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    Clinical Trial Results:
    An open-label, randomized, single-center, parallel group study of the effects of artemether-lumefantrine (Coartem®) atovaquone-proguanil (Malarone®) and artesunate-mefloquine on auditory function following the treatment of acute uncomplicated Plasmodium falciparum malaria in patients 12 years of age or older

    Summary
    EudraCT number
    		 2016-004321-16
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    22 Nov 2008

    Results information
    Results version number
    		 v1(current)
    This version publication date
    16 Nov 2017
    First version publication date
    16 Nov 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CCOA566A2417
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00444106
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    CH-4002, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111,
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma 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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    22 Nov 2008
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Nov 2008
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study was to assess the auditory safety of artemetherlumefantrine after 3 days of treatment in patients with acute, uncomplicated falciparum malaria by testing the null hypothesis that the rate of auditory brainstem pathway abnormalities as assessed by ABR at Day 7) is ≥ 15% in such patients. An “auditory brainstem pathway abnormality” was defined as a greater than 0.30 msec change in Wave III latency from baseline to Day 7
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    02 May 2007
    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
    Colombia: 265
    Worldwide total number of subjects
    265
    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)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    90
    Adults (18-64 years)
    175
    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 were randomized in a 3:1:1 ratio to artemether-lumefantrine, atovaquone-proguanil (Malarone®,GlaxoSmithkline) or artesunate-mefloquine (Plasmotrim® + Mephaquin®, Mepha).

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Artemether-lumefantrine (Coartem)
    Arm description
    		 Artemether-lumefantrine (Coartem) tablets containing 20 mg artemether and 120 mg lumefantrine twice a day for 3 days dosage dependent on body weight.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Artemether-lumefantrine (Coartem)
    Investigational medicinal product code
    COA566
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Artemether-lumefantrine (Coartem) tablets containing 20 mg artemether and 120 mg lumefantrine twice a day for 3 days, dosage dependent on body weight.

    Arm title
    		 Atovaquone-proguanil (Malarone)
    Arm description
    		 Atovaquone-proguanil (Malarone) tablets containing 250 mg atovaquone and 100 mg proguanil hydrochloride once daily for 3 days dosage dependent on body weight.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Atovaquone-proguanil (Malarone)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Atovaquone-proguanil (Malarone) tablets containing 250 mg atovaquone and 100 mg proguanil hydrochloride once daily for 3 days, dosage dependent on body weight.

    Arm title
    		 Artesunate-mefloquine
    Arm description
    		 Artesunate (Plasmotrim) 50 mg tablet; based on body weight for a dosage of 4 mg/kg/day for 3 days- mefloquine (Mephaquin) 250 mg tablets; based on body weight for a total dosage of 25 mg/kg once daily on days 2 and 3.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Artesunate-mefloquine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Artesunate-mefloquine tablets containing 50 mg artesunate (Plasmotrim) and 250 mg mefloquine (Mephaquin). Artesunate 4 mg/kg/day (for 3 days) and mefloquine 25 mg/kg/day (days 2 and 3) total dose was given once daily dependent upon body weight.

    Number of subjects in period 1
    		Artemether-lumefantrine (Coartem) Atovaquone-proguanil (Malarone) Artesunate-mefloquine
    Started
    159
    53
    53
    Completed Treatment Period
    159
    53
    53
    Completed
    157
    52
    52
    Not completed
    2
    1
    1
         Abnormal Test Procedure Results
    -
    -
    1
         Lost to follow-up
    2
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Artemether-lumefantrine (Coartem)
    Reporting group description
    		 Artemether-lumefantrine (Coartem) tablets containing 20 mg artemether and 120 mg lumefantrine twice a day for 3 days dosage dependent on body weight.

    Reporting group title
    Atovaquone-proguanil (Malarone)
    Reporting group description
    		 Atovaquone-proguanil (Malarone) tablets containing 250 mg atovaquone and 100 mg proguanil hydrochloride once daily for 3 days dosage dependent on body weight.

    Reporting group title
    Artesunate-mefloquine
    Reporting group description
    		 Artesunate (Plasmotrim) 50 mg tablet; based on body weight for a dosage of 4 mg/kg/day for 3 days- mefloquine (Mephaquin) 250 mg tablets; based on body weight for a total dosage of 25 mg/kg once daily on days 2 and 3.

    Reporting group values
    		 Artemether-lumefantrine (Coartem) Atovaquone-proguanil (Malarone) Artesunate-mefloquine Total
    Number of subjects
    		 159 53 53 265
    Age categorical
    Units: Subjects
        in Utero
    		 0 0 0 0
        Preterm newborns infants
    		 0 0 0 0
        0 - <28 d
    		 0 0 0 0
        28 d-<2 y
    		 0 0 0 0
        2 y -<12 y
    		 0 0 0 0
        12 y - <18 y
    		 51 21 18 90
        18 y - <65 y
    		 108 32 35 175
        65 y - <85 y
    		 0 0 0 0
        >85 y
    		 0 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 25.6 ± 11.6 25.1 ± 11.16 25.2 ± 11.26 -
    Gender, Male/Female
    Units: Subjects
        Female
    		 63 19 22 104
        Male
    		 96 34 31 161

    End points

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    End points reporting groups
    Reporting group title
    Artemether-lumefantrine (Coartem)
    Reporting group description
    		 Artemether-lumefantrine (Coartem) tablets containing 20 mg artemether and 120 mg lumefantrine twice a day for 3 days dosage dependent on body weight.

    Reporting group title
    Atovaquone-proguanil (Malarone)
    Reporting group description
    		 Atovaquone-proguanil (Malarone) tablets containing 250 mg atovaquone and 100 mg proguanil hydrochloride once daily for 3 days dosage dependent on body weight.

    Reporting group title
    Artesunate-mefloquine
    Reporting group description
    		 Artesunate (Plasmotrim) 50 mg tablet; based on body weight for a dosage of 4 mg/kg/day for 3 days- mefloquine (Mephaquin) 250 mg tablets; based on body weight for a total dosage of 25 mg/kg once daily on days 2 and 3.

    Subject analysis set title
    Artemether-lumefantrine
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Artemether-lumefantrine (Coartem) tablets containing 20 mg artemether and 120 mg lumefantrine twice a day for 3 days dosage dependent on body weight.

    Primary: Percentage of participants with Auditory abnormalities at Day 7 assessed by Auditory Brainstem Response (ABR) Wave III latency changes on Day 7(a type of hearing test)

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    End point title
    		 Percentage of participants with Auditory abnormalities at Day 7 assessed by Auditory Brainstem Response (ABR) Wave III latency changes on Day 7(a type of hearing test) [1] [2]
    End point description
    To demonstrate the safety of artemether-lumefantrine after 3 days of treatment in patients with acute, uncomplicated falciparum malaria by testing the null hypothesis that the rate of auditory abnormalities is ≥ 15% in the population treated with artemether-lumefantrine as assessed by ABR at Day 7 following initiation of treatment compared with their baseline values. An "auditory nerve abnormality" is here defined as a greater than 0.30 ms change in Wave III latency from baseline to Day 7. Exact Pearson-Clopper two-sided 95% confidence limits were constructed for all three treatment groups.
    End point type
    Primary
    End point timeframe
    7 days
    Notes
    [1] - 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: Stat analysis was conducted for one arm artemether-lumefantrine but system does not allow us to report statistical analysis for a single arm. The P Value was <0.0001.
    [2] - 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 primary objective of the study was to evaluate the effects of artemether-lumefantrine on the auditory system based on ABR and pure-tone threshold findings after treatment in adults and adolescents suffering from acute uncomplicated malaria. Hence, the other two arms are not compared.
    End point values
    		 Artemether-lumefantrine (Coartem)
    Number of subjects analysed
    151
    Units: Percentage of Participants
        number (confidence interval 95%)
    2.6 (0.7 to 6.6)
    No statistical analyses for this end point

    Secondary: Auditory changes following 3 days of treatment at Days 3, 7, 28, and 42 days as assessed by pure tone thresholds assessments (a type of hearing test)

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    End point title
    		 Auditory changes following 3 days of treatment at Days 3, 7, 28, and 42 days as assessed by pure tone thresholds assessments (a type of hearing test)
    End point description
    Audiometric measurements such as pure-tone threshold (air conduction tested at 250 to 8000 HZ) day 3, 7, 28 and 42 following initiation of treatment, including changes from baseline. Pure-tone average (PTA) calculated for each ear by averaging the pure-tone threshold values at 500, 1000, 2000 and 3000 HZ.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1), 3, 7, 28 and Day 42
    End point values
    		 Artemether-lumefantrine (Coartem) Atovaquone-proguanil (Malarone) Artesunate-mefloquine
    Number of subjects analysed
    148
    51
    47
    Units: dB
    arithmetic mean (confidence interval 95%)
        Baseline Right Ear
    12.2 (11.4 to 13.0)
    12.0 (10.5 to 13.6)
    12.7 (11.2 to 14.2)
        Change from baseline to Day 3 Right Ear
    -2.5 (-3.1 to -1.9)
    -2.4 (-3.6 to -1.2)
    -1.9 (-3.0 to -0.7)
        Change from baseline to Day 7 Right Ear
    -2.2 (-2.9 to -1.5)
    -2.6 (-4.0 to -1.1)
    -2.6 (-3.9 to -1.3)
        Change from baseline to Day 28 Right Ear
    -2.7 (-3.5 to -1.9)
    -2.6 (-4.2 to -1.0)
    -3.6 (-4.8 to -2.3)
        Change from baseline to Day 42 Right Ear
    -3.0 (-3.8 to -2.2)
    -3.3 (-4.9 to -1.7)
    -3.1 (-4.2 to -1.9)
        Baseline Left Ear
    11.4 (10.5 to 12.3)
    11.3 (9.9 to 12.7)
    12.5 (10.8 to 14.3)
        Change from baseline to Day 3 Left Ear
    -1.2 (-1.8 to -0.5)
    -1.5 (-2.6 to -0.3)
    -1.2 (-2.2 to -0.1)
        Change from baseline to Day 7 Left Ear
    -1.7 (-2.4 to -0.9)
    -1.3 (-2.8 to 0.2)
    -1.4 (-2.8 to -0.1)
        Change from baseline to Day 28 Left Ear
    -2.0 (-2.8 to -1.1)
    -1.8 (-3.0 to -0.5)
    -2.5 (-4.3 to -0.7)
        Change from baseline to Day 42 Left Ear
    -1.5 (-2.7 to -0.4)
    -2.1 (-3.5 to -0.6)
    -3.0 (-4.7 to -1.3)
    No statistical analyses for this end point

    Secondary: Relationship between changes in auditory function and treatment groups

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    End point title
    		 Relationship between changes in auditory function and treatment groups
    End point description
    ABR Wave III latency (ms) changes from baseline to Day 7 in the three drug exposure groups.
    End point type
    Secondary
    End point timeframe
    From Baseline to Day 7
    End point values
    		 Artemether-lumefantrine (Coartem) Atovaquone-proguanil (Malarone) Artesunate-mefloquine
    Number of subjects analysed
    151
    50
    45
    Units: ms
    arithmetic mean (confidence interval 95%)
        Baseline Right Ear
    3.86 (3.83 to 3.90)
    3.89 (3.84 to 3.94)
    3.86 (3.8 to 3.93)
        Change from baseline to Day 7 Right Ear
    0.01 (-0.01 to 0.03)
    -0.01 (-0.04 to 0.02)
    -0.04 (-0.08 to 0.01)
        Baseline Left Ear
    3.85 (3.82 to 3.88)
    3.88 (3.84 to 3.93)
    3.82 (3.77 to 3.88)
        Change from baseline to Day 7 Left Ear
    0.01 (-0.01 to 0.03)
    -0.01 (-0.04 to 0.02)
    -0.03 (-0.07 to 0.0)
    No statistical analyses for this end point

    Secondary: Efficacy of Polymerase Chain Reaction (PCR) adjusted malaria cure rates of the three treatment regimens at Days 14, 28 and 42

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    End point title
    		 Efficacy of Polymerase Chain Reaction (PCR) adjusted malaria cure rates of the three treatment regimens at Days 14, 28 and 42
    End point description
    Percentage of patients with clearance of asexual parasitemia (observed by optical microscopy) within 7 days of initiation of trial treatment without recrudescence within 14, 28 and 42 days respectively after initiation of treatment. Patients with recurrent parasitemia and paired PCR results were classified as either a new infection (different paired genotypes) or a recrudescence (matching paired genotypes). Patients without paired PCR results or ambiguous results were classified as treatment failures.
    End point type
    Secondary
    End point timeframe
    Days 14, 28 and 42
    End point values
    		 Artemether-lumefantrine (Coartem) Atovaquone-proguanil (Malarone) Artesunate-mefloquine
    Number of subjects analysed
    151
    53
    53
    Units: Percentage of Participants
    number (confidence interval 95%)
        Day 14
    99.4 (96.5 to 100.0)
    100.0 (93.3 to 100.0)
    98.1 (89.9 to 100.0)
        Day 28
    98.7 (95.5 to 99.8)
    98.1 (89.9 to 100.0)
    98.1 (89.9 to 100.0)
        Day 42
    97.5 (93.7 to 99.3)
    98.1 (89.7 to 100.0)
    98.1 (89.9 to 100.00)
    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.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    12.0
    Reporting groups
    Reporting group title
    Artemether lumefantrine
    Reporting group description
    		 Artemether lumefantrine

    Reporting group title
    Artesunate mefloquine
    Reporting group description
    		 Artesunate mefloquine

    Reporting group title
    Atovaquone proguanil
    Reporting group description
    		 Atovaquone proguanil

    Serious adverse events
    		 Artemether lumefantrine Artesunate mefloquine Atovaquone proguanil
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 53 (1.89%)
    0 / 53 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 53 (1.89%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Artemether lumefantrine Artesunate mefloquine Atovaquone proguanil
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    23 / 159 (14.47%)
    30 / 53 (56.60%)
    17 / 53 (32.08%)
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    9 / 159 (5.66%)
    14 / 53 (26.42%)
    5 / 53 (9.43%)
         occurrences all number
    10
    15
    5
    Headache
         subjects affected / exposed
    5 / 159 (3.14%)
    7 / 53 (13.21%)
    7 / 53 (13.21%)
         occurrences all number
    5
    7
    7
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    6 / 159 (3.77%)
    2 / 53 (3.77%)
    4 / 53 (7.55%)
         occurrences all number
    6
    2
    4
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    3 / 159 (1.89%)
    4 / 53 (7.55%)
    2 / 53 (3.77%)
         occurrences all number
    3
    4
    2
    Diarrhoea
         subjects affected / exposed
    3 / 159 (1.89%)
    7 / 53 (13.21%)
    2 / 53 (3.77%)
         occurrences all number
    3
    7
    2
    Vomiting
         subjects affected / exposed
    2 / 159 (1.26%)
    15 / 53 (28.30%)
    9 / 53 (16.98%)
         occurrences all number
    2
    15
    9
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    0 / 159 (0.00%)
    4 / 53 (7.55%)
    0 / 53 (0.00%)
         occurrences all number
    0
    4
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    30 Jan 2008
    The main purpose of this amendment was to clarify the use of primaquine as concomitant medication in this study. The Ministry of Health policy in Colombia stipulates that primaquine is administered to patients with uncomplicated P. falciparum malaria. Primaquine is primarily active against the sexual stages (gametocytes) of P. falciparum with only a weak effect on its asexual blood stages that cause the disease in humans. Despite the absence of documented interaction between Coartem and primaquine which would impact efficacy or the auditory brainstem pathway response, it was deemed necessary to define the conditions of its use in order to preclude any confounding effects that may affect the study outcome. As per the present amendment, it is now recommended to administer primaquine only at Day 7, once the study primary endpoint has been assessed. Audiometric testing specific exclusion criteria were ambiguously worded in the study synopsis and have been corrected. Pharmacokinetic sampling was reduced by one blood sample that was incorrectly included in the visit schedule.

    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.
    None reported
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