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    Clinical Trial Results:
    Phase 2, Open-label, Multiple-dose Trial to Assess the Safety, Tolerability, Pharmacokinetics, and Efficacy of Delamanid (OPC-67683) in Pediatric Multidrug-resistant Tuberculosis Patients on Therapy With an Optimized Background Regimen of Antituberculosis Drugs over a 6-Month Treatment Period

    Summary
    EudraCT number
    		 2012-004620-38
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    13 Jan 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    29 Jul 2020
    First version publication date
    29 Jul 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    242-12-233
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01859923
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Otsuka Pharmaceutical Development & Commercialization, Inc.
    Sponsor organisation address
    2440 Research Boulevard, Rockville, United States, 20850
    Public contact
    Global Clinical Development, Otsuka Pharmaceutical Development & Commercialization, Inc., +1 609-524-6788, clinicaltransparency@otsuka-us.com
    Scientific contact
    Global Clinical Development, Otsuka Pharmaceutical Development & Commercialization, Inc., +1 609-524-6788, clinicaltransparency@otsuka-us.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-001113-PIP01-10
    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
    13 Jan 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    13 Jan 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of this trial was to assess the safety, tolerability, pharmacokinetics, and efficacy of long-term (6-month) treatment with delamanid plus an optimized background regimen (OBR) of other anti-tuberculosis drugs in paediatric participants who completed Study 242-12-232 (NCT01856634; 2012-004473-25).
    Protection of trial subjects
    This study was conducted in accordance with International Conference on Harmonisation (ICH) Good Clinical Practice, and the principles of the Declaration of Helsinki, in addition to following the laws and regulations of the country or countries in which the study was conducted.
    Background therapy
    		 All participants were required to be on a standard-of-care, optimized background regimen (OBR) for at least 2 weeks prior to baseline assessments. Medications for the OBR for Multidrug-resistant tuberculosis (MDR-TB) treatment for each trial participant were procured through the standard mechanisms available for a given site ordinarily used for procurement of OBR medications for treating MDR-TB participants. Selection and administration of the treatment medications were based on World Health Organization's Guidelines for the programmatic management of MDR-TB, in conjunction with national TB program guidelines in each country.
    Evidence for comparator
    		 This study did not include a comparator as it involved only a single investigational therapy (delamanid) that was administered to participants already receiving a standard-of-care OBR for MDR-TB.
    Actual start date of recruitment
    20 Jul 2013
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 6 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    South Africa: 12
    Country: Number of subjects enrolled
    Philippines: 25
    Worldwide total number of subjects
    37
    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)
    7
    Children (2-11 years)
    23
    Adolescents (12-17 years)
    7
    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
    		 Participants took part in the study at 3 investigative sites in Philippines and South Africa from July 20, 2013 to January 13, 2020. Participants received delamanid up to Day 182 in the treatment period and were followed up to Day 365 for safety and efficacy and up to Day 730 (Month 24) for treatment outcome.

    Pre-assignment
    Screening details
    		 Pediatric participants with a diagnosis of MDR-TB who were on therapy with an optimized background regimen (OBR) of anti-tuberculosis drugs and completed study 242-12-232 (NCT01856634; 2012-004473-25) were enrolled in this extension study 242-12-233 to receive delamanid based on the participant's age and weight.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Group 1: 12 to 17 Years of Age
    Arm description
    		 Participants 12 to 17 years old (inclusive) received adult formulation of delamanid 100 milligrams (mg) (2x50 mg tablets), orally, twice daily (BID) plus optimized background regimen (OBR) up to Day 182. Participants continued to receive OBR up to Day 365.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Delamanid
    Investigational medicinal product code
    Other name
    OPC-67683
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received adult formulation delamanid as per regimen specified in the arm description. Morning dose of the delamanid BID regimen was given within 30 minutes after the start of a standard breakfast meal. The evening dose of the BID dose regimen was given 10 hours post morning dose and within 30 minutes after the start of a standard dinner meal.

    Arm title
    		 Group 2: 6 to 11 Years of Age
    Arm description
    		 Participants 6 to 11 years old (inclusive) received adult formulation delamanid 50 mg (1x50 mg tablet), orally, BID plus OBR up to Day 182. Participants continued to receive OBR up to Day 365.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Delamanid
    Investigational medicinal product code
    Other name
    OPC-67683
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received adult formulation delamanid as per regimen specified in the arm description. Morning dose of the delamanid BID regimen was given within 30 minutes after the start of a standard breakfast meal. The evening dose of the BID dose regimen was given 10 hours post morning dose and within 30 minutes after the start of a standard dinner meal.

    Arm title
    		 Group 3: 3 to 5 Years of Age
    Arm description
    		 Participants 3 to 5 years old (inclusive) received 25 mg pediatric formulation of delamanid (DPF - suspension prepared using dispersible tablet), orally, BID plus OBR up to Day 182. Participants continued to receive OBR up to Day 365.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Delamanid
    Investigational medicinal product code
    Other name
    OPC-67683, Delamanid Pediatric Formulation (DPF)
    Pharmaceutical forms
    Dispersible tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received delamanid as an extemporaneous suspension using the delamanid pediatric dispersible tablet formulation. Morning dose of the delamanid BID/once daily (QD) regimen was given within 30 minutes after the start of a standard breakfast meal. The evening dose of the BID dose regimen was given 10 hours post morning dose and within 30 minutes after the start of a standard meal.

    Arm title
    		 Group 4: Birth to 2 Years of Age
    Arm description
    		 Participants from birth to 2 years old (inclusive) received DPF (suspension prepared using dispersible tablet) for 182 days plus OBR. Participants continued to receive OBR up to Day 365. The DPF dose was based on the participant's body weight during the baseline visit: • Participants >10 kilograms (kg) received DPF 10 mg BID plus OBR • Participants >8 kg and ≤10 kg received DPF 5 mg BID plus OBR • Participants ≥5.5 kg and ≤8 kg received DPF 5 mg once per day (QD) plus OBR Delamanid dose was adjusted as needed for Group 4 participants based on the weight measurement at specified study visits [Visits 5 (Day 28), 7 (Day 56), 9 (Day 84), 11 (Day 126) and 12 (Day 154)].
    Arm type
    		 Experimental

    Investigational medicinal product name
    Delamanid
    Investigational medicinal product code
    Other name
    OPC-67683, Delamanid Pediatric Formulation (DPF)
    Pharmaceutical forms
    Dispersible tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received delamanid as an extemporaneous suspension using the delamanid pediatric dispersible tablet formulation. Morning dose of the delamanid BID/once daily (QD) regimen was given within 30 minutes after the start of a standard breakfast meal. The evening dose of the BID dose regimen was given 10 hours post morning dose and within 30 minutes after the start of a standard meal.

    Number of subjects in period 1
    		Group 1: 12 to 17 Years of Age Group 2: 6 to 11 Years of Age Group 3: 3 to 5 Years of Age Group 4: Birth to 2 Years of Age
    Started
    7
    6
    12
    12
    Completed
    7
    6
    11
    11
    Not completed
    0
    0
    1
    1
         Adverse event, serious fatal
    -
    -
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Group 1: 12 to 17 Years of Age
    Reporting group description
    		 Participants 12 to 17 years old (inclusive) received adult formulation of delamanid 100 milligrams (mg) (2x50 mg tablets), orally, twice daily (BID) plus optimized background regimen (OBR) up to Day 182. Participants continued to receive OBR up to Day 365.

    Reporting group title
    Group 2: 6 to 11 Years of Age
    Reporting group description
    		 Participants 6 to 11 years old (inclusive) received adult formulation delamanid 50 mg (1x50 mg tablet), orally, BID plus OBR up to Day 182. Participants continued to receive OBR up to Day 365.

    Reporting group title
    Group 3: 3 to 5 Years of Age
    Reporting group description
    		 Participants 3 to 5 years old (inclusive) received 25 mg pediatric formulation of delamanid (DPF - suspension prepared using dispersible tablet), orally, BID plus OBR up to Day 182. Participants continued to receive OBR up to Day 365.

    Reporting group title
    Group 4: Birth to 2 Years of Age
    Reporting group description
    		 Participants from birth to 2 years old (inclusive) received DPF (suspension prepared using dispersible tablet) for 182 days plus OBR. Participants continued to receive OBR up to Day 365. The DPF dose was based on the participant's body weight during the baseline visit: • Participants >10 kilograms (kg) received DPF 10 mg BID plus OBR • Participants >8 kg and ≤10 kg received DPF 5 mg BID plus OBR • Participants ≥5.5 kg and ≤8 kg received DPF 5 mg once per day (QD) plus OBR Delamanid dose was adjusted as needed for Group 4 participants based on the weight measurement at specified study visits [Visits 5 (Day 28), 7 (Day 56), 9 (Day 84), 11 (Day 126) and 12 (Day 154)].

    Reporting group values
    		 Group 1: 12 to 17 Years of Age Group 2: 6 to 11 Years of Age Group 3: 3 to 5 Years of Age Group 4: Birth to 2 Years of Age Total
    Number of subjects
    		 7 6 12 12 37
    Age categorical
    Units: Subjects
        Infants and toddlers (28 days-23 months)
    		 0 0 0 7 7
        Children (2-11 years)
    		 0 6 12 5 23
        Adolescents (12-17 years)
    		 7 0 0 0 7
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 15.37 ( 1.63 ) 9.51 ( 1.49 ) 4.37 ( 0.98 ) 1.79 ( 0.59 ) -
    Gender categorical
    Units: Subjects
        Female
    		 3 4 6 6 19
        Male
    		 4 2 6 6 18
    Race
    Units: Subjects
        Black or African American
    		 0 0 2 0 2
        Asian
    		 7 4 8 6 25
        Other
    		 0 2 2 6 10
    Ethnicity
    Units: Subjects
        Not Hispanic or Latino
    		 7 6 12 12 37

    End points

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    End points reporting groups
    Reporting group title
    Group 1: 12 to 17 Years of Age
    Reporting group description
    		 Participants 12 to 17 years old (inclusive) received adult formulation of delamanid 100 milligrams (mg) (2x50 mg tablets), orally, twice daily (BID) plus optimized background regimen (OBR) up to Day 182. Participants continued to receive OBR up to Day 365.

    Reporting group title
    Group 2: 6 to 11 Years of Age
    Reporting group description
    		 Participants 6 to 11 years old (inclusive) received adult formulation delamanid 50 mg (1x50 mg tablet), orally, BID plus OBR up to Day 182. Participants continued to receive OBR up to Day 365.

    Reporting group title
    Group 3: 3 to 5 Years of Age
    Reporting group description
    		 Participants 3 to 5 years old (inclusive) received 25 mg pediatric formulation of delamanid (DPF - suspension prepared using dispersible tablet), orally, BID plus OBR up to Day 182. Participants continued to receive OBR up to Day 365.

    Reporting group title
    Group 4: Birth to 2 Years of Age
    Reporting group description
    		 Participants from birth to 2 years old (inclusive) received DPF (suspension prepared using dispersible tablet) for 182 days plus OBR. Participants continued to receive OBR up to Day 365. The DPF dose was based on the participant's body weight during the baseline visit: • Participants >10 kilograms (kg) received DPF 10 mg BID plus OBR • Participants >8 kg and ≤10 kg received DPF 5 mg BID plus OBR • Participants ≥5.5 kg and ≤8 kg received DPF 5 mg once per day (QD) plus OBR Delamanid dose was adjusted as needed for Group 4 participants based on the weight measurement at specified study visits [Visits 5 (Day 28), 7 (Day 56), 9 (Day 84), 11 (Day 126) and 12 (Day 154)].

    Subject analysis set title
    Delamanid
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received delamanid 25, 50 or 100 mg based on age and weight plus OBR up to Day 182. Participants continued to receive OBR up to Day 365.

    Primary: Number of Participants With At Least One Treatment Emergent Adverse Event (TEAE)

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    End point title
    		 Number of Participants With At Least One Treatment Emergent Adverse Event (TEAE) [1]
    End point description
    An adverse event (AE) is defined as any untoward medical occurrence in a clinical trial participant and that does not necessarily have a causal relationship with the treatment. A TEAE is defined as an AE that occurred after the administration of investigational medicinal product (IMP). The Safety Sample included participants who received any amount of IMP in this study, regardless of any protocol deviation or violation.
    End point type
    Primary
    End point timeframe
    From the first dose of study drug up to the end of the Post-treatment Follow-up Period (Up to Day 365)
    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: Inferential statistical analyses was not performed for the safety endpoints. Descriptive statistics are included (number of participants).
    End point values
    		 Group 1: 12 to 17 Years of Age Group 2: 6 to 11 Years of Age Group 3: 3 to 5 Years of Age Group 4: Birth to 2 Years of Age
    Number of subjects analysed
    7
    6
    12
    12
    Units: subjects
    7
    6
    12
    12
    No statistical analyses for this end point

    Primary: Number of Participants With Abnormal Physical Examination Values

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    End point title
    		 Number of Participants With Abnormal Physical Examination Values [2]
    End point description
    Physical examination included the examination of the abdomen; extremities; head, eyes, ears, nose (HEENT); neurological; skin and mucosae; thorax; urogenital; audiometry assessment and visual assessment. Participants with abnormal values, as assessed by the investigator were reported. The Safety Sample included participants who received any amount of IMP in this study, regardless of any protocol deviation or violation. Number of participants analysed are the participants with data available for analyses.
    End point type
    Primary
    End point timeframe
    From the first dose of study drug up to the end of the Post-treatment Follow-up Period (Up to Day 365)
    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: Inferential statistical analyses was not performed for the safety endpoints. Descriptive statistics are included (number of participants).
    End point values
    		 Group 1: 12 to 17 Years of Age Group 2: 6 to 11 Years of Age Group 3: 3 to 5 Years of Age Group 4: Birth to 2 Years of Age
    Number of subjects analysed
    7
    6
    12
    11
    Units: subjects
        Abdomen
    1
    1
    4
    2
        Extremities
    2
    0
    1
    1
        HEENT
    7
    6
    12
    10
        Neurological
    1
    0
    1
    1
        Skin and Mucosae
    2
    6
    6
    8
        Thorax
    5
    2
    6
    7
        Urogenital
    0
    0
    1
    3
        Audiometry Assessment
    4
    3
    9
    7
        Visual Assessment
    0
    1
    0
    1
    No statistical analyses for this end point

    Primary: Number of Participants With Clinically Significant Abnormal Vital Sign Values

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    End point title
    		 Number of Participants With Clinically Significant Abnormal Vital Sign Values [3]
    End point description
    Vital signs included weight (kg), height (cm), body temperature (degree Celsius), heart rate (beats/min), respiratory rate (breaths/minute), systolic and diastolic blood pressure (mm Hg), body mass index (BMI) (kg/m^2). The criteria for clinically significant abnormal value for weight was decrease or increase of >=5% in body weight relative to Baseline. Only categories with data for potentially clinically significant abnormal vital sign parameter values are reported. The Safety Sample included participants who received any amount of IMP in this study, regardless of any protocol deviation or violation. Number of participants analysed are the participants with data available for analyses.
    End point type
    Primary
    End point timeframe
    From the first dose of study drug up to the end of the Post-treatment Follow-up Period (Up to Day 365)
    Notes
    [3] - 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: Inferential statistical analyses was not performed for the safety endpoints. Descriptive statistics are included (number of participants).
    End point values
    		 Group 1: 12 to 17 Years of Age Group 2: 6 to 11 Years of Age Group 3: 3 to 5 Years of Age Group 4: Birth to 2 Years of Age
    Number of subjects analysed
    7
    6
    12
    11
    Units: subjects
        Decrease of >=5% in Body Weight
    0
    2
    0
    1
        Increase of >=5% in Body Weight
    4
    2
    10
    10
    No statistical analyses for this end point

    Primary: Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG)

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    End point title
    		 Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) [4]
    End point description
    Criteria for clinically significant abnormal ECG values were ventricular rate outlier (<50 bpm and decrease of >=25%, >100 bpm and increase of >=25%), PR outlier (increase of >=25% when PR >200 milliseconds (ms), QRS outlier (increase of >=25% when QRS >100 ms), QT (new onset (in treatment period but not at Baseline) [>500 ms]), QT interval corrected by Bazett’s formula (QTcB) (new onset [>450, >480, >500 ms], increase of >=30 ms and <= 60 ms or increase of >60 ms), QT interval corrected by Fridericia’s formula (QTcF) (new onset [>450, >480, >500 ms], increase of >=30 ms and <= 60 ms or increase of >60 ms), new abnormal U waves, new ST segment changes, new T wave changes, new abnormal rhythm, new conduction abnormality were reported as categories. Only categories with data are reported. Safety Sample included participants who received any amount of IMP, regardless of any protocol deviation or violation. Number of participants analysed are participants with data available for analyses.
    End point type
    Primary
    End point timeframe
    From the first dose of study drug up to the end of the Post-treatment Follow-up Period (Up to Day 365)
    Notes
    [4] - 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: Inferential statistical analyses was not performed for the safety endpoints. Descriptive statistics are included (number of participants).
    End point values
    		 Group 1: 12 to 17 Years of Age Group 2: 6 to 11 Years of Age Group 3: 3 to 5 Years of Age Group 4: Birth to 2 Years of Age
    Number of subjects analysed
    7
    6
    12
    11
    Units: subjects
        Ventricular Rate Outliers, Notable Increases
    1
    0
    1
    4
        QRS Outliers
    1
    0
    0
    0
        QTcB, New Onset (>480 ms)
    1
    1
    1
    0
        QTcB, New Onset (>450 ms)
    7
    2
    8
    5
        QTcB, New Onset (Change >= 30 and <=60 ms)
    5
    3
    8
    9
        QTcB, New Onset (Change > 60 ms)
    1
    0
    0
    2
        QTcF, New Onset (>450 ms)
    3
    2
    0
    0
        QTcF, New Onset (Change >= 30 and <=60 ms)
    5
    2
    6
    9
        QTcF, New Onset (Change > 60 ms)
    1
    0
    0
    1
        New Abnormal Rhythm
    5
    4
    6
    1
        New Conduction Abnormality
    6
    5
    5
    8
    No statistical analyses for this end point

    Primary: Number of Participants With Clinically Significant Laboratory Test Abnormalities

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    End point title
    		 Number of Participants With Clinically Significant Laboratory Test Abnormalities [5]
    End point description
    Laboratory assessments included parameters for serum chemistry, hematology and urinalysis along with adrenocorticotropic hormone, serum cortisol, free thyroxine, thyroid stimulating hormone (TSH), and high sensitivity C-reactive protein cell count. The participants were categorized based on the clinically significant laboratory values as per protocol predefined criteria. The categories with at least one participant with clinically significant value outside the normal range for laboratory assessments are reported. The normal ranges for those laboratory parameters were potassium 3.4 - 5.4 milliequivalents per liter (mEq/L, uric acid 3.9 - 8.2 mg/dL, partial thromboplastin time (PTT) 9.7 - 12.3 sec, platelet count 180 - 440 thousands platelets/μL. The Safety Sample included participants who received any amount of IMP in this study, regardless of any protocol deviation or violation.
    End point type
    Primary
    End point timeframe
    From the first dose of study drug up to the end of the Post-treatment Follow-up Period (Up to Day 365)
    Notes
    [5] - 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: Inferential statistical analyses was not performed for the safety endpoints. Descriptive statistics are included (number of participants).
    End point values
    		 Group 1: 12 to 17 Years of Age Group 2: 6 to 11 Years of Age Group 3: 3 to 5 Years of Age Group 4: Birth to 2 Years of Age
    Number of subjects analysed
    7
    6
    12
    12
    Units: subjects
        Elevated Potassium
    0
    0
    0
    1
        Elevated Uric Acid
    1
    0
    1
    0
        Elevated PTT
    0
    1
    2
    0
        Low Platelet Count
    0
    0
    0
    1
    No statistical analyses for this end point

    Primary: Population Pharmacokinetic (POPPK) Model Point Estimate for Central Clearance (L) and Inter-compartmental Clearance (Q) of Delamanid

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    End point title
    		 Population Pharmacokinetic (POPPK) Model Point Estimate for Central Clearance (L) and Inter-compartmental Clearance (Q) of Delamanid [6]
    End point description
    Central clearance is defined as plasma volume in the vascular compartment that is cleared of drug per unit of time. Inter-compartmental clearance is defined as a ratio of the drug's distribution rate between the central compartment and the peripheral compartments over its circulating concentration (L/hr). Population point estimates were based on POPPK analysis to find one measure each for both L and Q. The exposure data were pooled across visits and participants to identify POPPK parameter estimates and were reported for delamanid. Population Pharmacokinetic (PK)/Pharmacodynamic (PD) analysis sample included all the participants with data available for PK/PD analysis.
    End point type
    Primary
    End point timeframe
    Predose on Days 1, 56, 154, and 182, 210 and at any time point on Days 14, 98, 189, 196, 203, and 238
    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: Inferential statistical analysis (comparison between groups) was not performed for the PK/PD endpoints.
    End point values
    		 Delamanid
    Number of subjects analysed
    37
    Units: L/hr
    number (not applicable)
        Central Clearance (L)
    18.1
        Inter-compartmental Clearance (Q)
    105
    No statistical analyses for this end point

    Primary: POPPK Model Point Estimate for Central Volume of Distribution (Vc) and Peripheral Volume of Distribution (Vp) of Delamanid

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    End point title
    		 POPPK Model Point Estimate for Central Volume of Distribution (Vc) and Peripheral Volume of Distribution (Vp) of Delamanid [7]
    End point description
    Vc is defined as the theoretical volume that would be necessary to contain the total amount of an administered drug at the same concentration that it is observed in the blood plasma. Vp is defined as the apparent volume needed to account for the total amount of drug in the body if the drug was evenly distributed throughout the body and in the same concentration as the site of sample collection such as peripheral venous plasma. Population point estimates were based on POPPK analysis to find one measure each for both Vc and Vp. The exposure data were pooled across visits and participants to identify POPPK parameter estimates and were reported for delamanid. Population PK/PD analysis sample included all the participants with data available for PK/PD analysis.
    End point type
    Primary
    End point timeframe
    Predose on Days 1, 56, 154, and 182, 210 and at any time point on Days 14, 98, 189, 196, 203, and 238
    Notes
    [7] - 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: Inferential statistical analysis (comparison between groups) was not performed for the PK/PD endpoints.
    End point values
    		 Delamanid
    Number of subjects analysed
    Units: litres (L)
        Central Volume of Distribution (Vc)
    254
        Peripheral Volume of Distribution (Vp)
    347
    No statistical analyses for this end point

    Primary: POPPK Model Point Estimate for Absorption Rate Constant (Ka) of Delamanid

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    End point title
    		 POPPK Model Point Estimate for Absorption Rate Constant (Ka) of Delamanid [8]
    End point description
    Ka is defined as a measure of rate at which a drug enters into the circulatory system. Population point estimate for Ka was based on population PK analysis to find one measure. Population point estimates were based on POPPK analysis to find one measure for Ka. The exposure data were pooled across visits and participants to identify POPPK parameter estimates and were reported for delamanid. Population PK/PD analysis sample included all the participants with data available for PK/PD analysis.
    End point type
    Primary
    End point timeframe
    Predose on Days 1, 56, 154, and 182, 210 and at any time point on Days 14, 98, 189, 196, 203, and 238
    Notes
    [8] - 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: Inferential statistical analysis (comparison between groups) was not performed for the PK/PD endpoints.
    End point values
    		 Delamanid
    Number of subjects analysed
    37
    Units: per hour (1/hr)
        number (not applicable)
    0.254
    No statistical analyses for this end point

    Primary: POPPK Model Point Estimate for Absorption Lag Time (ALAG1) of Delamanid

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    End point title
    		 POPPK Model Point Estimate for Absorption Lag Time (ALAG1) of Delamanid [9]
    End point description
    ALAG1 is defined as the time delay prior to the commencement of drug absorption. Population point estimates were based on POPPK analysis to find one measure for ALAG1. The exposure data were pooled across visits and participants to identify POPPK parameter estimates and were reported for delamanid. Population PK/PD analysis sample included all the participants with data available for PK/PD analysis.
    End point type
    Primary
    End point timeframe
    Predose on Days 1, 56, 154, and 182, 210 and at any time point on Days 14, 98, 189, 196, 203, and 238
    Notes
    [9] - 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: Inferential statistical analysis (comparison between groups) was not performed for the PK/PD endpoints.
    End point values
    		 Delamanid
    Number of subjects analysed
    37
    Units: hour (hr)
        number (not applicable)
    1.38
    No statistical analyses for this end point

    Secondary: Baseline QT Interval Corrected by Bazett’s Formula (QTcB) Effect

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    End point title
    		 Baseline QT Interval Corrected by Bazett’s Formula (QTcB) Effect
    End point description
    The 12-lead ECG was performed to obtain recordings of heart rate (QT interval) to analyze QTcB effect. Population PK/PD analysis sample included all the participants with data available for PK/PD analysis.
    End point type
    Secondary
    End point timeframe
    Baseline (Day -1)
    End point values
    		 Delamanid
    Number of subjects analysed
    37
    Units: ms
    arithmetic mean (confidence interval 90%)
        Delamanid
    0.0318 (-0.113 to 0.177)
        Metabolite DM-6705
    0.0309 (-0.112 to 0.174)
    No statistical analyses for this end point

    Secondary: PK/PD Relationship: POPPK Model Point Estimate for Slope of Linear Mixed Effects Model for Change in QTcB Interval Versus Delamanid Plasma Concentrations

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    End point title
    		 PK/PD Relationship: POPPK Model Point Estimate for Slope of Linear Mixed Effects Model for Change in QTcB Interval Versus Delamanid Plasma Concentrations
    End point description
    The linear mixed effects model was applied to characterize the concentration-QTcB relationship of delamanid/DM-6705 to obtain population slope estimate.
    End point type
    Secondary
    End point timeframe
    Predose on Days 1, 56, 154, and 182, 210 and at any time point on Days 14, 98, 189, 196, 203, and 238
    End point values
    		 Delamanid
    Number of subjects analysed
    37
    Units: ms/[ng/mL]
    arithmetic mean (confidence interval 90%)
        Delamanid
    0.00792 (-0.00132 to 0.0172)
        Metabolite DM-6705
    0.0613 (0.016 to 0.107)
    No statistical analyses for this end point

    Secondary: Number of Participants With Treatment Outcome as Assessed by Principal Investigator

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    End point title
    		 Number of Participants With Treatment Outcome as Assessed by Principal Investigator
    End point description
    Treatment outcome was defined as favorable (cured and completed treatment) and unfavorable (lost to follow-up or died).The Safety Sample included participants who received any amount of IMP in this study, regardless of any protocol deviation or violation.
    End point type
    Secondary
    End point timeframe
    Month 24
    End point values
    		 Group 1: 12 to 17 Years of Age Group 2: 6 to 11 Years of Age Group 3: 3 to 5 Years of Age Group 4: Birth to 2 Years of Age
    Number of subjects analysed
    7
    6
    12
    12
    Units: subjects
        Favorable (Cured + Treatment Completed)
    6
    6
    10
    11
        Unfavorable (Lost To Follow-up + Died)
    1
    0
    2
    1
    No statistical analyses for this end point

    Secondary: Number of Participants With Abnormal Chest X-ray

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    End point title
    		 Number of Participants With Abnormal Chest X-ray
    End point description
    The data for the chest X-ray with abnormality, as assessed by investigator is reported. The Safety Sample included participants who received any amount of IMP in this study, regardless of any protocol deviation or violation.
    End point type
    Secondary
    End point timeframe
    From the first dose of study drug up to the end of the Post-treatment Follow-up Period (Up to Day 365)
    End point values
    		 Group 1: 12 to 17 Years of Age Group 2: 6 to 11 Years of Age Group 3: 3 to 5 Years of Age Group 4: Birth to 2 Years of Age
    Number of subjects analysed
    7
    6
    12
    12
    Units: subjects
    7
    6
    12
    11
    No statistical analyses for this end point

    Secondary: Number of Participants With Investigator-Assessed Signs and Symptoms of Tuberculosis

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    End point title
    		 Number of Participants With Investigator-Assessed Signs and Symptoms of Tuberculosis
    End point description
    The following signs and symptoms of tuberculosis were assessed by the investigator: cough, fever, weight loss, failure to thrive, hemoptysis, dyspnea, chest pain, night sweats and loss of appetite. The Safety Sample included participants who received any amount of IMP in this study, regardless of any protocol deviation or violation.
    End point type
    Secondary
    End point timeframe
    From the first dose of study drug up to the end of the Post-treatment Follow-up Period (Up to Day 365)
    End point values
    		 Group 1: 12 to 17 Years of Age Group 2: 6 to 11 Years of Age Group 3: 3 to 5 Years of Age Group 4: Birth to 2 Years of Age
    Number of subjects analysed
    7
    6
    12
    12
    Units: subjects
        Cough
    6
    4
    3
    7
        Fever
    1
    2
    2
    5
        Weight Loss
    3
    5
    7
    9
        Failure to Thrive
    0
    1
    0
    3
        Hemoptysis
    2
    0
    0
    0
        Dyspnea
    1
    1
    3
    2
        Chest Pain
    1
    1
    0
    0
        Night Sweats
    0
    0
    1
    2
        Loss of Appetite
    1
    2
    2
    6
    No statistical analyses for this end point

    Secondary: Sputum Culture Conversion (SCC)

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    End point title
    		 Sputum Culture Conversion (SCC)
    End point description
    SCC was defined as a sputum specimen from a participant negative for growth of mycobacterium tuberculosis (MTB), followed by at least one confirmatory negative sputum culture at least 27 days after the first negative sputum test and not followed by any sputum cultures positive for growth.
    End point type
    Secondary
    End point timeframe
    From the first dose of study drug up to the end of the Post-treatment Follow-up Period (Up to Day 365)
    End point values
    		 Group 1: 12 to 17 Years of Age Group 2: 6 to 11 Years of Age Group 3: 3 to 5 Years of Age Group 4: Birth to 2 Years of Age
    Number of subjects analysed
    0 [10]
    0 [11]
    0 [12]
    0 [13]
    Units: subjects
    Notes
    [10] - Data for SCC could not be collected due to the paucity of sputum production in the participants.
    [11] - Data for SCC could not be collected due to the paucity of sputum production in the participants.
    [12] - Data for SCC could not be collected due to the paucity of sputum production in the participants.
    [13] - Data for SCC could not be collected due to the paucity of sputum production in the participants.
    No statistical analyses for this end point

    Secondary: Number of Participants With Palatability Score as Assessed by the Investigator

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    End point title
    		 Number of Participants With Palatability Score as Assessed by the Investigator [14]
    End point description
    The palatability of the pediatric formulation was assessed using an age-appropriate visual hedonic scale and clinical assessment (Groups 3 and 4 only). The palatability result was based on 1 of 5 responses: 1=“Dislike very much”, 2=“Dislike a little”, 3=“Neither liked nor disliked”, 4=“Like a little”, 5=“Like very much”. Participants were categorized based on different scores. The data per the investigator score are reported. Participants were categorized based on different scores. Participants from the safety sample aged below 5 years (Groups 3 and 4) and who received any amount of IMP in this study, regardless of any protocol deviation or violation were analyzed for this outcome measure. 'n' is the number of participants with data available for analyses at the given time point.
    End point type
    Secondary
    End point timeframe
    Days 1, 28, 56 and 182
    Notes
    [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was assessed only in Groups 3 and 4.
    End point values
    		 Group 3: 3 to 5 Years of Age Group 4: Birth to 2 Years of Age
    Number of subjects analysed
    12
    12
    Units: subjects
        Day 1: Dislike Very Much (n= 12, 12)
    0
    0
        Day 1: Dislike a Little (n= 12, 12)
    0
    2
        Day 1: Neither Liked Nor Disliked (n= 12, 12)
    1
    0
        Day 1: Like a Little (n= 12, 12)
    2
    2
        Day 1: Like Very Much (n= 12, 12)
    9
    8
        Day 28: Dislike Very Much (n= 12, 11)
    0
    0
        Day 28: Dislike a Little (n= 12, 11)
    0
    0
        Day 28: Neither Liked Nor Disliked (n= 12, 11)
    2
    0
        Day 28: Like a Little (n= 12, 11)
    1
    2
        Day 28: Like Very Much (n= 12, 11)
    9
    9
        Day 56: Dislike Very Much (n= 12, 11)
    0
    0
        Day 56: Dislike a Little (n= 12, 11)
    0
    0
        Day 56: Neither Liked Nor Disliked (n= 12, 11)
    0
    0
        Day 56: Like a Little (n= 12, 11)
    2
    0
        Day 56: Like Very Much (n= 12, 11)
    10
    11
        Day 182: Dislike Very Much (n= 12, 11)
    0
    0
        Day 182: Dislike a Little (n= 12, 11)
    0
    1
        Day 182: Neither Liked Nor Disliked (n= 12, 11)
    0
    0
        Day 182: Like a Little (n= 12, 11)
    1
    5
        Day 182: Like Very Much (n= 12, 11)
    11
    5
    No statistical analyses for this end point

    Secondary: Number of Participants With Palatability Score as Assessed by the Parent or Participant

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    End point title
    		 Number of Participants With Palatability Score as Assessed by the Parent or Participant [15]
    End point description
    The palatability of the pediatric formulation was assessed using an age-appropriate visual hedonic scale and clinical assessment (Groups 3 and 4 only). The palatability result was based on 1 of 5 responses: 1=“Dislike very much”, 2=“Dislike a little”, 3=“Neither liked nor disliked”, 4=“Like a little”, 5=“Like very much”. The data per parent/patient score are reported. Participants were categorized based on different scores. Participants from the safety sample aged below 5 years (Groups 3 and 4) and who received any amount of IMP in this study, regardless of any protocol deviation or violation were analyzed for this outcome measure. 'n' is the number of participants with data available for analyses at the given time point.
    End point type
    Secondary
    End point timeframe
    Days 1, 28, 56 and 182
    Notes
    [15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was assessed only in Groups 3 and 4.
    End point values
    		 Group 3: 3 to 5 Years of Age Group 4: Birth to 2 Years of Age
    Number of subjects analysed
    12
    12
    Units: subjects
        Day 1: Dislike Very Much (n= 12, 12)
    0
    0
        Day 1: Dislike a Little (n= 12, 12)
    0
    1
        Day 1: Neither Liked Nor Disliked (n= 12, 12)
    1
    1
        Day 1: Like a Little (n= 12, 12)
    2
    3
        Day 1: Like Very Much (n= 12, 12)
    9
    7
        Day 28: Dislike Very Much (n= 12, 11)
    0
    0
        Day 28: Dislike a Little (n= 12, 11)
    1
    0
        Day 28: Neither Liked Nor Disliked (n= 12, 11)
    0
    0
        Day 28: Like a Little (n= 12, 11)
    1
    3
        Day 28: Like Very Much (n= 12, 11)
    10
    8
        Day 56: Dislike Very Much (n= 12, 11)
    0
    0
        Day 56: Dislike a Little (n= 12, 11)
    0
    0
        Day 56: Neither Liked Nor Disliked (n= 12, 11)
    1
    0
        Day 56: Like a Little (n= 12, 11)
    0
    0
        Day 56: Like Very Much (n= 12, 11)
    11
    11
        Day 182: Dislike Very Much (n= 12, 11)
    0
    0
        Day 182: Dislike a Little (n= 12, 11)
    0
    0
        Day 182: Neither Liked Nor Disliked (n= 12, 11)
    0
    1
        Day 182: Like a Little (n= 12, 11)
    1
    4
        Day 182: Like Very Much (n= 12, 11)
    11
    6
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the first dose of study drug up to the end of the Post-treatment Follow-up Period (Up to Day 365)
    Adverse event reporting additional description
    The Safety Sample included participants who received any amount of investigational medicinal product (IMP) in this study, regardless of any protocol deviation or violation.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.1
    Reporting groups
    Reporting group title
    Group 1: 12 to 17 Years of Age
    Reporting group description
    		 Participants 12 to 17 years old (inclusive) received adult formulation of delamanid 100 mg (2x50 mg tablets), orally, BID plus OBR up to Day 182. Participants continued to receive OBR up to Day 365.

    Reporting group title
    Group 2: 6 to 11 Years of Age
    Reporting group description
    		 Participants 6 to 11 years old (inclusive) received adult formulation delamanid 50 mg (1x50 mg tablet), orally, BID plus OBR up to Day 182. Participants continued to receive OBR up to Day 365.

    Reporting group title
    Group 3: 3 to 5 Years of Age
    Reporting group description
    		 Participants 3 to 5 years old (inclusive) received 25 mg pediatric formulation of delamanid (DPF - suspension prepared using dispersible tablet), orally, BID plus OBR up to Day 182. Participants continued to receive OBR up to Day 365.

    Reporting group title
    Group 4: Birth to 2 Years of Age
    Reporting group description
    		 Participants from birth to 2 years old (inclusive) received DPF (suspension prepared using dispersible tablet) for 182 days plus OBR. Participants continued to receive OBR up to Day 365. The DPF dose was based on the participant's body weight during the baseline visit: • Participants >10 kilograms (kg) received DPF 10 mg BID plus OBR • Participants >8 kg and ≤10 kg received DPF 5 mg BID plus OBR • Participants ≥5.5 kg and ≤8 kg received DPF 5 mg once per day (QD) plus OBR Delamanid dose was adjusted as needed for Group 4 participants based on the weight measurement at specified study visits [Visits 5 (Day 28), 7 (Day 56), 9 (Day 84), 11 (Day 126) and 12 (Day 154)].

    Serious adverse events
    		 Group 1: 12 to 17 Years of Age Group 2: 6 to 11 Years of Age Group 3: 3 to 5 Years of Age Group 4: Birth to 2 Years of Age
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    2 / 12 (16.67%)
    5 / 12 (41.67%)
         number of deaths (all causes)
    0
    0
    1
    1
         number of deaths resulting from adverse events
    0
    0
    1
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Non-Hodgkin's lymphoma
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Lethargy
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Immune thrombocytopenic purpura
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Bronchial hyperreactivity
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oral candidiasis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    2 / 12 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    Vulvovaginal candidiasis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Group 1: 12 to 17 Years of Age Group 2: 6 to 11 Years of Age Group 3: 3 to 5 Years of Age Group 4: Birth to 2 Years of Age
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    7 / 7 (100.00%)
    6 / 6 (100.00%)
    12 / 12 (100.00%)
    11 / 12 (91.67%)
    Vascular disorders
    Haematoma
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    2
    0
    General disorders and administration site conditions
    Infusion site extravasation
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Pain
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Pyrexia
         subjects affected / exposed
    2 / 7 (28.57%)
    0 / 6 (0.00%)
    2 / 12 (16.67%)
    1 / 12 (8.33%)
         occurrences all number
    2
    0
    2
    1
    Social circumstances
    Sexual abuse
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Reproductive system and breast disorders
    Menorrhagia
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Cough
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Oropharyngeal pain
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Psychiatric disorders
    Abnormal behaviour
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Aggression
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Depression
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Hallucination
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Insomnia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Investigations
    Activated partial thromboplastin time prolonged
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Blood corticotrophin increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    2 / 12 (16.67%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    2
    1
    Coagulation time prolonged
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Liver function test increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    2 / 12 (16.67%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    2
    1
    Prothrombin time prolonged
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    2 / 12 (16.67%)
         occurrences all number
    0
    0
    1
    2
    Weight decreased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    3 / 12 (25.00%)
         occurrences all number
    0
    0
    1
    3
    Injury, poisoning and procedural complications
    Animal bite
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Concussion
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Contusion
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Craniocerebral injury
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    0
    0
    0
    2
    Eye injury
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Muscle strain
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Skin abrasion
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Skin laceration
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    2 / 12 (16.67%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    2
    1
    Tooth injury
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Cardiac disorders
    Wolff-Parkinson-White syndrome
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Nervous system disorders
    Amnesia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Dizziness
         subjects affected / exposed
    2 / 7 (28.57%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Headache
         subjects affected / exposed
    5 / 7 (71.43%)
    3 / 6 (50.00%)
    2 / 12 (16.67%)
    0 / 12 (0.00%)
         occurrences all number
    7
    3
    4
    0
    Paraesthesia
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Psychomotor hyperactivity
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    1
    Eosinophilia
         subjects affected / exposed
    2 / 7 (28.57%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Immune thrombocytopenic purpura
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    3
    Ear and labyrinth disorders
    Cerumen impaction
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Conductive deafness
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Deafness neurosensory
         subjects affected / exposed
    2 / 7 (28.57%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    2
    0
    1
    0
    Middle ear effusion
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Eye disorders
    Conjunctivitis allergic
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Vernal keratoconjunctivitis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 6 (16.67%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    2
    1
    1
    0
    Abdominal pain lower
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Abdominal pain upper
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Aphthous ulcer
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Constipation
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Dental caries
         subjects affected / exposed
    2 / 7 (28.57%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    2
    0
    1
    0
    Dyspepsia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Gingival swelling
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Lip dry
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Lip ulceration
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Mouth ulceration
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Oral discomfort
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Toothache
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 6 (33.33%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    3
    1
    0
    Vomiting
         subjects affected / exposed
    2 / 7 (28.57%)
    1 / 6 (16.67%)
    2 / 12 (16.67%)
    1 / 12 (8.33%)
         occurrences all number
    2
    2
    2
    1
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Butterfly rash
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    0
    1
    Dermatitis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Dermatitis diaper
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Eczema
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Rash maculo-papular
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Rash papular
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Skin discolouration
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Skin fissures
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Skin hyperpigmentation
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Skin lesion
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Urticaria
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Urticaria papular
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    2 / 7 (28.57%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    2 / 12 (16.67%)
    2 / 12 (16.67%)
         occurrences all number
    0
    1
    2
    2
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    3 / 7 (42.86%)
    2 / 6 (33.33%)
    3 / 12 (25.00%)
    0 / 12 (0.00%)
         occurrences all number
    3
    2
    4
    0
    Arthritis
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Bone pain
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Bursitis
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Costochondritis
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Muscular weakness
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Myalgia
         subjects affected / exposed
    2 / 7 (28.57%)
    1 / 6 (16.67%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    4
    1
    0
    0
    Pain in extremity
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    0
    3
    Soft tissue swelling
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Infections and infestations
    Acarodermatitis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    3 / 12 (25.00%)
         occurrences all number
    0
    0
    0
    3
    Ascariasis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Bronchitis
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    2
    0
    1
    0
    Folliculitis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Gastroenteritis
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 6 (16.67%)
    1 / 12 (8.33%)
    4 / 12 (33.33%)
         occurrences all number
    1
    1
    1
    4
    Genital candidiasis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Gingivitis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Helminthic infection
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Impetigo
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    2 / 12 (16.67%)
    2 / 12 (16.67%)
         occurrences all number
    0
    1
    2
    2
    Mumps
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    3 / 7 (42.86%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    6
    0
    0
    0
    Oral candidiasis
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Otitis media
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    3 / 12 (25.00%)
         occurrences all number
    0
    0
    1
    3
    Otitis media acute
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Parasitic gastroenteritis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    0
    0
    0
    2
    Pharyngotonsillitis
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 6 (16.67%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    1
    1
    1
    0
    Pneumonia
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 6 (16.67%)
    2 / 12 (16.67%)
    0 / 12 (0.00%)
         occurrences all number
    3
    1
    2
    0
    Pustule
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Pyelonephritis acute
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Pyuria
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Respiratory tract infection
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    4 / 12 (33.33%)
         occurrences all number
    0
    0
    2
    9
    Respiratory tract infection viral
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Rhinitis
         subjects affected / exposed
    1 / 7 (14.29%)
    2 / 6 (33.33%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    4
    0
    0
    Rubella
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Subcutaneous abscess
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Systemic viral infection
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Tinea infection
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Tinea versicolour
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Tooth abscess
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Upper respiratory tract infection
         subjects affected / exposed
    4 / 7 (57.14%)
    3 / 6 (50.00%)
    5 / 12 (41.67%)
    2 / 12 (16.67%)
         occurrences all number
    9
    5
    9
    2
    Urinary tract infection
         subjects affected / exposed
    3 / 7 (42.86%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    4
    0
    0
    0
    Viral infection
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 6 (16.67%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Viral upper respiratory tract infection
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 6 (16.67%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    2
    0
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Hyperuricaemia
         subjects affected / exposed
    2 / 7 (28.57%)
    1 / 6 (16.67%)
    4 / 12 (33.33%)
    3 / 12 (25.00%)
         occurrences all number
    2
    1
    5
    3
    Hypokalaemia
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    3
    0
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 Mar 2013
    The following updates were made as per Amendment 01: • Revision of introduction; modification of exclusion criteria • Revision of schedule of assessments • Addition of details regarding several procedures • Clarification of text
    14 Oct 2014
    The following updates were made as per Amendment 02: • Modification of inclusion/exclusion criteria • Update of prohibited medications • Addition of PK blood draw at the early termination visit • Clarification of text
    29 Jun 2015
    The following updates were made as per Amendment 03: • Addition of information for Groups 3 and 4 • Clarification of safety monitoring • Clarification of text
    04 Oct 2016
    Addition of information for Group 4; clarification of text; modification of blood sampling schedule; update of sponsor representative information.
    28 Feb 2019
    The following update was made as per Amendment 04: • Addition of an interim analysis

    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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