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    Clinical Trial Results:
    Antibodies against Nogo-A to enhance plasticity, regeneration and functional recovery after acute spinal cord injury

    Summary
    EudraCT number
    		 2016-001227-31
    Trial protocol
    		 DE   CZ  
    Global end of trial date
    31 Jan 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    26 Mar 2025
    First version publication date
    26 Mar 2025
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    NISCI
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03935321
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University Zurich (UZH) University Hospital Balgrist
    Sponsor organisation address
    Forchstrasse 340, Zürich, Switzerland, 8008
    Public contact
    Spinal Cord Injury Center, Prof. Dr. Armin Curt Forchstrasse 3, CH-Zürich, +41 44 3863901, armin.curt@balgrist.ch
    Scientific contact
    Spinal Cord Injury Center, Prof. Dr. Armin Curt Forchstrasse 340, CH-Zürich, +41 44 3863901, armin.curt@balgrist.ch
    Sponsor organisation name
    University Hospital Heidelberg
    Sponsor organisation address
    Im Neuenheimer Fled 672, Heidelberg, Germany, 69120
    Public contact
    Sponsors legel representative in the EU, Prof. Dr. Norbert Weidner, +49 6221 5626321, norbert.weidner@med.uni-heidelberg.de
    Scientific contact
    Sponsors legel representative in the EU, Prof. Dr. Norbert Weidner, +49 6221 5626321, norbert.weidner@med.uni-heidelberg.de
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    29 Nov 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 Jan 2023
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Jan 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate efficacy of acute treatment (initiation of drug treatment within 4 - 28 days post-injury) with NG-101 by repeated intrathecal (i.t.) bolus injections on day 168.
    Protection of trial subjects
    Extensive screening examination was undertaken.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    17 Apr 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
    Czechia: 2
    Country: Number of subjects enrolled
    Germany: 90
    Country: Number of subjects enrolled
    Spain: 4
    Country: Number of subjects enrolled
    Switzerland: 33
    Worldwide total number of subjects
    129
    EEA total number of subjects
    96
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    110
    From 65 to 84 years
    19
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study population consisted of tetraplegic patients ranging from 18 to 70 years of age, with an acute cervical SCI classified as AIS A-D at screening. The study was conducted in Europe and Switzerland in conjunction with the European multinational spinal cord injury trial network (EMSCI) network (www.emsci.org).

    Pre-assignment
    Screening details
    		 During the screeing period, the patient was assessed for study eligibility. The following assessment were conducted: inclusion/exclusion criteria, Medical history, vital signs, height/weight, pregnancy test (for females), concomitant medication, ISNCSCI protocol, assessments of pain, bladder, neurophysiology, MRI, blood samples

    Period 1
    Period 1 title
    All patients (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    All patients and study site staff (excluding staff receiving IMP shipments and preparing the injections) remained blinded to the treatment assignment.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intrathecal use
    Dosage and administration details
    6 doses of 3 mL Placebo intrathecal bolus injection

    Arm title
    		 NG-101
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    NG-101
    Investigational medicinal product code
    Other name
    ATI355, anti-Nogo-A antibody
    Pharmaceutical forms
    Injection
    Routes of administration
    Intrathecal use
    Dosage and administration details
    repeated intrathecal bolus injections: 6 injections of 45 mg [in 3 mL] each

    Number of subjects in period 1
    		Placebo NG-101
    Started
    50
    79
    Completed
    48
    78
    Not completed
    2
    1
         never received treatment
    2
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group title
    NG-101
    Reporting group description
    		 -

    Reporting group values
    		 Placebo NG-101 Total
    Number of subjects
    		 50 79 129
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 41 67 108
        From 65-84 years
    		 9 12 21
    Age continuous
    Mean age was calculated from truncated date of birth (performed for data protection).
    Units: years
        arithmetic mean (full range (min-max))
    		 46.83 (19 to 70) 46.60 (18 to 70) -
    Gender categorical
    Units: Subjects
        Female
    		 9 11 20
        Male
    		 41 68 109
    Subject analysis sets

    Subject analysis set title
    Full analysis set, placebo arm
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The full analysis set (FAS) comprises all patients, with a valid informed consent, who were randomized into the placebo arm and received the placebo at least once.

    Subject analysis set title
    Full analysis set, NG-101 arm
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All patients randomised to the treatment arm, receiving study treatment at least once

    Subject analysis sets values
    		 Full analysis set, placebo arm Full analysis set, NG-101 arm
    Number of subjects
    48
    78
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    40
    67
        From 65-84 years
    8
    11
    Age continuous
    Mean age was calculated from truncated date of birth (performed for data protection).
    Units: years
        arithmetic mean (full range (min-max))
    46.25 (19 to 70)
    46,34 (18 to 70)
    Gender categorical
    Units: Subjects
        Female
    19
        Male
    107

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group title
    NG-101
    Reporting group description
    		 -

    Subject analysis set title
    Full analysis set, placebo arm
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The full analysis set (FAS) comprises all patients, with a valid informed consent, who were randomized into the placebo arm and received the placebo at least once.

    Subject analysis set title
    Full analysis set, NG-101 arm
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All patients randomised to the treatment arm, receiving study treatment at least once

    Primary: Mean bilateral upper extremity motor scores

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    End point title
    		 Mean bilateral upper extremity motor scores
    End point description
    End point type
    Primary
    End point timeframe
    Day 168
    End point values
    		 Full analysis set, placebo arm Full analysis set, NG-101 arm
    Number of subjects analysed
    44
    68
    Units: Score value
        arithmetic mean (standard deviation)
    29.98 ( 11.87 )
    29.69 ( 14.62 )
    Statistical analysis title
    		 Primary endpoint
    Statistical analysis description
    The UEMS change 168 days after randomization, as the primary response, was estimated using a linear mixed model with 1 month, 12 weeks and 24 weeks measurements as response. All analyses were performed on the full analysis set using all randomized patients.
    Comparison groups
    Full analysis set, NG-101 arm v Full analysis set, placebo arm
    Number of subjects included in analysis
    112
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.868
    Method
    		 Linear mixed model
    Parameter type
    		 Mean difference (final values)
    Confidence interval

    Secondary: Mean lower extremity motor scores day 168

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    End point title
    		 Mean lower extremity motor scores day 168
    End point description
    End point type
    Secondary
    End point timeframe
    Day 168
    End point values
    		 Full analysis set, placebo arm Full analysis set, NG-101 arm
    Number of subjects analysed
    44
    68
    Units: Score value
        arithmetic mean (standard deviation)
    24.82 ( 19.568 )
    25.04 ( 21.580 )
    No statistical analyses for this end point

    Secondary: Mean Light touch scores bilateral mean values

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    End point title
    		 Mean Light touch scores bilateral mean values
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to day 168
    End point values
    		 Full analysis set, placebo arm Full analysis set, NG-101 arm
    Number of subjects analysed
    Units: Score readings
    arithmetic mean (standard deviation)
        Baseline
    60.91 ( 24.407 )
    52.62 ( 30.521 )
        Day 168
    71.84 ( 27.192 )
    64.24 ( 29.568 )
    No statistical analyses for this end point

    Secondary: Pin Prick score bilateral

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    End point title
    		 Pin Prick score bilateral
    End point description
    End point type
    Secondary
    End point timeframe
    From Baseline to day 168
    End point values
    		 Full analysis set, placebo arm Full analysis set, NG-101 arm
    Number of subjects analysed
    47 [1]
    78 [2]
    Units: Score values
    arithmetic mean (standard deviation)
        Baseline
    34.40 ( 24.407 )
    34.42 ( 27.985 )
        Day 168
    47.73 ( 30.434 )
    46.94 ( 31.162 )
    Notes
    [1] - Day 168: 44 patients analysed
    [2] - Analysed at time point day 168: 68 patients
    No statistical analyses for this end point

    Secondary: SCIM-III (FAS), aspect Self Care, mean values

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    End point title
    		 SCIM-III (FAS), aspect Self Care, mean values
    End point description
    There was no significant treatment effect of NG-101 against Placebo at day 168 in the self care score: The effect estimate was 1.121 (standard error 1.141, 95% CI [-1.13,3.37]. However, in an additional analysis, the numerical superiority observed in this analysis translated into functional recovery according to the Spinal Cord Independence Measure (SCIM self-care change +1.58, 95% CI: [0.13, 3.03], p = 0.033).
    End point type
    Secondary
    End point timeframe
    From Baseline to day 168
    End point values
    		 Full analysis set, placebo arm Full analysis set, NG-101 arm
    Number of subjects analysed
    48 [3]
    78 [4]
    Units: Score values
    arithmetic mean (standard deviation)
        Baseline
    0.79 ( 1.556 )
    0.67 ( 1.576 )
        Day 168
    8.00 ( 6.310 )
    8.55 ( 7.415 )
    Notes
    [3] - Analysed at time point day 168 45 patients
    [4] - Analysed at day 168: 69 patients.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    from first application to day 168 after application
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    27
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group title
    NG-101
    Reporting group description
    		 -

    Serious adverse events
    		 Placebo NG-101
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 48 (12.50%)
    11 / 78 (14.10%)
         number of deaths (all causes)
    1
    0
         number of deaths resulting from adverse events
    1
    0
    Injury, poisoning and procedural complications
    Subdural haematoma
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 48 (0.00%)
    2 / 78 (2.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac arrest
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Low cardiac output syndrome
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Aphasia
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coma
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscle spasticity
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Acute abdomen
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal rupture
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal perforation
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    1 / 48 (2.08%)
    3 / 78 (3.85%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax spontaneous
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary infarction
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hepatobiliary disorders
    Cholangitis sclerosing
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Decubitus ulcer
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 78 (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
    Pneumonia
         subjects affected / exposed
    0 / 48 (0.00%)
    2 / 78 (2.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo NG-101
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    48 / 48 (100.00%)
    78 / 78 (100.00%)
    Vascular disorders
    All AEs in the SOC Vascular disorders
         subjects affected / exposed
    6 / 48 (12.50%)
    14 / 78 (17.95%)
         occurrences all number
    6
    17
    General disorders and administration site conditions
    All AEs in the SOC general disorders and administration site conditions
         subjects affected / exposed
    15 / 48 (31.25%)
    15 / 78 (19.23%)
         occurrences all number
    22
    21
    Respiratory, thoracic and mediastinal disorders
    All AEs in the SOC respiratory, thoracic and mediastinal disorders
         subjects affected / exposed
    10 / 48 (20.83%)
    14 / 78 (17.95%)
         occurrences all number
    11
    18
    Psychiatric disorders
    All AEs in the SOC psychiatric disorders
         subjects affected / exposed
    11 / 48 (22.92%)
    14 / 78 (17.95%)
         occurrences all number
    13
    19
    Investigations
    All AEs in the SOC Investigations
         subjects affected / exposed
    11 / 48 (22.92%)
    9 / 78 (11.54%)
         occurrences all number
    19
    10
    Injury, poisoning and procedural complications
    All AEs in the SOC injury, poisoning and procedural complications
         subjects affected / exposed
    19 / 48 (39.58%)
    21 / 78 (26.92%)
         occurrences all number
    29
    31
    Cardiac disorders
    All AEs in the SOC Cardiac Disorders
         subjects affected / exposed
    4 / 48 (8.33%)
    8 / 78 (10.26%)
         occurrences all number
    5
    11
    Nervous system disorders
    All AEs in the SOC nervous system disorders
         subjects affected / exposed
    32 / 48 (66.67%)
    41 / 78 (52.56%)
         occurrences all number
    73
    82
    Gastrointestinal disorders
    All AEs in the SOC gastrointestinal disorders
         subjects affected / exposed
    11 / 48 (22.92%)
    14 / 78 (17.95%)
         occurrences all number
    19
    40
    Skin and subcutaneous tissue disorders
    All AEs in the SOC Skin and subcutaneous tissue disorders
         subjects affected / exposed
    14 / 48 (29.17%)
    36 / 78 (46.15%)
         occurrences all number
    20
    69
    Renal and urinary disorders
    All AEs in the SOC renal and urinary disorders
         subjects affected / exposed
    12 / 48 (25.00%)
    16 / 78 (20.51%)
         occurrences all number
    12
    19
    Musculoskeletal and connective tissue disorders
    All AEs in the SOC Musculosceletal and connective tissue disorders
         subjects affected / exposed
    23 / 48 (47.92%)
    36 / 78 (46.15%)
         occurrences all number
    43
    72
    Infections and infestations
    All AEs in the SOC Infections and Infestations
    Additional description: A total of 214 non-serious events in this SOC was documented under the preferred terms 'urinary tract infection' or 'cystitis' (90 in the placebo group and 124 in the NG-101 group)
         subjects affected / exposed
    44 / 48 (91.67%)
    65 / 78 (83.33%)
         occurrences all number
    126
    182
    Metabolism and nutrition disorders
    All AEs in the SOC Metabolism and nutritional disorders
         subjects affected / exposed
    10 / 48 (20.83%)
    13 / 78 (16.67%)
         occurrences all number
    12
    22

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 Nov 2020
    No amendments were made in the Czech Republic. In Germany and Switzerland the treatment allocation was changed from 1:1 to an aim of 1:2 (placebo: NG-101)

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/39706632
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