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    Clinical Trial Results:
    A Phase 1/2A, Dose Escalation, Randomized, Placebo Controlled Study of the Safety, Feasibility, and Efficacy of Subcutaneous Plasminogen (Human) 10 for the Treatment of Chronic Tympanic Membrane Perforation

    Summary
    EudraCT number
    		 2017-002927-68
    Trial protocol
    		 SE  
    Global end of trial date
    04 Feb 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    28 May 2021
    First version publication date
    28 May 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    2002C015G
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Prometic Biotherapeutics Ltd
    Sponsor organisation address
    1330 Piccard Dr # 201, Rockville, United States,
    Public contact
    Medical Officer, Joseph Parker, MD , clinical@prometic.com
    Scientific contact
    Medical Officer, Joseph Parker, MD , clinical@prometic.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
    04 Feb 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    04 Feb 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    04 Feb 2019
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To assess the safety and tolerability of 5 mg and 10 mg Plasminogen (Human) 10 injected subcutaneously (SC) near the tympanic membrane in adult subjects with chronic tympanic membrane perforation (TMP).
    Protection of trial subjects
    The protocol and the amendments were submitted to a properly constituted IEC and the concerned CA, in accordance with the International Council for Harmonization (ICH) of Technical Requirements for Pharmaceuticals for Human Use guidelines, the applicable European Directives, and local legal requirements, for approval of the study. Approvals had been obtained in writing before the first subject was recruited. The study was conducted in compliance with the protocol, regulatory requirements, good clinical practice (GCP), and the ethical principles of the latest revision of the Declaration of Helsinki as adopted by the World Medical Association. All subjects received written and verbal information regarding the study at a prior interview. The given information emphasized that participation in the study was voluntary and that the subject could withdraw from the study at any time and for any reason. All subjects were given the opportunity to ask questions about the study and were given sufficient time to decide whether to participate in the study. Before any study-related procedures, the ICF was signed and personally dated by the subject (or their legally acceptable representative and/or witness, as applicable) and by the person who conducted the informed consent discussion.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    16 Feb 2018
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Sweden: 9
    Worldwide total number of subjects
    9
    EEA total number of subjects
    9
    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)
    8
    From 65 to 84 years
    1
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Recruitment was stopped after 9 subjects had been included and completed the study.

    Pre-assignment
    Screening details
    		 Consenting subjects were screened for eligibility per the defined inclusion/exclusion criteria during the 2 weeks preceding the first injection at the baseline visit.

    Period 1
    Period 1 title
    overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 0.5 mL IMP - 5 mg SC Plasminogen (human)
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    SC Plasminogen (human)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for suspension for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    During each low dose injection session, 0.5 mL IMP - 5 mg SC Plasminogen (human), divided into 4 (approximately 125 µL aliquots), were injected.

    Arm title
    		 0.5 mL placebo
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    0.9% [w/v] NaCl
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    During each low dose injection session, 0.5 mL of placebo divided into 4 (approximately 125 µL aliquots) were injected.

    Number of subjects in period 1
    		0.5 mL IMP - 5 mg SC Plasminogen (human) 0.5 mL placebo
    Started
    7
    2
    Completed
    7
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    0.5 mL IMP - 5 mg SC Plasminogen (human)
    Reporting group description
    		 -

    Reporting group title
    0.5 mL placebo
    Reporting group description
    		 -

    Reporting group values
    		 0.5 mL IMP - 5 mg SC Plasminogen (human) 0.5 mL placebo Total
    Number of subjects
    		 7 2 9
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 6 2 8
        From 65-84 years
    		 1 0 1
    Age continuous
    Units: years
        arithmetic mean (full range (min-max))
    		 35 (19 to 67) 62.5 (62 to 63) -
    Gender categorical
    Units: Subjects
        Female
    		 4 1 5
        Male
    		 3 1 4
    Weight
    Units: kilogram(s)
        arithmetic mean (full range (min-max))
    		 75.7 (51.5 to 108.0) 63.8 (58.8 to 68.8) -

    End points

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    End points reporting groups
    Reporting group title
    0.5 mL IMP - 5 mg SC Plasminogen (human)
    Reporting group description
    		 -

    Reporting group title
    0.5 mL placebo
    Reporting group description
    		 -

    Primary: Number, type, severity, and causality of TEAEs by treatment

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    End point title
    		 Number, type, severity, and causality of TEAEs by treatment [1]
    End point description
    End point type
    Primary
    End point timeframe
    AEs were recorded during the study period from administration of first dose of study drug (Visit 2) to the completion of the End-of-study visit (Visit 6).
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The statistical analysis methods described in the protocol for primary and secondary endpoints were planned according to the intended number of subjects to be included. With only 9 subjects included in the study, it was not considered meaningful to do the safety and efficacy analyses as planned and was thus not conducted.
    End point values
    		 0.5 mL IMP - 5 mg SC Plasminogen (human) 0.5 mL placebo
    Number of subjects analysed
    7
    2
    Units: adverse event
        Severity - MILD
    20
    2
        Severity - MODERATE
    1
    0
        Severity - SEVERE
    0
    0
        Causality - not related
    7
    0
        Causality - possible
    6
    0
        Causality - probable
    2
    1
        Causality - definite
    6
    1
    No statistical analyses for this end point

    Secondary: Proportion of injections that are technically feasible by treatment, defined as the ability to insert needle SC in the ear canal less or equal to 5 mm from the tympanic annulus and deliver entire volume of IMP or placebo SC without spillage.

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    End point title
    		 Proportion of injections that are technically feasible by treatment, defined as the ability to insert needle SC in the ear canal less or equal to 5 mm from the tympanic annulus and deliver entire volume of IMP or placebo SC without spillage.
    End point description
    End point type
    Secondary
    End point timeframe
    Recorded during the study period from administration of first dose of study drug (Visit 2) to the completion of the End-of-study visit (Visit 6).
    End point values
    		 0.5 mL IMP - 5 mg SC Plasminogen (human) 0.5 mL placebo
    Number of subjects analysed
    7
    2
    Units: number
        visit 2 - less than 20% not injected
    5
    1
        visit 2 - no spillage reported
    2
    1
        visit 3 - less than 20% not injected
    4
    1
        visit 3 - no spillage reported
    2
    1
        visit 4 - less than 20% not injected
    2
    1
        visit 4 - no spillage reported
    4
    1
        visit 3 - 20-50% not injected
    1
    0
        visit 4 - 20-50% not injected
    1
    0
    No statistical analyses for this end point

    Secondary: Proportion of subjects with more than 50% reduction in the percentage of TMSA occupied by the TMP at 1 month compared with baseline by treatment.

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    End point title
    		 Proportion of subjects with more than 50% reduction in the percentage of TMSA occupied by the TMP at 1 month compared with baseline by treatment.
    End point description
    End point type
    Secondary
    End point timeframe
    assessed at 1 month
    End point values
    		 0.5 mL IMP - 5 mg SC Plasminogen (human) 0.5 mL placebo
    Number of subjects analysed
    7
    2
    Units: number
        equal or more than 50% reduction
    1
    0
        less than 50% reduction
    6
    2
    No statistical analyses for this end point

    Secondary: Proportion of subjects with TMP closure at 1 month compared with baseline by treatment, defined as the absence of visible perforation by otomicroscopy AND the presence of tympanic membrane movement with pneumatic pressure change in the ear canal.

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    End point title
    		 Proportion of subjects with TMP closure at 1 month compared with baseline by treatment, defined as the absence of visible perforation by otomicroscopy AND the presence of tympanic membrane movement with pneumatic pressure change in the ear canal.
    End point description
    End point type
    Secondary
    End point timeframe
    assessed at 1 month
    End point values
    		 0.5 mL IMP - 5 mg SC Plasminogen (human) 0.5 mL placebo
    Number of subjects analysed
    7
    2
    Units: number
        TMP closure at 1 month
    0
    0
    No statistical analyses for this end point

    Secondary: Proportion of subjects with more than 50% reduction in the percentage of TMSA occupied by the TMP at 3 months compared with baseline by treatment.

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    End point title
    		 Proportion of subjects with more than 50% reduction in the percentage of TMSA occupied by the TMP at 3 months compared with baseline by treatment.
    End point description
    End point type
    Secondary
    End point timeframe
    assessed at 3 months
    End point values
    		 0.5 mL IMP - 5 mg SC Plasminogen (human) 0.5 mL placebo
    Number of subjects analysed
    7
    2
    Units: number
        equal or more than 50% reduction
    1
    0
        less than 50% reduction
    6
    2
    No statistical analyses for this end point

    Secondary: Proportion of subjects with TMP closure at 3 months compared with baseline by treatment, defined as the absence of visible perforation by otomicroscopy AND the presence of tympanic membrane movement with pneumatic pressure change in the ear canal.

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    End point title
    		 Proportion of subjects with TMP closure at 3 months compared with baseline by treatment, defined as the absence of visible perforation by otomicroscopy AND the presence of tympanic membrane movement with pneumatic pressure change in the ear canal.
    End point description
    End point type
    Secondary
    End point timeframe
    assessed at 3 months
    End point values
    		 0.5 mL IMP - 5 mg SC Plasminogen (human) 0.5 mL placebo
    Number of subjects analysed
    7
    2
    Units: number
        TMP closure at 3 months
    0
    0
    No statistical analyses for this end point

    Secondary: Change in visual analogue scale (VAS) score for ear discomfort (pain or other unpleasant sensation) at 1 month compared with baseline by treatment.

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    End point title
    		 Change in visual analogue scale (VAS) score for ear discomfort (pain or other unpleasant sensation) at 1 month compared with baseline by treatment.
    End point description
    End point type
    Secondary
    End point timeframe
    assessed at 1 month
    End point values
    		 0.5 mL IMP - 5 mg SC Plasminogen (human) 0.5 mL placebo
    Number of subjects analysed
    7
    1
    Units: number
        improved ear discomfort
    2
    1
        similar ear discomfort
    2
    0
        worsened ear discomfort
    3
    1
    No statistical analyses for this end point

    Secondary: Change in VAS score for ear discomfort at 3 months compared with baseline by treatment.

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    End point title
    		 Change in VAS score for ear discomfort at 3 months compared with baseline by treatment.
    End point description
    End point type
    Secondary
    End point timeframe
    assessed at 3 months
    End point values
    		 0.5 mL IMP - 5 mg SC Plasminogen (human) 0.5 mL placebo
    Number of subjects analysed
    7
    2
    Units: number
        improved ear discomfort
    2
    1
        similar ear discomfort
    2
    0
        worsened ear discomfort
    3
    1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs were recorded during the study period from the administration of the first dose of the study drug (Visit 2) to the completion of the End-of-study visit (Visit 6).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    0.5 mL IMP - 5 mg SC Plasminogen (human)
    Reporting group description
    		 -

    Reporting group title
    0.5 mL Placebo
    Reporting group description
    		 -

    Serious adverse events
    		 0.5 mL IMP - 5 mg SC Plasminogen (human) 0.5 mL Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 2 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 0.5 mL IMP - 5 mg SC Plasminogen (human) 0.5 mL Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    6 / 7 (85.71%)
    2 / 2 (100.00%)
    Nervous system disorders
    Lethargy
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    Balance disorder
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    Headache
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    Fatigue
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    Ear and labyrinth disorders
    Dizziness
         subjects affected / exposed
    2 / 7 (28.57%)
    0 / 2 (0.00%)
         occurrences all number
    2
    0
    Ear pain
         subjects affected / exposed
    5 / 7 (71.43%)
    2 / 2 (100.00%)
         occurrences all number
    5
    2
    Nasal congestion
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    Ear infection
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Skin reaction
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    Psychiatric disorders
    Sleep disorder
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    Viral upper respiratory tract infection
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Feb 2018
    Update of: inclusion/exclusion criteria, identified risks, and minimization actions, urinalysis, time windows for follow-up and end-of-study visit, study the administrative structure of the study, and contact prior safety reporting. Other implemented changes: revision of needle and syringe specifications, modification of screening number format, and clarification of safety procedure– unblinding.
    24 Sep 2018
    Some changes were implemented on the protocol in relation to the addition of an interim analysis after the last subject in cohort 1 completed a 1-month follow-up, and clarification of the study stopping rules for dose escalation and dose-limiting toxicities and added unblinding of subjects with SNHL assessed to be at least possibly related to study drug administration; update of language about masking of the non-test ear during PTA and removed the 0.25 kHz frequency for bone conduction, local anesthetic dosage, and chemistry tests; revision of timing of TMP size measurement, estimated last subject last visit date, and section to reflect under what circumstances unblinding would occur. At last, it was also clarified the injection performance language, the specific serum virology tests performed by the site’s laboratory, and added asymptomatic abnormal physical examination finding to AE criteria.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    04 Feb 2019
    The study was prematurely terminated after 9 subjects were included. Study termination was due to slow enrollment and Prometic’s development of a new formulation, and not based on any safety concerns.
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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