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    Clinical Trial Results:
    Reduction of post-traumatic systemic inflammatory response by Phlogenzym® using total hip replacement as a model.

    Summary
    EudraCT number
    		 2016-003078-41
    Trial protocol
    		 CZ  
    Global end of trial date
    15 Oct 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    28 Aug 2022
    First version publication date
    28 Aug 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    MUC-2/16
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    MUCOS Pharma CZ
    Sponsor organisation address
    Uhříněveská 448, Průhonice, Czechia, 25243
    Public contact
    Clinical department, MUCOS Pharma CZ, +420 267 750 003, akocar@mucos.cz
    Scientific contact
    Clinical department, MUCOS Pharma CZ, +420 267 750 003, akocar@mucos.cz
    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
    23 Sep 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    15 Oct 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Oct 2020
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The objective of the study is to explore the validity and clinical feasibility of methods for assessment of perioperative efficacy of Phlogenzym in terms of symptoms of systemic (CRP, hemocoagulation) and local inflammation and short- and mid-term course of rehabilitation.
    Protection of trial subjects
    The subjects were closely monitored during hospitalization and rehabilitation period via physical and laboratory examinations. Occurrence of adverse events was monitored and evaluated at each study visit. The subjects were provided with contact details for emergent situations.
    Background therapy
    		 Planned concomitant medication per protocol involves: • rivaroxaban (Xarelto®) as prevention of thromboembolism • standard analgesics medication • antibiotics i.v. or s.c. to cover the postoperative inflammatory complications per local standard. • Rescue analgesic medication (its consumption evaluated as an efficacy variable)
    Evidence for comparator
    		 An identically appearing placebo was used as comparator
    Actual start date of recruitment
    19 Mar 2019
    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
    Czechia: 34
    Worldwide total number of subjects
    34
    EEA total number of subjects
    34
    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)
    12
    From 65 to 84 years
    22
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study subjects were recruited on orthopedics department in Czech republic from patients considered for planned total hip replacement. The recruitment started on 19MAR2019 and was finished prematurely due to the COVID-19 epidemic on 15OCT2020.

    Pre-assignment
    Screening details
    		 40 patients with primary diagnosis of Non-Inflammatory Degenerative Joint Disease, candidates for total hip replacement, 20 in each treatment group and stratified by gender in 1:1 ratio, were planned to be enrolled to the study

    Period 1
    Period 1 title
    Pre-operation phase
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Assessor
    Blinding implementation details
    The random numbers were generated using SAS in constant block size of 4 subjects; Verum/placebo 1:1.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Phlogenzym
    Arm description
    		 Subjects using active IMP Phlogenzym in a double-blind manner
    Arm type
    		 registered drug

    Investigational medicinal product name
    Phlogenzym
    Investigational medicinal product code
    marketing authorization No. 87/084/95-C
    Other name
    Composition: Trypsinum 48 mg (corresponds to 24 μkat), Bromelaina 90 mg (corresponds to 450 F.I.P.-u.), and Rutosidum trihydricum 100 mg and additional compound
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Dosing of Phlogenzym® or Placebo was fixed-changing according to the following schedule: • preoperative day -4 to -2: 3 tbl b.i.d. (Σ = 18 tbl); • preoperative Day - 1: 3 tbl in the morning (Σ = 3 tbl); • operation day: no dosing; • postoperative Day 1 - 7: 6 tbl b.i.d. (Σ = 84 tbl); • postoperative Day 8 - 42: 5 tbl b.i.d. (Σ = 350 tbl). A total dose of Phlogenzym® / placebo per study is 455 tablets provided all visits take place exactly as scheduled.

    Arm title
    		 Placebo
    Arm description
    		 Subjects treated with placebo
    Arm type
    		 Placebo

    Investigational medicinal product name
    placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Dosing of Phlogenzym® or Placebo was fixed-changing according to the following schedule: • preoperative day -4 to -2: 3 tbl b.i.d. (Σ = 18 tbl); • preoperative Day - 1: 3 tbl in the morning (Σ = 3 tbl); • operation day: no dosing; • postoperative Day 1 - 7: 6 tbl b.i.d. (Σ = 84 tbl); • postoperative Day 8 - 42: 5 tbl b.i.d. (Σ = 350 tbl). A total dose of Phlogenzym® / placebo per study is 455 tablets provided all visits take place exactly as scheduled.

    Number of subjects in period 1
    		Phlogenzym Placebo
    Started
    16
    18
    Completed
    15
    18
    Not completed
    1
    0
         Adverse event, non-fatal
    1
    -
    Period 2
    Period 2 title
    Post-operation phase
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Assessor
    Blinding implementation details
    The random numbers were generated using SAS in constant block size of 4 subjects; Verum/placebo 1:1

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Phlogenzym
    Arm description
    		 Subjects using active IMP Phlogenzym in a double-blind manner
    Arm type
    		 registered drug

    Investigational medicinal product name
    Phlogenzym
    Investigational medicinal product code
    marketing authorization No. 87/084/95-C
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Dosing of Phlogenzym® or Placebo was fixed-changing according to the following schedule: • preoperative day -4 to -2: 3 tbl b.i.d. (Σ = 18 tbl); • preoperative Day - 1: 3 tbl in the morning (Σ = 3 tbl); • operation day: no dosing; • postoperative Day 1 - 7: 6 tbl b.i.d. (Σ = 84 tbl); • postoperative Day 8 - 42: 5 tbl b.i.d. (Σ = 350 tbl). A total dose of Phlogenzym® / placebo per study is 455 tablets provided all visits take place exactly as scheduled.

    Arm title
    		 Placebo
    Arm description
    		 Subjects using placebo in a double-blind manner
    Arm type
    		 Placebo

    Investigational medicinal product name
    placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Dosing of Phlogenzym® or Placebo was fixed-changing according to the following schedule: • preoperative day -4 to -2: 3 tbl b.i.d. (Σ = 18 tbl); • preoperative Day - 1: 3 tbl in the morning (Σ = 3 tbl); • operation day: no dosing; • postoperative Day 1 - 7: 6 tbl b.i.d. (Σ = 84 tbl); • postoperative Day 8 - 42: 5 tbl b.i.d. (Σ = 350 tbl). A total dose of Phlogenzym® / placebo per study is 455 tablets provided all visits take place exactly as scheduled.

    Number of subjects in period 2
    		Phlogenzym Placebo
    Started
    15
    18
    Completed
    10
    18
    Not completed
    5
    0
         Consent withdrawn by subject
    2
    -
         Adverse event, non-fatal
    3
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Phlogenzym
    Reporting group description
    		 Subjects using active IMP Phlogenzym in a double-blind manner

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects treated with placebo

    Reporting group values
    		 Phlogenzym Placebo Total
    Number of subjects
    		 16 18 34
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 4 8 12
        From 65-84 years
    		 12 10 22
        85 years and over
    		 0 0 0
    Gender categorical
    Units: Subjects
        Female
    		 9 10 19
        Male
    		 7 8 15
    Subject analysis sets

    Subject analysis set title
    Per Protocol
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Subjects without major protocol deviation

    Subject analysis sets values
    		 Per Protocol
    Number of subjects
    33
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    12
        From 65-84 years
    21
        85 years and over
    0
    Age continuous
    Units:
        
    ±
    Gender categorical
    Units: Subjects
        Female
    19
        Male
    14

    End points

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    End points reporting groups
    Reporting group title
    Phlogenzym
    Reporting group description
    		 Subjects using active IMP Phlogenzym in a double-blind manner

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects treated with placebo
    Reporting group title
    Phlogenzym
    Reporting group description
    		 Subjects using active IMP Phlogenzym in a double-blind manner

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects using placebo in a double-blind manner

    Subject analysis set title
    Per Protocol
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Subjects without major protocol deviation

    Primary: 2- Local pain at rest (VAS)

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    End point title
    		 2- Local pain at rest (VAS)
    End point description
    Self-assessment of pain on 100 mm scale; The endpoint was evaluated by ANOVA for statistical significance of the interaction of the effect of treatment (grouping variable) and visit (repeating variable), see the attachment.
    End point type
    Primary
    End point timeframe
    Day 1 to Day 7 following operation, average of the morning + evening assessment.
    End point values
    		 Phlogenzym Placebo
    Number of subjects analysed
    15
    18
    Units: cm
    arithmetic mean (standard deviation)
        V2_Day1
    2.8 ± 1.5
    2.0 ± 1.6
        V3_Day2
    2.2 ± 1.9
    2.7 ± 1.7
        V4_Day3
    2.0 ± 1.2
    3.0 ± 1.7
        V5_Day5
    1.9 ± 1.5
    2.5 ± 1.9
        V6_Day7
    1.8 ± 1.7
    1.7 ± 1.4
    Attachments
    		 EP2
    Statistical analysis title
    		 Visual Analogue Scale (VAS)
    Statistical analysis description
    ANOVA with treatment as grouping variable and visit as repeating variable
    Comparison groups
    Phlogenzym v Placebo
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.005 [1]
    Method
    		 ANOVA
    Confidence interval
    Notes
    [1] - Interaction ofd treatment vs. visit No adjustment for multiplicity

    Primary: 9- Local pain at rest (VAS), weekly morning+evening average assessments, Day 7 to Day 42

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    End point title
    		 9- Local pain at rest (VAS), weekly morning+evening average assessments, Day 7 to Day 42
    End point description
    The a\verage of the morning and evening assessment of pain on the 100 mm visual analogue scale, performer by patient The endpoint was evaluated by ANOVA for statistical significance of the interaction of the effect of treatment (grouping variable) and visit (repeating variable), see the attachment.
    End point type
    Primary
    End point timeframe
    Day 7 to Day 42 following operation
    End point values
    		 Phlogenzym Placebo
    Number of subjects analysed
    12
    18
    Units: cm
    arithmetic mean (standard deviation)
        V6_Day 7
    1.8 ± 1.7
    1.7 ± 1.4
        V7_Day 14
    1.0 ± 0.8
    0.8 ± 0.8
        V8_Day 21
    0.7 ± 0.7
    0.9 ± 1.1
        V9_Day 28
    0.3 ± 0.3
    0.5 ± 0.4
        V10_Day 42
    0.2 ± 0.2
    0.4 ± 0.6
    Attachments
    		 Endpoint 9_Local pain at rest
    Statistical analysis title
    		 Local pain at rest (VAS)
    Statistical analysis description
    ANOVA with treatment as grouping variable and visit as repeating variable
    Comparison groups
    Phlogenzym v Placebo
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    P-value
    		 = 0.958
    Method
    		 ANOVA
    Confidence interval
    Notes
    [2] - No interaction of treatment vs. visit No adjustment for multiplicity

    Other pre-specified: 1- CRP postoperative

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    End point title
    		 1- CRP postoperative
    End point description
    CRP in serum
    End point type
    Other pre-specified
    End point timeframe
    Day 1 to Day 7 following operation
    End point values
    		 Phlogenzym Placebo
    Number of subjects analysed
    15
    18
    Units: AUC
        arithmetic mean (standard deviation)
    222 ± 84.6
    327.3 ± 165.9
    Attachments
    		 CRP in serum, Day 1 to Day 7 following operation
    Statistical analysis title
    		 CRP 7 days after operation
    Statistical analysis description
    Analysis of non-monotonous change
    Comparison groups
    Phlogenzym v Placebo
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.034 [3]
    Method
    		 ANOVA
    Confidence interval
    Notes
    [3] - No adjustment for multiplicity

    Other pre-specified: 3- Redon Drain Discharge

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    End point title
    		 3- Redon Drain Discharge
    End point description
    Discharge of drain in the operation wound The endpoint was evaluated by ANOVA for statistical significance of the interaction of the effect of treatment (grouping variable) and visit (repeating variable).
    End point type
    Other pre-specified
    End point timeframe
    Day 1 to Day 7 following operation
    End point values
    		 Phlogenzym Placebo
    Number of subjects analysed
    15
    18
    Units: L.
    arithmetic mean (standard deviation)
        V2_D1
    0.398 ± 0.231
    0.428 ± 0.214
        V3_D2
    0.178 ± 0.144
    0.181 ± 0.151
        Cumulative Redon drain discharge
    0.576 ± 0.290
    0.576 ± 0.609
    Statistical analysis title
    		 Redon Drain Discharge
    Statistical analysis description
    ANOVA with treatment as grouping variable and visit as repeating variable
    Comparison groups
    Phlogenzym v Placebo
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.723 [4]
    Method
    		 ANOVA
    Confidence interval
    Notes
    [4] - No interaction of treatment vs. visit No adjustment for multiplicity

    Other pre-specified: 4- Thigh circumference on Day 1 to Day 7 following operation

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    End point title
    		 4- Thigh circumference on Day 1 to Day 7 following operation
    End point description
    Thigh circumference measured by a flexible ruler The endpoint was evaluated by ANOVA for statistical significance of the interaction of the effect of treatment (grouping variable) and visit (repeating variable), see the attachment.
    End point type
    Other pre-specified
    End point timeframe
    Day 1 to Day 7 following operation
    End point values
    		 Phlogenzym Placebo
    Number of subjects analysed
    15
    18
    Units: cm
    arithmetic mean (standard deviation)
        V2_Day 1
    44.3 ± 7
    48.9 ± 7
        V3_Day 2
    47 ± 5
    49.6 ± 5.8
        V4_Day 3
    47.4 ± 4.9
    50.1 ± 5.6
        V5_Day 5
    48 ± 4.4
    50.7 ± 6
        V6_Day 7
    48.2 ± 5.5
    50.9 ± 6.1
    Attachments
    		 EP4
    Statistical analysis title
    		 Thigh circumference on Day 1 to Day 7
    Statistical analysis description
    ANOVA with treatment as grouping variable and visit as repeating variable
    Comparison groups
    Phlogenzym v Placebo
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.448 [5]
    Method
    		 ANOVA
    Confidence interval
    Notes
    [5] - No interaction od treatment vs. visit No adjustment for multiplicity

    Other pre-specified: 5- Calf circumference on Day 1 to Day 7 following operation

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    End point title
    		 5- Calf circumference on Day 1 to Day 7 following operation
    End point description
    Calf circumference measured by a flexible ruler. The endpoint was evaluated by ANOVA for statistical significance of the interaction of the effect of treatment (grouping variable) and visit (repeating variable), see the attachment.
    End point type
    Other pre-specified
    End point timeframe
    Day 1 to Day 7 following operation
    End point values
    		 Phlogenzym Placebo
    Number of subjects analysed
    15
    18
    Units: cm
    arithmetic mean (standard deviation)
        V2_Day 1
    35.8 ± 3.1
    37.6 ± 4.0
        V3_Day 2
    36.0 ± 3.7
    37.6 ± 3.9
        V4_Day 3
    36.1 ± 3.6
    37.7 ± 3.8
        V5_Day 5
    36.7 ± 4.2
    38.8 ± 4.0
        V6_Day 7
    36.9 ± 4.7
    38.7 ± 4.1
    Attachments
    		 EP5
    Statistical analysis title
    		 Calf circumference on Day 1 to Day 7
    Statistical analysis description
    ANOVA with treatment as grouping variable and visit as repeating variable
    Comparison groups
    Phlogenzym v Placebo
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.776 [6]
    Method
    		 ANOVA
    Confidence interval
    Notes
    [6] - No interaction odf treatment vs. visit No adjustment for multiplicity

    Other pre-specified: 6- Temperature in axilla

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    End point title
    		 6- Temperature in axilla
    End point description
    Body temperature measured in axilla in the morning. The endpoint was evaluated by ANOVA for statistical significance of the interaction of the effect of treatment (grouping variable) and visit (repeating variable), see the attachment.
    End point type
    Other pre-specified
    End point timeframe
    Day 1 to Day 7 following operation
    End point values
    		 Phlogenzym Placebo
    Number of subjects analysed
    15
    18
    Units: °C
    arithmetic mean (standard deviation)
        V2_Day 1
    36.7 ± 0.3
    36.6 ± 0.2
        V3_Day 2
    36.6 ± 0.1
    36.7 ± 0.2
        V4_Day 3
    36.5 ± 0.2
    36.7 ± 0.3
        V5_Day 5
    36.5 ± 0.1
    36.6 ± 0.2
        V6_Day 7
    36.4 ± 0.1
    36.5 ± 0.2
    Attachments
    		 EP6
    Statistical analysis title
    		 Temperature in axilla on Day 1 to Day 7
    Statistical analysis description
    ANOVA with treatment as grouping variable and visit as repeating variable
    Comparison groups
    Phlogenzym v Placebo
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.167 [7]
    Method
    		 ANOVA
    Confidence interval
    Notes
    [7] - No interaction of treatment vs. visit; No adjustment for multiplicity

    Other pre-specified: 7- Knee extension strength, Day 5 and Day 7 after operation

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    End point title
    		 7- Knee extension strength, Day 5 and Day 7 after operation
    End point description
    Maximal isometric knee-extension force measured by means of a hand-held dynamometer The endpoint was evaluated by ANOVA for statistical significance of the interaction of the effect of treatment (grouping variable) and visit (repeating variable), see the attachment.
    End point type
    Other pre-specified
    End point timeframe
    Day 5 to and Day 7 following operation
    End point values
    		 Phlogenzym Placebo
    Number of subjects analysed
    13
    18
    Units: N*m*kg-1
    arithmetic mean (standard deviation)
        V5_D5
    3.0 ± 1.1
    2.9 ± 1.0
        V6_D7
    3.5 ± 1.2
    3.1 ± 1.1
    Attachments
    		 Endpoint 7 Knee extension strenght
    Statistical analysis title
    		 Knee extension strength, D5 and D7 after operation
    Statistical analysis description
    ANOVA with treatment as grouping variable and visit as repeating variable
    Comparison groups
    Phlogenzym v Placebo
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [8]
    P-value
    		 = 0.074
    Method
    		 ANOVA
    Confidence interval
    Notes
    [8] - No interaction of treatment vs. visit No adjustment for multiplicity

    Other pre-specified: 8- Harris Hip Score, performance from Day 7 to Day 42

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    End point title
    		 8- Harris Hip Score, performance from Day 7 to Day 42
    End point description
    Hip function questionnaire which includes items reflecting a patient's ability to perform normal daily activities and the goniometric assessments The endpoint was evaluated by ANOVA for statistical significance of the interaction of the effect of treatment (grouping variable) and visit (repeating variable), see the attachment.
    End point type
    Other pre-specified
    End point timeframe
    Day 7 to Day 42 following operation
    End point values
    		 Phlogenzym Placebo
    Number of subjects analysed
    15
    18
    Units: score
    arithmetic mean (standard deviation)
        V1_screening
    60.1 ± 12.7
    62.2 ± 15.5
        V6_Day 7
    56.0 ± 8.7
    54.3 ± 7.7
        V7_Day 14
    66.5 ± 14.4
    63.0 ± 10.5
        V8_Day 21
    78.1 ± 11.4
    73.7 ± 9.9
        V9_Day 28
    80.4 ± 9.5
    78.4 ± 7.3
        V10_Day 42
    84.6 ± 5.4
    84.1 ± 2.7
    Attachments
    		 Endpoint 8_Harris Hip Score
    Statistical analysis title
    		 Harris Hip Score, performance from Day 7 to Day 42
    Statistical analysis description
    ANOVA with treatment as grouping variable and visit as repeating variable
    Comparison groups
    Phlogenzym v Placebo
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [9]
    P-value
    		 = 0.297
    Method
    		 ANOVA
    Confidence interval
    Notes
    [9] - No interaction of treatment vs. visit No adjustment for multiplicity

    Other pre-specified: 10- Knee Extension Strength of operated leg, weekly assessments, Day 7 to Day 42

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    End point title
    		 10- Knee Extension Strength of operated leg, weekly assessments, Day 7 to Day 42
    End point description
    Maximal isometric knee-extension force measured by means of a hand-held dynamometer The endpoint was evaluated by ANOVA for statistical significance of the interaction of the effect of treatment (grouping variable) and visit (repeating variable), see the attachment.
    End point type
    Other pre-specified
    End point timeframe
    Day 7 to Day 42 following operation
    End point values
    		 Phlogenzym Placebo
    Number of subjects analysed
    12
    18
    Units: Nm/kg
    arithmetic mean (standard deviation)
        V6_Day 7
    199.7 ± 71.3
    186.6 ± 70.3
        V7_Day 14
    210.4 ± 69.8
    220.0 ± 76.7
        V8_Day 21
    248.6 ± 68.6
    251.5 ± 87.0
        V0_Day 28
    277.8 ± 93.0
    266.6 ± 98.0
        V10_Day 42
    298.5 ± 86.9
    284.1 ± 81.2
    Attachments
    		 Endpoint 10_Knee extension strengh
    Statistical analysis title
    		 Knee Extension Strength of operated leg, weekly as
    Statistical analysis description
    ANOVA with treatment as grouping variable and visit as repeating variable
    Comparison groups
    Phlogenzym v Placebo
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [10]
    P-value
    		 = 0.074
    Method
    		 ANOVA
    Confidence interval
    Notes
    [10] - No interaction od of treatment vs. visit No adjustment for multiplicity

    Other pre-specified: 11- Performance in timed Up&Go Test (TUG)

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    End point title
    		 11- Performance in timed Up&Go Test (TUG)
    End point description
    The time (in seconds) it takes the patients to rise from a chair as quickly and safely as possible, walk 3 m to a line drawn on the floor, and return to the chair. The endpoint was evaluated by ANOVA for statistical significance of the interaction of the effect of treatment (grouping variable) and visit (repeating variable), see the attachment.
    End point type
    Other pre-specified
    End point timeframe
    Day 7 to Day 42 following operation
    End point values
    		 Phlogenzym Placebo
    Number of subjects analysed
    12
    18
    Units: seconds
    arithmetic mean (standard deviation)
        V6_Day 7
    22.9 ± 6.2
    23.0 ± 7.5
        V7_Day 14
    14.6 ± 6.7
    18.7 ± 6.7
        V8_Day 21
    12.4 ± 4.5
    15.7 ± 4.5
        V9_Day 28
    12.3 ± 5.6
    14.0 ± 5.6
        V10_Day 42
    9.7 ± 3.4
    11.9 ± 3.4
    Attachments
    		 Endpoint 11_Performance in timed
    Statistical analysis title
    		 Performance in timed Up&Go Test (TUG)
    Statistical analysis description
    ANOVA with treatment as grouping variable and visit as repeating variable
    Comparison groups
    Phlogenzym v Placebo
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [11]
    P-value
    		 = 0.772 [12]
    Method
    		 ANOVA
    Confidence interval
    Notes
    [11] - No interaction of treatment vs. visit No adjustment for multiplicity
    [12] - No interaction od of treatment vs. visit No adjustment for multiplicity

    Other pre-specified: 12- Thigh circumference, weekly assessments, Day 7 to Day 42

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    End point title
    		 12- Thigh circumference, weekly assessments, Day 7 to Day 42
    End point description
    Thigh circumference measured by a flexible ruler. The endpoint was evaluated by ANOVA for statistical significance of the interaction of the effect of treatment (grouping variable) and visit (repeating variable), see the attachment.
    End point type
    Other pre-specified
    End point timeframe
    Day 7 to Day 42 following operation
    End point values
    		 Phlogenzym Placebo
    Number of subjects analysed
    12
    18
    Units: cm
    arithmetic mean (standard deviation)
        V6_Day 7
    48.2 ± 5.5
    50.9 ± 6.1
        V7_Day 14
    45.7 ± 4.5
    49.2 ± 5.8
        V8_Day 21
    44.4 ± 4.7
    48.2 ± 6.1
        V9_Day 28
    44.8 ± 5.8
    47.5 ± 8.3
        V10_Day 42
    45.3 ± 5.9
    48.9 ± 6.2
    Attachments
    		 Untitled (Filename: Endpoint 12_Thigh circumference-weekly assessment.docx)
    Statistical analysis title
    		 Thigh circumference, weekly assessments
    Statistical analysis description
    ANOVA with treatment as grouping variable and visit as repeating variable
    Comparison groups
    Phlogenzym v Placebo
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [13]
    P-value
    		 = 0.074
    Method
    		 ANOVA
    Confidence interval
    Notes
    [13] - No interaction of treatment vs. visit No adjustment for multiplicity

    Other pre-specified: 13- Calf circumference, weekly assessments, Day 7 to Day 42.

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    End point title
    		 13- Calf circumference, weekly assessments, Day 7 to Day 42.
    End point description
    Calf circumference measured by a flexible ruler. The endpoint was evaluated by ANOVA for statistical significance of the interaction of the effect of treatment (grouping variable) and visit (repeating variable), see the attachment.
    End point type
    Other pre-specified
    End point timeframe
    Day 7 to Day 42 following operation
    End point values
    		 Phlogenzym Placebo
    Number of subjects analysed
    12
    18
    Units: cm
    arithmetic mean (standard deviation)
        V6_Day 7
    36.9 ± 4.7
    38.7 ± 4.1
        V7_Day 14
    35.7 ± 3.8
    38.9 ± 4.7
        V8_Day 21
    35.3 ± 3.3
    37.8 ± 3.8
        V9_Day 28
    35.7 ± 4.1
    38.0 ± 3.2
        V10_Day 42
    35.4 ± 3.2
    38.2 ± 4.4
    Attachments
    		 Untitled (Filename: Endpoint 13_Calf circumference-weekly assessment.docx)
    Statistical analysis title
    		 Calf circumference, weekly assessments
    Statistical analysis description
    ANOVA with treatment as grouping variable and visit as repeating variable
    Comparison groups
    Phlogenzym v Placebo
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [14]
    P-value
    		 = 0.074 [15]
    Method
    		 ANOVA
    Confidence interval
    Notes
    [14] - No interaction of treatment vs. visit No adjustment for multiplicity
    [15] - No interaction of treatment vs. visit No adjustment for multiplicity

    Other pre-specified: 14- CGI Change Score by subject, weekly assessments, Day 7 to Day 42

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    End point title
    		 14- CGI Change Score by subject, weekly assessments, Day 7 to Day 42
    End point description
    Self-assessment of global change of the subject´s general condition during the observation period. The endpoint was evaluated by ANOVA for statistical significance of the interaction of the effect of treatment (grouping variable) and visit (repeating variable), see the attachment.
    End point type
    Other pre-specified
    End point timeframe
    Day 7 to Day 42 following operation
    End point values
    		 Phlogenzym Placebo
    Number of subjects analysed
    12
    18
    Units: score
    arithmetic mean (standard deviation)
        V6_Day 7
    1.8 ± 0.6
    1.7 ± 0.8
        V7_Day 14
    1.6 ± 0.9
    1.6 ± 0.7
        V8_Day 21
    1.4 ± 0.7
    1.6 ± 1.0
        V9_day 28
    1.3 ± 0.5
    1.3 ± 0.5
        V10_Day 42
    1.2 ± 0.4
    1.3 ± 0.6
    Statistical analysis title
    		 CGI Change Score by subject, weekly assesment
    Statistical analysis description
    ANOVA with treatment as grouping variable and visit as repeating variable
    Comparison groups
    Phlogenzym v Placebo
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [16]
    P-value
    		 = 0.943
    Method
    		 ANOVA
    Confidence interval
    Notes
    [16] - No interaction of treatment vs. visit No adjustment for multiplicity

    Other pre-specified: 15- CGI Change Score by investigator, weekly assessments

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    End point title
    		 15- CGI Change Score by investigator, weekly assessments
    End point description
    Assessment by the investigator of the global change of the subject´s general condition during the observation period. The endpoint was evaluated by ANOVA for statistical significance of the interaction of the effect of treatment (grouping variable) and visit (repeating variable), see the attachment.
    End point type
    Other pre-specified
    End point timeframe
    Day 7 to Day 42 following operation
    End point values
    		 Phlogenzym Placebo
    Number of subjects analysed
    12
    18
    Units: score
    arithmetic mean (standard deviation)
        V6_Day 7
    1.4 ± 0.5
    1.6 ± 0.7
        V7_Day 14
    1.7 ± 1.0
    1.3 ± 0.5
        V8_Day 21
    1.3 ± 0.5
    1.3 ± 0.6
        V9_Day 28
    1.3 ± 0.5
    1.2 ± 0.4
        V10_Day 42
    1.2 ± 0.4
    1.1 ± 0.3
    Attachments
    		 Untitled (Filename: Endpoint 15_CGI Change Score by Investigator.docx)
    Statistical analysis title
    		 CGI Change Score by investigator
    Statistical analysis description
    ANOVA with treatment as grouping variable and visit as repeating variable
    Comparison groups
    Phlogenzym v Placebo
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [17]
    P-value
    		 = 0.943
    Method
    		 ANOVA
    Confidence interval
    Notes
    [17] - No interaction of treatment vs. visit No adjustment for multiplicity

    Other pre-specified: 16- Cumulative number of the DDDs of rescue analgesics medication, Day 7 to Day 42

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    End point title
    		 16- Cumulative number of the DDDs of rescue analgesics medication, Day 7 to Day 42
    End point description
    Count of DDDs of rescue analgesic medication doses between the study visits.
    End point type
    Other pre-specified
    End point timeframe
    Day 7 to Day 42 following operation
    End point values
    		 Phlogenzym Placebo
    Number of subjects analysed
    11
    18
    Units: DDD
    arithmetic mean (standard deviation)
        V7
    0.7 ± 0.8
    1.5 ± 2.1
        V7+V8
    1.0 ± 1.4
    2.1 ± 2.3
        V7+V8+V9
    1.2 ± 1.5
    2.2 ± 2.3
        V7+V8+V9+V10
    1.4 ± 2.1
    2.2 ± 2.3
    Statistical analysis title
    		 Cumulative number of the DDDs of rescue analgesics
    Statistical analysis description
    Mann-Whitney U-test for cumulative number of the DDDs of rescue analgesics, Day 7 to Day 42
    Comparison groups
    Phlogenzym v Placebo
    Number of subjects included in analysis
    29
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05 [18]
    Method
    		 Mann-Whitney U-test
    Confidence interval
    Notes
    [18] - No adjustment for multiplicity

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Screening till final visit
    Adverse event reporting additional description
    AEs were reported at study visits for all subjects.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Phlogenzym
    Reporting group description
    		 Subjects using active IMP Phlogenzym in a double-blind manner

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects treated with placebo

    Serious adverse events
    		 Phlogenzym Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 18 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Renal and urinary disorders
    Urinary infection
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Phlogenzym Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    15 / 16 (93.75%)
    8 / 18 (44.44%)
    Surgical and medical procedures
    wound discharge increase
         subjects affected / exposed
    3 / 16 (18.75%)
    1 / 18 (5.56%)
         occurrences all number
    3
    1
    Intraoperative blood loss
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Cardiac disorders
    palpitation
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    bradycardia
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    nausea
         subjects affected / exposed
    3 / 16 (18.75%)
    3 / 18 (16.67%)
         occurrences all number
    3
    3
    diarrhea
         subjects affected / exposed
    2 / 16 (12.50%)
    0 / 18 (0.00%)
         occurrences all number
    2
    0
    vomiting
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 18 (5.56%)
         occurrences all number
    1
    1
    Respiratory, thoracic and mediastinal disorders
    pneumonia
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    urticaria
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Renal and urinary disorders
    Infection urinary tract
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    back pain
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Infections and infestations
    Gingivitis
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Metabolism and nutrition disorders
    appetite lost
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 18 (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? No

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    15 Oct 2020
    Termination of recruitment
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    The planned number of subjects was not enrolled because of preliminary recruitment termination due to the COVID situation.
    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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