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    Clinical Trial Results:
    Phase 1, Open-label, Multiple-dose, and Age De-escalation Trial to Assess the Pharmacokinetics, Safety, and Tolerability of Delamanid (OPC-67683) in Pediatric Multidrug-resistant Tuberculosis Patients on Therapy With an Optimized Background Regimen of Antituberculosis Drugs

    Summary
    EudraCT number
    		 2012-004473-25
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    28 Dec 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    02 Nov 2018
    First version publication date
    02 Nov 2018
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    242-12-232
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01856634
    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
    Otsuka Transparency Department, Otsuka Pharmaceutical Development & Commercialization, Inc., DT-inquiry@otsuka.jp
    Scientific contact
    Otsuka Transparency Department, Otsuka Pharmaceutical Development & Commercialization, Inc., DT-inquiry@otsuka.jp
    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
    28 Dec 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Dec 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of this trial was to determine the pediatric dose of delamanid equivalent to the adult dose already shown to be effective against multidrug-resistant tuberculosis (MDR-TB).
    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 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
    14 Jun 2013
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 1 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Philippines: 25
    Country: Number of subjects enrolled
    South Africa: 12
    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)
    8
    Children (2-11 years)
    22
    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
    		 Investigators and their staff coordinate with the National TB Program and with different TB treatment centers for referral of pediatric participants diagnosed with MDR-TB.

    Pre-assignment
    Screening details
    		 Parents of MDR-TB pediatric participants referred to the sites were invited to visit the research site to learn more about the study. Investigators explained study availability and entry. Informed consent was conducted once interest to join was confirmed. Screening procedures began after the consent and assent forms were signed.

    Period 1
    Period 1 title
    Delamanid (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    This was an open-label trial; blinding procedures were not applicable.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Group 1: 12-17 Years
    Arm description
    		 Participants 12-17 years old (inclusive) received 100 milligrams (mg) delamanid twice per day (BID) for 10 days plus OBR.
    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 100 mg BID (administered as 2 × 50-mg tablets). The 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: 6-11 Years
    Arm description
    		 Participants 6-11 years old (inclusive) received 50 mg delamanid BID for 10 days plus OBR.
    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 50 mg BID (administered as 1 × 50-mg tablet). The 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: 3-5 Years
    Arm description
    		 Participants 3-5 years old (inclusive) received 25 mg delamanid pediatric formulation (DPF) BID for 10 days plus OBR.
    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 (25 mg BID) as an extemporaneous suspension using the delamanid pediatric dispersible tablet formulation (administered as 1 × 25-mg tablet). The 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 meal.

    Arm title
    		 Group 4: 0-2 Years
    Arm description
    		 Participants from birth to 2 years old (inclusive) received DPF for 10 days plus OBR. The DPF dose was based on the participant’s body weight during the baseline visit: • Participants >10 kilograms (kg) received DPF 10 mg BID + OBR • Participants >8 kg and ≤10 kg received DPF 5 mg BID + OBR • Participants ≥5.5 kg and ≤8 kg received DPF 5 mg once per day (QD) + OBR
    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. The dose was based on body weight during baseline visit: • Participants with weight >10 kg received DPF 10 mg BID (administered as 2 × 5-mg dispersible tablets) • Participants with weight >8 and ≤10 kg received DPF 5 mg BID (administered as 1 × 5-mg dispersible tablet) • Participants with weight ≥5.5 kg and ≤8 kg received DPF 5 mg QD (administered as 1 × 5-mg dispersible tablet) The 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. For the QD regimen, delamanid was administered within 30 minutes after the start of a standard breakfast meal.

    Number of subjects in period 1
    		Group 1: 12-17 Years Group 2: 6-11 Years Group 3: 3-5 Years Group 4: 0-2 Years
    Started
    7
    6
    12
    12
    Received at Least 1 Dose of Study Drug
    7
    6
    12
    12
    Completed
    7
    6
    12
    12

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Group 1: 12-17 Years
    Reporting group description
    		 Participants 12-17 years old (inclusive) received 100 milligrams (mg) delamanid twice per day (BID) for 10 days plus OBR.

    Reporting group title
    Group 2: 6-11 Years
    Reporting group description
    		 Participants 6-11 years old (inclusive) received 50 mg delamanid BID for 10 days plus OBR.

    Reporting group title
    Group 3: 3-5 Years
    Reporting group description
    		 Participants 3-5 years old (inclusive) received 25 mg delamanid pediatric formulation (DPF) BID for 10 days plus OBR.

    Reporting group title
    Group 4: 0-2 Years
    Reporting group description
    		 Participants from birth to 2 years old (inclusive) received DPF for 10 days plus OBR. The DPF dose was based on the participant’s body weight during the baseline visit: • Participants >10 kilograms (kg) received DPF 10 mg BID + OBR • Participants >8 kg and ≤10 kg received DPF 5 mg BID + OBR • Participants ≥5.5 kg and ≤8 kg received DPF 5 mg once per day (QD) + OBR

    Reporting group values
    		 Group 1: 12-17 Years Group 2: 6-11 Years Group 3: 3-5 Years Group 4: 0-2 Years Total
    Number of subjects
    		 7 6 12 12 37
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 8 8
        Children (2-11 years)
    		 0 6 12 4 22
        Adolescents (12-17 years)
    		 7 0 0 0 7
        Adults (18-64 years)
    		 0 0 0 0 0
        From 65-84 years
    		 0 0 0 0 0
        85 years and over
    		 0 0 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 15.29 ( 1.62 ) 9.42 ( 1.53 ) 4.28 ( 0.97 ) 1.64 ( 0.58 ) -
    Gender categorical
    Units: Subjects
        Female
    		 3 4 6 6 19
        Male
    		 4 2 6 6 18
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 0 0 0 0 0
        Not Hispanic or Latino
    		 7 6 12 12 37
    Race
    Units: Subjects
        Asian
    		 7 4 8 6 25
        Black or African
    		 0 0 2 0 2
        White
    		 0 0 0 0 0
        American Indian or Alaska Native
    		 0 0 0 0 0
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0 0
        Other
    		 0 2 2 6 10

    End points

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    End points reporting groups
    Reporting group title
    Group 1: 12-17 Years
    Reporting group description
    		 Participants 12-17 years old (inclusive) received 100 milligrams (mg) delamanid twice per day (BID) for 10 days plus OBR.

    Reporting group title
    Group 2: 6-11 Years
    Reporting group description
    		 Participants 6-11 years old (inclusive) received 50 mg delamanid BID for 10 days plus OBR.

    Reporting group title
    Group 3: 3-5 Years
    Reporting group description
    		 Participants 3-5 years old (inclusive) received 25 mg delamanid pediatric formulation (DPF) BID for 10 days plus OBR.

    Reporting group title
    Group 4: 0-2 Years
    Reporting group description
    		 Participants from birth to 2 years old (inclusive) received DPF for 10 days plus OBR. The DPF dose was based on the participant’s body weight during the baseline visit: • Participants >10 kilograms (kg) received DPF 10 mg BID + OBR • Participants >8 kg and ≤10 kg received DPF 5 mg BID + OBR • Participants ≥5.5 kg and ≤8 kg received DPF 5 mg once per day (QD) + OBR

    Subject analysis set title
    Safety Population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants who took at least 1 dose of delamanid.

    Primary: Area Under The Plasma-time Concentration Curve From Time Zero To 24 Hours (AUC0-24h) For Delamanid And DM-6705 Metabolite On Day 1 And Day 10

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    End point title
    		 Area Under The Plasma-time Concentration Curve From Time Zero To 24 Hours (AUC0-24h) For Delamanid And DM-6705 Metabolite On Day 1 And Day 10 [1]
    End point description
    The pharmacokinetic (PK) parameter of AUC0-24h for delamanid and its metabolite (DM-6705), in combination with OBR, in pediatric MDR-TB participants on Day 1 and Day 10 is presented. This parameter was calculated using noncompartmental analysis. Blood collection for PK analysis occurred on Days 1 and 10. Approximately 3 milliliters (mL) of blood was collected per PK sample for the participants in Group 1, 2 mL for participants in Groups 2 and 3, and 0.6 mL for participants in Group 4. Plasma samples were analyzed for delamanid and DM-6705 using a specific and validated ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method. Plasma PK parameter calculations and descriptive statistics were performed using Statistical Analysis System (SAS) version 9.4 or higher. Values of AUC0-24h were estimated using the linear up/log down trapezoidal rule. Results are reported in nanograms times hour/mL (ng*hr/mL).
    End point type
    Primary
    End point timeframe
    Day 1, Day 10
    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 analysis was not performed for the PK endpoints. Descriptive statistics are included (median and full range).
    End point values
    		 Group 1: 12-17 Years Group 2: 6-11 Years Group 3: 3-5 Years Group 4: 0-2 Years
    Number of subjects analysed
    7 [2]
    6 [3]
    12 [4]
    12 [5]
    Units: ng*hr/mL
    median (full range (min-max))
        Delamanid: Day 1
    3910 (1910 to 5270)
    4080 (3240 to 7090)
    3580 (1940 to 4920)
    949 (262 to 1930)
        Delamanid: Day 10
    9790 (6170 to 13000)
    12000 (9810 to 13300)
    9290 (5180 to 12900)
    2740 (701 to 4910)
        DM-6705: Day 1
    114 (89.4 to 224)
    122 (81.1 to 351)
    120 (77.9 to 223)
    25.2 (2.49 to 61.8)
        DM-6705: Day 10
    1780 (1210 to 2010)
    1880 (1210 to 2210)
    1370 (671 to 2160)
    291 (49.6 to 774)
    Notes
    [2] - Safety Population
    [3] - Safety Population
    [4] - Safety Population
    [5] - Safety Population
    No statistical analyses for this end point

    Primary: Peak (Maximal) Concentration Of Drug In Plasma (Cmax) For Delamanid And DM-6705 Metabolite On Day 1 And Day 10

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    End point title
    		 Peak (Maximal) Concentration Of Drug In Plasma (Cmax) For Delamanid And DM-6705 Metabolite On Day 1 And Day 10 [6]
    End point description
    The PK parameter of Cmax for delamanid and DM-6705, in combination with OBR, in MDR-TB participants on Day 1 and Day 10 is presented. This parameter was calculated using noncompartmental analysis. Blood collection for PK analysis occurred on Days 1 and 10. Approximately 3 mL of blood was collected per PK sample for the participants in Group 1, 2 mL for participants in Groups 2 and 3, and 0.6 mL for participants in Group 4. Plasma samples were analyzed for delamanid and DM-6705 using a specific and validated UPLC-MS/MS method. Plasma PK parameter calculations and descriptive statistics were performed using SAS version 9.4 or higher. Values of Cmax were determined directly from the observed data. Results are reported in ng/mL.
    End point type
    Primary
    End point timeframe
    Day 1, Day 10
    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 was not performed for the PK endpoints. Descriptive statistics are included (median and full range).
    End point values
    		 Group 1: 12-17 Years Group 2: 6-11 Years Group 3: 3-5 Years Group 4: 0-2 Years
    Number of subjects analysed
    7 [7]
    6 [8]
    12 [9]
    12 [10]
    Units: ng/mL
    median (full range (min-max))
        Delamanid: Day 1
    268 (164 to 420)
    315 (205 to 454)
    207 (150 to 364)
    80.3 (26.2 to 121)
        Delamanid: Day 10
    557 (304 to 803)
    573 (485 to 682)
    500 (287 to 919)
    179 (45.2 to 298)
        DM-6705: Day 1
    8.60 (6.86 to 15.5)
    7.68 (6.07 to 23.1)
    8.35 (5.03 to 15.1)
    2.01 (0.5 to 4.17)
        DM-6705: Day 10
    81.7 (52.9 to 93.2)
    90.0 (62.4 to 112)
    68.7 (33.7 to 95.0)
    14.2 (2.38 to 35.9)
    Notes
    [7] - Safety Population
    [8] - Safety Population
    [9] - Safety Population
    [10] - Safety Population
    No statistical analyses for this end point

    Secondary: Palatability Of The DPF

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    End point title
    		 Palatability Of The DPF [11]
    End point description
    The palatability of the DPF is presented. This parameter was assessed within 25 to 30 minutes after the morning dose on Day 1 and Day 10 using an age-appropriate visual hedonic scale and clinical assessment. Palatability data was assessed only for Groups 3 and 4 (participants between 0-5 years old). The palatability result was based on 1 of 5 responses: “Dislike very much”, “Dislike a little”, “Neither liked nor disliked”, “Like a little”, “Like very much”. The test result was scored by the investigator and either a parent or participant. The frequency counts for the participants with each score were summarized at visits that palatability were assessed (Day 1 and Day 10). The data for the parent/participant scores are reported.
    End point type
    Secondary
    End point timeframe
    Day 1, Day 10
    Notes
    [11] - 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: Palatability testing was assessed only for Groups 3 and 4.
    End point values
    		 Group 3: 3-5 Years Group 4: 0-2 Years
    Number of subjects analysed
    12 [12]
    12 [13]
    Units: Participants
        Day 1: Dislike Very Much
    0
    0
        Day 1: Dislike A Little
    0
    0
        Day 1: Neither Liked Nor Disliked
    1
    0
        Day 1: Like A Little
    1
    5
        Day 1: Like Very Much
    10
    5
        Day 10: Dislike Very Much
    0
    0
        Day 10: Dislike A Little
    0
    1
        Day 10: Neither Liked Nor Disliked
    0
    1
        Day 10: Like A Little
    2
    5
        Day 10: Like Very Much
    10
    5
    Notes
    [12] - Safety Population
    [13] - Safety Population
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Day 1 through follow-up period (30 days post last dose).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    Group 1: 12 to 17 Years
    Reporting group description
    		 Participants 12-17 years old (inclusive) received 100 mg delamanid BID for 10 days plus OBR.

    Reporting group title
    Group 2: 6 to 11 Years
    Reporting group description
    		 Participants 6-11 years old (inclusive) received 50 mg delamanid BID for 10 days plus OBR.

    Reporting group title
    Group 3: 3 to 5 Years
    Reporting group description
    		 Participants 3-5 years old (inclusive) received 25 mg DPF BID for 10 days plus OBR.

    Reporting group title
    Group 4: 0-2 Years
    Reporting group description
    		 Participants from birth to 2 years old (inclusive) received DPF for 10 days plus OBR. The DPF dose was based on the participant’s body weight during the baseline visit: • Participants >10 kg received DPF 10 mg BID + OBR • Participants >8 kg and ≤10 kg received DPF 5 mg BID + OBR • Participants ≥5.5 kg and ≤8 kg received DPF 5 mg QD + OBR

    Serious adverse events
    		 Group 1: 12 to 17 Years Group 2: 6 to 11 Years Group 3: 3 to 5 Years Group 4: 0-2 Years
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    1 / 12 (8.33%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Infections and infestations
    Hepatitis A
         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
    Lower respiratory tract infection
         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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Group 1: 12 to 17 Years Group 2: 6 to 11 Years Group 3: 3 to 5 Years Group 4: 0-2 Years
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    5 / 7 (71.43%)
    5 / 6 (83.33%)
    9 / 12 (75.00%)
    12 / 12 (100.00%)
    Vascular disorders
    Haematoma
         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
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    2 / 7 (28.57%)
    0 / 6 (0.00%)
    4 / 12 (33.33%)
    1 / 12 (8.33%)
         occurrences all number
    2
    0
    4
    1
    Asthenia
         subjects affected / exposed
    3 / 7 (42.86%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    3
    0
    0
    0
    Catheter site pain
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 6 (33.33%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Crepitations
         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
    Injection site 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
    Vessel puncture site 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
    Vessel puncture site pruritus
         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
    Immune system disorders
    Hypersensitivity
         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
    Respiratory, thoracic and mediastinal disorders
    Bronchial hyperreactivity
         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
    Dyspnoea
         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
    Haemoptysis
         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
    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
    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
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Investigations
    Electrocardiogram QT prolonged
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    2 / 12 (16.67%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Electrocardiogram PR prolongation
         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
    Electrocardiogram U wave present
         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
    Prothrombin 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
    Injury, poisoning and procedural complications
    Craniocerebral 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
    Eye contusion
         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
    Cyanosis
         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
    Headache
         subjects affected / exposed
    2 / 7 (28.57%)
    1 / 6 (16.67%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    7
    1
    5
    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
    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
    Eosinophilia
         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
    Neutropenia
         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
    Ear and labyrinth disorders
    Ear pain
         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
    Vomiting
         subjects affected / exposed
    2 / 7 (28.57%)
    2 / 6 (33.33%)
    3 / 12 (25.00%)
    2 / 12 (16.67%)
         occurrences all number
    5
    2
    3
    2
    Nausea
         subjects affected / exposed
    4 / 7 (57.14%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    7
    0
    1
    0
    Toothache
         subjects affected / exposed
    1 / 7 (14.29%)
    2 / 6 (33.33%)
    2 / 12 (16.67%)
    0 / 12 (0.00%)
         occurrences all number
    3
    2
    2
    0
    Abdominal pain
         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
    Diarrhoea
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 6 (33.33%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    3
    0
    0
    Mouth ulceration
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    2 / 12 (16.67%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Abdominal discomfort
         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
    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
    Faeces soft
         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
    Gastritis
         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
    Gingival 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
    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
    Oral 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
    Skin and subcutaneous tissue disorders
    Dermatitis diaper
         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
    Pruritus
         subjects affected / exposed
    2 / 7 (28.57%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    3
    0
    0
    0
    Butterfly rash
         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
    Night sweats
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    4
    0
    0
    0
    Rash maculo-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
    Rash 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
    Skin hyperpigmentation
         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
    Endocrine disorders
    Hypothyroidism
         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
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 7 (28.57%)
    1 / 6 (16.67%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    3
    1
    3
    0
    Muscle spasms
         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
    Musculoskeletal 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
    Pain in extremity
         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
    Soft tissue swelling
         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
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 12 (0.00%)
    3 / 12 (25.00%)
         occurrences all number
    0
    1
    0
    3
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    3 / 12 (25.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    3
    0
    Respiratory tract infection
         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
    4
    Gastroenteritis
         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
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Pneumonia
         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
    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
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Skin candida
         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
    Viral upper respiratory tract 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
    Metabolism and nutrition disorders
    Hyperuricaemia
         subjects affected / exposed
    2 / 7 (28.57%)
    1 / 6 (16.67%)
    0 / 12 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    2
    1
    0
    2
    Decreased appetite
         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
    Hypokalaemia
         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
    Hypomagnesaemia
         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

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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