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    Clinical Trial Results:
    A Phase I, Open-Label, Multicentre Study to Assess the Pharmacokinetics and Safety of Naloxegol in Paediatric Patients Ages ≥ 6 Months to < 18 Years Receiving Treatment with Opioids

    Summary
    EudraCT number
    		 2013-003935-32
    Trial protocol
    		 GB   ES   NO   DK  
    Global end of trial date
    22 Apr 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    28 Jul 2022
    First version publication date
    28 Jul 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    D3820C00016
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02099591
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Kyowa Kirin Pharmaceutical Development Ltd
    Sponsor organisation address
    Galabank Business Park, Galashiels, United Kingdom, TD1 1QH
    Public contact
    Clinical Trial Information , Kyowa Kirin Pharmaceutical Development Ltd., +44 1896664000, kkd.clintrial.82@kyowakirin.com
    Scientific contact
    Clinical Trial Information, Kyowa Kirin Pharmaceutical Development Ltd., +44 1896664000, kkd.clintrial.82@kyowakirin.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-001146-PIP01-11
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    22 Apr 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    22 Apr 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Apr 2021
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To characterize the pharmacokinetics (PK) of naloxegol after single oral dose and through population PK in paediatric patients with opioid induced constipation (OIC) or at risk of OIC.
    Protection of trial subjects
    The Principal Investigators were responsible for the conduct and administration of the study in accordance with the protocol and ICH E6-GCP (CPMP/ICH/135/95) guidelines, for collecting, recording, and reporting the data accurately and properly as well as the applicable country-specific requirements and in accordance with the ethical principles enunciated in the current version of the Declaration of Helsinki. The Investigator’s staff was responsible for preparing the study-specific written consent document for this study. The documents incorporated the required elements for informed consent, including the possible treatment risks and necessary documentation as required by the Declaration of Helsinki, 21 CFR Part 50, and the ICH-GCP (CPMP/ICH/135/95) guidelines. The ICF also was to contain any additional information required by local laws relating to IRB/IEC review. The ICF was approved by the IRB/IEC and the Sponsor. The subject’s willingness to participate in the study was documented in writing (signed and dated by the subject and by the person who conducted the ICF discussion) with a copy provided to the subject. The Investigators kept the original consent forms. A Safety and Pharmacokinetic Review Committee oversaw safety in the study, including a staggered enrolment scheme, which began with the oldest paediatric subjects before proceeding to the youngest.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    15 Jul 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Norway: 19
    Country: Number of subjects enrolled
    Spain: 19
    Country: Number of subjects enrolled
    United Kingdom: 20
    Country: Number of subjects enrolled
    Denmark: 1
    Country: Number of subjects enrolled
    Israel: 2
    Worldwide total number of subjects
    61
    EEA total number of subjects
    59
    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)
    5
    Children (2-11 years)
    26
    Adolescents (12-17 years)
    30
    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
    		 The study was conducted at 14 investigative sites located centers in Denmark, Norway, Spain, the United Kingdom, and Israel with Investigators experienced in conducting clinical studies paediatric studies. The study was initiated 12-Nov-14 and all subjects were screened for eligibility to participate in the trial. Recruitment closed in April 2021.

    Pre-assignment
    Screening details
    		 Subjects were screened for study entry after the subject, parent or legal guardian signed the ICF. A subject was enrolled into the study only if all inclusion criteria and none of the exclusion criteria were fulfilled. A total of 61 subjects were screened for inclusion, 57 subjects were enrolled and assigned treatment and 46 subjects were treated.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cohort 1
    Arm description
    		 ≥12 years to <18 years lower dose targeted to achieve similar exposure to adults dosed at 12.5 mg
    Arm type
    		 Experimental

    Investigational medicinal product name
    Naloxegol
    Investigational medicinal product code
    Other name
    Moventig
    Pharmaceutical forms
    Oral solution, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Naloxegol (12.5 mg adult equivalent dose) was administered once daily as an oral dose and was taken on an empty stomach in the morning at the same time of day throughout the study. Subjects were dosed with a single oral dose of naloxegol on Day 1 (Visit 2) in the clinic. Subjects stayed in the clinic overnight or for at least 10 hours following the first dose of naloxegol for PK sampling and for post first dose safety and tolerability assessments. If a subject continued treatment with naloxegol beyond Day 1, the second dose was administered in the clinic on Day 2 (Visit 3). Subjects could have continued treatment for up to 6 months (26 weeks) depending on duration of opioid treatment and tolerability of study drug as determined by the investigator and Study Physician.

    Arm title
    		 Cohort 2
    Arm description
    		 ≥12 years to <18 years higher dose targeted to achieve similar exposure to adults dosed at 25 mg
    Arm type
    		 Experimental

    Investigational medicinal product name
    Naloxegol
    Investigational medicinal product code
    Other name
    Moventig
    Pharmaceutical forms
    Oral solution, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Naloxegol (25 mg adult equivalent dose) was administered once daily as an oral dose and was taken on an empty stomach in the morning at the same time of day throughout the study. Subjects were dosed with a single oral dose of naloxegol on Day 1 (Visit 2) in the clinic. Subjects stayed in the clinic overnight or for at least 10 hours following the first dose of naloxegol for PK sampling and for post first dose safety and tolerability assessments. If a subject continued treatment with naloxegol beyond Day 1, the second dose was administered in the clinic on Day 2 (Visit 3). Subjects could have continued treatment for up to 6 months (26 weeks) depending on duration of opioid treatment and tolerability of study drug as determined by the investigator and Study Physician.

    Arm title
    		 Cohort 3
    Arm description
    		 ≥6 years to <12 years lower dose targeted to achieve similar exposure to adults dosed at 12.5 mg
    Arm type
    		 Experimental

    Investigational medicinal product name
    Naloxegol
    Investigational medicinal product code
    Other name
    Moventig
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Naloxegol (12.5 mg adult equivalent dose) was administered once daily as an oral dose and was taken on an empty stomach in the morning at the same time of day throughout the study. Subjects were dosed with a single oral dose of naloxegol on Day 1 (Visit 2) in the clinic. Subjects stayed in the clinic overnight or for at least 10 hours following the first dose of naloxegol for PK sampling and for post first dose safety and tolerability assessments. If a subject continued treatment with naloxegol beyond Day 1, the second dose was administered in the clinic on Day 2 (Visit 3). Subjects could have continued treatment for up to 6 months (26 weeks) depending on duration of opioid treatment and tolerability of study drug as determined by the investigator and Study Physician.

    Arm title
    		 Cohort 4
    Arm description
    		 ≥6 years to <12 years higher dose targeted to achieve similar exposure to adults dosed at 25 mg
    Arm type
    		 Experimental

    Investigational medicinal product name
    Naloxegol
    Investigational medicinal product code
    Other name
    Moventig
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Naloxegol (25 mg adult equivalent dose) was administered once daily as an oral dose and was taken on an empty stomach in the morning at the same time of day throughout the study. Those subjects already enrolled in Cohort 4 prior to Protocol Version 6.0, were dosed with a single oral dose of naloxegol on Day 1 (Visit 2) in the clinic. Subjects stayed in the clinic overnight or for at least 10 hours following the first dose of naloxegol for PK sampling and for post first dose safety and tolerability assessments. If a subject continued treatment with naloxegol beyond Day 1, the second dose was administered in the clinic on Day 2 (Visit 3). Those subjects enrolled in Cohort 4 after Protocol Version 6.0 were dosed with a single oral dose of naloxegol on Day 1 in the clinic. Subjects could have continued treatment for up to 6 months (26 weeks) depending on duration of opioid treatment and tolerability of study drug as determined by the investigator and Study Physician.

    Arm title
    		 Cohort 5
    Arm description
    		 ≥6 months to <6 years lower dose targeted to achieve similar exposure to adults dosed at 12.5 mg
    Arm type
    		 Experimental

    Investigational medicinal product name
    Naloxegol
    Investigational medicinal product code
    Other name
    Moventig
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Naloxegol (12.5 mg adult equivalent dose) was administered once daily as an oral dose and was taken on an empty stomach in the morning at the same time of day throughout the study. Subjects in Cohort 5 were dosed with a single oral dose of naloxegol on Day 1 in the clinic. Subjects could have continued treatment for up to 6 months (26 weeks) depending on duration of opioid treatment and tolerability of study drug as determined by the investigator and Study Physician.

    Number of subjects in period 1
    		Cohort 1 Cohort 2 Cohort 3 Cohort 4 Cohort 5
    Started
    12
    18
    10
    9
    12
    Completed
    8
    12
    9
    4
    6
    Not completed
    4
    6
    1
    5
    6
         Consent withdrawn by subject
    -
    -
    -
    1
    2
         Screen Failure
    1
    3
    1
    3
    1
         Adverse event, non-fatal
    -
    1
    -
    -
    -
         Difficulty swallowing tablets
    -
    -
    -
    1
    -
         Stopped Analgesia
    1
    1
    -
    -
    -
         Failed Blood Draw
    -
    -
    -
    -
    1
         Protocol deviation
    2
    1
    -
    -
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort 1
    Reporting group description
    		 ≥12 years to <18 years lower dose targeted to achieve similar exposure to adults dosed at 12.5 mg

    Reporting group title
    Cohort 2
    Reporting group description
    		 ≥12 years to <18 years higher dose targeted to achieve similar exposure to adults dosed at 25 mg

    Reporting group title
    Cohort 3
    Reporting group description
    		 ≥6 years to <12 years lower dose targeted to achieve similar exposure to adults dosed at 12.5 mg

    Reporting group title
    Cohort 4
    Reporting group description
    		 ≥6 years to <12 years higher dose targeted to achieve similar exposure to adults dosed at 25 mg

    Reporting group title
    Cohort 5
    Reporting group description
    		 ≥6 months to <6 years lower dose targeted to achieve similar exposure to adults dosed at 12.5 mg

    Reporting group values
    		 Cohort 1 Cohort 2 Cohort 3 Cohort 4 Cohort 5 Total
    Number of subjects
    		 12 18 10 9 12 61
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0 0
        Adolescents (12-17 years)
    		 12 18 0 0 0 30
        Adults (18-64 years)
    		 0 0 0 0 0 0
        From 65-84 years
    		 0 0 0 0 0 0
        85 years and over
    		 0 0 0 0 0 0
        6 months to < 6 years
    		 0 0 0 0 12 12
        6 yrs to < 12 years
    		 0 0 10 9 0 19
    Gender categorical
    Units: Subjects
        Female
    		 11 15 5 3 6 40
        Male
    		 1 3 5 6 6 21
    Subject analysis sets

    Subject analysis set title
    Safety Analysis
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All subjects who: - received at least 1 dose of naloxegol on the administration of study drug CRF page, and - for whom any postdose data were available

    Subject analysis set title
    Acceptability Analysis Set
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All subjects who: - received at least 1 dose of naloxegol on the administration of study drug CRF page, and - for whom any postdose palatability or ability to swallow tablet data were available on the CRF

    Subject analysis sets values
    		 Safety Analysis Acceptability Analysis Set
    Number of subjects
    46
    29
    Age categorical
    Units: Subjects
        In utero
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
        Newborns (0-27 days)
    0
    0
        Adolescents (12-17 years)
    26
    23
        Adults (18-64 years)
    0
    0
        From 65-84 years
    0
    0
        85 years and over
    0
    0
        6 months to < 6 years
    6
    3
        6 yrs to < 12 years
    14
    3
    Age continuous
    Units:
        
    ( )
    ( )
    Gender categorical
    Units: Subjects
        Female
    33
        Male
    13

    End points

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    End points reporting groups
    Reporting group title
    Cohort 1
    Reporting group description
    		 ≥12 years to <18 years lower dose targeted to achieve similar exposure to adults dosed at 12.5 mg

    Reporting group title
    Cohort 2
    Reporting group description
    		 ≥12 years to <18 years higher dose targeted to achieve similar exposure to adults dosed at 25 mg

    Reporting group title
    Cohort 3
    Reporting group description
    		 ≥6 years to <12 years lower dose targeted to achieve similar exposure to adults dosed at 12.5 mg

    Reporting group title
    Cohort 4
    Reporting group description
    		 ≥6 years to <12 years higher dose targeted to achieve similar exposure to adults dosed at 25 mg

    Reporting group title
    Cohort 5
    Reporting group description
    		 ≥6 months to <6 years lower dose targeted to achieve similar exposure to adults dosed at 12.5 mg

    Subject analysis set title
    Safety Analysis
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All subjects who: - received at least 1 dose of naloxegol on the administration of study drug CRF page, and - for whom any postdose data were available

    Subject analysis set title
    Acceptability Analysis Set
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All subjects who: - received at least 1 dose of naloxegol on the administration of study drug CRF page, and - for whom any postdose palatability or ability to swallow tablet data were available on the CRF

    Primary: AUC 0-∞

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    End point title
    		 AUC 0-∞ [1] [2]
    End point description
    End point type
    Primary
    End point timeframe
    Day 1 to Day 7
    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: The objective was to evaluate naloxegol exposures, full statistical analysis was not performed.
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Summary Statistics: Naloxegol exhibited dose-linear kinetics across the adult equivalent 12.5 and 25mg doses in pediatric subjects receiving opioids from ≥6 yrs to <18 yrs. The geometric mean Cmax and AUC0-∞ values for pediatric subjects from ≥12 yrs to <18 yrs receiving the adult equivalent 12.5mg dose was 11.6 ng/mL and 96.6 hr*ng/mL. The geometric mean Cmax and AUC values for pediatric subjects from ≥6 yrs to <12 yrs receiving the adult equivalent 12.5mg dose was 9.26 ng/mL and 46.1 hr*ng/mL
    End point values
    		 Cohort 1 Cohort 2 Cohort 3 Cohort 4
    Number of subjects analysed
    7
    8
    8
    4
    Units: hr*ng/mL
        geometric mean (geometric coefficient of variation)
    96.6 ( 48.3 )
    182 ( 53.5 )
    46.1 ( 90.9 )
    65.4 ( 67.8 )
    No statistical analyses for this end point

    Primary: Cmax

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    End point title
    		 Cmax [3] [4]
    End point description
    End point type
    Primary
    End point timeframe
    Day 1 to Day 7
    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: The objective was to evaluate naloxegol exposures, full statistical analysis was not performed.
    [4] - 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: Summary Statistics: Naloxegol exhibited dose-linear kinetics across the adult equivalent 12.5 and 25mg doses in pediatric subjects receiving opioids from ≥6 yrs to <18 yrs. The geometric mean Cmax and AUC0-∞ values for pediatric subjects from ≥12 yrs to <18 yrs receiving the adult equivalent 12.5mg dose was 11.6 ng/mL and 96.6 hr*ng/mL. The geometric mean Cmax and AUC values for pediatric subjects from ≥6 yrs to <12 yrs receiving the adult equivalent 12.5mg dose was 9.26 ng/mL and 46.1 hr*ng/mL
    End point values
    		 Cohort 1 Cohort 2 Cohort 3 Cohort 4
    Number of subjects analysed
    7
    8
    8
    4
    Units: ng/mL
        geometric mean (geometric coefficient of variation)
    11.6 ( 40.6 )
    31.7 ( 81.4 )
    9.26 ( 95.0 )
    21.5 ( 60.9 )
    No statistical analyses for this end point

    Secondary: Palatability of Liquid Formulation

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    End point title
    		 Palatability of Liquid Formulation [5]
    End point description
    Subjects ≥6 years old were asked to evaluate palatability immediately after dosing using the visual analogue scale (VAS) with 100 mm facial hedonic scale. For subjects under 6 years of age down to 6 months, a nurse’s assessment of the subject’s willingness to swallow and how the subject’s response compared to the subject’s response to all other oral medication currently being given was performed.
    End point type
    Secondary
    End point timeframe
    Day 1 and Day 2
    Notes
    [5] - 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: Mean palatability score of naloxegol liquid oral formulation at Visit 2 was reported as 59.6 for subjects in the age group ≥6 yrs to <12 yrs, and 50.0 in the age group ≥12 yrs to <18 yrs. At Visit 3, results were available for only 1 subject, age group ≥6 yrs to <12 yrs, who scored 100. For acceptability, all subjects in the age group ≥12 yrs to <18 yrs were able to swallow tablets on Day 1 and data were only available for 2 subjects for low dose and 5 subjects for high-dose on Day 2.
    End point values
    		 Cohort 2 Cohort 3
    Number of subjects analysed
    1
    5
    Units: Visual Analogue Scale
        number (not applicable)
    50
    59.6
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events and serious adverse events were collected from the time of signature of informed consent/assent, throughout the treatment period, and up to and including the follow up visit (Visit 12)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17
    Reporting groups
    Reporting group title
    Safety Analysis Set
    Reporting group description
    		 All subjects who: - received at least 1 dose of naloxegol on the administration of study drug CRF page, and - for whom any postdose data were available

    Serious adverse events
    		 Safety Analysis Set
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 46 (2.17%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Respiratory, thoracic and mediastinal disorders
    Laryngeal obstruction
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Psychiatric disorders
    Withdrawal Syndrome
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 Safety Analysis Set
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    35 / 46 (76.09%)
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    4 / 46 (8.70%)
         occurrences all number
    4
    Injury, poisoning and procedural complications
    Procedural pain
         subjects affected / exposed
    3 / 46 (6.52%)
         occurrences all number
    3
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    3 / 46 (6.52%)
         occurrences all number
    3
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    4 / 46 (8.70%)
         occurrences all number
    4
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    10 / 46 (21.74%)
         occurrences all number
    10
    Vomiting
         subjects affected / exposed
    8 / 46 (17.39%)
         occurrences all number
    8
    Constipation
         subjects affected / exposed
    7 / 46 (15.22%)
         occurrences all number
    7
    Abdominal pain
         subjects affected / exposed
    4 / 46 (8.70%)
         occurrences all number
    4
    Skin and subcutaneous tissue disorders
    Erythema
         subjects affected / exposed
    3 / 46 (6.52%)
         occurrences all number
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    07 Jul 2014
    Protocol Version 2.0, 13 May 2014 The key changes to Version 2.0 of the protocol included: • An adjustment to the palatability of formulation assessments to include subjects who switch from 1 formulation to another; • Changes to the exclusion criteria for absolute neutrophil count and hemoglobin levels; • Clarification to the restricted concomitant treatment section; • An update to the blood volume schedule.
    25 Oct 2016
    Protocol Version 4.0, 09 Sep 2016 Version 4.0 of the protocol updated the name of the Sponsor from AstraZeneca AB to Kyowa Kirin Pharmaceutical Development Ltd. Protocol version 3.0 (20 Jun 2016) was included in the submissions as a non-substantial amendment
    19 Jun 2019
    Protocol Version 5.0, 21 Mar 2019 The key changes to Version 5.0 of the protocol included: • An update to the commonly reported ADRs; • Updates to the exclusion criteria; • Addition of the ability to conduct the follow-up visit by telephone if necessary.
    28 Nov 2019
    Protocol Version 6.0, 07 Nov 2019 The key changes to Version 6.0 of the protocol included: • Updated safety profile of naloxegol; • Modification of exclusion criteria to allow more flexible subject enrollment; • Reduction in the number of subjects in some cohorts; • Changes to the PK dosing schedule for some cohorts; • Changes to food restrictions and fasting requirements to aid recruitment; • Follow-ups in the form of phone calls instead of site visits for some cohorts; • Clarification of primary and secondary objectives following changes to the protocol; • Clarification of what constitutes a formal BM.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    31 Mar 2020
    Recruitment was temporarily halted on 31 Mar 2020 due to the Coronavirus disease-19 pandemic. Sites were then reopened individually from late Jun 2020 to early Nov 2020.
    19 Jun 2020

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    The last subject visit was 22 April 2021, however the study remained open until a modification to the PIP to reduce the number of subjects was accepted in December 2021.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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