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    Clinical Trial Results:
    Effects of N-Acetyl-L-Leucine on Niemann-Pick disease type C (NPC): A multinational, multi-center, open-label, rater-blinded Phase II study

    Summary
    EudraCT number
    2018-004331-71
    Trial protocol
    DE   GB   ES   SK  
    Global end of trial date
    07 Nov 2022

    Results information
    Results version number
    v1(current)
    This version publication date
    11 Nov 2023
    First version publication date
    11 Nov 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    IB1001-201
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT03759639
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    IntraBio Ltd.
    Sponsor organisation address
    Begbroke Science Park, Begbroke Hill; Woodstock Road, Begbroke, United Kingdom, OX5 1PF
    Public contact
    Taylor Fields, IntraBio Ltd, +44 7426956368, tfields@intrabio.com
    Scientific contact
    Taylor Fields, IntraBio Ltd, +44 7426956368, tfields@intrabio.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-002796-PIP01-20
    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
    15 Aug 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    07 Nov 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Nov 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective is to evaluate the efficacy of N-Acetyl-L-Leucine based on blinded raters’ clinical impression of change in severity (CI-CS) in the treatment of NPC. For the Extension Phase: The primary objective in the Extension Phase was to evaluate the efficacy of N-Acetyl-L-Leucine based on the 5-Domain Niemann-Pick Type C Clinical Severity Scale (NPC-CSS) with success defined as no change or a decrease in the 5-domain NPC-CSS score from Visit 7 to Visit 9.
    Protection of trial subjects
    The study was performed in accordance with the requirements of the Declaration of Helsinki, ICH-GCP, Directive 2001/20/EC, and by the Food and Drug Administration (FDA) CFR as well as the requirements of national drug and data protection laws and other applicable regulatory requirements. Informed consent was obtained from each patient or their legal representative in writing prior to any study-related procedures.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    04 Sep 2019
    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
    Spain: 10
    Country: Number of subjects enrolled
    United Kingdom: 10
    Country: Number of subjects enrolled
    Germany: 7
    Country: Number of subjects enrolled
    Slovakia: 4
    Country: Number of subjects enrolled
    United States: 2
    Worldwide total number of subjects
    33
    EEA total number of subjects
    21
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    4
    Adolescents (12-17 years)
    6
    Adults (18-64 years)
    23
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The study was performed from 04-SEP-2019 (first informed consent) to 07-November-2022 (extension phase completion date). Subjects were recruited at sites in Germany, Slovakia, Spain, the United Kingdom, and the United States.

    Pre-assignment
    Screening details
    At the initial screening visit, patients were classified as either “naïve” or “non-naïve” depending on their use of prohibited medications within the past 42 days.

    Period 1
    Period 1 title
    Treatment with IB1001
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded
    Blinding implementation details
    As the study only had one treatment arm, blinding of treatment was not applicable. However, the primary CI-CS and secondary CI-S assessments were performed by centralized, independent blinded raters based on videos of each patient performing a designated primary anchor test - the 9HPT-D or 8MWT

    Arms
    Arm title
    Total Treatment with IB1001
    Arm description
    All subjects in the parent study
    Arm type
    Experimental

    Investigational medicinal product name
    N-Acetyl-L-Leucine
    Investigational medicinal product code
    IB1001
    Other name
    Pharmaceutical forms
    Suspension for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    IB1001 was administered orally. Patients aged ≥13 years in Europe and aged ≥18 years in the United States received 4 g/day, patients aged 6-12 years weighing ≥35 kg received 4 g/day, patients aged 6-12 years weighing 25 to <35 kg received 3 g/day, patients aged 6-12 years weighing 15 to <25 kg received 2 g/day.

    Number of subjects in period 1
    Total Treatment with IB1001
    Started
    33
    Completed
    31
    Not completed
    2
         Intake of study drug did not lead to benefit
    1
         Adverse event, non-fatal
    1
    Period 2
    Period 2 title
    Post-Treatment Washout
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    Total Post-Treatment Washout
    Arm description
    After the 6-week treatment period, patients entered a 6-week post-treatment washout period.
    Arm type
    No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 2
    Total Post-Treatment Washout
    Started
    31
    Completed
    31

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Treatment with IB1001
    Reporting group description
    -

    Reporting group values
    Treatment with IB1001 Total
    Number of subjects
    33 33
    Age categorical
    Units: Subjects
        In utero
    0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0
        Newborns (0-27 days)
    0 0
        Infants and toddlers (28 days-23 months)
    0 0
        Children (2-11 years)
    4 4
        Adolescents (12-17 years)
    6 6
        Adults (18-64 years)
    23 23
        From 65-84 years
    0 0
        85 years and over
    0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    28.8 ± 15.1 -
    Gender categorical
    Units: Subjects
        Female
    10 10
        Male
    23 23
    Miglustat at baseline
    Subjects with miglustat use at baseline
    Units: Subjects
        Yes
    30 30
        No
    3 3
    Subject analysis sets

    Subject analysis set title
    SAF population
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    The Safety Analysis Set (SAF) consisted of all patients who received at least one dose of study drug (N-Acetyl-L-Leucine).

    Subject analysis set title
    mITT
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    The modified ITT (mITT) analysis set consisted of all patients in the SAF with a video recording at either Visit 1 or Visit 2 (or both) and one video recording at either Visit 3 or Visit 4 (or both).

    Subject analysis sets values
    SAF population mITT
    Number of subjects
    33
    32
    Age categorical
    Units: Subjects
        In utero
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
        Newborns (0-27 days)
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
        Children (2-11 years)
    4
    4
        Adolescents (12-17 years)
    6
    5
        Adults (18-64 years)
    23
    23
        From 65-84 years
    0
    0
        85 years and over
    0
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    28.8 ± 15.1
    29.3 ± 15.0
    Gender categorical
    Units: Subjects
        Female
    10
    10
        Male
    23
    22
    Miglustat at baseline
    Subjects with miglustat use at baseline
    Units: Subjects
        Yes
    30
    29
        No
    3
    3

    End points

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    End points reporting groups
    Reporting group title
    Total Treatment with IB1001
    Reporting group description
    All subjects in the parent study
    Reporting group title
    Total Post-Treatment Washout
    Reporting group description
    After the 6-week treatment period, patients entered a 6-week post-treatment washout period.

    Subject analysis set title
    SAF population
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    The Safety Analysis Set (SAF) consisted of all patients who received at least one dose of study drug (N-Acetyl-L-Leucine).

    Subject analysis set title
    mITT
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    The modified ITT (mITT) analysis set consisted of all patients in the SAF with a video recording at either Visit 1 or Visit 2 (or both) and one video recording at either Visit 3 or Visit 4 (or both).

    Primary: Clinical impression of (Change) in Severity

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    End point title
    Clinical impression of (Change) in Severity [1]
    End point description
    The primary efficacy endpoint was based on the blinded raters’ CI-CS score on either the 9-Hole Peg Test of the Dominant Hand (9HPT-D) or the 8-Meter Walk Test (8MWT). The primary endpoint was defined as the CI-CS comparing the end of treatment (Visit 4) with baseline (Visit 2) minus the CI-CS comparing the end of washout (Visit 6) with the end of treatment (Visit 4). A one-sided Wilcoxon signed-rank test was performed to investigate statistical significance of the primary efficacy endpoint as compared to a value of 0 for the mITT population. The (pseudo-) median of the difference in CI-CS using the Hodges-Lehmann estimator was 1.00 (90% CI: 0.25, 1.75). The CI-CS primary endpoint of the study reached statistical significance with p-value: 0.029
    End point type
    Primary
    End point timeframe
    Primary endpoint for the partent study; CI-CS comparing the End of treatment (Visit 4) with baseline (Visit 2) minus the CI-CS comparing the end of washout (Visit 6) with the end of treatment (Visit 4)
    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: This was a single-arm study. Thus, inferential statistics comparing two groups were not done.
    End point values
    mITT
    Number of subjects analysed
    32
    Units: CI-CS Score
        arithmetic mean (standard deviation)
    0.86 ± 2.52
    No statistical analyses for this end point

    Secondary: Key Secondary Endpoint: Individual Components of the CI-CS

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    End point title
    Key Secondary Endpoint: Individual Components of the CI-CS
    End point description
    The Clinical Impression of Change in Severity assessment will instruct the blinded rater to consider: 'compared to the first video, how has the severity of their performance on the 9 Hole Peg Test of the Dominant Hand (9HPT-D) or 8 Meter Walk Test (8MWT) changed (improved or worsened) in 6-weeks as observed in the second video?' The Clinical Impression of Change in Severity is evaluated on a 7 point Likert scale (+3=significantly improved to -3= significantly worse).
    End point type
    Secondary
    End point timeframe
    Treatment with IB1001: comparing the End of treatment (Visit 4) with baseline (Visit 2); Post-treatment washout: comparing the end of washout (Visit 6) with the end of treatment (Visit 4)
    End point values
    Total Treatment with IB1001 Total Post-Treatment Washout
    Number of subjects analysed
    32
    28
    Units: Score
        arithmetic mean (standard deviation)
    0.48 ± 1.34
    -0.38 ± 1.45
    No statistical analyses for this end point

    Secondary: Key Secondary Endpoint: Change in Severity Based on Average CI-S

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    End point title
    Key Secondary Endpoint: Change in Severity Based on Average CI-S
    End point description
    The Clinical Impression of Change in Severity assessment will instruct the blinded rater to consider: 'compared to the first video, how has the severity of their performance on the 9 Hole Peg Test of the Dominant Hand (9HPT-D) or 8 Meter Walk Test (8MWT) changed (improved or worsened) in 6-weeks as observed in the second video?' The Clinical Impression of Change in Severity is evaluated on a 7 point Likert scale (+3=significantly improved to -3=significantly worse).
    End point type
    Secondary
    End point timeframe
    CI-CS comparing baseline period and end of treatment period minus thechange in CI-S between end of treatment period and end of washout period.
    End point values
    mITT
    Number of subjects analysed
    32
    Units: Score
        arithmetic mean (standard deviation)
    0.08 ± 1.12
    No statistical analyses for this end point

    Secondary: Key Secondary Endpoint: CI-CS Score Reclassified on a 3-Point Scale

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    End point title
    Key Secondary Endpoint: CI-CS Score Reclassified on a 3-Point Scale
    End point description
    The Clinical Impression of Change in Severity assessment will instruct the blinded rater to consider: 'compared to the first video, how has the severity of their performance on the 9 Hole Peg Test of the Dominant Hand (9HPT-D)or 8 Meter Walk Test (8MWT) changed (improved or worsened) in 6-weeks as observed in the second video?' The Clinical Impression of Change in Severity is evaluated on a 7 point Likert scale (+3=significantly improved to -3=significantly worse). CI-CS scores <0 were reclassified as worsened (-1), CI-CS scores 0 remained classified as not changed (0), and CI-CS scores >0 were reclassified as improved (+1).
    End point type
    Secondary
    End point timeframe
    Baseline to end of treatment with IB1001 (Parent Study 6-weekstreatment); End of treatment with IB1001 to the end of post 6-week treatment washout
    End point values
    Total Treatment with IB1001 Total Post-Treatment Washout
    Number of subjects analysed
    32
    28
    Units: participants
        -1 (Worsened)
    9
    16
        0 (No observable Change)
    3
    2
        +1 (Improved)
    20
    10
    No statistical analyses for this end point

    Secondary: Key Secondary Endpoint: CI-CS Score for the Non-Primary Anchor Test

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    End point title
    Key Secondary Endpoint: CI-CS Score for the Non-Primary Anchor Test
    End point description
    The Clinical Impression of Change in Severity is evaluated on a 7 point Likert scale (+3=significantly improved to -3= significantly worse).
    End point type
    Secondary
    End point timeframe
    CI-CS of the non-primary anchor test was evaluated, comparing the CI-CS of Visit 4 versus Visit 2 and of Visit 6 versus Visit 4 as done for the primary anchor test.
    End point values
    Total Treatment with IB1001 Total Post-Treatment Washout
    Number of subjects analysed
    32
    26
    Units: Score
        arithmetic mean (standard deviation)
    -0.20 ± 1.41
    0.15 ± 1.40
    No statistical analyses for this end point

    Secondary: Spinocerebellar Ataxia Functional Index (SCAFI) [Schmitz-Hübsch et al, 2008]

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    End point title
    Spinocerebellar Ataxia Functional Index (SCAFI) [Schmitz-Hübsch et al, 2008]
    End point description
    Spinocerebellar Ataxia Functional Index is composed of the 8 Meter Walk Test(timed assessment), the 9-Hole Peg Test of the Dominant and Non-DominantHand (9HPT-D/9HPT-ND) (timed assessment) and the PATA rate (countednumber of "PATA"), a measure of speech performance.
    End point type
    Secondary
    End point timeframe
    Baseline to end of treatment with IB1001 (Parent Study 6-weeks treatment);End of treatment with IB1001 to the end of post 6-week treatment washout
    End point values
    Total Treatment with IB1001 Total Post-Treatment Washout
    Number of subjects analysed
    30
    26
    Units: Score
        arithmetic mean (standard deviation)
    0.0995 ± 0.3058
    0.0076 ± 0.3584
    No statistical analyses for this end point

    Secondary: Scale for Assessment and Rating of Ataxia (SARA) Score [Schmitz-Hübsch etal, 2006; Subramony, 2007]

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    End point title
    Scale for Assessment and Rating of Ataxia (SARA) Score [Schmitz-Hübsch etal, 2006; Subramony, 2007]
    End point description
    The Scale for Assessment and Rating of Ataxia has 8 items that are related togait, stance, sitting, speech, finger-chase test, nose-finger test, fast alternating movements, and heel-shin test. The range is 0-40 points, with a lower score representing neurological improvement and a higher score representing neurological worsening.
    End point type
    Secondary
    End point timeframe
    Baseline to end of treatment with IB1001 (Parent Study 6-weeks treatment); End of treatment with IB1001 to the end of post 6-week treatment washout
    End point values
    Total Treatment with IB1001 Total Post-Treatment Washout
    Number of subjects analysed
    31
    28
    Units: Score
        arithmetic mean (standard deviation)
    -1.19 ± 2.02
    1.45 ± 2.56
    No statistical analyses for this end point

    Secondary: EuroQuol- 5 Dimension (EQ-5D) Quality of Life Scale

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    End point title
    EuroQuol- 5 Dimension (EQ-5D) Quality of Life Scale
    End point description
    The results of EuroQuol- 5 Dimension-5L (for patients 18 years +) as well asthe EuroQuol- 5 Dimension- Y (patients <18 years) were combined into a 5-digit number presenting the health status of the patient. Frequency tables were presented per visit for the 5 domains, as well as for the 5-digit number of the EQ-5D-5L and the EQ-5D-Y separately. EQ-5D VAS was recorded where a score of 0 is worst and 100 is best.
    End point type
    Secondary
    End point timeframe
    Baseline to end of treatment with IB1001 (Parent Study 6-weeks treatment);End of treatment with IB1001 to the end of post 6-week treatment washout
    End point values
    Total Treatment with IB1001 Total Post-Treatment Washout
    Number of subjects analysed
    26
    26
    Units: Score
        arithmetic mean (standard deviation)
    72.7 ± 19.3
    68.5 ± 17.7
    No statistical analyses for this end point

    Secondary: Modified Disability Rating Scale (mDRS) [Iturriaga et al. 2006]

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    End point title
    Modified Disability Rating Scale (mDRS) [Iturriaga et al. 2006]
    End point description
    Overall neurological status based on six domains (ambulation, manipulation,language, swallowing, seizures and ocular movements). The Modified Disability Rating Scale ranges from 0-24, where 0 is the best neurological status and 24 is the worst.
    End point type
    Secondary
    End point timeframe
    Baseline to end of treatment with IB1001 (Parent Study 6-weeks treatment); End of treatment with IB1001 to the end of post 6-week treatment washout
    End point values
    Total Treatment with IB1001 Total Post-Treatment Washout
    Number of subjects analysed
    31
    28
    Units: Score
        arithmetic mean (standard deviation)
    -0.012 ± 0.050
    0.016 ± 0.051
    No statistical analyses for this end point

    Secondary: Investigator's Clinical Global Impressions of Change (CGI-C)

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    End point title
    Investigator's Clinical Global Impressions of Change (CGI-C)
    End point description
    The Clinical Global Impression of Change assessed by the investigator is evaluated on a 7 point Likert scale ranging from 1='very much improved' to 7='very much worse'
    End point type
    Secondary
    End point timeframe
    Baseline to end of treatment with IB1001 (Parent Study 6-weeks treatment); End of treatment with IB1001 to the end of post 6-week treatment washout
    End point values
    Total Treatment with IB1001 Total Post-Treatment Washout
    Number of subjects analysed
    31
    28
    Units: Score
        arithmetic mean (standard deviation)
    3.4 ± 0.9
    4.5 ± 0.9
    No statistical analyses for this end point

    Secondary: Parent/Caregiver's Clinical Global Impression of Change (CGI-C)

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    End point title
    Parent/Caregiver's Clinical Global Impression of Change (CGI-C)
    End point description
    The Clinical Global Impression of Change assessed by the parent/caregiver is evaluated on a 7 point Likert scale ranging from 1='very much improved' to 7='very much worse'.
    End point type
    Secondary
    End point timeframe
    Baseline to end of treatment with IB1001 (Parent Study 6-weeks treatment); End of treatment with IB1001 to the end of post 6-week treatment washout
    End point values
    Total Treatment with IB1001 Total Post-Treatment Washout
    Number of subjects analysed
    30
    27
    Units: Score
        arithmetic mean (standard deviation)
    3.4 ± 1.0
    4.4 ± 1.1
    No statistical analyses for this end point

    Secondary: Patient's Clinical Global Impressions (CGI) if Able

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    End point title
    Patient's Clinical Global Impressions (CGI) if Able
    End point description
    The Clinical Global Impression of Change assessed by the patient (if able) is evaluated on a 7 point Likert scale ranging from 1='very much improved' to 7='very much worse'.
    End point type
    Secondary
    End point timeframe
    Baseline to end of treatment with IB1001 (Parent Study 6-weeks treatment); End of treatment with IB1001 to the end of post 6-week treatment washout
    End point values
    Total Treatment with IB1001 Total Post-Treatment Washout
    Number of subjects analysed
    25
    25
    Units: Score
        arithmetic mean (standard deviation)
    3.3 ± 1.0
    4.3 ± 0.9
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All AEs occurring during the clinical study were to be documented, commencing with the signing of the ICF through the End of Study (EOS) Visit (scheduled at 42 days post last IB1001 dose).
    Adverse event reporting additional description
    A treatment emergent adverse event (TEAE) was defined as an AE that appeared during or after study treatment and was absent before, or an AE which was present before treatment and worsened while on treatment.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    Parent Study - Treatment with IB1001
    Reporting group description
    The Safety Analysis Set (SAF) in the parent study consisted of all patients who received at least one dose of study drug (N-Acetyl-L-Leucine).

    Reporting group title
    Parent study - Post-treatment washout
    Reporting group description
    -

    Serious adverse events
    Parent Study - Treatment with IB1001 Parent study - Post-treatment washout
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 33 (12.12%)
    0 / 31 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Parent Study - Treatment with IB1001 Parent study - Post-treatment washout
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    11 / 33 (33.33%)
    5 / 31 (16.13%)
    Nervous system disorders
    Seizure
         subjects affected / exposed
    3 / 33 (9.09%)
    1 / 31 (3.23%)
         occurrences all number
    3
    1
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    3 / 33 (9.09%)
    1 / 31 (3.23%)
         occurrences all number
    4
    1
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 31 (0.00%)
         occurrences all number
    2
    2
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 31 (6.45%)
         occurrences all number
    0
    2
    Rash pruritic
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 31 (0.00%)
         occurrences all number
    2
    0
    Infections and infestations
    Rhinitis
         subjects affected / exposed
    2 / 33 (6.06%)
    1 / 31 (3.23%)
         occurrences all number
    2
    1

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 Oct 2019
    The reason for this amendment was feedback from United States Food and Drug Administration (FDA) following the Investigational New Drug (IND) review and European National Regulatory Agencies (including Germany, Spain, Slovakia, and United Kingdom) during the review of Clinical Trial Applications and for general protocol updates regarding updates and/or corrections to the study procedures. Key changes were: • Visit 1 for “naïve” patients reclassified as “non-naïve” was not to be confirmed as Visit 0; patients instead returned for a repeat Visit 1 after study run-in; • Addition of a secondary endpoint examining CI-CS for the non-primary anchor test to further directly supplement the analysis of the primary endpoint; • Addition of NPC-CSS at Visit 1 to provide an additional measurement of disease severity at baseline of the Parent Study; • If consensus could not be achieved between 2 blinded raters on the CI-CS assessment, a third rater was used to agree with one of the 2 raters so that a final rating could be determined to improve the process for allowing a final CI CS rating for analysis to be selected; • Detailing of adjudication process for secondary CI-S assessment to improve process for allowing a final CI-S rating for analysis to be selected; • Addition of study protocol for the Extension Phase in Appendix 6 to provide procedures and design of the Extension Phase protocol.
    04 Feb 2020
    The reason for this amendment was the inclusion of the new IB1001 sachet formulation manufactured for clinical use in the Extension Phase of the IB1001-201 study Key changes were: • Addition that written informed consent could be obtained by an impartial witness to clarify that it was permissible for an impartial witness to sign the ICF on behalf of an adult patient who was mentally able to consent, physically unable to, and provided verbal consent to participate in the study; • Updating informed consent procedures for identifying adults lacking capacity to consent and legal representatives to ensure correct informed consent was obtained from each eligible participant; • Addition of new IMP dosage form for clinical use in the Extension Phase.
    14 Sep 2020
    The reason for this amendment was the inclusion of the impact of COVID-19 pandemic on the IB1001 201 study and inclusion of an additional 1-year treatment period in the Extension Phase. Key changes were: • Modifications to original study schema and study conduct (including, but not limited to, study duration, patient withdrawal, dose scheduling, remote assessments, vital signs, ECGs, safety laboratory measurements, monitoring, reconsent, DSMB involvement [DSMB reviewed the Sponsor guidances related to changes to the protocol due to COVID-19]) to reflect the impact of COVID-19 on the IB1001-201 study; • Addition of 1-year treatment period (Visit 11, Visit 12) in the Extension Phase; • Addition of ITT population and updated definition of mITT population; • Addition of key subgroups; • Addition of sensitivity measurement of secondary endpoint CI-CS on a 3-point scale, caregiver and patient CGI-C measures and EQ-5D VAS to be evaluated descriptively to reflect procedures defined in the SAP; • Updating procedures for analyzing the mITT population, including LOCF approach and sensitivity analysis
    10 Oct 2022
    The reason for this amendment was to align the Extension Phase analysis plan with the Pivotal IB1001-301 clinical trial Extension Phase design. Key changes were: • 5-Domain NPC-CSS instated as primary endpoint for the Extension Phase; • All other efficacy endpoints in the Extension Phase were to be considered exploratory and evaluated descriptively. (The amendment was dated 10-Oct-2022 and approved by the regulatory authority on 28-Nov-2022).

    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.
    This study was ongoing during the COVID-19 pandemic, and the conduct of this study was impacted by the COVID-19 pandemic.
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    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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