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    Clinical Trial Results:
    A randomized, investigator-blinded, multicenter, parallel group study to compare efficacy, safety and tolerability of Coartem® dispersible tablet formulation vs. Coartem® 6-dose crushed tablet in the treatment of acute uncomplicated Plasmodium falciparum malaria in infants and children Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results. Please use https://www.novctrd.com/CtrdWeb/home.novfor complete trial results.

    Summary
    EudraCT number
    		 2012-001333-14
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    02 Mar 2007

    Results information
    Results version number
    		 v1(current)
    This version publication date
    06 Jul 2018
    First version publication date
    06 Jul 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CCOA566B2303
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00386763
    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)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-000777-PIP01-09
    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
    02 Mar 2007
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Mar 2007
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To confirm the efficacy of the Coartem pediatric formulation in infants and children with a body weight of ≥5 kg and <35 kg suffering from P. falciparum malaria by testing the hypothesis that Coartem 6-dose regimen pediatric formulation is non-inferior to the presently used Coartem 6-dose regimen of crushed conventional tablet formulation on the 28-day Polymerase Chain Reaction (PCR)-corrected parasitological cure rate.
    Protection of trial subjects
    Rescue treatment involved therapy with an effective antimalarial available locally. Administration may have been orally or parenterally depending on the child’s clinical condition. In line with the treatment policy for that area, the best possible treatment option was provided, e.g. an effective 1st or 2nd-line antimalarial available in the country.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    08 Aug 2006
    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
    Mali: 225
    Country: Number of subjects enrolled
    Kenya: 193
    Country: Number of subjects enrolled
    Tanzania, United Republic of: 269
    Country: Number of subjects enrolled
    Mozambique: 102
    Country: Number of subjects enrolled
    Benin: 110
    Worldwide total number of subjects
    899
    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)
    1
    Infants and toddlers (28 days-23 months)
    219
    Children (2-11 years)
    669
    Adolescents (12-17 years)
    10
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Patients taking daily cotrimoxazole and those who received any anti-malarial drug known to influence cardiac function within 4 weeks prior to the screening visit and those taking drugs that are known to influence cardiac function and to prolong the QTc interval were excluded.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Single blind
    Roles blinded
    		 Investigator [1]

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Dispersible tablet
    Arm description
    		 Coartem® was provided as dispersible tablets (each tablet containing 20 mg artemether and 120 mg lumefantrine) and supplied in 3 blisters of 8 tablets.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Coartem®
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Eighteen dispersible tablets were for regular treatment according to body weight and six replacement dispersible tablets in case of vomiting. Tablets given should have been followed whenever possible by food/drink.

    Arm title
    		 Crushed tablet
    Arm description
    		 Coartem® was provided as standard tablets (each tablet containing 20 mg artemether and 120 mg lumefantrine) and supplied in 3 blisters of 8 tablets.
    Arm type
    		 Reference therapy

    Investigational medicinal product name
    Coartem®
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Eighteen tablets were for regular treatment according to body weight and six replacement tablets in case of vomiting. Tablets given should have been followed whenever possible by food/drink. Tablets were to be crushed and dissolved before being taken.

    Notes
    [1] - The roles blinded appear inconsistent with a simple blinded trial.
    Justification: For a double-blind trial, a double-dummy technique would need to be applied, whereby each patient would receive active drug plus placebo at each dosing point. This would require the patients to take an unnecessary large number of tablets. In addition, placebo tablets have not been developed for Coartem® dispersible or crushed tablets. Therefore in this study, in order to keep the safety assessment as objective as possible, the investigator remained blinded.
    Number of subjects in period 1
    		Dispersible tablet Crushed tablet
    Started
    447
    452
    Treated (at least one full dose)
    444
    446
    Completed treatment period
    431
    435
    Completed
    394
    388
    Not completed
    53
    64
         Adverse event, serious fatal
    2
    1
         Consent withdrawn by subject
    6
    11
         Adverse event, non-fatal
    30
    40
         Lost to follow-up
    15
    12

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Dispersible tablet
    Reporting group description
    		 Coartem® was provided as dispersible tablets (each tablet containing 20 mg artemether and 120 mg lumefantrine) and supplied in 3 blisters of 8 tablets.

    Reporting group title
    Crushed tablet
    Reporting group description
    		 Coartem® was provided as standard tablets (each tablet containing 20 mg artemether and 120 mg lumefantrine) and supplied in 3 blisters of 8 tablets.

    Reporting group values
    		 Dispersible tablet Crushed tablet Total
    Number of subjects
    		 447 452 899
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 1 0 1
        Infants and toddlers (28 days-23 months)
    		 110 109 219
        Children (2-11 years)
    		 331 338 669
        Adolescents (12-17 years)
    		 5 5 10
        Adults (18-64 years)
    		 0 0 0
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 3.6 ( 2.69 ) 3.7 ( 2.84 ) -
    Gender categorical
    Units: Subjects
        Female
    		 215 205 420
        Male
    		 232 247 479

    End points

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    End points reporting groups
    Reporting group title
    Dispersible tablet
    Reporting group description
    		 Coartem® was provided as dispersible tablets (each tablet containing 20 mg artemether and 120 mg lumefantrine) and supplied in 3 blisters of 8 tablets.

    Reporting group title
    Crushed tablet
    Reporting group description
    		 Coartem® was provided as standard tablets (each tablet containing 20 mg artemether and 120 mg lumefantrine) and supplied in 3 blisters of 8 tablets.

    Primary: Polymerase chain reaction (PCR)-corrected 28-day cure rate, by treatment

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    End point title
    		 Polymerase chain reaction (PCR)-corrected 28-day cure rate, by treatment
    End point description
    The proportion of patients who were clinically free of parasitemia at 28 days as measured by a 28-day PCR-corrected parasitological cure rate. PCR was used to determine whether reappearance of parasites was due to recrudescence or new infection. Populkations evaluated were: Primary Analysis (PA) – all ITT patients that completed 28 days with a valid PCR evaluation (if parasitemia present at Day 28) OR all ITT patients that would be classified as treatment failures prior to Day 28. Per Protocol (PP) – all PA patients that took at least 80% of scheduled study drug; had parasite counts between 2000 and 200,000 /µL at baseline and had a body weight of ≥5 kg and <35 kg Intent-to-treat (ITT) – all randomized patients with acute, uncomplicated P. falciparum malaria at baseline, had at least one relevant post-baseline efficacy assessment, and who had at least one dose of study drug.
    End point type
    Primary
    End point timeframe
    Day 28
    End point values
    		 Dispersible tablet Crushed tablet
    Number of subjects analysed
    447 [1]
    452 [2]
    Units: percent
    number (confidence interval 95%)
        PA (primary) population
    97.8 (96.3 to 99.2)
    98.5 (97.4 to 99.7)
        PP population
    98.2 (96.9 to 99.5)
    98.5 (97.3 to 99.7)
        ITT population
    95 (92.9 to 97.1)
    96.2 (94.4 to 98)
    Notes
    [1] - n = 403, 398, 418
    [2] - n = 409, 406, 423
    Statistical analysis title
    		 PA - Dispersible minus crushed tablet group
    Comparison groups
    Crushed tablet v Dispersible tablet
    Number of subjects included in analysis
    899
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 < 0.0001 [3]
    Method
    		 Hauck-Anderson correction
    Parameter type
    		 Treatment group difference, (%)
    Point estimate
    -0.8
    Confidence interval
         level
    		 97.5%
         sides
    1-sided
         lower limit
    		 -2.7
         upper limit
    		 -
    Notes
    [3] - For testing the null hypothesis of inferiority of proportions versus the alternative hypothesis of non-inferiority of proportions.
    Statistical analysis title
    		 PP - Dispersible minus crushed tablet group
    Comparison groups
    Dispersible tablet v Crushed tablet
    Number of subjects included in analysis
    899
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 < 0.0001 [4]
    Method
    		 Hauck-Anderson correction
    Parameter type
    		 Treatment group difference, (%)
    Point estimate
    -1.2
    Confidence interval
         level
    		 97.5%
         sides
    1-sided
         lower limit
    		 -2.2
         upper limit
    		 -
    Notes
    [4] - For testing the null hypothesis of inferiority of proportions versus the alternative hypothesis of non-inferiority of proportions.
    Statistical analysis title
    		 ITT - Dispersible minus crushed tablet group
    Comparison groups
    Dispersible tablet v Crushed tablet
    Number of subjects included in analysis
    899
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.0039 [5]
    Method
    		 Hauck-Anderson correction
    Parameter type
    		 Treatment group difference, (%)
    Point estimate
    -1.2
    Confidence interval
         level
    		 97.5%
         sides
    1-sided
         lower limit
    		 -4
         upper limit
    		 -
    Notes
    [5] - For testing the null hypothesis of inferiority of proportions versus the alternative hypothesis of noninferiority of proportions.

    Primary: PCR-corrected 28-day cure rate, by treatment and body weight group

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    End point title
    		 PCR-corrected 28-day cure rate, by treatment and body weight group [6]
    End point description
    PCR = polymerase chain reaction, used to determine whether reappearance of parasites was due to recrudescence or new infection.
    End point type
    Primary
    End point timeframe
    Day 28
    Notes
    [6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses have been reported for this primary end point.
    End point values
    		 Dispersible tablet Crushed tablet
    Number of subjects analysed
    447 [7]
    452 [8]
    Units: percent cured
    number (confidence interval 95%)
        5 ≤ 15 kg
    97.5 (95.4 to 99.5)
    99.2 (98 to 100)
        15 ≤ 25 kg
    98.6 (96.6 to 100)
    97.1 (94.3 to 99.9)
        25 ≤ 35 kg
    96.4 (89.6 to 100)
    100 (100 to 100)
    Notes
    [7] - PA population; n = 236, 139, 28
    [8] - n = 241, 138, 30
    No statistical analyses for this end point

    Secondary: PCR-corrected 14- and 42-day cure rates

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    End point title
    		 PCR-corrected 14- and 42-day cure rates
    End point description
    End point type
    Secondary
    End point timeframe
    Day 14 and day 42
    End point values
    		 Dispersible tablet Crushed tablet
    Number of subjects analysed
    447 [9]
    452 [10]
    Units: percent cured
    number (confidence interval 95%)
        ITT 14 days
    97.2 (95.6 to 98.8)
    97.9 (96.6 to 99.3)
        ITT 42 days
    91 (88.1 to 93.9)
    93.3 (90.7 to 95.8)
        PA 14 days
    99.5 (98.8 to 100)
    99.8 (99.3 to 100)
        PA 42 days
    96 (94 to 98.1)
    96.9 (95.1 to 98.7)
        PP 14 days
    100 (100 to 100)
    99.8 (99.3 to 100)
        PP 42 days
    96.6 (94.6 to 98.5)
    96.9 (95.1 to 98.7)
    Notes
    [9] - PA, ITT and PP population: n = 429, 377, 403, 354, 398, 349
    [10] - n = 433, 372, 409, 355, 406, 352
    No statistical analyses for this end point

    Secondary: Time to parasite clearance and time to fever clearance in hours

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    End point title
    		 Time to parasite clearance and time to fever clearance in hours
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 48 hours
    End point values
    		 Dispersible tablet Crushed tablet
    Number of subjects analysed
    447 [11]
    452 [12]
    Units: hour
    median (confidence interval 95%)
        Time to parasite clearance
    34.3 (24.6 to 35.5)
    34.9 (25.2 to 35.6)
        Time to fever clearance
    7.9 (7.8 to 8)
    7.8 (7.8 to 7.9)
    Notes
    [11] - ITT population: n = 442, 441
    [12] - n = 444, 443
    No statistical analyses for this end point

    Secondary: Number (%) of patients with patients with parasite clearance by hours

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    End point title
    		 Number (%) of patients with patients with parasite clearance by hours
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 72 hours
    End point values
    		 Dispersible tablet Crushed tablet
    Number of subjects analysed
    442 [13]
    444
    Units: percent
    number (not applicable)
        >0 - 24 hours
    38.5
    37.4
        >24 - 48 hours
    50
    52
        >48-72 hours
    7.5
    7.4
        >72 hours
    0.7
    0.7
        Parasite clearance not achieved
    3.4
    2.5
    Notes
    [13] - ITT population
    No statistical analyses for this end point

    Secondary: Number (%) of patients with gametocytes by time in the trial

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    End point title
    		 Number (%) of patients with gametocytes by time in the trial
    End point description
    End point type
    Secondary
    End point timeframe
    After Day 8; after start of treatment
    End point values
    		 Dispersible tablet Crushed tablet
    Number of subjects analysed
    442 [14]
    444
    Units: percent
    number (not applicable)
        Baseline
    4.5
    4.7
        >0-72 hours
    9.7
    10.6
        >72 hours to Day 8
    1.4
    1.2
        After Day 8
    0.5
    1.2
    Notes
    [14] - ITT population
    No statistical analyses for this end point

    Secondary: Descriptive statistics of artemether and DHA plasma maximum concentrations (Cmax) per bodyweight group in pediatric patients treated with 6-dose regimen Coartem crushed or dispersible tablets

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    End point title
    		 Descriptive statistics of artemether and DHA plasma maximum concentrations (Cmax) per bodyweight group in pediatric patients treated with 6-dose regimen Coartem crushed or dispersible tablets
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 2 hours after the first dose
    End point values
    		 Dispersible tablet Crushed tablet
    Number of subjects analysed
    91 [15]
    93 [16]
    Units: ng/mL
    arithmetic mean (standard deviation)
        Cmax artemether (group 5-<15 kg)
    196 ( 204 )
    223 ( 309 )
        Cmax artemether (group 15-<25 kg)
    150 ( 106 )
    198 ( 179 )
        Cmax artemether (group 25-<35 kg)
    134 ( 56.7 )
    174 ( 145 )
        Cmax DHA (group 5-<15 kg)
    67.8 ( 74.7 )
    54.7 ( 58.9 )
        Cmax DHA (group 15-<25 kg)
    66.5 ( 49 )
    79.8 ( 80.5 )
        Cmax DHA (group 25-<35 kg)
    73.9 ( 48.7 )
    65.3 ( 23.6 )
    Notes
    [15] - body weight groups; n = 52, 30, 9
    [16] - n = 55, 29, 8
    No statistical analyses for this end point

    Secondary: Lumefantrine Cmax per body weight group in PK population treated with 6-dose regimen Coartem crushed or dispersible tablets

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    End point title
    		 Lumefantrine Cmax per body weight group in PK population treated with 6-dose regimen Coartem crushed or dispersible tablets
    End point description
    End point type
    Secondary
    End point timeframe
    6 hours after dose 3, 6 hours after dose 5, Day 3, Day 7 and Day 14
    End point values
    		 Dispersible tablet Crushed tablet
    Number of subjects analysed
    310 [17]
    315 [18]
    Units: µg/mL
    arithmetic mean (standard deviation)
        Cmax (5-<15 kg group)
    5.16 ( 3.41 )
    6.13 ( 5.62 )
        Cmax (15-<25 kg group)
    8.03 ( 4.78 )
    9.37 ( 4.26 )
        Cmax (25-<35 kg group)
    12.3 ( 10.3 )
    21.9 ( 999.9 )
    Notes
    [17] - PK subset; n = 14, 48, 3
    [18] - n = 101, 53, 1 999.9 = represents only one value/patient sampled at this timepoint
    No statistical analyses for this end point

    Secondary: Lumefantrine AUC0-last per body weight group in PK population treated with 6-dose regimen Coartem crushed or dispersible tablets

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    End point title
    		 Lumefantrine AUC0-last per body weight group in PK population treated with 6-dose regimen Coartem crushed or dispersible tablets
    End point description
    End point type
    Secondary
    End point timeframe
    6 hours after dose 3, 6 hours after dose 5, Day 3, Day 7 and Day 14
    End point values
    		 Dispersible tablet Crushed tablet
    Number of subjects analysed
    310 [19]
    315 [20]
    Units: µg·h/mL
    number (not applicable)
        AUC0-last (5-<15 kg group)
    441
    577
        AUC0-last (15-<25 kg group)
    704
    699
        AUC0-last (25-<35 kg group)
    1260
    1150
    Notes
    [19] - PK subset; n = 14, 48, 3
    [20] - n = 101, 53, 1
    No statistical analyses for this end point

    Secondary: Lumefantrine exposure and cure rates in patients treated with 6-dose regimen Coartem crushed or dispersible tablets

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    End point title
    		 Lumefantrine exposure and cure rates in patients treated with 6-dose regimen Coartem crushed or dispersible tablets
    End point description
    End point type
    Secondary
    End point timeframe
    Day 28
    End point values
    		 Dispersible tablet Crushed tablet
    Number of subjects analysed
    310 [21]
    315 [22]
    Units: percent
    number (not applicable)
        28-day cure rate (5-<15 kg group)
    97.5
    99.2
        28-day cure rate (15-<25 kg group)
    98.6
    97.1
        28-day cure rate (25-<35 kg group)
    96.4
    100
    Notes
    [21] - PK subset; n = 14, 48, 3
    [22] - n = 101, 53, 1
    No statistical analyses for this end point

    Secondary: Lumefantrine exposure and cure rates in patients treated with 6-dose regimen Coartem crushed or dispersible tablets

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    End point title
    		 Lumefantrine exposure and cure rates in patients treated with 6-dose regimen Coartem crushed or dispersible tablets
    End point description
    End point type
    Secondary
    End point timeframe
    Day 28
    End point values
    		 Dispersible tablet Crushed tablet
    Number of subjects analysed
    310 [23]
    315 [24]
    Units: mg/kg
    arithmetic mean (standard deviation)
        Lumefantrine dose (5-<15 kg group)
    68.6 ( 16.9 )
    66.7 ( 15.3 )
        Lumefantrine dose (15-<25 kg group)
    80.6 ( 11.5 )
    82.9 ( 11 )
        Lumefantrine dose (25-<35 kg group)
    77.8 ( 8.57 )
    75.9 ( 7.21 )
    Notes
    [23] - PK subset; n= 191, 102, 17
    [24] - n = 194, 102, 19
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    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
    10.0
    Reporting groups
    Reporting group title
    Crushed tablet
    Reporting group description
    		 Crushed tablet

    Reporting group title
    Dispersible tablet
    Reporting group description
    		 Dispersible tablet

    Serious adverse events
    		 Crushed tablet Dispersible tablet
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 452 (1.33%)
    7 / 447 (1.57%)
         number of deaths (all causes)
    1
    2
         number of deaths resulting from adverse events
    0
    0
    Investigations
    Haemoglobin decreased
         subjects affected / exposed
    0 / 452 (0.00%)
    1 / 447 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Haemorrhage
         subjects affected / exposed
    0 / 452 (0.00%)
    1 / 447 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Nervous system disorders
    Convulsion
         subjects affected / exposed
    1 / 452 (0.22%)
    1 / 447 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 452 (0.22%)
    1 / 447 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Iron deficiency anaemia
         subjects affected / exposed
    0 / 452 (0.00%)
    1 / 447 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Face oedema
         subjects affected / exposed
    1 / 452 (0.22%)
    0 / 447 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 452 (0.22%)
    1 / 447 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    0 / 452 (0.00%)
    1 / 447 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 452 (0.00%)
    1 / 447 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Infection
         subjects affected / exposed
    0 / 452 (0.00%)
    1 / 447 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Laryngotracheo bronchitis
         subjects affected / exposed
    1 / 452 (0.22%)
    0 / 447 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 452 (0.00%)
    1 / 447 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Plasmodium falciparum infection
         subjects affected / exposed
    4 / 452 (0.88%)
    2 / 447 (0.45%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 452 (0.22%)
    0 / 447 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 452 (0.00%)
    1 / 447 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oral intake reduced
         subjects affected / exposed
    0 / 452 (0.00%)
    1 / 447 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Crushed tablet Dispersible tablet
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    282 / 452 (62.39%)
    283 / 447 (63.31%)
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    20 / 452 (4.42%)
    27 / 447 (6.04%)
         occurrences all number
    22
    30
    Nervous system disorders
    Headache
         subjects affected / exposed
    33 / 452 (7.30%)
    33 / 447 (7.38%)
         occurrences all number
    39
    36
    Blood and lymphatic system disorders
    Splenomegaly
         subjects affected / exposed
    30 / 452 (6.64%)
    30 / 447 (6.71%)
         occurrences all number
    32
    32
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    165 / 452 (36.50%)
    166 / 447 (37.14%)
         occurrences all number
    249
    258
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    31 / 452 (6.86%)
    37 / 447 (8.28%)
         occurrences all number
    35
    47
    Diarrhoea
         subjects affected / exposed
    26 / 452 (5.75%)
    35 / 447 (7.83%)
         occurrences all number
    31
    37
    Vomiting
         subjects affected / exposed
    76 / 452 (16.81%)
    74 / 447 (16.55%)
         occurrences all number
    81
    79
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    113 / 452 (25.00%)
    105 / 447 (23.49%)
         occurrences all number
    132
    128
    Infections and infestations
    Plasmodium falciparum infection
         subjects affected / exposed
    97 / 452 (21.46%)
    86 / 447 (19.24%)
         occurrences all number
    99
    86
    Metabolism and nutrition disorders
    Anorexia
         subjects affected / exposed
    30 / 452 (6.64%)
    28 / 447 (6.26%)
         occurrences all number
    36
    32

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 Jan 2007
    Changes included: • incorporate all changes resulting from Amendments 1 and 2 that were applicable to a limited number of sites and/or countries. • revise the definition of the PA and ITT populations and the method to construct the confidence interval for the cure rate difference. • improve protocol clarity by correcting inconsistencies, typographical errors and omissions.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results. Please use https://www.novctrd.com/CtrdWeb/home.novfor complete trial results.
    For support, Contact us.
    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
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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