 8th day. This was not mentioned before in the original protocol by error. • To clarify that an emigrant who returns permanently to a study cluster (after being away for > 3 months) will be treated as an immigrant (following the protocol guidance for immigrants). Therefore, a new ICF will be obtained if the subject would like to enter the study again. As subjects will keep the same DSS (demographic surveillance system) identifier, the CRF will be able to capture that the same subject has re-entered the study, despite being assigned a distinct subject number. • Correction of the study code in Appendix 1 Section: PK sample handling, labeling andshipment instructions as per ethics committee request.
    18 Oct 2011
    • Refining of the definition of symptomatic malaria used for the primary analysis to include a parasite density cut-off of 5000/µL (microscopy-measured) to help elicit true malaria episodes. Malarial episode now defined by RDT-confirmed plus signs and symptoms [fever, either measured (≥37.5°C) or by history], and a parasite density >5000/µL • Describing more accurately the total body weight categories (Coartem/Coartem dispersible treatment dosing recommendation). • Clarifying a discrepancy between protocol and ICF regarding the process for random selection of the qRT-PCR sub-group. • Adding a term, SMRC5000 in Glossary of Terms: In addition to “Symptomatic malaria episodes, RDT confirmed (SMRC)”, SMRC5000 will describe the primary analysis viz “Malaria episode defined by signs and symptoms [fever, either measured (≥37.5°C) or by history], RDT-confirmed and associated with a parasite density >5000/µL
    16 Jan 2012
    • Extending the follow-up of the population of the current study by 1 year • Treating and following up all symptomatic malaria episodes in the current population over the additional 1 year period • Implementing an additional screening campaign (CSC 5) after the 1-year extension, to assess the prevalence of asymptomatic carriers

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    12 May 2012
    The 1-year extension was stopped as the outcome of the original study was unfavorable. The investigator was informed of additional procedures to be followed and he was to inform IECs of the early termination of the trial.
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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