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    Clinical Trial Results:
    An Open Label, Non-Comparative Study To Evaluate Parasitological Clearance Rates And Pharmacokinetics Of Azithromycin And Chloroquine Following Administration Of A Fixed Dose Combination Of Azithromycin And Chloroquine (AZCQ) In Asymptomatic Pregnant Women With Plasmodium Falciparum Parasitemia In Sub-Saharan Africa.

    Summary
    EudraCT number
    2014-004906-14
    Trial protocol
    Outside EU/EEA  
    Global end of trial date
    25 Oct 2013

    Results information
    Results version number
    v1(current)
    This version publication date
    25 May 2016
    First version publication date
    31 Jul 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    A0661201
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01103713
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Pfizer, Inc.
    Sponsor organisation address
    235 E 42nd Street, New York, United States, NY 10017
    Public contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., 001 1-800-718-1021, ClinicalTrials.gov_Inquiries@pfizer.com
    Scientific contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., 001 1-800-718-1021, ClinicalTrials.gov_Inquiries@pfizer.com
    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
    06 Aug 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Oct 2013
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective was to evaluate the peripheral parasitological clearance rate of Azithromycin/chloroquine (AZCQ) on Day 28 (Polymerase chain-reaction [PCR] corrected) following first dose of 3-day dosing regimen of AZCQ in asymptomatic pregnant women with P. falciparum parasitemia.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were followed.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    07 Mar 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Tanzania, United Republic of: 1
    Country: Number of subjects enrolled
    Uganda: 49
    Country: Number of subjects enrolled
    Benin: 1
    Country: Number of subjects enrolled
    Kenya: 67
    Country: Number of subjects enrolled
    Malawi: 50
    Worldwide total number of subjects
    168
    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)
    41
    Adults (18-64 years)
    127
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Subjects were enrolled at 5 active sites in 5 countries: Benin (site 1012), Kenya (site 1004), Malawi (site 1015), Tanzania (site 1008), and Uganda (site 1013). The enrollment of the first subject took place on 07 March 2011 and the last subject last visit was on 25 October 2013.

    Pre-assignment
    Screening details
    A total of 404 subjects were screened and 168 subjects were assigned to study drug, enrolled and treated. Of the 168 subjects, two subjects were excluded from the pharmacokinetic (PK) analysis, modified intent-to-treat (MITT), intent-to-treat (ITT) and per protocol (PP) populations due to informed consent protocol deviations.

    Period 1
    Period 1 title
    overall study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    Azithromycin (AZ)/Chloroquine (CQ)
    Arm description
    Study drug AZCQ is a fixed dose combination tablet of AZ and CQ given orally once daily for 3 days (Days 0, 1, 2).
    Arm type
    Experimental

    Investigational medicinal product name
    AZCQ fixed dose combination tablet
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Study drug AZCQ is a fixed dose combination tablet of AZ and CQ containing 250 milligram (mg) AZ and 155 mg CQ base. The dosing regimen evaluated in this study consisted of four AZCQ tablets (a total of 1000 mg AZ/620 mg CQ base), given orally once daily for 3 days (Days 0, 1, 2).

    Number of subjects in period 1
    Azithromycin (AZ)/Chloroquine (CQ)
    Started
    168
    Completed
    155
    Not completed
    13
         Not specified
    1
         Study terminated by sponsor
    2
         Consent withdrawn by subject
    8
         Lost to follow-up
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Azithromycin (AZ)/Chloroquine (CQ)
    Reporting group description
    Study drug AZCQ is a fixed dose combination tablet of AZ and CQ given orally once daily for 3 days (Days 0, 1, 2).

    Reporting group values
    Azithromycin (AZ)/Chloroquine (CQ) Total
    Number of subjects
    168 168
    Age, Customized
    Units: subjects
        <16 years
    0 0
        16-17 years
    41 41
        18-25 years
    125 125
        26-30 years
    1 1
        31-35 years
    1 1
        >35 years
    0 0
    Gender, Male/Female
    Units: subjects
        Female
    168 168
        Male
    0 0

    End points

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    End points reporting groups
    Reporting group title
    Azithromycin (AZ)/Chloroquine (CQ)
    Reporting group description
    Study drug AZCQ is a fixed dose combination tablet of AZ and CQ given orally once daily for 3 days (Days 0, 1, 2).

    Primary: Percentage of Subjects With Parasitologic Response (Polymerase Chain Reaction (PCR) Corrected) at Day 28 Post First Dose of Study Medication

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    End point title
    Percentage of Subjects With Parasitologic Response (Polymerase Chain Reaction (PCR) Corrected) at Day 28 Post First Dose of Study Medication [1]
    End point description
    The proportion of subjects with parasitological response was estimated from the Kaplan Meier curve based on the time to the first occurrence of parasitological failure (PCR corrected). A subject will be a parasitological responder if she has a zero parasite count on the Day 7 visit without subsequent recurrence (PCR corrected) through the day of consideration, otherwise she is a parasitological failure. Modified Intent To Treat (MITT) population was used. MITT is a subset of the Intent To Treat (ITT) population who had Plasmodium falciparum monoinfection (confirmed by microscopy) parasite count in the range of 80-100,000/microlitre on their baseline blood smear. Two subjects were excluded because they had protocol deviations regarding the informed consent process.
    End point type
    Primary
    End point timeframe
    Day 28
    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: Only descriptive data was planned to be reported for this endpoint.
    End point values
    Azithromycin (AZ)/Chloroquine (CQ)
    Number of subjects analysed
    163
    Units: percentage of subjects
        number (confidence interval 95%)
    99.35 (97.76 to 100)
    No statistical analyses for this end point

    Primary: Percentage of Subjects With Parasitologic Response (PCR Corrected) at Day 28 Post First Dose of Study Medication

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    End point title
    Percentage of Subjects With Parasitologic Response (PCR Corrected) at Day 28 Post First Dose of Study Medication [2]
    End point description
    The proportion of subjects with parasitological response was estimated from the Kaplan Meier curve based on the time to the first occurrence of parasitological failure (PCR corrected). A subjects will be a parasitological responder if she has a zero parasite count on the Day 7 visit without subsequent recurrence (PCR corrected) through the day of consideration, otherwise she is a parasitological failure. Per Protocol (PP) population was used. PP is a subset of MITT population who had received all 3 days of study medication. Two subjects were excluded because they had protocol deviations regarding the informed consent process.
    End point type
    Primary
    End point timeframe
    Day 28
    Notes
    [2] - 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: Only descriptive data was planned to be reported for this endpoint.
    End point values
    Azithromycin (AZ)/Chloroquine (CQ)
    Number of subjects analysed
    158
    Units: percentage of subjects
        number (confidence interval 95%)
    99.35 (97.76 to 100)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Parasitologic Response (PCR Corrected) at Days 7, 14, 21, 35, and 42 Post First Dose of Study Medication

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    End point title
    Percentage of Subjects With Parasitologic Response (PCR Corrected) at Days 7, 14, 21, 35, and 42 Post First Dose of Study Medication
    End point description
    The proportion of subjects with parasitological response was estimated from the Kaplan Meier curve based on the time to the first occurrence of parasitological failure (PCR corrected). A subjects will be a parasitological responder if she has a zero parasite count on the Day 7 visit without subsequent recurrence (PCR corrected) through the day of consideration, otherwise she is a parasitological failure. MITT population was used. MITT is a subset of the ITT population who had Plasmodium falciparum monoinfection (confirmed by microscopy) parasite count in the range of 80-100,000/microlitre on their baseline blood smear. Two subjects were excluded because they had protocol deviations regarding the informed consent process.
    End point type
    Secondary
    End point timeframe
    Days 7, 14, 21, 35, and 42
    End point values
    Azithromycin (AZ)/Chloroquine (CQ)
    Number of subjects analysed
    163
    Units: percentage of subjects
    number (confidence interval 95%)
        Day 7 (n=156)
    100 (97.66 to 100)
        Day 14 (n=154)
    100 (97.63 to 100)
        Day 21 (n=154)
    100 (97.63 to 100)
        Day 35 (n=148)
    96.65 (93.42 to 99.87)
        Day 42 (n=138)
    95.19 (91.35 to 99.03)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Parasitologic Response (PCR Corrected) at Days 7, 14, 21, 35, and 42 , Post First Dose of Study Medication

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    End point title
    Percentage of Subjects With Parasitologic Response (PCR Corrected) at Days 7, 14, 21, 35, and 42 , Post First Dose of Study Medication
    End point description
    The proportion of subjects with parasitological response was estimated from the Kaplan Meier curve based on the time to the first occurrence of parasitological failure (PCR corrected). A subjects will be a parasitological responder if she has a zero parasite count on the Day 7 visit without subsequent recurrence (PCR corrected) through the day of consideration, otherwise she is a parasitological failure. PP population was used. PP is a subset of MITT population who had received all 3 days of study medication. Two subjects were excluded because they had protocol deviations regarding the informed consent process.
    End point type
    Secondary
    End point timeframe
    Days 7, 14, 21, 35, and 42
    End point values
    Azithromycin (AZ)/Chloroquine (CQ)
    Number of subjects analysed
    158
    Units: percentage of subjects
    number (confidence interval 95%)
        Day 7 (n=156)
    100 (97.66 to 100)
        Day 14 (n=154)
    100 (97.63 to 100)
        Day 21 (n=154)
    100 (97.63 to 100)
        Day 35 (n=148)
    96.65 (93.42 to 99.87)
        Day 42 (n=138)
    95.19 (91.35 to 99.03)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Parasitologic Response (PCR Corrected) at Days 7, 14, 21, 28, 35, and 42 Post First Dose of Study Medication

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    End point title
    Percentage of Subjects With Parasitologic Response (PCR Corrected) at Days 7, 14, 21, 28, 35, and 42 Post First Dose of Study Medication
    End point description
    The proportion of subjects with parasitological response was estimated from the Kaplan Meier curve based on the time to the first occurrence of parasitological failure (PCR corrected). A subject will be a parasitological responder if she has a zero parasite count on the Day 7 visit without subsequent recurrence (PCR corrected) through the day of consideration, otherwise she is a parasitological failure. ITT population was used. ITT is defined as all subjects who received at least one dose of study medication and who had a baseline blood smear positive for Plasmodium falciparum monoinfection, asexual parasitemia. Two subjects were excluded because they had protocol deviations regarding the informed consent process.
    End point type
    Secondary
    End point timeframe
    Days 7, 14, 21, 28, 35, and 42
    End point values
    Azithromycin (AZ)/Chloroquine (CQ)
    Number of subjects analysed
    165
    Units: percentage of subjects
    number (confidence interval 95%)
        Day 7 (n=158)
    100 (97.69 to 100)
        Day 14 (n=156)
    100 (97.66 to 100)
        Day 21 (n=156)
    100 (97.66 to 100)
        Day 28 (n=156)
    99.36 (97.79 to 100)
        Day 35 (n=150)
    96.69 (93.51 to 99.88)
        Day 42 (n=140)
    95.26 (91.47 to 99.05)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Parasitologic Response (PCR Uncorrected) at Days 7, 14, 21, 28, 35, and 42 Post First Dose of Study Medication

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    End point title
    Percentage of Subjects With Parasitologic Response (PCR Uncorrected) at Days 7, 14, 21, 28, 35, and 42 Post First Dose of Study Medication
    End point description
    The proportion of subjects with parasitological response was estimated from the Kaplan Meier curve based on the time to the first occurrence of parasitological failure (PCR uncorrected). A subject will be a parasitological responder if she has a zero parasite count on the Day 7 visit without subsequent recurrence (PCR uncorrected) through the day of consideration, otherwise she is a parasitological failure. MITT population was used. MITT is a subset of the ITT population who had Plasmodium falciparum monoinfection (confirmed by microscopy) parasite count in the range of 80-100,000/microlitre on their baseline blood smear.
    End point type
    Secondary
    End point timeframe
    Days 7, 14, 21, 28, 35, and 42
    End point values
    Azithromycin (AZ)/Chloroquine (CQ)
    Number of subjects analysed
    163
    Units: percentage of subjects
    number (confidence interval 95%)
        Day 7 (n=156)
    100 (97.66 to 100)
        Day 14 (n=154)
    100 (97.63 to 100)
        Day 21 (n=154)
    100 (97.63 to 100)
        Day 28 (n=154)
    95.45 (91.84 to 99.07)
        Day 35 (n=154)
    87.66 (82.14 to 93.18)
        Day 42 (n=152)
    78.43 (71.59 to 85.28)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Parasitologic Response (PCR Uncorrected) at Days 7, 14, 21, 28, 35, and 42 Post First Dose of Study Medication

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    End point title
    Percentage of Subjects With Parasitologic Response (PCR Uncorrected) at Days 7, 14, 21, 28, 35, and 42 Post First Dose of Study Medication
    End point description
    The proportion of subjects with parasitological response was estimated from the Kaplan Meier curve based on the time to the first occurrence of parasitological failure (PCR uncorrected). A subject will be a parasitological responder if she has a zero parasite count on the Day 7 visit without subsequent recurrence (PCR uncorrected) through the day of consideration, otherwise she is a parasitological failure. PP population was used. PP is a subset of MITT population who received all 3 days of study medication. Two subjects were excluded because they had protocol deviations regarding the informed consent process.
    End point type
    Secondary
    End point timeframe
    Days 7, 14, 21, 28, 35, and 42
    End point values
    Azithromycin (AZ)/Chloroquine (CQ)
    Number of subjects analysed
    158
    Units: percentage of subjects
    number (confidence interval 95%)
        Day 7 (n=156)
    100 (97.66 to 100)
        Day 14 (n=154)
    100 (97.63 to 100)
        Day 21 (n=154)
    100 (97.63 to 100)
        Day 28 (n=154)
    95.45 (91.84 to 99.07)
        Day 35 (n=154)
    87.66 (82.14 to 93.18)
        Day 42 (n=152)
    78.43 (71.59 to 85.28)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Parasitologic Response (PCR Uncorrected) at Days 7, 14, 21, 28, 35, and 42 Post First Dose of Study Medication

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    End point title
    Percentage of Subjects With Parasitologic Response (PCR Uncorrected) at Days 7, 14, 21, 28, 35, and 42 Post First Dose of Study Medication
    End point description
    The proportion of subjects with parasitological response was estimated from the Kaplan Meier curve based on the time to the first occurrence of parasitological failure (PCR uncorrected). A subject will be a parasitological responder if she has a zero parasite count on the Day 7 visit without subsequent recurrence (PCR uncorrected) through the day of consideration, otherwise she is a parasitological failure. ITT population was used. ITT is defined as all subjects who received at least one dose of study medication and had a baseline blood smear positive for Plasmodium falciparum monoinfection, asexual parasitemia. Two subjects were excluded because they had protocol deviations regarding the informed consent process.
    End point type
    Secondary
    End point timeframe
    Days 7, 14, 21, 28, 35, and 42
    End point values
    Azithromycin (AZ)/Chloroquine (CQ)
    Number of subjects analysed
    165
    Units: percentage of subjects
    number (confidence interval 95%)
        Day 7 (n=158)
    100 (97.69 to 100)
        Day 14 (n=156)
    100 (97.66 to 100)
        Day 21 (n=156)
    100 (97.66 to 100)
        Day 28 (n=156)
    95.51 (91.94 to 99.08)
        Day 35 (n=156)
    87.82 (82.37 to 93.27)
        Day 42 (n=154)
    78.71 (71.94 to 85.48)
    No statistical analyses for this end point

    Secondary: Number of Asexual P. Falciparum per Microliter of Blood at Days 7, 14, 21, 28, 35, and 42 Post First Dose of Study Medication

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    End point title
    Number of Asexual P. Falciparum per Microliter of Blood at Days 7, 14, 21, 28, 35, and 42 Post First Dose of Study Medication
    End point description
    Parasite counts (actual counts per microliter of blood) was measured at various time points. ITT population was used. ITT is defined as all subjects who received at least one dose of study medication and had a baseline blood smear positive for Plasmodium falciparum monoinfection, asexual parasitemia. Two subjects were excluded because they had protocol deviations regarding the informed consent process.
    End point type
    Secondary
    End point timeframe
    Days 7, 14, 21, 28, 35, and 42
    End point values
    Azithromycin (AZ)/Chloroquine (CQ)
    Number of subjects analysed
    165
    Units: parasite count per microliter
    arithmetic mean (standard error)
        Day 7 (n=155)
    0 ± 0
        Day 14 (n=154)
    0 ± 0
        Day 21 (n=156)
    0 ± 0
        Day 28 (n=156)
    216.91 ± 110.04
        Day 35 (n=156)
    555.36 ± 246.77
        Day 42 (n=155)
    907.88 ± 470.82
    No statistical analyses for this end point

    Secondary: Number of Asexual P. Falciparum per Microliter of Blood at Days 7, 14, 21, 28, 35, and 42 Post First Dose of Study Medication

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    End point title
    Number of Asexual P. Falciparum per Microliter of Blood at Days 7, 14, 21, 28, 35, and 42 Post First Dose of Study Medication
    End point description
    Parasite counts (actual counts per microliter of blood) was measured at various time points. MITT population was used. MITT is a subset of the ITT population who had Plasmodium falciparum monoinfection (confirmed by microscopy) parasite count in the range of 80-100,000/microlitre on their baseline blood smear. Two subjects were excluded because they had protocol deviations regarding the informed consent process.
    End point type
    Secondary
    End point timeframe
    Days 7, 14, 21, 28, 35, and 42
    End point values
    Azithromycin (AZ)/Chloroquine (CQ)
    Number of subjects analysed
    163
    Units: parasite count per microliter
    arithmetic mean (standard error)
        Day 7 (n=153)
    0 ± 0
        Day 14 (n=152)
    0 ± 0
        Day 21 (n=154)
    0 ± 0
        Day 28 (n=154)
    219.73 ± 111.46
        Day 35 (n=154)
    562.57 ± 249.94
        Day 42 (n=153)
    919.75 ± 476.92
    No statistical analyses for this end point

    Secondary: Number of Asexual P. Falciparum per Microliter of Blood at Days 7, 14, 21, 28, 35, and 42 Post First Dose of Study Medication

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    End point title
    Number of Asexual P. Falciparum per Microliter of Blood at Days 7, 14, 21, 28, 35, and 42 Post First Dose of Study Medication
    End point description
    Parasite counts (actual counts per microliter of blood) was measured at various time points. PP population was used. PP is a subset of MITT population who received all 3 days of study medication. Two subjects were excluded because they had protocol deviations regarding the informed consent process.
    End point type
    Secondary
    End point timeframe
    Days 7, 14, 21, 28, 35, and 42
    End point values
    Azithromycin (AZ)/Chloroquine (CQ)
    Number of subjects analysed
    158
    Units: parasite count per microliter
    arithmetic mean (standard error)
        Day 7 (n=153)
    0 ± 0
        Day 14 (n=152)
    0 ± 0
        Day 21 (n=154)
    0 ± 0
        Day 28 (n=154)
    219.73 ± 111.46
        Day 35 (n=154)
    562.57 ± 249.94
        Day 42 (n=153)
    919.75 ± 476.92
    No statistical analyses for this end point

    Other pre-specified: Summary of Pregnancy Outcome: Location of Delivery

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    End point title
    Summary of Pregnancy Outcome: Location of Delivery
    End point description
    All subjects were followed up for exposure-in-utero (EIU) safety assessments following delivery or termination of pregnancy. The safety analysis set consists of subjects who received at least one dose of study medication. Data was available for 160 subjects only.
    End point type
    Other pre-specified
    End point timeframe
    Following delivery or pregnancy termination
    End point values
    Azithromycin (AZ)/Chloroquine (CQ)
    Number of subjects analysed
    160
    Units: subjects
    number (not applicable)
        Medical facility
    130
        Home
    27
        Other (Not specified)
    3
    No statistical analyses for this end point

    Other pre-specified: Summary of Pregnancy Outcome: Mode of Delivery

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    End point title
    Summary of Pregnancy Outcome: Mode of Delivery
    End point description
    All subjects were followed up for EIU safety assessments following delivery or termination of pregnancy. The safety analysis set consists of subjects who received at least one dose of study medication. Data was available for 160 subjects only.
    End point type
    Other pre-specified
    End point timeframe
    Following delivery or pregnancy termination
    End point values
    Azithromycin (AZ)/Chloroquine (CQ)
    Number of subjects analysed
    160
    Units: subjects
    number (not applicable)
        Vaginal
    145
        Cesarean section
    15
    No statistical analyses for this end point

    Other pre-specified: Summary of Pregnancy Outcome: Delivery Assisted by Trained Obstetric Personnel?

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    End point title
    Summary of Pregnancy Outcome: Delivery Assisted by Trained Obstetric Personnel?
    End point description
    All subjects were followed up for EIU safety assessments following delivery or termination of pregnancy. The safety analysis set consists of subjects who received at least one dose of study medication. Data was available for 159 subjects only.
    End point type
    Other pre-specified
    End point timeframe
    Following delivery or pregnancy termination
    End point values
    Azithromycin (AZ)/Chloroquine (CQ)
    Number of subjects analysed
    159
    Units: subjects
    number (not applicable)
        Yes
    132
        No
    27
    No statistical analyses for this end point

    Other pre-specified: Summary of Pregnancy Outcome: Labor Induced?

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    End point title
    Summary of Pregnancy Outcome: Labor Induced?
    End point description
    All subjects were followed up for EIU safety assessments following delivery or termination of pregnancy. The safety analysis set consists of subjects who received at least one dose of study medication. Data was available for 158 subjects only.
    End point type
    Other pre-specified
    End point timeframe
    Following delivery or pregnancy termination
    End point values
    Azithromycin (AZ)/Chloroquine (CQ)
    Number of subjects analysed
    158
    Units: subjects
    number (not applicable)
        Yes
    3
        No
    155
    No statistical analyses for this end point

    Other pre-specified: Summary of Pregnancy Outcome: Complications During Delivery?

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    End point title
    Summary of Pregnancy Outcome: Complications During Delivery?
    End point description
    All subjects were followed up for EIU safety assessments following delivery or termination of pregnancy. The safety analysis set consists of subjects who received at least one dose of study medication. Data was available for 159 subjects only.
    End point type
    Other pre-specified
    End point timeframe
    Following delivery or pregnancy termination
    End point values
    Azithromycin (AZ)/Chloroquine (CQ)
    Number of subjects analysed
    159
    Units: subjects
    number (not applicable)
        Yes
    42
        No
    117
    No statistical analyses for this end point

    Other pre-specified: Summary of Pregnancy Outcome: Outcome of Birth

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    End point title
    Summary of Pregnancy Outcome: Outcome of Birth
    End point description
    All subjects were followed up for EIU safety assessments following delivery or termination of pregnancy. The safety analysis set consists of subjects who received at least one dose of study medication. Data was available for 160 subjects only.
    End point type
    Other pre-specified
    End point timeframe
    Following delivery or pregnancy termination
    End point values
    Azithromycin (AZ)/Chloroquine (CQ)
    Number of subjects analysed
    160
    Units: subjects
    number (not applicable)
        Full term live birth
    151
        Premature birth
    6
        Stillbirth
    3
        Spontaneous abortion
    0
        Induced/elective abortion
    0
    No statistical analyses for this end point

    Other pre-specified: Incidence of Fever Based on Oral Temperature

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    End point title
    Incidence of Fever Based on Oral Temperature
    End point description
    Oral temp was taken by the fieldworker through Day 42. ITT is defined as all subjects who received at least one dose of study medication and who had a baseline blood smear positive for Plasmodium falciparum monoinfection, asexual parasitemia. Two subjects were excluded because they had protocol deviations regarding the informed consent process.
    End point type
    Other pre-specified
    End point timeframe
    Baseline, Days 1, 2, 7, 14, 21, 28, 35, and 42
    End point values
    Azithromycin (AZ)/Chloroquine (CQ)
    Number of subjects analysed
    168
    Units: subjects
    number (not applicable)
        Baseline (n=165)
    0
        Day 1 (n=161)
    0
        Day 2 (n=160)
    0
        Day 7 (n=156)
    0
        Day 14 (n=155)
    0
        Day 21 (n=155)
    0
        Day 28 (n=156)
    0
        Day 35 (n=156)
    0
        Day 42 (n=155)
    4
    No statistical analyses for this end point

    Other pre-specified: Summary of Hemoglobin Concentration: Abnormal Hemoglobin Level

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    End point title
    Summary of Hemoglobin Concentration: Abnormal Hemoglobin Level
    End point description
    Abnormal hemoglobin level on Day 42 was measured. The hemoglobin levels were measured with HemoCueTM, via finger stick or peripheral blood collection. The reference range was 10-16g/dL. Any value <0.8 times lower limit of normal was considered clinically significant. The safety analysis set consists of subjects who received at least one dose of study medication.
    End point type
    Other pre-specified
    End point timeframe
    Day 42
    End point values
    Azithromycin (AZ)/Chloroquine (CQ)
    Number of subjects analysed
    168
    Units: subjects
        number (not applicable)
    1
    No statistical analyses for this end point

    Other pre-specified: Summary of Serum Azithromycin Concentration Versus Time

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    End point title
    Summary of Serum Azithromycin Concentration Versus Time
    End point description
    AZ concentrations in the serum was determined at specified time points as PK endpoints. Analyses population included all subjects who received at least one dose of study medication and had at least one blood sample collected for PK analysis. Here, "99999" in the arithmetic mean and standard deviation signifies data is not estimable (NA) as the summary statistics has been calculated by setting concentration values below the lower limit of quantification to zero.
    End point type
    Other pre-specified
    End point timeframe
    Planned time: 0 (Day 0), 48 (Day 2), 50 (Day 2), 56 (Day 2), 168 (Day 7), and 336 (Day 14) hours post the first dose. Note: Assuming "hour not specified" as 0 hours on Day 7 and Day 14 for planned time post first dose calculation.
    End point values
    Azithromycin (AZ)/Chloroquine (CQ)
    Number of subjects analysed
    166
    Units: ng/mL (nanogram/milliliter)
    arithmetic mean (standard deviation)
        Hour 0 (Day 0) (n=161)
    99999 ± 99999
        Hour 48 (Day 2) (n=158)
    194.145 ± 63.76829
        Hour 50 (Day 2) (n=147)
    994.463 ± 552.2373
        Hour 56 (Day 2) (n=159)
    707.682 ± 326.7237
        Hour 168 (Day 7) (n=155)
    54.444 ± 24.34615
        Hour 336 (Day 14) (n=153)
    20.307 ± 31.57879
    No statistical analyses for this end point

    Other pre-specified: Summary of Plasma Chloroquine Concentration Versus Time

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    End point title
    Summary of Plasma Chloroquine Concentration Versus Time
    End point description
    CQ concentrations in the plasma were determined at specified time points as PK endpoints. Analyses population included all subjects who received at least one dose of study medication and had at least one blood sample collected for PK analysis. Here, "99999" in the arithmetic mean and standard deviation signifies data is not estimable (NA) as the summary statistics has been calculated by setting concentration values below the lower limit of quantification to zero.
    End point type
    Other pre-specified
    End point timeframe
    Planned time: 0 (Day 0), 48 (Day 2), 50 (Day 2), 56 (Day 2), 168 (Day 7), 336 (Day 14), 504 (Day 21) and 672 (Day 28) post first dose. Note: Assuming "hour not specified" as 0 hours on Days 7, 14, 21 and 28 for planned time post first dose calculation.
    End point values
    Azithromycin (AZ)/Chloroquine (CQ)
    Number of subjects analysed
    166
    Units: ng/mL
    arithmetic mean (standard deviation)
        Hour 0 (Day 0) (n=160)
    99999 ± 99999
        Hour 48 (Day 2) (n=158)
    305.827 ± 129.0277
        Hour 50 (Day 2) (n=147)
    621.134 ± 329.9273
        Hour 56 (Day 2) (n=159)
    640.679 ± 297.9762
        Hour 168 (Day 7) (n=155)
    129.835 ± 92.19161
        Hour 336 (Day 14) (n=154)
    43.119 ± 44.97312
        Hour 504 (Day 21) (n=156)
    22.382 ± 46.83029
        Hour 672 (Day 28) (n=156)
    12.721 ± 29.0538
    No statistical analyses for this end point

    Other pre-specified: Summary of Plasma Desethylchloroquine Concentration Versus Time

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    End point title
    Summary of Plasma Desethylchloroquine Concentration Versus Time
    End point description
    CQ concentrations in the plasma were determined at specified time points as PK endpoints. Analyses population included all subjects who received at least one dose of study medication and had at least one blood sample collected for PK analysis. Here, "99999" in the arithmetic mean and standard deviation signifies data is not estimable (NA) as the summary statistics has been calculated by setting concentration values below the lower limit of quantification to zero.
    End point type
    Other pre-specified
    End point timeframe
    Planned time: 0 (Day 0), 48 (Day 2), 50 (Day 2), 56 (Day 2), 168 (Day 7), 336 (Day 14), 504 (Day 21) and 672 (Day 28) post first dose. Note: Assuming "hour not specified" as 0 hours on Days 7, 14, 21 and 28 for planned time post first dose calculation.
    End point values
    Azithromycin (AZ)/Chloroquine (CQ)
    Number of subjects analysed
    168
    Units: ng/mL
    arithmetic mean (standard deviation)
        Hour 0 (Day 0) (n=158)
    99999 ± 99999
        Hour 48 (Day 2) (n=158)
    183.622 ± 118.8648
        Hour 50 (Day 2) (n=147)
    220.424 ± 130.4834
        Hour 56 (Day 2) (n=159)
    241.831 ± 137.8858
        Hour 168 (Day 7) (n=155)
    144.088 ± 123.663
        Hour 336 (Day 14) (n=154)
    55.513 ± 54.78967
        Hour 504 (Day 21) (n=156)
    29.825 ± 32.418
        Hour 672 (Day 28) (n=156)
    19.439 ± 19.52079
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Day 42 follow-up visit for treatment emergent AEs for mothers and 14 days post delivery for neonates
    Adverse event reporting additional description
    No treatment emergent serious adverse events (SAEs) were observed in mothers. Events related to neonatal malformation/anomalies, premature delivery, low birth weight neonates, developmental assessment, kernicterus, or any other neonatal illness, hospitalization, drug therapy etc, were recorded and presented under the "familial status = neonates"
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Azithromycin/Chloroquine (Familial Status = Neonate)
    Reporting group description
    AZCQ (Familial Status = Neonate). Number of deaths due to adverse events = 4. Number of deaths related to treatment = 0.

    Reporting group title
    Azithromycin/Chloroquine (Familial Status = Mother)
    Reporting group description
    ACZQ (Familial Status = Mother)

    Serious adverse events
    Azithromycin/Chloroquine (Familial Status = Neonate) Azithromycin/Chloroquine (Familial Status = Mother)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    9 / 157 (5.73%)
    0 / 168 (0.00%)
         number of deaths (all causes)
    4
    0
         number of deaths resulting from adverse events
    Congenital, familial and genetic disorders
    Hypospadias
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 168 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Polydactyly
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 168 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Neonatal asphyxia
         subjects affected / exposed
    4 / 157 (2.55%)
    0 / 168 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Premature baby
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 168 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    General disorders and administration site conditions
    Sudden infant death syndrome
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 168 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Infections and infestations
    Sepsis neonatal
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 168 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Azithromycin/Chloroquine (Familial Status = Neonate) Azithromycin/Chloroquine (Familial Status = Mother)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    20 / 157 (12.74%)
    92 / 168 (54.76%)
    Investigations
    White blood cells urine positive
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 168 (0.60%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Nasal congestion
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 168 (0.00%)
         occurrences all number
    1
    0
    Neonatal asphyxia
         subjects affected / exposed
    3 / 157 (1.91%)
    0 / 168 (0.00%)
         occurrences all number
    3
    0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 168 (0.00%)
         occurrences all number
    1
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 168 (0.60%)
         occurrences all number
    0
    1
    Nervous system disorders
    Burning sensation
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 168 (0.60%)
         occurrences all number
    0
    1
    Dizziness
         subjects affected / exposed
    0 / 157 (0.00%)
    33 / 168 (19.64%)
         occurrences all number
    0
    33
    Headache
         subjects affected / exposed
    0 / 157 (0.00%)
    10 / 168 (5.95%)
         occurrences all number
    0
    10
    Pregnancy, puerperium and perinatal conditions
    False labour
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 168 (0.60%)
         occurrences all number
    0
    1
    Low birth weight baby
         subjects affected / exposed
    8 / 157 (5.10%)
    0 / 168 (0.00%)
         occurrences all number
    8
    0
    Premature baby
         subjects affected / exposed
    6 / 157 (3.82%)
    0 / 168 (0.00%)
         occurrences all number
    6
    0
    Umbilical cord around neck
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 168 (0.00%)
         occurrences all number
    1
    0
    Eye disorders
    Vision blurred
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 168 (0.60%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 157 (0.00%)
    3 / 168 (1.79%)
         occurrences all number
    0
    3
    Chills
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 168 (0.60%)
         occurrences all number
    0
    1
    Fatigue
         subjects affected / exposed
    0 / 157 (0.00%)
    7 / 168 (4.17%)
         occurrences all number
    0
    7
    Pain
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 168 (0.60%)
         occurrences all number
    0
    1
    Macrosomia
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 168 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    0 / 157 (0.00%)
    2 / 168 (1.19%)
         occurrences all number
    0
    2
    Abdominal pain
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 168 (0.60%)
         occurrences all number
    0
    1
    Abdominal pain lower
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 168 (0.60%)
         occurrences all number
    0
    1
    Abdominal pain upper
         subjects affected / exposed
    0 / 157 (0.00%)
    2 / 168 (1.19%)
         occurrences all number
    0
    2
    Diarrhoea
         subjects affected / exposed
    0 / 157 (0.00%)
    3 / 168 (1.79%)
         occurrences all number
    0
    3
    Food poisoning
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 168 (0.60%)
         occurrences all number
    0
    1
    Nausea
         subjects affected / exposed
    0 / 157 (0.00%)
    6 / 168 (3.57%)
         occurrences all number
    0
    6
    Vomiting
         subjects affected / exposed
    0 / 157 (0.00%)
    35 / 168 (20.83%)
         occurrences all number
    0
    35
    Hepatobiliary disorders
    Jaundice
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 168 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    0 / 157 (0.00%)
    13 / 168 (7.74%)
         occurrences all number
    0
    13
    Pruritus generalised
         subjects affected / exposed
    0 / 157 (0.00%)
    9 / 168 (5.36%)
         occurrences all number
    0
    9
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 168 (0.60%)
         occurrences all number
    0
    1
    Infections and infestations
    Infection parasitic
         subjects affected / exposed
    0 / 157 (0.00%)
    12 / 168 (7.14%)
         occurrences all number
    0
    12
    Malaria
         subjects affected / exposed
    0 / 157 (0.00%)
    8 / 168 (4.76%)
         occurrences all number
    0
    8
    Trichomoniasis
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 168 (0.60%)
         occurrences all number
    0
    1
    Upper respiratory tract infection
         subjects affected / exposed
    3 / 157 (1.91%)
    7 / 168 (4.17%)
         occurrences all number
    3
    7
    Urinary tract infection
         subjects affected / exposed
    0 / 157 (0.00%)
    4 / 168 (2.38%)
         occurrences all number
    0
    4
    Vulvovaginal candidiasis
         subjects affected / exposed
    0 / 157 (0.00%)
    4 / 168 (2.38%)
         occurrences all number
    0
    4
    Neonatal infection
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 168 (0.00%)
         occurrences all number
    1
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? No

    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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