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    Clinical Trial Results:
    Effects of Wobenzym® plus in healthy, sportive people after eccentric exercise - a randomized, two-stage, double-blind, placebo-controlled cross-over trial

    Summary
    EudraCT number
    		 2012-005003-40
    Trial protocol
    		 DE  
    Global end of trial date
    13 Aug 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    10 Jul 2016
    First version publication date
    10 Jul 2016
    Other versions
    Summary report(s)
    		 Synopsis

    Trial information

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    Trial identification
    Sponsor protocol code
    BTS651/12
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01845558
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    BioTesys GmbH
    Sponsor organisation address
    Schelztorstraße 54-56, Esslingen, Germany, 73728
    Public contact
    Clinical Trial Information , BioTeSys GmbH, 0049 71131057147, c.reule@biotesys.de
    Scientific contact
    Clinical Trial Information , BioTeSys GmbH, 0049 71131057147, c.reule@biotesys.de
    Sponsor organisation name
    Mucos Pharma GmbH & Co. KG
    Sponsor organisation address
    Bajuwarenring 5, Oberhaching, Germany, 82041
    Public contact
    MUCOS Pharma GmbH & Co. KG , MUCOS Pharma GmbH & Co. KG, +49 89 638372400, info@mucos.de
    Scientific contact
    MUCOS Pharma GmbH & Co. KG , MUCOS Pharma GmbH & Co. KG, Dr. Stefanie Rau, +49 89 638372404, s.rau@mucos.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
    13 Jul 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    13 Aug 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    13 Aug 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The aim of the current study is to investigate the therapeutic effect of Wobenzym® plus, an anti-inflammatory drug containing proteolytic enzymes, on exercise induced muscle damage (eiMD) and recovery time in male amateur sportsmen with medium proficiency level compared to placebo. As primary objective, the reduction of maximal isokinetic strength after exercise in the stronger leg and subjective pain after exercise are assumed to be the most promising parameters. Therefore these parameters are combined in a multidimensional approach summarizing different parameters and points of time to strengthen the power. The period after the stress test will be separately calculated for the acute phase (3h, 6h) and the recovery phase (24h-48h).
    Protection of trial subjects
    Informed consent after explanation of aims, methods, benefits and potential hazards. Screening visit to exclude patient with diseases, allergic reactions ect (see exclusion criteria). Every volunteer is free to refuse to participate in the study or withrdaw their consent at any time and for any reason without incurring any penalty. Study site with Emergency Management Plan and Equipment.
    Background therapy
    		 Not applicable.
    Evidence for comparator
    		 No Comparator used (Placebo-controlled trial).
    Actual start date of recruitment
    01 Feb 2013
    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
    Germany: 74
    Worldwide total number of subjects
    74
    EEA total number of subjects
    74
    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)
    74
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Monocenter, double-blind, randomized, placebo-controlled, crossover study (stage I) designed to assess acute phase and recovery after eccentric stress test. Stage II: parallel group design.

    Pre-assignment
    Screening details
    		 Stage I cross-over design: Group 1 (N=15) Wobenzym plus from day 1 to day 7 and placebo from day 29 to day 35 Group 2 (N=15) Placebo from day 1 to day 7 and Wobenzym plus from day 29 to day 35 Wash-out phase of 21 days. Stage II: parallell design, 2x22 randomized to Wobenzym plus or Placebo

    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, Carer

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Placebo Arm: Stage 1 Crossover Design (15) + stage II parallel design (22)
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Four tablets three times per day. Medication will be taken 30 minutes before each meal on an empty stomach with one glass of water.

    Arm title
    		 Verum
    Arm description
    		 Active comparator Wobenzym plus
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Wobenzym plus
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Four tablets three times per day. Medication will be taken 30 minutes before each meal on an empty stomach with one glass of water.

    Number of subjects in period 1
    		Placebo Verum
    Started
    37
    37
    Completed
    33
    34
    Not completed
    4
    3
         Consent withdrawn by subject
    1
    -
         Protocol deviation
    1
    3
         Not treated
    2
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    		 -

    Reporting group values
    		 Overall trial Total
    Number of subjects
    		 74 74
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 74 74
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 31.6 ( 9.3 ) -
    Gender categorical
    Units: Subjects
        Female
    		 0 0
        Male
    		 74 74

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Placebo Arm: Stage 1 Crossover Design (15) + stage II parallel design (22)

    Reporting group title
    Verum
    Reporting group description
    		 Active comparator Wobenzym plus

    Primary: Acute phase Primary endpoints

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    End point title
    		 Acute phase Primary endpoints
    End point description
    Multidimensional: Reduction of maximal concentric strenght after stress test + pressure induced pain (Algometry) in the middle of the muscle belly of m. rectus femoris
    End point type
    Primary
    End point timeframe
    Acute phase: 3 h and 6 h post stress test
    End point values
    		 Placebo Verum
    Number of subjects analysed
    33
    34
    Units: NM + NM/cm2
        number (not applicable)
    33
    34
    Statistical analysis title
    		 Multivariate test Stage 1
    Statistical analysis description
    Multivariate test of first vonfirmatory hypothesis of stage 1 (multidimensional ensemble of peak torque and pressure induced pain at 3h and 6h)
    Comparison groups
    Placebo v Verum
    Number of subjects included in analysis
    67
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.0332
    Method
    		 Wei-Lachin
    Confidence interval
         level
    		 97.5%
         sides
    1-sided
         lower limit
    		 -
         upper limit
    		 0.4922
    Notes
    [1] - one-sided, directional test for superiority, Wei-Lachin procedure
    Statistical analysis title
    		 Mann-Whitney stage 1
    Statistical analysis description
    Associated effect size Mann-Whitney for hypothesis stage 1 acute phase
    Comparison groups
    Placebo v Verum
    Number of subjects included in analysis
    67
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6153
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Mann-Whitney
    Point estimate
    0.6153
    Confidence interval
         level
    		 97.5%
         sides
    1-sided
         lower limit
    		 0.4922
         upper limit
    		 -
    Statistical analysis title
    		 Multivariate test Stage 2
    Statistical analysis description
    multidimensional ensemble of peak torque and pressure induced pain at 3h and 6 hours (acute phase)
    Comparison groups
    Placebo v Verum
    Number of subjects included in analysis
    67
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8596
    Method
    		 Wei-Lachin
    Confidence interval
         level
    		 97.5%
         sides
    1-sided
         lower limit
    		 -
         upper limit
    		 0.325
    Statistical analysis title
    		 Mann-Whitney stage 2
    Comparison groups
    Placebo v Verum
    Number of subjects included in analysis
    67
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4379
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Mann-Whitney
    Point estimate
    0.4379
    Confidence interval
         level
    		 97.5%
         sides
    1-sided
         lower limit
    		 0.325
         upper limit
    		 -

    Primary: Recovery phase: Primary endpoint

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    End point title
    		 Recovery phase: Primary endpoint
    End point description
    Multidimensional: Reduction of maximal concentric strenght after stress test + pressure induced pain (Algometry) in the middle of the muscle belly of m. rectus femoris
    End point type
    Primary
    End point timeframe
    24 h and 48 h after stress test
    End point values
    		 Placebo Verum
    Number of subjects analysed
    33
    34
    Units: NM / NM/cm2
        number (not applicable)
    33
    34
    Statistical analysis title
    		 Multivariate test Stage 1
    Statistical analysis description
    multidimensional ensemble of peak torque and pressure induced pain at 24h and 48h
    Comparison groups
    Placebo v Verum
    Number of subjects included in analysis
    67
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0934
    Method
    		 Wei-Lachin
    Parameter type
    		 Wei-Lachin
    Point estimate
    0.0934
    Confidence interval
         level
    		 97.5%
         sides
    1-sided
         lower limit
    		 -
         upper limit
    		 0.4556
    Statistical analysis title
    		 Mann-Whitney stage 1
    Comparison groups
    Placebo v Verum
    Number of subjects included in analysis
    67
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5917
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Mann-Whitney
    Point estimate
    0.5917
    Confidence interval
         level
    		 97.5%
         sides
    1-sided
         lower limit
    		 0.4556
         upper limit
    		 -
    Statistical analysis title
    		 Multivariate test Stage 2
    Statistical analysis description
    multidimensional ensemble of peak torque and pressure induced pain at 24h and 48h
    Comparison groups
    Placebo v Verum
    Number of subjects included in analysis
    67
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8783
    Method
    		 Wei-Lachin
    Parameter type
    		 Wei-Lachin
    Point estimate
    0.8783
    Confidence interval
         level
    		 97.5%
         sides
    1-sided
         lower limit
    		 0.3035
         upper limit
    		 -
    Statistical analysis title
    		 Mann-Whitney Stage 2
    Comparison groups
    Placebo v Verum
    Number of subjects included in analysis
    67
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4267
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Mann-Whitney
    Point estimate
    0.4267
    Confidence interval
         level
    		 97.5%
         sides
    1-sided
         lower limit
    		 0.3035
         upper limit
    		 -

    Secondary: Secondary endpoints: Biomarkers

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    End point title
    		 Secondary endpoints: Biomarkers
    End point description
    IL-6, Prostaglandin E metabolite derived from cyclooxygenase 2, Creatin kinase, LDH, Lactate, NK-cell-test, Redox-Status (TOS/TAS)
    End point type
    Secondary
    End point timeframe
    pre, 0h, 10 min, 30 min, 3h, 6h, 24h - depending on marker
    End point values
    		 Placebo Verum
    Number of subjects analysed
    33
    34
    Units: not applicable
        number (not applicable)
    33
    34
    Statistical analysis title
    		 Multivariate test pooled biomarkers
    Comparison groups
    Placebo v Verum
    Number of subjects included in analysis
    67
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0001 [2]
    Method
    		 Wei-Lachin
    Parameter type
    		 Wei-Lachin
    Point estimate
    0.0001
    Confidence interval
         level
    		 97.5%
         sides
    1-sided
         lower limit
    		 -
         upper limit
    		 0.5407
    Notes
    [2] - Combined Stages 1 and 2
    Statistical analysis title
    		 Mann-Whitney pooled Biomarkers
    Comparison groups
    Placebo v Verum
    Number of subjects included in analysis
    67
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5847
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Mann-Whitney
    Point estimate
    0.5847
    Confidence interval
         level
    		 97.5%
         sides
    1-sided
         lower limit
    		 0.5407
         upper limit
    		 -

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    At each visit
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    Stage 1
    Reporting group description
    		 -

    Reporting group title
    Stage 2
    Reporting group description
    		 -

    Serious adverse events
    		 Stage 1 Stage 2
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 44 (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
    		 Stage 1 Stage 2
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    13 / 28 (46.43%)
    1 / 44 (2.27%)
    Surgical and medical procedures
    Wisdom teeth extraction
    Additional description: Assessed as Not Related
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 44 (2.27%)
         occurrences all number
    0
    1
    Nervous system disorders
    Headache
    Additional description: All assessed as Not Related
         subjects affected / exposed
    5 / 28 (17.86%)
    0 / 44 (0.00%)
         occurrences all number
    5
    0
    Gastrointestinal disorders
    Diarrhea
    Additional description: Assessed as Possible
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 44 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Sore throat
    Additional description: Assessed as Not Related
         subjects affected / exposed
    2 / 28 (7.14%)
    0 / 44 (0.00%)
         occurrences all number
    2
    0
    Tonsillitis
    Additional description: Assessed as Not Related
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 44 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Skin eruption
    Additional description: Assessed as Unlikely
         subjects affected / exposed
    2 / 28 (7.14%)
    0 / 44 (0.00%)
         occurrences all number
    2
    0
    Rash
    Additional description: Acne-like rash, Assessed as Possible
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 44 (2.27%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Muscle strain
    Additional description: Assessed as Not Related
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 44 (0.00%)
         occurrences all number
    1
    0
    Disruption of Clavicle
    Additional description: Assessed as Not Related
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 44 (0.00%)
         occurrences all number
    1
    0
    Effusion
    Additional description: Assessed as Not Related
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 44 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Coryza
    Additional description: Assessed as Not Related
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 44 (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
    09 May 2014
    Within the framework of the pre-planned two-stage procedure according to Bauer-Köhne the following decision was made: - The study will be continued with Stage II. -Due to statistically significant carryover effects the stage II of the trial will be based on a simple parallel group scheme with one phase only (no crossover design). -The measurement of movement induced pain will be skipped due to zerodominated data in stage I. -The recalculated total sample size for stage II is 2 x 22 patients (sample size reassessment according to protocol and final SAP, one phase, no crossover design in stage II). - This decision is established within the framework of the adaptive design features of the two-stage procedure according to Bauer-Köhne and based on the definitions of the protocol and of the final SAP of stage I. - Stage I results and rationale for stage II decision are kept confidential as defined in the protocol (section 7.11) and in the final statistical analysis plan (SAP Stage I Version Final 1.0 from January 20th, 2014, Section 5.4.3).

    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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    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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