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    Clinical Trial Results:
    A Historically-Controlled Phase II/III study to Evaluate Efficacy and Safety of Kedrion Human Plasminogen Eye Drop Preparation in Patients Diagnosed with Ligneous Conjunctivitis

    Summary
    EudraCT number
    		 2012-001340-21
    Trial protocol
    		 IT  
    Global end of trial date
    04 Dec 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    26 Dec 2021
    First version publication date
    26 Dec 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    KB046
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01554956
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 14953: IND Number
    Sponsors
    Sponsor organisation name
    Kedrion SpA
    Sponsor organisation address
    Loc. Ai Conti , Castelvecchio Pascoli Barga (Lucca), Italy, 55051
    Public contact
    Clinical Operations, Kedrion SpA, +39 05831969231, a.lotti@kedrion.com
    Scientific contact
    Clinical Operations, Kedrion SpA, +39 05831969231, a.lotti@kedrion.com
    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
    20 Jul 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    25 Apr 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    04 Dec 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    1.Evaluation of the efficacy of the IMP, Kedrion Human Plasminogen eye drop preparation, for the treatment of Ligneous Conjunctivitis associated with Type I plasminogen deficiency in symptomatic subjects, measured by relapse of pseudomembranes after complete regression due to surgery or treatment with the IMP . 2.Evaluation of the safety of the IMP in symptomatic subjects and asymptomatic subjects with a history of ocular pseudomembranes.
    Protection of trial subjects
    This study was conducted in compliance with the United States (US) Food and Drug Administration (FDA) regulations and guidelines, International Conference on harmonization (ICH) Guideline for Good Clinical Practice (GCP) E6 (R1 and R2), 2002, European Medicinal Agency (EMA) regulations, Italian applicable regulations, and guidelines and principles of the Declaration of Helsinki. Informed consent or assent for patients deemed legally incompetent (such as a minor child) was obtained in compliance with GCP, the recommendations of the Declaration of Helsinki before entering into the study or commencement of study procedure/investigations. An additional Consent Form for Genetic Test optional was collected. There also was a separate ICF and/or assent for additional subjects entering only into the Part 2 of the study (Continuation Segment).
    Background therapy
    		 Kedrion Human Plasminogen is a sterile human plasma derived plasminogen preparation in the pharmaceutical form of an eye drop solution for topical ocular use. The final plasminogen eluate was formulated in saline, concentrated to a protein concentration of 1 g/L, nanofiltered, and dispensed. The IMP was a frozen solution, supplied in a vial of neutral clear glass containing 1ml of a 1 mg/ml sterile solution of protein of which at least 93% is plasminogen.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    22 May 2013
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 77 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Italy: 4
    Country: Number of subjects enrolled
    United States: 8
    Worldwide total number of subjects
    12
    EEA total number of subjects
    4
    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)
    3
    Children (2-11 years)
    7
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    2
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 13 subjects were screened (11 in Part 1 and 2 in Part 2) of which 12 subjects (24 eyes) were enrolled in the study (11 in Part 1 and 1 in Part 2) and 1 subject who failed screeening in Part 2. All subjects enrolled in Part 1 of the study were symptomatic at screening, so all were included in Group 1. No subjects were included in Group 2.

    Pre-assignment
    Screening details
    		 The study was divided in Part 1 (Segment 1 and Segment 2) and Part 2 (Continuation Segment). The screening procedures were performed within a 30-day window prior to receiving the first study IMP administration. A second screening for additional two subjects was performed before entering in the Part 2 of the study.

    Period 1
    Period 1 title
    Treatment (part 1 + part 2) (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Group 1 (1A)
    Arm description
    		 Symptomatic subjects with ocular pseudomembranes in one or both eyes at screening who received the IMP for 4 weeks (Segment 1) and with eyes showing complete pseudomembranes regression (defined as >90%). They have continued to received IMP at a reduced dose for an additional 8 weeks (Segment 2).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Kedrion Plasminogen (Human) eye drop preparation
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Eye drops, solution
    Routes of administration
    Ocular use
    Dosage and administration details
    The study product was administered at a dose of 2 drops/eye, 8 times/day for 4 weeks (Segment 1). Then the IMP was administered at a reduced dose of 2 drops/eye 6 times/day for an additional 8 weeks (Segment 2). Subjects self-applied IMP by dropping solution into the open eye, directly from a syringe barrel. Subjects were given strict instructions about the storage and use of the IMP during their home treatment regimen. Study participants collected data on IMP administrations occurring at home in a Sponsor-issued Subject Diary.

    Arm title
    		 Group 1 ( 1B)
    Arm description
    		 Symptomatic subjects with ocular pseudomembranes in one or both eyes at screening who received the IMP for 4 weeks (Segment 1) and with eyes showing partial (defined as between 20% and 90%) or no pseudomembranes regression (defined as <20%). They were to undergo surgery, within 2 weeks from the end of Segment 1, to remove the pseudomembranes. After surgery, subjects were to continue receiving IMP for an additional 8 weeks, at the decreasing frequency.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Kedrion Plasminogen (Human) eye drop preparation
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Eye drops, solution
    Routes of administration
    Ocular use
    Dosage and administration details
    The study product was administreted at a dose of 2 drops/eye, 8 times/ for 4 weeks. After surgery, the IMP was administered 2 drops per eye at a descending dose for an additional 8 weeks: 12 times/day for 1 week, then 8 times/day for 3 weeks, and lastly, 6 times/day for the remaining 4 weeks. Subjects awaiting surgery (within 2 weeks from the end of Segment 1) were to receive up to 2-week continued IMP treatment at the Segment 1 dose. In case of relapse occurring more than 2 weeks after surgery, the subject was given the option to repeat the IMP treatment according to the above described descending dose frequency. Subjects self-applied IMP by dropping solution into the open eye, directly from a syringe barrel. Subjects were given strict instructions about the storage and use of the IMP during their home treatment regimen. Study participants collected data on IMP administrations occurring at home in a Sponsor-issued Subject Diary

    Arm title
    		 Continuation Segment (Part 2)
    Arm description
    		 Subjects demonstrating complete treatment success (defined as regression of pseudomembranes in Segment 1 and no relapse of pseudomembranes through Segment 2) at the end of the Segment 2 were entered the Continuation Segment and one additional patient, who entered directly in the Part 2, without previously completing the first part of the study.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Kedrion Plasminogen (Human) eye drop preparation
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Eye drops, solution
    Routes of administration
    Ocular use
    Dosage and administration details
    The study product was administreted at a dosage regimen of 2 drops/eye 4 to 6 times/day at Investigator’s discretion. Subjects self-applied IMP by dropping solution into the open eye, directly from a syringe barrel. Subjects were given strict instructions about the storage and use of the IMP during their home treatment regimen. Study participants collected data on IMP administrations occurring at home in a Sponsor-issued Subject Diary.

    Number of subjects in period 1
    		Group 1 (1A) Group 1 ( 1B) Continuation Segment (Part 2)
    Started
    4
    7
    10
    Completed
    4
    6
    11
    Not completed
    0
    1
    0
         Consent withdrawn by subject
    -
    1
    -
    Joined
    0
    0
    1
         Late recruitment
         Late recruitment reason:
    -
             
    -
             
    1
             due to amendment

    Baseline characteristics

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    Baseline characteristics reporting groups [1]
    Reporting group title
    Group 1 (1A)
    Reporting group description
    		 Symptomatic subjects with ocular pseudomembranes in one or both eyes at screening who received the IMP for 4 weeks (Segment 1) and with eyes showing complete pseudomembranes regression (defined as >90%). They have continued to received IMP at a reduced dose for an additional 8 weeks (Segment 2).

    Reporting group title
    Group 1 ( 1B)
    Reporting group description
    		 Symptomatic subjects with ocular pseudomembranes in one or both eyes at screening who received the IMP for 4 weeks (Segment 1) and with eyes showing partial (defined as between 20% and 90%) or no pseudomembranes regression (defined as <20%). They were to undergo surgery, within 2 weeks from the end of Segment 1, to remove the pseudomembranes. After surgery, subjects were to continue receiving IMP for an additional 8 weeks, at the decreasing frequency.

    Reporting group title
    Continuation Segment (Part 2)
    Reporting group description
    		 Subjects demonstrating complete treatment success (defined as regression of pseudomembranes in Segment 1 and no relapse of pseudomembranes through Segment 2) at the end of the Segment 2 were entered the Continuation Segment and one additional patient, who entered directly in the Part 2, without previously completing the first part of the study.

    Notes
    [1] - The number of subjects reported to be in the baseline period is not equal to the worldwide number of subjects enrolled in the trial. It is expected that these numbers will be the same.
    Justification: The worldwide number of subjects enrolled in the trial was 12. According to study design 11 subjects were enrolled in the first part of the study and an additional subject was enrollled directly in the second part of the study.
    Reporting group values
    		 Group 1 (1A) Group 1 ( 1B) Continuation Segment (Part 2) Total
    Number of subjects
    		 4 7 11 12
    Age categorical
    The Demographics and baseline characteristics were tabulated only for the reporting groups.
    Units: Subjects
        Infants and toddlers (28 days-23 months)
    		 2 1 3 3
        Children (2-11 years)
    		 1 5 7 7
        Adults (18-64 years)
    		 1 1 1 2
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 12.0 ( 21.34 ) 8.4 ( 10.66 ) 7.7 ( 12.41 ) -
    Gender categorical
    Units: Subjects
        Female
    		 3 4 7 7
        Male
    		 1 3 4 5
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0 0
        Asian
    		 0 0 0 0
        White
    		 4 7 11 12
        Black or African American
    		 0 0 0 0
        Native Hawaiian or other Pacific Islander
    		 0 0 0 0
        other
    		 0 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Group 1 (1A)
    Reporting group description
    		 Symptomatic subjects with ocular pseudomembranes in one or both eyes at screening who received the IMP for 4 weeks (Segment 1) and with eyes showing complete pseudomembranes regression (defined as >90%). They have continued to received IMP at a reduced dose for an additional 8 weeks (Segment 2).

    Reporting group title
    Group 1 ( 1B)
    Reporting group description
    		 Symptomatic subjects with ocular pseudomembranes in one or both eyes at screening who received the IMP for 4 weeks (Segment 1) and with eyes showing partial (defined as between 20% and 90%) or no pseudomembranes regression (defined as <20%). They were to undergo surgery, within 2 weeks from the end of Segment 1, to remove the pseudomembranes. After surgery, subjects were to continue receiving IMP for an additional 8 weeks, at the decreasing frequency.

    Reporting group title
    Continuation Segment (Part 2)
    Reporting group description
    		 Subjects demonstrating complete treatment success (defined as regression of pseudomembranes in Segment 1 and no relapse of pseudomembranes through Segment 2) at the end of the Segment 2 were entered the Continuation Segment and one additional patient, who entered directly in the Part 2, without previously completing the first part of the study.

    Subject analysis set title
    Group 1A_mITT
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Modified ITT (mITT) population consists of all eyes of subjects assigned to Groups 1A at the start of Study Segment 2, who received at least one dose of the study treatment, and underwent at least one efficacy assessment in Segment 2

    Subject analysis set title
    Group 1B _mITT
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Modified ITT (mITT) population consists of all eyes of subjects assigned to Group 1B at the start of Study Segment 2, who received at least one dose of the study treatment, and underwent at least one efficacy assessment in Segment 2

    Subject analysis set title
    Group 1_ mITT
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    mITT Population consists of all eyes assigned to Groups 1A and 1B at the start of study segment 2, who received at least one dose of the study treatment, and had at least one efficacy assessment in Segment 2.

    Subject analysis set title
    Group 1A_PP
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Per Protocol population consists of all eyes of Group 1A subjects included in the mITT population, who have completed both Segment 1 and Segment 2 of the study and received at least 80% of the protocol-required doses of the study treatment without any major protocol violations or exceptions that could impact the integrity of study data.

    Subject analysis set title
    Group 1B_PP
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Per Protocol population consists all eyes of Gruop 1B subjects included in the mITT population, who have completed both Segment 1 and Segment 2 of the study and received at least 80% of the protocol-required doses of the study treatment without any major protocol violations or exceptions that could impact the integrity of study data.

    Subject analysis set title
    Group 1_PP
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Per Protocol population includes all eyes of patients included in the mITT population, who have completed both Segment 1 and Segment 2 of the study and received at least 80% of the protocol-required doses of the study treatment without any major protocol violations or exceptions that could impact the integrity of study data.

    Subject analysis set title
    Group 1A_Safety population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Safety population consists of all Group 1A enrolled subjects who received at least one dose of the study treatment

    Subject analysis set title
    Group 1B_Safety population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Safety population consists of all Group 1B enrolled subjects who received at least one dose of the study treatment

    Subject analysis set title
    Continuation Segment_Safety population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Safety population includes all subjects who received at least one dose of the study drug in the continuation segment period.

    Primary: Proportion of Success to Prevent Pseudomembranes Relapse

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    End point title
    		 Proportion of Success to Prevent Pseudomembranes Relapse [1]
    End point description
    The primary endpoint (prevention of pseudomembrane relapse) was presented descriptively based on the predefined success levels: complete success (defined as no relapse by the end of Segment 2), partial success(defined as relapse appearing 2 weeks or longer after the start of Segment 2, or if following the 3 rd cycle of Segment 2 for Group 1A no relapse occurred while maintaining the higher dose) or failure (defined as relapse within 2 weeks of the start of Segment 2 or if at repeat cycles of Segment 1 for Group 1A, the pseudomembranes did not regress after Segment 1). Ninety-five percent confidence intervals for the relapse rate (complete success, and complete plus partial success) were calculated on the assumption of a binomial distribution. The responses were tabulated for the mITT and Per Protocol populations.
    End point type
    Primary
    End point timeframe
    The prevention of pseudomembrane relapse was calculated in the Segment 2 after initial total regression at the end of Segment 1 or after surgical excision in cases where there was no regression of pseudomembranes or partial regression.
    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: Descriptive statistics was applied to describe the study observations.
    End point values
    		 Group 1A_mITT Group 1B _mITT Group 1A_PP Group 1B_PP
    Number of subjects analysed
    4 [2]
    7 [3]
    3 [4]
    6 [5]
    Units: percentage of eyes
    number (confidence interval 95%)
        success
    75 (19.4 to 99.4)
    81.8 (48.2 to 97.7)
    100 (29.2 to 100)
    100 (66.4 to 100)
        partial success
    0 (0 to 60.2)
    18.2 (2.3 to 51.8)
    0 (0 to 70.8)
    0 (0 to 33.6)
        failure
    25 (0.6 to 80.6)
    0 (0 to 28.5)
    0 (0 to 70.8)
    0 (0 to 33.6)
    Notes
    [2] - number of eyes evaluable = 4
    [3] - number of eyes evaluable = 11
    [4] - number of eyes evaluable = 3
    [5] - number of eyes evaluable = 9
    No statistical analyses for this end point

    Secondary: Regression in Surface Area of Existing Ligneous Pseudomembranes

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    End point title
    		 Regression in Surface Area of Existing Ligneous Pseudomembranes
    End point description
    The secondary endpoint was presented descriptively based on the predefined success levels: complete success (defined as regression of PSAs >90%), partial success (defined as regression of PSAs between 20% and 90%) or failure (defined as regression of PSAs <20%). The responses were tabulated for the mITT and the Per Protocol populations.
    End point type
    Secondary
    End point timeframe
    The regression of pseudomembrane surface area (PSA) of Existing Ligneous Pseudomembranes was calculated from baseline to the end of Segment 1.
    End point values
    		 Group 1_ mITT Group 1_PP
    Number of subjects analysed
    11 [6]
    9 [7]
    Units: percentage of eyes
    number (confidence interval 95%)
        complete success
    20 (4.3 to 48.1)
    25 (5.5 to 57.2)
        partial success
    46.7 (21.3 to 73.4)
    58.3 (27.7 to 84.8)
        failure
    33.3 (11.8 to 61.6)
    16.7 (2.1 to 48.4)
    Notes
    [6] - number of eyes evaluable = 15
    [7] - number of eyes evaluable = 12
    No statistical analyses for this end point

    Other pre-specified: Antibody Development against aprotinin

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    End point title
    		 Antibody Development against aprotinin
    End point description
    The safety parameters were presented descriptively and tabulated for the Gruop 1A, Group 1B and Continuation Segment safety population.
    End point type
    Other pre-specified
    End point timeframe
    The antibody development was detected during Part 1 and Part 2 of the study.
    End point values
    		 Group 1A_Safety population Group 1B_Safety population Continuation Segment_Safety population
    Number of subjects analysed
    4
    7
    11
    Units: number of subjects
        New antibody development
    0
    3
    3
        Antibodies Increasing
    0
    1
    0
        Antibody Decreasing
    0
    1
    0
        Antibody no changes
    0
    1
    0
    No statistical analyses for this end point

    Other pre-specified: Antibody Development against human plasminogen

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    End point title
    		 Antibody Development against human plasminogen
    End point description
    The safety parameters were presented descriptively and tabulated for the Gruop 1A, Group 1B and Continuation Segment safety population.
    End point type
    Other pre-specified
    End point timeframe
    The antibody development was detected during the Part 1 and Part 2 of the study.
    End point values
    		 Group 1A_Safety population Group 1B_Safety population Continuation Segment_Safety population
    Number of subjects analysed
    4
    7
    11
    Units: number of subjects
        New Antibodies Development
    0
    1
    1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs were collected from the screening visit and throughout the study.
    Adverse event reporting additional description
    AEs were collected by spontaneous reporting by the patient, by review of the Subject Diaries, and, during the visits at site, by asking the patient non-leading questions about how they felt since their last study visit
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Group 1 (1A)
    Reporting group description
    		 Patients with eyes showing complete pseudomembranes regression (defined as >90%) who have received IMP at a dose of 2 drops/eye 6 times/day for 8 weeks.

    Reporting group title
    Group 1 ( 1B)
    Reporting group description
    		 Patients with eyes showing partial (defined as between 20% and 90%) or no pseudomembranes regression (defined as <20%) were to undergo surgery, within 2 weeks from the end of Segment 1, to remove the pseudomembranes. After surgery, patients were to continue receiving IMP (2 drops/eye) for an additional 8 weeks, at the decreasing frequency.

    Reporting group title
    Continuation Segment
    Reporting group description
    		 Subjects demonstrating complete treatment success (defined as regression of pseudomembranes in Segment 1 and no relapse of pseudomembranes through Segment 2) at the end of part 1 and one additional patient, who entered directly, without previously completing the first part of the study were to receive IMP at a dosage regimen of 2 drops/eye 4 to 6 times/day at Investigator’s discretion.

    Serious adverse events
    		 Group 1 (1A) Group 1 ( 1B) Continuation Segment
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 4 (50.00%)
    3 / 7 (42.86%)
    3 / 11 (27.27%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Investigations
    Blood alkaline phosphatase increased
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 7 (14.29%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Drug specific antibody present
    Additional description: Anti-plasminogen antibody
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
    1 / 11 (9.09%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Conjunctivitis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 7 (0.00%)
    1 / 11 (9.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Autoimmune hepatitis
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 7 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Varicella
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetic ketoacidosis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 7 (0.00%)
    1 / 11 (9.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Group 1 (1A) Group 1 ( 1B) Continuation Segment
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    4 / 4 (100.00%)
    7 / 7 (100.00%)
    10 / 11 (90.91%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cholesteatoma
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 7 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 7 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    Surgical and medical procedures
    Tooth extraction
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 7 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    General disorders and administration site conditions
    Pain
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1
    1
    Pyrexia
         subjects affected / exposed
    3 / 4 (75.00%)
    3 / 7 (42.86%)
    7 / 11 (63.64%)
         occurrences all number
    3
    3
    7
    Axillary pain
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 7 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    Fatigue
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 7 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    Injection site pain
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 7 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    Immune system disorders
    Multiple allergies
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 7 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    Seasonal allergy
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 7 (0.00%)
    2 / 11 (18.18%)
         occurrences all number
    0
    0
    2
    Reproductive system and breast disorders
    Cervix disorder
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 7 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    Genital labial adhesions
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 7 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    Vaginal haemorrhage
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 7 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    3 / 4 (75.00%)
    2 / 7 (28.57%)
    6 / 11 (54.55%)
         occurrences all number
    3
    2
    6
    Epistaxis
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    Nasal congestion
         subjects affected / exposed
    3 / 4 (75.00%)
    0 / 7 (0.00%)
    2 / 11 (18.18%)
         occurrences all number
    3
    0
    2
    Rhinorrhoea
         subjects affected / exposed
    2 / 4 (50.00%)
    1 / 7 (14.29%)
    3 / 11 (27.27%)
         occurrences all number
    2
    1
    3
    Sneezing
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 7 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    0
    Oropharyngeal pain
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 7 (0.00%)
    4 / 11 (36.36%)
         occurrences all number
    0
    0
    4
    Paranasal sinus hypersecretion
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 7 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    Pharyngeal erythema
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 7 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    Rhinitis allergic
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 7 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    Wheezing
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 7 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    Investigations
    Liver palpable subcostal
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 7 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    0
    Antibody test positive
    Additional description: Antibody anti-aprotinin
         subjects affected / exposed
    0 / 4 (0.00%)
    4 / 7 (57.14%)
    4 / 11 (36.36%)
         occurrences all number
    0
    4
    4
    Blood glucose increased
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 7 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    Blood pressure increased
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 7 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    Heart rate irregular
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 7 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    Thermal burn
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 7 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    0
    Accident
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 7 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    Contusion
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 7 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    Laceration
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 7 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    Procedural pain
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 7 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    Headache
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 7 (14.29%)
    2 / 11 (18.18%)
         occurrences all number
    1
    1
    2
    Blood and lymphatic system disorders
    Iron deficiency anaemia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 7 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    Ear and labyrinth disorders
    Conductive deafness
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 7 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    Ear pain
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 7 (0.00%)
    3 / 11 (27.27%)
         occurrences all number
    0
    0
    3
    Middle ear effusion
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 7 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    Tympanic membrane perforation
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 7 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    Tympanic membrane hyperaemia
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    Eye disorders
    Chalazion
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 7 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    Conjunctivitis bacterial
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 7 (0.00%)
    2 / 11 (18.18%)
         occurrences all number
    1
    0
    2
    Ectropion
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    Eye haemorrhage
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    Eye pain
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1
    1
    Eyelid margin crusting
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    Lacrimation increased
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    Ocular hyperaemia
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
    3 / 11 (27.27%)
         occurrences all number
    0
    1
    3
    Ocular hypertension
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
    2 / 11 (18.18%)
         occurrences all number
    0
    1
    2
    Blepharitis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 7 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    Cataract
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 7 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    Conjunctival disorder
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 7 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    Conjunctival oedema
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 7 (0.00%)
    2 / 11 (18.18%)
         occurrences all number
    0
    0
    2
    Conjunctivitis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 7 (0.00%)
    4 / 11 (36.36%)
         occurrences all number
    0
    0
    4
    Eye discharge
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 7 (0.00%)
    3 / 11 (27.27%)
         occurrences all number
    0
    0
    3
    Eye swelling
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 7 (0.00%)
    2 / 11 (18.18%)
         occurrences all number
    0
    0
    2
    Pinguecula
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 7 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    2 / 4 (50.00%)
    0 / 7 (0.00%)
    2 / 11 (18.18%)
         occurrences all number
    2
    0
    2
    Hypoaesthesia oral
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    Toothache
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    Vomiting
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 7 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    1
    0
    1
    Constipation
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 7 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    Dental caries
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 7 (0.00%)
    2 / 11 (18.18%)
         occurrences all number
    0
    0
    2
    Gingival disorder
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 7 (0.00%)
    2 / 11 (18.18%)
         occurrences all number
    0
    0
    2
    Gingival oedema
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 7 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    Nausea
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 7 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    Rectal prolapse
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 7 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    Teething
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 7 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    Tooth loss
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 7 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    Skin and subcutaneous tissue disorders
    Dermatitis diaper
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1
    1
    Eczema
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1
    1
    Rash papular
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 7 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    0
    Subcutaneous haematoma
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    Erythema
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 7 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    Excoriation
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 7 (0.00%)
    2 / 11 (18.18%)
         occurrences all number
    0
    0
    2
    Rash
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 7 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    Renal and urinary disorders
    Urinary retention
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 7 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    Musculoskeletal and connective tissue disorders
    Osteoarthritis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 7 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    Synovial cyst
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 7 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    Infections and infestations
    Candida nappy rash
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    Ear infection
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 7 (0.00%)
    5 / 11 (45.45%)
         occurrences all number
    1
    0
    5
    Nasopharyngitis
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
    5 / 11 (45.45%)
         occurrences all number
    0
    1
    5
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
    2 / 11 (18.18%)
         occurrences all number
    0
    1
    2
    Vulvovaginal candidiasis
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    Vulvovaginitis
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    Acute tonsillitis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 7 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    Bronchitis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 7 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    Cellulitis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 7 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    Gingivitis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 7 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    Hand-foot-and-mouth disease
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 7 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    Herpangina
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 7 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    Influenza
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 7 (0.00%)
    3 / 11 (27.27%)
         occurrences all number
    0
    0
    3
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 7 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    Molluscum contagiosum
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 7 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    Skin infection
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 7 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    Otitis media
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 7 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    Pharyngitis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 7 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    Pharyngitis streptococcal
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 7 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    Pneumonia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 7 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    Sinusitis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 7 (0.00%)
    4 / 11 (36.36%)
         occurrences all number
    0
    0
    4
    Skin papilloma
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 7 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    Tonsillitis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 7 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    Metabolism and nutrition disorders
    Type 1 diabetes mellitus
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 7 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    10 Oct 2013
    Protocol Amendment 1 - The main revisions were: Revision of the Inclusion and Exclusion Criteria for further clarity. Addition in the primary and secondary efficacy endpoints of the definitions: of “no-”, “partial-”, and “complete pseudomembranes regression”. Clarification of the requirements for the Follow-up and Continuation Periods. Clarification of the procedures to be followed in each Study Segment. Revision of the Duration of Treatment section for each Segment to better explain the options of Group Assignment depending on the presence, absence, relapse, or regression of the pseudomembranes.
    19 Jun 2014
    Protocol Amendment 2 - The main revisions were: Provisions for the enrolment of up to two additional asymptomatic patients directly into the Continuation Segment (i.e., without completing Segments 1 and 2), after Groups 1 and 2 are fully enrolled. The dosing regimen and assessment schedule for these patients were also clarified. Clarification that enrolment in Group 2 is not mandatory, but should not exceed 5 patients. Clarification of the requirements for taking photographs as part of the ophthalmology examinations. Addition of a mandatory visit (Visit 5) 6 months after the start of the Continuation Segment. Clarification regarding the viral screening tests. The schedule of immunogenicity assessments have been corrected. The maximum study duration was clarified.
    08 Jun 2015
    Protocol Amendment 3 - The main revisions were: Extension of the Continuation Segment, with follow-up visits completed every 6 months, to collect safety information. Clarification that any additional (unscheduled) visits and assessments (apart from the 6-month visits) during the Continuation Segment will occur at the investigator’s discretion. The ranges for plasminogen antigen and activity for the diagnosis of Type 1 Plasminogen deficiency, were defined. Inclusion of rules for reporting of AEs related to development/increase in the titre of antibodies against plasminogen and aprotinin. End of study was defined as the last safety follow-up visit scheduled after product licensure.
    01 Sep 2016
    Protocol Amendment 4 - The main revisions were: The frequency of immunogenicity evaluations during the Continuation Segment was revised from every 6 months to every 2 months. Clarification of assay methods for immunogenicity testing (Enzyme-Linked Immunosorbent Assay [ELISA]), plasminogen antigen (nephelometric immunoassay), and plasminogen activity (chromogenic assay).
    04 Jan 2017
    Protocol Amendment 5 - The main revisions were: Provisions for (optional) utilization of a Home Health Agency to collect samples every 2 months outside of the investigational site during the Continuation Segment. These provisions applied to the immunogenicity samples collected every 2 months (apart from the 6-month visits collected at the site), and required patient consent prior to implementation. Requirement to report all events of anti-human plasminogen antibody positivity to Kedrion no later than 48 hours after learning about the event.
    10 Jan 2019
    Protocol Amendment 6 - The main revisions were: In order to better monitor the effect of possible development of anti-plasminogen antibodies, specific safety questions were included in the monthly phone calls. Clarification that any event of anti-plasminogen antibody positivity was to be treated as expedited even if this finding was not indicative of the presence of neutralizing antibodies based on clinical evidence. Clarification that patients withdrawn from the study would not be replaced. Removal of the requirement to report AEs occurring during or within 24 hours following treatment with IMP as treatment-related (due to the IMP administration schedule, this requirement was not applicable to the current study). Change in the efficacy analysis population, from ITT to the mITT and Per Protocol populations. Clarification that for each patient, each eye was to be analyzed independently of the other eye.
    13 Jan 2020
    Protocol Amendment 7 - The main revisions were: Removal of the plasminogen antigen and activity evaluation at the Termination 2 Visit, considering that 1) the level of serum plasminogen and its activity are not expected to be affected by the treatment; 2) The large majority of the study population are children and it is therefore appropriate to avoid unnecessary blood draws.
    15 Sep 2020
    Protocol Amendment 8 - The main revisions were: In order to allow continued product availability and treatment to patients before commercialization, a Sponsor-Initiated EAP was developed in the US. As of 2 April 2020, no patient was treated under the KB046 protocol in Italy. Accordingly, treatment and follow-up in the Continuation Segment was to continue until the Sponsor-Initiated EAP was initiated (instead of until commercialization). End of study was redefined as the last safety follow-up information (immunogenicity results) received by investigators.

    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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