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    Clinical Trial Results:
    A Randomized, Double-Blind, Double Dummy, Placebo-Controlled, Parallel Group Study to Evaluate the Efficacy of LF-PB 10 mg, 20 mg, and 30 mg to Treat Lymphorrhea Post Axillary Dissection in Breast Cancer

    Summary
    EudraCT number
    		 2012-000114-10
    Trial protocol
    		 IT  
    Global end of trial date
    30 Sep 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    09 Oct 2019
    First version publication date
    09 Oct 2019
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    LF-PB/11/04
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01754285
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Chemi S.p.A
    Sponsor organisation address
    Via dei Lavoratori, 54, Cinisello Balsamo, Italy, 20092
    Public contact
    Clinical Trial Transparency Manager, Chemi S.p.A. , Chemi S.p.A., 0039 02 64431, info@chemi.com
    Scientific contact
    Clinical Trial Transparency Manager, Chemi S.p.A. , Chemi S.p.A., 0039 02 6443 1, info@chemi.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
    19 Mar 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    21 May 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Sep 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the effect of the extended release of octreotide (LF-PB) 10 mg, 20 mg, and 30 mg on time to resolution of lymphorrhea To evaluate safety and tolerability of LF-PB 10 mg, 20 mg, and 30 mg
    Protection of trial subjects
    Informed consent was obtained before a patient was enrolled in the study and before the commencement of any protocol-driven activities. The investigator met with the patient and explained the study in sufficient detail to permit an informed decision to participate. The trial was performed in accordance International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) guidelines, the Declaration of Helsinki, and applicable local regulatory requirements and laws.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    22 Nov 2012
    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
    Italy: 114
    Worldwide total number of subjects
    114
    EEA total number of subjects
    114
    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)
    82
    From 65 to 84 years
    32
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Female patients aged 18 to 80 years inclusive, diagnosed with BC who underwent breast surgery with ALND, body mass index (BMI) ≥18 kg/m2.

    Pre-assignment
    Screening details
    		 Randomization was stratified and balanced by surgery in “conservative surgery + dissection surgery without mammary prosthesis placement (Type I)” versus “dissection surgery with mammary prosthesis placement (Type II)

    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, Data analyst, Carer, Assessor
    Blinding implementation details
    The study was blinded to patients, investigators, and the sponsor. In order to assure/maintain the blind, a double-dummy technique was used.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 LF-PB 10 mg
    Arm description
    		 LF-PB extended-release of octreotide at dose of 10 mg was given as 2 separate bolus IM injections of 1 mL
    Arm type
    		 Experimental

    Investigational medicinal product name
    LF-PB
    Investigational medicinal product code
    Other name
    extended-release octreotide
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intramuscular use
    Dosage and administration details
    LF-PB was administered as 2 separate bolus IM injections of 1 mL. LF-PB 10 mg: 2 injections = placebo + LF-PB 10 mg. 1 injection of LF-PB 10 mg/mL (obtained by reconstituting an octreotide 10 mg red-capped vial) and 1 injection of placebo for LF-PB 20 mg/mL (obtained by reconstituting a placebo 20 mg brown-capped vial).

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Placebo for LF-PB 10 mg octreotide/vial: a vial of lyophilized purified soybean lecithin (10 mg/vial) and hydroxypropyl-beta-cyclodextrin (5 mg/vial). Placebo was given as 2 separate bolus IM injections of 1 mL.

    Arm title
    		 LF-PB 20 mg
    Arm description
    		 LF-PB extended-release of octreotide at dose of 20 mg was given as 2 separate bolus IM injections of 1 mL
    Arm type
    		 Experimental

    Investigational medicinal product name
    LF-PB
    Investigational medicinal product code
    Other name
    extended-release octreotide
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intramuscular use
    Dosage and administration details
    LF-PB was administered as 2 separate bolus IM injections of 1 mL. LF-PB 20 mg: 2 injections = placebo + LF-PB 20 mg. 1 injection of placebo for LF-PB 10 mg/mL (obtained by reconstituting a placebo 10 mg red-capped vial) and 1 injection of LF-PB 20 mg/mL (obtained by reconstituting an octreotide 20 mg brown-capped vial).

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Placebo for LF-PB 20 mg octreotide/vial: a vial of lyophilized purified soybean lecithin (10 mg/vial) and hydroxypropyl-beta-cyclodextrin (5 mg/vial). Placebo was given as 2 separate bolus IM injections of 1 mL.

    Arm title
    		 LF-PB 30 mg
    Arm description
    		 LF-PB extended-release of octreotide at dose of 30 mg was given as 2 separate bolus IM injections of 1 mL.
    Arm type
    		 Experimental

    Investigational medicinal product name
    LF-PB
    Investigational medicinal product code
    Other name
    extended-release octreotide
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intramuscular use
    Dosage and administration details
    LF-PB was administered as 2 separate bolus IM injections of 1 mL. LF-PB 30 mg: 2 injections = LF-PB 10 mg + LF-PB 20 mg 1 injection of LF-PB 10 mg/mL (obtained by reconstituting an octreotide 10 mg red-capped vial) and 1 injection of LF-PB 20 mg/mL (obtained by reconstituting an octreotide 20 mg brown-capped vial).

    Arm title
    		 Placebo
    Arm description
    		 Placebo for LF-PB 10 mg octreotide/vial and 20 mg octreotide/vial was given as 2 separate bolus IM injections of 1 mL
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intramuscular use
    Dosage and administration details
    2 injections of placebo given as 1 injection of placebo for LF-PB 10 mg/mL (obtained by reconstituting a placebo 10 mg red-capped vial) and 1 injection of placebo for LF-PB 20 mg/mL (obtained by reconstituting a placebo 20 mg brown-capped vial).

    Number of subjects in period 1
    		LF-PB 10 mg LF-PB 20 mg LF-PB 30 mg Placebo
    Started
    29
    29
    28
    28
    Completed
    29
    27
    28
    28
    Not completed
    0
    2
    0
    0
         Consent withdrawn by subject
    -
    1
    -
    -
         Lost to follow-up
    -
    1
    -
    -

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    		 -

    Reporting group values
    		 Overall trial Total
    Number of subjects
    		 114 114
    Age categorical
    Age <65 subjects 82 (71.9%) Age >=65 subjects 32 (28.1%)
    Units: Subjects
        Adults (18-64 years)
    		 82 82
        From 65 to 80 years
    		 32 32
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 55.9 ( 12.08 ) -
    Gender categorical
    All females
    Units: Subjects
        Female
    		 114 114
    Subject analysis sets

    Subject analysis set title
    LF-PB 10 mg - ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The ITT population included all patients who were enrolled and randomized into the treatment groups. The evaluable population included all patients who received the due dose of LF-PB or placebo and had at least 1 post-baseline disease assessment (duration of lymphorrhea or volume of lymph).

    Subject analysis set title
    LF-PB 20 mg - ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The ITT population included all patients who were enrolled and randomized into the treatment groups. The evaluable population included all patients who received the due dose of LF-PB or placebo and had at least 1 post-baseline disease assessment (duration of lymphorrhea or volume of lymph).

    Subject analysis set title
    LF-PB 30 mg - ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The ITT population included all patients who were enrolled and randomized into the treatment groups. The evaluable population included all patients who received the due dose of LF-PB or placebo and had at least 1 post-baseline disease assessment (duration of lymphorrhea or volume of lymph).

    Subject analysis set title
    Placebo - ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The ITT population included all patients who were enrolled and randomized into the treatment groups. The evaluable population included all patients who received the due dose of LF-PB or placebo and had at least 1 post-baseline disease assessment (duration of lymphorrhea or volume of lymph).

    Subject analysis set title
    LF-PB 10 mg - PP
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The PP population included 112 patients who received the due dose of LF-PB or placebo and had no major protocol violations; the 2 patients omitted from the PP group had major protocol violations.

    Subject analysis set title
    LF-PB 20 mg - PP
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The PP population included 112 patients who received the due dose of LF-PB or placebo and had no major protocol violations; the 2 patients omitted from the PP group had major protocol violations.

    Subject analysis set title
    LF-PB 30 mg - PP
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The PP population included 112 patients who received the due dose of LF-PB or placebo and had no major protocol violations; the 2 patients omitted from the PP group had major protocol violations.

    Subject analysis set title
    Placebo - PP
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The PP population included 112 patients who received the due dose of LF-PB or placebo and had no major protocol violations; the 2 patients omitted from the PP group had major protocol violations.

    Subject analysis set title
    LF-PB 10 mg - PK
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Pk population

    Subject analysis set title
    LF-PB 20 mg - PK
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    PK population

    Subject analysis set title
    LF-PB 30 mg - PK
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    PK population

    Subject analysis sets values
    		 LF-PB 10 mg - ITT LF-PB 20 mg - ITT LF-PB 30 mg - ITT Placebo - ITT LF-PB 10 mg - PP LF-PB 20 mg - PP LF-PB 30 mg - PP Placebo - PP LF-PB 10 mg - PK LF-PB 20 mg - PK LF-PB 30 mg - PK
    Number of subjects
    29
    29
    28
    28
    29
    28
    27
    28
    27
    28
    28
    Age categorical
    Age <65 subjects 82 (71.9%) Age >=65 subjects 32 (28.1%)
    Units: Subjects
        Adults (18-64 years)
    18
    19
    23
    22
    18
    19
    23
    22
        From 65 to 80 years
    11
    10
    5
    6
    11
    9
    4
    6
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    57.6 ( 12.81 )
    59.4 ( 10.11 )
    52.7 ( 11.48 )
    53.7 ( 13.06 )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    Gender categorical
    All females
    Units: Subjects
        Female
    29
    29
    28
    28
    29
    28
    27
    28

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    LF-PB 10 mg
    Reporting group description
    		 LF-PB extended-release of octreotide at dose of 10 mg was given as 2 separate bolus IM injections of 1 mL

    Reporting group title
    LF-PB 20 mg
    Reporting group description
    		 LF-PB extended-release of octreotide at dose of 20 mg was given as 2 separate bolus IM injections of 1 mL

    Reporting group title
    LF-PB 30 mg
    Reporting group description
    		 LF-PB extended-release of octreotide at dose of 30 mg was given as 2 separate bolus IM injections of 1 mL.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo for LF-PB 10 mg octreotide/vial and 20 mg octreotide/vial was given as 2 separate bolus IM injections of 1 mL

    Subject analysis set title
    LF-PB 10 mg - ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The ITT population included all patients who were enrolled and randomized into the treatment groups. The evaluable population included all patients who received the due dose of LF-PB or placebo and had at least 1 post-baseline disease assessment (duration of lymphorrhea or volume of lymph).

    Subject analysis set title
    LF-PB 20 mg - ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The ITT population included all patients who were enrolled and randomized into the treatment groups. The evaluable population included all patients who received the due dose of LF-PB or placebo and had at least 1 post-baseline disease assessment (duration of lymphorrhea or volume of lymph).

    Subject analysis set title
    LF-PB 30 mg - ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The ITT population included all patients who were enrolled and randomized into the treatment groups. The evaluable population included all patients who received the due dose of LF-PB or placebo and had at least 1 post-baseline disease assessment (duration of lymphorrhea or volume of lymph).

    Subject analysis set title
    Placebo - ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The ITT population included all patients who were enrolled and randomized into the treatment groups. The evaluable population included all patients who received the due dose of LF-PB or placebo and had at least 1 post-baseline disease assessment (duration of lymphorrhea or volume of lymph).

    Subject analysis set title
    LF-PB 10 mg - PP
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The PP population included 112 patients who received the due dose of LF-PB or placebo and had no major protocol violations; the 2 patients omitted from the PP group had major protocol violations.

    Subject analysis set title
    LF-PB 20 mg - PP
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The PP population included 112 patients who received the due dose of LF-PB or placebo and had no major protocol violations; the 2 patients omitted from the PP group had major protocol violations.

    Subject analysis set title
    LF-PB 30 mg - PP
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The PP population included 112 patients who received the due dose of LF-PB or placebo and had no major protocol violations; the 2 patients omitted from the PP group had major protocol violations.

    Subject analysis set title
    Placebo - PP
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The PP population included 112 patients who received the due dose of LF-PB or placebo and had no major protocol violations; the 2 patients omitted from the PP group had major protocol violations.

    Subject analysis set title
    LF-PB 10 mg - PK
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Pk population

    Subject analysis set title
    LF-PB 20 mg - PK
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    PK population

    Subject analysis set title
    LF-PB 30 mg - PK
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    PK population

    Primary: Duration of lymphorrhea

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    End point title
    		 Duration of lymphorrhea
    End point description
    Duration of lymphorrhea was evaluated by collecting lymph by a drain placed in the axillary fossa during the first 15 days after surgery. At the resolution of lymphorrhea or, in any case, 15 days after surgery, the drain was removed. On the first day, the drain was emptied and the lymph discarded. From that moment, the pocket drain containing lymph was emptied at the same time of the day into a graduated container. If the volume of lymph collected was ≥50 mL the patient discarded the lymph. If it was <50 mL, the patient kept the lymph in the graduated container, covered the container with the provided cap, and stored it in the refrigerator. If the following day the volume was still <50 mL, the same procedure was followed and the 2 containers were taken to the site to allow the investigator to confirm the lymphorrhea resolution. If the volume on the 2nd day was ≥50 mL, the patient discarded all the lymph and continued the daily collection.
    End point type
    Primary
    End point timeframe
    Throughout the 12-week study: Day 1 (first day after surgery), Discharge (Visit 2), Visit 3-6 (2 times a week until Day 15 after surgery), Day 22 (Visit 7), Day 29 (Visit 8), Day 56 (Visit 9), Day 84 (Visit 10).
    End point values
    		 LF-PB 10 mg - ITT LF-PB 20 mg - ITT LF-PB 30 mg - ITT Placebo - ITT
    Number of subjects analysed
    29
    29
    28
    28
    Units: days
        median (confidence interval 95%)
    9.0 (6.0 to 13.0)
    8.0 (5.0 to 14.0)
    7.0 (6.0 to 12.0)
    6.0 (5.0 to 7.0)
    Statistical analysis title
    		 LF-PB 10 mg vs Placebo
    Statistical analysis description
    This is a primary analysis of the primary efficacy endpoint
    Comparison groups
    LF-PB 10 mg - ITT v Placebo - ITT
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.2502
    Method
    		 Logrank
    Confidence interval
    Notes
    [1] - The duration of lymphorrhea was evaluated using the Kaplan-Meier method and comparisons among the treatment groups were performed using log-rank test.
    Statistical analysis title
    		 LF-PB 20 mg vs Placebo
    Statistical analysis description
    This is a primary analysis of the primary efficacy endpoint.
    Comparison groups
    LF-PB 20 mg - ITT v Placebo - ITT
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    P-value
    		 = 0.2152
    Method
    		 Logrank
    Confidence interval
    Notes
    [2] - The duration of lymphorrhea was evaluated using the Kaplan-Meier method and comparisons among the treatment groups were performed using log-rank test.
    Statistical analysis title
    		 LF-PB 30 mg vs Placebo
    Statistical analysis description
    This is a primary analysis of the primary efficacy endpoint.
    Comparison groups
    LF-PB 30 mg - ITT v Placebo - ITT
    Number of subjects included in analysis
    56
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 = 0.4637
    Method
    		 Logrank
    Confidence interval
    Notes
    [3] - The duration of lymphorrhea was evaluated using the Kaplan-Meier method and comparisons among the treatment groups were performed using log-rank test.
    Statistical analysis title
    		 LF-PB 20 mg vs LF-PB 10 mg
    Statistical analysis description
    This is a primary analysis of the primary efficacy endpoint.
    Comparison groups
    LF-PB 10 mg - ITT v LF-PB 20 mg - ITT
    Number of subjects included in analysis
    58
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [4]
    P-value
    		 = 0.5453
    Method
    		 Logrank
    Confidence interval
    Notes
    [4] - The duration of lymphorrhea was evaluated using the Kaplan-Meier method and comparisons among the treatment groups were performed using log-rank test.
    Statistical analysis title
    		 LF-PB 30 mg vs LF-PB 10 mg
    Statistical analysis description
    This is a primary analysis of the primary efficacy endpoint.
    Comparison groups
    LF-PB 10 mg - ITT v LF-PB 30 mg - ITT
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    P-value
    		 = 0.4815
    Method
    		 Logrank
    Confidence interval
    Notes
    [5] - The duration of lymphorrhea was evaluated using the Kaplan-Meier method and comparisons among the treatment groups were performed using log-rank test.
    Statistical analysis title
    		 LF-PB 30 mg vs LF-PB 20 mg
    Statistical analysis description
    This is a primary analysis of the primary efficacy endpoint.
    Comparison groups
    LF-PB 30 mg - ITT v LF-PB 20 mg - ITT
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [6]
    P-value
    		 = 0.2424
    Method
    		 Logrank
    Confidence interval
    Notes
    [6] - The duration of lymphorrhea was evaluated using the Kaplan-Meier method and comparisons among the treatment groups were performed using log-rank test.

    Secondary: Daily volume of lymph collected when drain is in place

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    End point title
    		 Daily volume of lymph collected when drain is in place
    End point description
    the daily volume of lymph collected when the drain was in place is reported daily by the patient. Only data of the 2nd and the 15th Days are reported. For the full timepoints data see the table attached
    End point type
    Secondary
    End point timeframe
    Daily From Day 1 (first day after surgery) until Day 15 (when the drain is removed)
    End point values
    		 LF-PB 10 mg - ITT LF-PB 20 mg - ITT LF-PB 30 mg - ITT Placebo - ITT
    Number of subjects analysed
    29 [7]
    29 [8]
    28 [9]
    28 [10]
    Units: mL
    arithmetic mean (standard deviation)
        Day 2
    118.6 ( 68.70 )
    105.7 ( 68.25 )
    98.8 ( 52.77 )
    91.1 ( 55.68 )
        Day 15
    68.0 ( 23.87 )
    67.5 ( 23.30 )
    92.5 ( 29.86 )
    70.0 ( 55.83 )
    Attachments
    		 Daily volume of lymph
    Notes
    [7] - n=5 at Day 15
    [8] - n=8 at Day 15
    [9] - n=4 at Day 15
    [10] - n=4 at Day 15
    Statistical analysis title
    		 LF-PB 10 mg vs Placebo
    Comparison groups
    LF-PB 10 mg - ITT v Placebo - ITT
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [11]
    P-value
    		 = 0.0827
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [11] - For secondary efficacy endpoints, the daily volume of lymph collected was analyzed using a mixed model repeated measures (MMRM) approach. The model included treatment group, surgery type, site (pooled), time, and treatment by time interaction as fixed effects. A continuous covariate for number of removed lymph nodes was also included.
    Statistical analysis title
    		 LF-PB 20 mg vs Placebo
    Comparison groups
    Placebo - ITT v LF-PB 20 mg - ITT
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [12]
    P-value
    		 = 0.0802
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [12] - For secondary efficacy endpoints, the daily volume of lymph collected was analyzed using a mixed model repeated measures (MMRM) approach. The model included treatment group, surgery type, site (pooled), time, and treatment by time interaction as fixed effects. A continuous covariate for the number of removed lymph nodes was also included.
    Statistical analysis title
    		 LF-PB 30 mg vs Placebo
    Comparison groups
    Placebo - ITT v LF-PB 30 mg - ITT
    Number of subjects included in analysis
    56
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [13]
    P-value
    		 = 0.1428
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [13] - For secondary efficacy endpoints, the daily volume of lymph collected was analyzed using a mixed model repeated measures (MMRM) approach. The model included treatment group, surgery type, site (pooled), time, and treatment by time interaction as fixed effects. A continuous covariate for number of removed lymph nodes was also included.
    Statistical analysis title
    		 LF-PB 20 mg vs LF-PB 10 mg
    Comparison groups
    LF-PB 20 mg - ITT v LF-PB 10 mg - ITT
    Number of subjects included in analysis
    58
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [14]
    P-value
    		 = 0.9504
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [14] - For secondary efficacy endpoints, the daily volume of lymph collected was analyzed using a mixed model repeated measures (MMRM) approach. The model included treatment group, surgery type, site (pooled), time, and treatment by time interaction as fixed effects. A continuous covariate for number of removed lymph nodes was also included.
    Statistical analysis title
    		 LF-PB 30 mg vs LF-PB 10 mg
    Comparison groups
    LF-PB 10 mg - ITT v LF-PB 30 mg - ITT
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [15]
    P-value
    		 = 0.751
    Method
    		 ANCOVA
    Confidence interval
         level
    		 95%
    Notes
    [15] - For secondary efficacy endpoints, the daily volume of lymph collected was analyzed using a mixed model repeated measures (MMRM) approach. The model included treatment group, surgery type, site (pooled), time, and treatment by time interaction as fixed effects. A continuous covariate for number of removed lymph nodes was also included.
    Statistical analysis title
    		 LF-PB 30 mg vs LF-PB 20 mg
    Comparison groups
    LF-PB 30 mg - ITT v LF-PB 20 mg - ITT
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [16]
    P-value
    		 = 0.7192
    Method
    		 ANCOVA
    Confidence interval
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -
    Notes
    [16] - For secondary efficacy endpoints, the daily volume of lymph collected was analyzed using a mixed model repeated measures (MMRM) approach. The model included treatment group, surgery type, site (pooled), time, and treatment by time interaction as fixed effects. A continuous covariate for number of removed lymph nodes was also included.

    Secondary: Time to drain removal

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    End point title
    		 Time to drain removal
    End point description
    Time to drain removal is defined as: Date of drain removal – surgery date. In the situation where the patient had the drain removed for another reason other than lymphorrhea resolution and the patient had not reached day 15 at the time of removal, the patient was included in the analysis as not having had the event (drain removal) and was censored at the time the drain was removed.
    End point type
    Secondary
    End point timeframe
    From Day 0 (day of surgery) to day of drain removal.
    End point values
    		 LF-PB 10 mg - ITT LF-PB 20 mg - ITT LF-PB 30 mg - ITT Placebo - ITT
    Number of subjects analysed
    27
    27
    27
    26
    Units: days
        median (confidence interval 95%)
    10.0 (7.0 to 14.0)
    9.0 (7.0 to 13.0)
    8.5 (7.0 to 13.0)
    7.0 (6.0 to 8.0)
    Statistical analysis title
    		 LF-PB 10 mg vs Placebo
    Comparison groups
    Placebo - ITT v LF-PB 10 mg - ITT
    Number of subjects included in analysis
    53
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [17]
    P-value
    		 = 0.0652
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.554
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.269
         upper limit
    		 1.038
    Notes
    [17] - Time to drain removal was analyzed using a Cox proportional hazards regression with the following covariates: number of removed lymph nodes, treatment group, surgery type and site (pooled).
    Statistical analysis title
    		 LF-PB 20 mg vs Placebo
    Comparison groups
    Placebo - ITT v LF-PB 20 mg - ITT
    Number of subjects included in analysis
    53
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [18]
    P-value
    		 = 0.2071
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.668
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.357
         upper limit
    		 1.25
    Notes
    [18] - Time to drain removal was analyzed using a Cox proportional hazards regression with the following covariates: number of removed lymph nodes, treatment group, surgery type and site (pooled).
    Statistical analysis title
    		 LF-PB 30 mg vs Placebo
    Comparison groups
    Placebo - ITT v LF-PB 30 mg - ITT
    Number of subjects included in analysis
    53
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [19]
    P-value
    		 = 0.5151
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.818
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.446
         upper limit
    		 1.5
    Notes
    [19] - Time to drain removal was analyzed using a Cox proportional hazards regression with the following covariates: number of removed lymph nodes, treatment group, surgery type and site (pooled).
    Statistical analysis title
    		 LF-PB 20 mg vs LF-PB 10 mg
    Comparison groups
    LF-PB 10 mg - ITT v LF-PB 20 mg - ITT
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [20]
    P-value
    		 = 0.5081
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.205
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.693
         upper limit
    		 2.097
    Notes
    [20] - Time to drain removal was analyzed using a Cox proportional hazards regression with the following covariates: number of removed lymph nodes, treatment group, surgery type and site (pooled).
    Statistical analysis title
    		 LF-PB 30 mg vs LF-PB 10 mg
    Comparison groups
    LF-PB 10 mg - ITT v LF-PB 30 mg - ITT
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [21]
    P-value
    		 = 0.178
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.476
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.838
         upper limit
    		 2.599
    Notes
    [21] - Time to drain removal was analyzed using a Cox proportional hazards regression with the following covariates: number of removed lymph nodes, treatment group, surgery type and site (pooled).
    Statistical analysis title
    		 LF-PB 30 mg vs LF-PB 20 mg
    Comparison groups
    LF-PB 20 mg - ITT v LF-PB 30 mg - ITT
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [22]
    P-value
    		 = 0.4889
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.224
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.69
         upper limit
    		 2.17
    Notes
    [22] - Time to drain removal was analyzed using a Cox proportional hazards regression with the following covariates: number of removed lymph nodes, treatment group, surgery type and site (pooled).

    Secondary: Percentage of responders at Day 4 after surgery

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    End point title
    		 Percentage of responders at Day 4 after surgery
    End point description
    Responders are patients for whom lymphorrhea was reduced to <50 mL in 2 consecutive daily collections.
    End point type
    Secondary
    End point timeframe
    Day 4 after surgery
    End point values
    		 LF-PB 10 mg - ITT LF-PB 20 mg - ITT LF-PB 30 mg - ITT Placebo - ITT
    Number of subjects analysed
    29
    29
    28
    28
    Units: percentage
    number (not applicable)
        Yes
    28.6
    17.2
    24.1
    25.0
        No
    71.4
    82.8
    75.9
    75.0
    Statistical analysis title
    		 LF-PB 10 mg vs Placebo
    Comparison groups
    LF-PB 10 mg - ITT v Placebo - ITT
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [23]
    P-value
    		 = 0.1578
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.341
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.077
         upper limit
    		 1.517
    Notes
    [23] - The percentage of responders at Day 4 was analyzed using logistic regression with the following explanatory variables: number of the removed lymph nodes, treatment group, surgery type, and site (pooled).
    Statistical analysis title
    		 LF-PB 20 mg vs Placebo
    Comparison groups
    Placebo - ITT v LF-PB 20 mg - ITT
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [24]
    P-value
    		 = 0.5659
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.664
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.164
         upper limit
    		 2.684
    Notes
    [24] - The percentage of responders at Day 4 was analyzed using logistic regression with the following explanatory variables: number of the removed lymph nodes, treatment group, surgery type, and site (pooled).
    Statistical analysis title
    		 LF-PB 30 mg vs Placebo
    Comparison groups
    Placebo - ITT v LF-PB 30 mg - ITT
    Number of subjects included in analysis
    56
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [25]
    P-value
    		 = 0.6439
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.729
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.191
         upper limit
    		 2.78
    Notes
    [25] - The percentage of responders at Day 4 was analyzed using logistic regression with the following explanatory variables: number of the removed lymph nodes, treatment group, surgery type, and site (pooled).
    Statistical analysis title
    		 LF-PB 20 mg vs LF-PB 10 mg
    Comparison groups
    LF-PB 10 mg - ITT v LF-PB 20 mg - ITT
    Number of subjects included in analysis
    58
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [26]
    P-value
    		 = 0.3617
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.946
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.465
         upper limit
    		 8.135
    Notes
    [26] - The percentage of responders at Day 4 was analyzed using logistic regression with the following explanatory variables: number of the removed lymph nodes, treatment group, surgery type, and site (pooled).
    Statistical analysis title
    		 LF-PB 30 mg vs LF-PB 10 mg
    Comparison groups
    LF-PB 10 mg - ITT v LF-PB 30 mg - ITT
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [27]
    P-value
    		 = 0.308
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.136
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.496
         upper limit
    		 9.196
    Notes
    [27] - The percentage of responders at Day 4 was analyzed using logistic regression with the following explanatory variables: number of the removed lymph nodes, treatment group, surgery type, and site (pooled).
    Statistical analysis title
    		 LF-PB 30 mg vs LF-PB 20 mg
    Comparison groups
    LF-PB 30 mg - ITT v LF-PB 20 mg - ITT
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [28]
    P-value
    		 = 0.8949
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.098
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.275
         upper limit
    		 4.388
    Notes
    [28] - The percentage of responders at Day 4 was analyzed using logistic regression with the following explanatory variables: number of the removed lymph nodes, treatment group, surgery type, and site (pooled).

    Secondary: Percentage of responders at 1 week after surgery

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    End point title
    		 Percentage of responders at 1 week after surgery
    End point description
    Responders are patients for whom lymphorrhea was reduced to <50 mL in 2 consecutive daily collections.
    End point type
    Secondary
    End point timeframe
    at 1 week after surgery
    End point values
    		 LF-PB 10 mg - ITT LF-PB 20 mg - ITT LF-PB 30 mg - ITT Placebo - ITT
    Number of subjects analysed
    29
    29
    28
    28
    Units: percentage
    number (not applicable)
        Yes
    44.8
    48.3
    53.6
    75.0
        No
    55.2
    51.7
    46.4
    25.0
    Statistical analysis title
    		 LF-PB 10 mg vs Placebo
    Comparison groups
    LF-PB 10 mg - ITT v Placebo - ITT
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [29]
    P-value
    		 = 0.0168
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.207
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.057
         upper limit
    		 0.752
    Notes
    [29] - Percentage of responders at 1 week was analyzed by logistic regression with the following explanatory variables: number of the removed lymph nodes, treatment group, surgery type, and site (pooled).
    Statistical analysis title
    		 LF-PB 20 mg vs Placebo
    Comparison groups
    Placebo - ITT v LF-PB 20 mg - ITT
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [30]
    P-value
    		 = 0.0565
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.298
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.086
         upper limit
    		 1.034
    Notes
    [30] - Percentage of responders at 1 week was analyzed by logistic regression with the following explanatory variables: number of the removed lymph nodes, treatment group, surgery type, and site (pooled).
    Statistical analysis title
    		 LF-PB 30 mg vs Placebo
    Comparison groups
    Placebo - ITT v LF-PB 30 mg - ITT
    Number of subjects included in analysis
    56
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [31]
    P-value
    		 = 0.1053
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.357
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.102
         upper limit
    		 1.242
    Notes
    [31] - Percentage of responders at 1 week was analyzed by logistic regression with the following explanatory variables: number of the removed lymph nodes, treatment group, surgery type, and site (pooled).
    Statistical analysis title
    		 LF-PB 20 mg vs LF-PB 10 mg
    Comparison groups
    LF-PB 20 mg - ITT v LF-PB 10 mg - ITT
    Number of subjects included in analysis
    58
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [32]
    P-value
    		 = 0.5243
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.439
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.469
         upper limit
    		 4.414
    Notes
    [32] - Percentage of responders at 1 week was analyzed by logistic regression with the following explanatory variables: number of the removed lymph nodes, treatment group, surgery type, and site (pooled).
    Statistical analysis title
    		 LF-PB 30 mg vs LF-PB 10 mg
    Comparison groups
    LF-PB 10 mg - ITT v LF-PB 30 mg - ITT
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [33]
    P-value
    		 = 0.3491
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.724
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.551
         upper limit
    		 5.392
    Notes
    [33] - Percentage of responders at 1 week was analyzed by logistic regression with the following explanatory variables: number of the removed lymph nodes, treatment group, surgery type, and site (pooled).
    Statistical analysis title
    		 LF-PB 30 mg vs LF-PB 20 mg
    Comparison groups
    LF-PB 30 mg - ITT v LF-PB 20 mg - ITT
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [34]
    P-value
    		 = 0.7579
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.198
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.38
         upper limit
    		 3.778
    Notes
    [34] - Percentage of responders at 1 week was analyzed by logistic regression with the following explanatory variables: number of the removed lymph nodes, treatment group, surgery type, and site (pooled).

    Secondary: Percentage of responders at drain removal

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    End point title
    		 Percentage of responders at drain removal
    End point description
    Responders are patients for whom lymphorrhea was reduced to <50 mL in 2 consecutive daily collections.
    End point type
    Secondary
    End point timeframe
    At Day 15
    End point values
    		 LF-PB 10 mg - ITT LF-PB 20 mg - ITT LF-PB 30 mg - ITT Placebo - ITT
    Number of subjects analysed
    29
    29
    28
    28
    Units: Percentage
    number (not applicable)
        Yes
    79.3
    69.0
    85.7
    89.3
        No
    20.7
    31.0
    14.3
    10.7
    Statistical analysis title
    		 LF-PB 10 mg vs Placebo
    Comparison groups
    Placebo - ITT v LF-PB 10 mg - ITT
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [35]
    P-value
    		 = 0.2019
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.352
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.071
         upper limit
    		 1.75
    Notes
    [35] - Percentage of responders at drain removal was analyzed by logistic regression with the following explanatory variables: number of the removed lymph nodes, treatment group, surgery type, and site (pooled).
    Statistical analysis title
    		 LF-PB 20 mg vs Placebo
    Comparison groups
    Placebo - ITT v LF-PB 20 mg - ITT
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [36]
    P-value
    		 = 0.0387
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.195
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.042
         upper limit
    		 0.919
    Notes
    [36] - Percentage of responders at drain removal was analyzed by logistic regression with the following explanatory variables: number of the removed lymph nodes, treatment group, surgery type, and site (pooled).
    Statistical analysis title
    		 LF-PB 30 mg vs Placebo
    Comparison groups
    Placebo - ITT v LF-PB 30 mg - ITT
    Number of subjects included in analysis
    56
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [37]
    P-value
    		 = 0.7929
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.151
         upper limit
    		 4.233
    Notes
    [37] - Percentage of responders at drain removal was analyzed by logistic regression with the following explanatory variables: number of the removed lymph nodes, treatment group, surgery type, and site (pooled).
    Statistical analysis title
    		 LF-PB 20 mg vs LF-PB 10 mg
    Comparison groups
    LF-PB 20 mg - ITT v LF-PB 10 mg - ITT
    Number of subjects included in analysis
    58
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [38]
    P-value
    		 = 0.3678
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.555
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.154
         upper limit
    		 1.999
    Notes
    [38] - Percentage of responders at drain removal was analyzed by logistic regression with the following explanatory variables: number of the removed lymph nodes, treatment group, surgery type, and site (pooled).
    Statistical analysis title
    		 LF-PB 30 mg vs LF-PB 10 mg
    Comparison groups
    LF-PB 10 mg - ITT v LF-PB 30 mg - ITT
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [39]
    P-value
    		 = 0.2731
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.272
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.524
         upper limit
    		 9.864
    Notes
    [39] - Percentage of responders at drain removal was analyzed by logistic regression with the following explanatory variables: number of the removed lymph nodes, treatment group, surgery type, and site (pooled).
    Statistical analysis title
    		 LF-PB 30 mg vs LF-PB 20 mg
    Comparison groups
    LF-PB 30 mg - ITT v LF-PB 20 mg - ITT
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [40]
    P-value
    		 = 0.0557
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    4.095
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.966
         upper limit
    		 17.35
    Notes
    [40] - Percentage of responders at drain removal was analyzed by logistic regression with the following explanatory variables: number of the removed lymph nodes, treatment group, surgery type, and site (pooled).

    Secondary: Percentage of patients with complications related to lymphorrea

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    End point title
    		 Percentage of patients with complications related to lymphorrea
    End point description
    A Cochran-Armitage test was used to detect if there was an association between increasing dose level of LF-PB and number of patients reporting complications related to lymphorrhea.
    End point type
    Secondary
    End point timeframe
    Throughout the 12-week study: Day 1 (first day after surgery), Discharge (Visit 2), Visit 3-6 (2 times a week until Day 15 after surgery), Day 22 (Visit 7), Day 29 (Visit 8), Day 56 (Visit 9), Day 84 (Visit 10).
    End point values
    		 LF-PB 10 mg - ITT LF-PB 20 mg - ITT LF-PB 30 mg - ITT Placebo - ITT
    Number of subjects analysed
    29
    29
    28
    28
    Units: percentage
    number (not applicable)
        Yes
    0.0
    0.0
    3.6
    0.0
        No
    100.0
    100.0
    96.4
    100.0
    No statistical analyses for this end point

    Secondary: Cmax

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    End point title
    		 Cmax
    End point description
    Cmax = maximal plasma concentration
    End point type
    Secondary
    End point timeframe
    Throughout the 12-week study: Day 0 (surgery), Day 1 (first day after surgery), Discharge (Visit 2), Visit 3-6 (2 times a week until Day 15 after surgery), Day 22 (Visit 7), Day 29 (Visit 8).
    End point values
    		 LF-PB 10 mg - PK LF-PB 20 mg - PK LF-PB 30 mg - PK
    Number of subjects analysed
    27
    28
    28
    Units: ng/mL
        arithmetic mean (standard deviation)
    3.36 ( 2.56 )
    10.9 ( 7.17 )
    11.3 ( 5.27 )
    No statistical analyses for this end point

    Secondary: Tmax

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    End point title
    		 Tmax
    End point description
    tmax = time of maximum plasma concentration
    End point type
    Secondary
    End point timeframe
    Throughout the 12-week study: Day 0 (surgery), Day 1 (first day after surgery), Discharge (Visit 2), Visit 3-6 (2 times a week until Day 15 after surgery), Day 22 (Visit 7), Day 29 (Visit 8).
    End point values
    		 LF-PB 10 mg - PK LF-PB 20 mg - PK LF-PB 30 mg - PK
    Number of subjects analysed
    27
    28
    28
    Units: hours
        median (full range (min-max))
    6 (2.95 to 207)
    24 (0 to 168)
    6 (3 to 141)
    No statistical analyses for this end point

    Secondary: AUClast

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    End point title
    		 AUClast
    End point description
    AUClast = area under the plasma concentration time up to the last detectable concentration
    End point type
    Secondary
    End point timeframe
    Throughout the 12-week study: Day 0 (surgery), Day 1 (first day after surgery), Discharge (Visit 2), Visit 3-6 (2 times a week until Day 15 after surgery), Day 22 (Visit 7), Day 29 (Visit 8).
    End point values
    		 LF-PB 10 mg - PK LF-PB 20 mg - PK LF-PB 30 mg - PK
    Number of subjects analysed
    27
    28
    28
    Units: ng⋅hr/mL
        arithmetic mean (standard deviation)
    495 ( 260 )
    1310 ( 593 )
    1480 ( 542 )
    No statistical analyses for this end point

    Secondary: AUC0-inf

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    End point title
    		 AUC0-inf
    End point description
    AUC∞ = area under the concentration-time curve up to the last quantified measurement
    End point type
    Secondary
    End point timeframe
    Throughout the 12-week study: Day 0 (surgery), Day 1 (first day after surgery), Discharge (Visit 2), Visit 3-6 (2 times a week until Day 15 after surgery), Day 22 (Visit 7), Day 29 (Visit 8).
    End point values
    		 LF-PB 10 mg - PK LF-PB 20 mg - PK LF-PB 30 mg - PK
    Number of subjects analysed
    14
    22
    24
    Units: ng*hour/mL
        arithmetic mean (standard deviation)
    548 ( 214 )
    1400 ( 570 )
    1580 ( 547 )
    No statistical analyses for this end point

    Secondary: t1/2z

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    End point title
    		 t1/2z
    End point description
    t1/2z = apparent terminal half-life
    End point type
    Secondary
    End point timeframe
    Throughout the 12-week study: Day 0 (surgery), Day 1 (first day after surgery), Discharge (Visit 2), Visit 3-6 (2 times a week until Day 15 after surgery), Day 22 (Visit 7), Day 29 (Visit 8).
    End point values
    		 LF-PB 10 mg - PK LF-PB 20 mg - PK LF-PB 30 mg - PK
    Number of subjects analysed
    14
    22
    24
    Units: hours
        arithmetic mean (standard deviation)
    72.5 ( 39.3 )
    91.1 ( 51.0 )
    92.4 ( 63.7 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Throughout the study, from Screening to Visit 1/Early Termination visit for patients who discontinued early.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15.0
    Reporting groups
    Reporting group title
    LF-PB 10 mg - Safety population
    Reporting group description
    		 The safety population included patients who have received at least one dose of the trial treatment.

    Reporting group title
    LF-PB 20 mg - Safety population
    Reporting group description
    		 The safety population included patients who have received at least one dose of the trial treatment.

    Reporting group title
    LF-PB 30 mg -Safety population
    Reporting group description
    		 The safety population included patients who have received at least one dose of the trial treatment.

    Reporting group title
    Placebo - Safety population
    Reporting group description
    		 The safety population included patients who have received at least one dose of the trial treatment.

    Serious adverse events
    		 LF-PB 10 mg - Safety population LF-PB 20 mg - Safety population LF-PB 30 mg -Safety population Placebo - Safety population
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 29 (3.45%)
    1 / 29 (3.45%)
    2 / 28 (7.14%)
    3 / 28 (10.71%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    Incision site haemorrhage
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 29 (0.00%)
    0 / 28 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Multi-organ failure
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 29 (0.00%)
    0 / 28 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 29 (0.00%)
    0 / 28 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 29 (0.00%)
    0 / 28 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Device related infection
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 29 (0.00%)
    0 / 28 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 29 (3.45%)
    1 / 28 (3.57%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyperglycemia
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 29 (0.00%)
    1 / 28 (3.57%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 LF-PB 10 mg - Safety population LF-PB 20 mg - Safety population LF-PB 30 mg -Safety population Placebo - Safety population
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    17 / 29 (58.62%)
    20 / 29 (68.97%)
    14 / 28 (50.00%)
    18 / 28 (64.29%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    2 / 29 (6.90%)
    3 / 29 (10.34%)
    5 / 28 (17.86%)
    5 / 28 (17.86%)
         occurrences all number
    2
    4
    8
    6
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 29 (3.45%)
    1 / 29 (3.45%)
    3 / 28 (10.71%)
    4 / 28 (14.29%)
         occurrences all number
    1
    1
    4
    5
    Injury, poisoning and procedural complications
    Post procedural haematoma
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 29 (0.00%)
    0 / 28 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    2
    0
    0
    1
    Procedural pain
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 29 (3.45%)
    2 / 28 (7.14%)
    4 / 28 (14.29%)
         occurrences all number
    0
    1
    2
    6
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 29 (0.00%)
    1 / 28 (3.57%)
    2 / 28 (7.14%)
         occurrences all number
    0
    0
    1
    2
    Lymphoedema
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 29 (0.00%)
    0 / 28 (0.00%)
    2 / 28 (7.14%)
         occurrences all number
    0
    0
    0
    2
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 29 (3.45%)
    1 / 29 (3.45%)
    1 / 28 (3.57%)
    4 / 28 (14.29%)
         occurrences all number
    1
    1
    2
    5
    Hyperpyrexia
         subjects affected / exposed
    0 / 29 (0.00%)
    2 / 29 (6.90%)
    2 / 28 (7.14%)
    1 / 28 (3.57%)
         occurrences all number
    0
    2
    2
    1
    Injection site erythema
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 29 (0.00%)
    1 / 28 (3.57%)
    2 / 28 (7.14%)
         occurrences all number
    0
    0
    1
    2
    Injection site pain
         subjects affected / exposed
    4 / 29 (13.79%)
    2 / 29 (6.90%)
    3 / 28 (10.71%)
    6 / 28 (21.43%)
         occurrences all number
    4
    2
    3
    6
    Pyrexia
         subjects affected / exposed
    2 / 29 (6.90%)
    3 / 29 (10.34%)
    0 / 28 (0.00%)
    6 / 28 (21.43%)
         occurrences all number
    2
    4
    0
    7
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 29 (0.00%)
    2 / 29 (6.90%)
    0 / 28 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Diarrhoea
         subjects affected / exposed
    3 / 29 (10.34%)
    7 / 29 (24.14%)
    2 / 28 (7.14%)
    0 / 28 (0.00%)
         occurrences all number
    3
    8
    3
    0
    Nausea
         subjects affected / exposed
    3 / 29 (10.34%)
    3 / 29 (10.34%)
    1 / 28 (3.57%)
    7 / 28 (25.00%)
         occurrences all number
    5
    4
    1
    8
    Vomiting
         subjects affected / exposed
    2 / 29 (6.90%)
    1 / 29 (3.45%)
    1 / 28 (3.57%)
    2 / 28 (7.14%)
         occurrences all number
    2
    1
    1
    2
    Skin and subcutaneous tissue disorders
    Erythema
         subjects affected / exposed
    0 / 29 (0.00%)
    2 / 29 (6.90%)
    0 / 28 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Musculoskeletal and connective tissue disorders
    Myalgia
         subjects affected / exposed
    0 / 29 (0.00%)
    2 / 29 (6.90%)
    0 / 28 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Infections and infestations
    Influenza
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 29 (0.00%)
    2 / 28 (7.14%)
    2 / 28 (7.14%)
         occurrences all number
    0
    0
    2
    2
    Postoperative wound infection
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 29 (0.00%)
    2 / 28 (7.14%)
    1 / 28 (3.57%)
         occurrences all number
    0
    0
    3
    2
    Urinary tract infection
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 29 (0.00%)
    0 / 28 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    2
    0
    0
    1
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    2 / 29 (6.90%)
    2 / 29 (6.90%)
    1 / 28 (3.57%)
    2 / 28 (7.14%)
         occurrences all number
    2
    2
    1
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 Sep 2012
    The original protocol (Version 1, Dated 02 Jul 2012) was amended on 06 Sep 2012 (Version 2) to include the following changes. •Following guidance from coordinating EC, the evaluation of the safety and tolerability of LF-PB was updated as primary rather than secondary objective. •Exclusion criteria #8 was removed from the protocol as this criteria was appropriate for the oral medication but not for drugs with subcutaneous administration. Furthermore, the diseases already listed in the protocol were the most important. •Per coordinating EC’s suggestions to include additional information about the safety of study drug, a new section, Background Information, on the safety of LF-PB in clinical trials, available as of September 2012, was included in the protocol. •To clarify the procedures that occur prior to and following surgery, Visit 1 was divided into 2 visits: randomization (Day 0) and Visit 1 (Day 1). •To obtain additional safety data on LF-PB, liver function tests were updated to include total bilirubin, AST, and ALT. •Section 3.3.7, Prior and Concomitant Illnesses and Treatments, was updated to clarify that chemotherapy cannot be initiated until resolution of lymphorrhea per the protocol definition. •The protocol was updated to also clarify that the patients should collect lymph from drain throughout the period prior to Day 15 regardless of date of discharge and that the duration of lymphorrhea persists when the volume of lymph is ≥50 mL rather than>50 mL.
    12 Feb 2013
    The protocol dated 06 Sep 2012 (Version 2) was amended on 12 Feb 2013 (Version 3.0) to include the following major changes: •The Exclusion Criteria in the synopsis and main body was elaborated as follows for clarity: Criterion 1 - Presence of any of the following conditions: a. Previous axillary surgery on the same armpit undergoing surgery in this study b. Previous chemotherapy or radiotherapy within 5 years from study drug administration c. Recurrent BC on the same breast undergoing surgery in this study d. Hypothyroidism. If a patient is being administered Euritox/Levothyroxine (or analogues) and levels of T3, T4, and TSH are confirmed to be within the normal ranges at screening, the patient can be enrolled in this study. Criterion 2 - History of radiotherapy on the breast or armpit undergoing surgery in this study Criterion 9 - Corticosteroid treatment on a long-term basis. Acute use of corticosteroids to prevent hypersensitivity reactions before surgery is not considered an exclusion criterion.

    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.
    No limitations or caveats to this summary of results.
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