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    Clinical Trial Results:
    Open-label, multi-center, randomized parallel group study to assess the pharmacokinetic (PK) profile of Zoreline 10.8 mg goserelin subcutaneous implant (test product, Novalon S.A.) and of Zoladex® LA 10.8 mg goserelin subcutaneous implant (reference product, AstraZeneca UK Limited) in male patients with prostate cancer

    Summary
    EudraCT number
    		 2015-001756-30
    Trial protocol
    		 BG  
    Global end of trial date
    08 Mar 2017

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

    Trial information

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    Trial identification
    Sponsor protocol code
    No0002-C201
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novalon S.A.
    Sponsor organisation address
    Rue Saint Georges, 5-7, Liège, Belgium, 4000
    Public contact
    Clinical Study Leader, Novalon S.A., +32 43492822, Clinical.Trials@mithra.com
    Scientific contact
    Clinical Study Leader, Novalon S.A., +32 43492822, Clinical.Trials@mithra.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    20 Dec 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Mar 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Characterize the goserelin plasma concentration profile based on primary PK endpoints from Day 1 to 85 (1 treatment cycle, Day 85 represents the end of treatment), after injection with Zoreline 10.8 mg or Zoladex® LA 10.8 mg subcutaneous implant in male patients with prostate cancer. Luteinizing hormone (LH)-releasing hormone (LHRH) agonists are potential therapies for prostate cancer. These agents block LH secretion and reduce testosterone concentrations to anorchid levels - a process also known as “medical orchiectomy”. A depot preparation of a LHRH agonist, goserelin (Zoladex® LA 10.8 mg subcutaneous implant, AstraZeneca UK Limited, UK) may be administered subcutaneously every 3 months. A new formulation of goserelin (Zoreline 10.8 mg subcutaneous implant) with a similar quantitative and qualitative composition to Zoladex® was developed by Novalon S.A., Belgium. A single subcutaneous implant dose of the 2 products was evaluated in this parallel arm study.
    Protection of trial subjects
    The study was conducted under the ethical principles that have their origin in the Declaration of Helsinki, the laws and regulations of the country in which the study was conducted, and the current version of the International Council on Harmonisation (ICH) E6 Good Clinical Practice (GCP) Consolidated Guidance. Appropriate procedures for coding were applied to ensure the anonymity of the subjects on all trial related documents. Safety was assessed by the monitoring of AEs volunteered, observed, and elicited by general questioning in a non-suggestive manner throughout the study. All new clinically relevant abnormalities, significant changes according to the opinion of the Investigator were reported as AEs in the case report form. Vital signs, electrocardiograms, clinical laboratory test results were monitored.
    Background therapy
    		 Background therapy -- Not applicable
    Evidence for comparator
    		 Evidence for comparators -- Not applicable LIST OF ABBREVIATIONS USED IN THIS STUDY ENTRY AE=Adverse event; AUC(0-t)=Area under the plasma concentration-time curve from administration to the last measurable concentration at time t in both groups; AUC(0-tcom)= Area under the plasma concentration-time curve from administration to the last common measurable time-point within all patients in both groups; BMI=Body mass index; C(day85)=Goserelin plasma concentration at the end of the treatment period; Cmax=Maximum measured plasma concentration; Cmin=Minimum measured post-dose plasma concentration; ECOG=Eastern Cooperative Oncology Group; GLSM=Geometric least square means; ITT=Intent-to-treat. The ITT set was composed of all subjects who received study drug and had at least 1 post-dose assessment; LH=Luteinizing hormone; LHRH=Luteinizing hormone releasing hormone; tmax=Time until the maximum measured goserelin plasma concentration is reached; PD=Pharmacodynamic; PP=Per Protocol. The PP set included all patients of the intention-to-treat (ITT) population who completed the treatment period, excluding patients with major protocol deviations, i.e. deviations that have major impact on the assessments of goserelin plasma concentrations. These included, but are not limited to, predefined not allowed concomitant medications and delayed visit schedules; PK=Pharmacokinetic; TEAE=Treatment-emergent adverse events; UPLC-MS/MS=Ultra-performance liquid chromatography method with triple quadrupole tandem mass spectrometric detection;
    Actual start date of recruitment
    29 Jan 2016
    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
    Poland: 15
    Country: Number of subjects enrolled
    Bulgaria: 43
    Worldwide total number of subjects
    58
    EEA total number of subjects
    58
    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
    45
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 Male adult subjects (18 years or older), with confirmed diagnosis of prostate adenocarcinoma were screened according to the study inclusion and exclusion criteria. Overall, 58 subjects were randomized (N=29 subjects in the test treatment group and N=29 subjects in the reference group).

    Pre-assignment
    Screening details
    		 At the screening visit (4 to 14 days before first study treatment administration), inclusion/exclusion criteria were assessed; subjects selected to enter in the study had ECOG score of ≤ 2 measured at screening. All subjects signed an Informed Consent Form prior to any study-related procedures were performed.

    Period 1
    Period 1 title
    Treatment (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Zoreline (Test product)
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Zoreline
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Implant
    Routes of administration
    Implantation
    Dosage and administration details
    Name : Zoreline Formulation: Goserelin acetate Strength of dosage form: 10.8 mg subcutaneous implant The test product was administered subcutaneously once, on Day 1 of the study, into the anterior abdominal wall below the navel line using an aseptic technique by a trained member of the clinical team. The use of local anaesthetic was allowed if this was part of local practice.

    Arm title
    		 Zoladex (Reference product)
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Zoladex® LA
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Implant
    Routes of administration
    Implantation
    Dosage and administration details
    Name : Zoladex® LA Formulation: Goserelin acetate Strength of dosage form: 10.8 mg subcutaneous implant The reference product was administered subcutaneously once, on Day 1 of the study, into the anterior abdominal wall below the navel line using an aseptic technique by a trained member of the clinical team. The use of local anaesthetic was allowed if this was part of local practice.

    Number of subjects in period 1
    		Zoreline (Test product) Zoladex (Reference product)
    Started
    29
    29
    Completed
    28
    26
    Not completed
    1
    3
         Consent withdrawn by subject
    1
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Zoreline (Test product)
    Reporting group description
    		 -

    Reporting group title
    Zoladex (Reference product)
    Reporting group description
    		 -

    Reporting group values
    		 Zoreline (Test product) Zoladex (Reference product) Total
    Number of subjects
    		 29 29 58
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 6 6 12
        From 65-84 years
    		 23 22 45
        85 years and over
    		 0 1 1
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 70.3 ( 6.81 ) 71.1 ( 8.29 ) -
    Gender categorical
    Units: Subjects
        Male
    		 29 29 58
    ECOG scale of Performance Status
    The ECOG performance status is a scale used to assess how a patient's disease is progressing, assess how the disease affects the daily living abilities of the patient, and determine appropriate treatment and prognosis Grade: 0 – Asymptomatic. Fully active. 1 – Symptomatic, but completely ambulatory. 2 – Symptomatic, <50% in bed during the day. 3 – Symptomatic, >50% in bed, but not bedbound. 4 – Bed bound. Completely disabled. ECOG=Eastern Cooperative Oncology Group
    Units: Subjects
        Grade 0
    		 23 21 44
        Grade 1
    		 6 7 13
        Grade 2
    		 0 1 1
        Grade 3
    		 0 0 0
        Grade 4
    		 0 0 0
    Body Mass Index (BMI)
    Units: (kg/m2
        arithmetic mean (standard deviation)
    		 26.67 ( 3.65 ) 27.16 ( 3.58 ) -
    Subject analysis sets

    Subject analysis set title
    Zoreline (Test product) - PP set
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Included all subjects who received Zoreline (Test product), had at least 1 post-dose assessment, and completed the treatment period, excluding patients with major protocol deviations, i.e. deviations that have major impact on the assessments of goserelin plasma concentrations. These included, but are not limited to, predefined not allowed concomitant medications and delayed visit schedules.

    Subject analysis set title
    Zoladex (Reference product) - PP set
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Included all subjects who received Zoladex (Reference product), had at least 1 post-dose assessment, and completed the treatment period, excluding patients with major protocol deviations, i.e. deviations that have major impact on the assessments of goserelin plasma concentrations. These included, but are not limited to, predefined not allowed concomitant medications and delayed visit schedules.

    Subject analysis sets values
    		 Zoreline (Test product) - PP set Zoladex (Reference product) - PP set
    Number of subjects
    27
    24
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    6
    6
        From 65-84 years
    21
    17
        85 years and over
    1
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    70.0 ( 6.97 )
    70.6 ( 8.5 )
    Gender categorical
    Units: Subjects
        Male
    27
    24
    ECOG scale of Performance Status
    The ECOG performance status is a scale used to assess how a patient's disease is progressing, assess how the disease affects the daily living abilities of the patient, and determine appropriate treatment and prognosis Grade: 0 – Asymptomatic. Fully active. 1 – Symptomatic, but completely ambulatory. 2 – Symptomatic, <50% in bed during the day. 3 – Symptomatic, >50% in bed, but not bedbound. 4 – Bed bound. Completely disabled. ECOG=Eastern Cooperative Oncology Group
    Units: Subjects
        Grade 0
    22
    18
        Grade 1
    5
    5
        Grade 2
    1
        Grade 3
        Grade 4
    Body Mass Index (BMI)
    Units: (kg/m2
        arithmetic mean (standard deviation)
    26.99 ( 3.56 )
    26.86 ( 3.34 )

    End points

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    End points reporting groups
    Reporting group title
    Zoreline (Test product)
    Reporting group description
    		 -

    Reporting group title
    Zoladex (Reference product)
    Reporting group description
    		 -

    Subject analysis set title
    Zoreline (Test product) - PP set
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Included all subjects who received Zoreline (Test product), had at least 1 post-dose assessment, and completed the treatment period, excluding patients with major protocol deviations, i.e. deviations that have major impact on the assessments of goserelin plasma concentrations. These included, but are not limited to, predefined not allowed concomitant medications and delayed visit schedules.

    Subject analysis set title
    Zoladex (Reference product) - PP set
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Included all subjects who received Zoladex (Reference product), had at least 1 post-dose assessment, and completed the treatment period, excluding patients with major protocol deviations, i.e. deviations that have major impact on the assessments of goserelin plasma concentrations. These included, but are not limited to, predefined not allowed concomitant medications and delayed visit schedules.

    Primary: 1_PK -- Cmax -- Maximum measured goserelin plasma concentration

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    End point title
    		 1_PK -- Cmax -- Maximum measured goserelin plasma concentration
    End point description
    Cmax: Maximum measured goserelin plasma concentration. Ultra-performance liquid chromatography method with triple quadrupole tandem mass spectrometric detection (UPLC-MS/MS) was used for the quantification of goserelin in human plasma. For all pharmacokinetic (PK) parameters, the results are presented for the per protocol (PP) population. The PP included all patients of the intention-to-treat (ITT) population who completed the treatment period, excluding patients with major protocol deviations, i.e. deviations that have major impact on the assessments of goserelin plasma concentrations. These included, but are not limited to, predefined not allowed concomitant medications and delayed visit schedules. Patients were analysed based on the treatment that they actually received. The intent-to-treat (ITT) population was composed of all subjects who received study drug and had at least 1 post-dose assessment.
    End point type
    Primary
    End point timeframe
    Blood sampling for evaluation of PK parameters of goserelin was performed: Day 1 -30 min (Baseline), and after implant injection on Day 1 at 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12 h; and on Day 2, 3, 4, 8, 15, 22, 29, 36, 43, 50, 57, 71, 78, 85 (per 24h)
    End point values
    		 Zoreline (Test product) Zoladex (Reference product)
    Number of subjects analysed
    27 [1]
    24 [2]
    Units: µg/L
        arithmetic mean (standard deviation)
    18.826 ( 7.9783 )
    7.951 ( 2.6393 )
    Notes
    [1] - Per Protocol Population
    [2] - Per Protocol Population
    Statistical analysis title
    		 1_Cmax
    Statistical analysis description
    ANCOVA was performed on log-transformed PK parameters AUC0-t, AUC0-tcom, and Cmax. The ANCOVA model included the treatment and body weight as fixed effects. From each ANCOVA, the geometric least square means (GLSM) adjusted for body weight with its 95% CI were computed for each treatment, by taking the anti-log of the least square means (LSM) adjusted for body weight and its 95% CI provided by the model. Ratio of GLSM (test product vs reference product) and its 90% CI are presented.
    Comparison groups
    Zoreline (Test product) v Zoladex (Reference product)
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    Method
    		 ANCOVA
    Parameter type
    		 Ratio of GLSM
    Point estimate
    2.32
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1.91
         upper limit
    		 2.81
    Notes
    [3] - The study in male patient with prostate cancer does not aim to demonstrate the PK bioequivalence, but to further support the safety comparison between of Zoreline 10.8 mg and Zoladex® LA 10.8 mg, as part of regulatory documentation.

    Primary: 2_PK -- AUC(0-t) -- Area under the goserelin plasma concentration curve -- To the last measurable concentration

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    End point title
    		 2_PK -- AUC(0-t) -- Area under the goserelin plasma concentration curve -- To the last measurable concentration
    End point description
    AUC(0-t): Area under the goserelin plasma concentration curve from administration to the last measurable concentration at time t in both groups.
    End point type
    Primary
    End point timeframe
    Blood sampling for evaluation of PK parameters of goserelin was performed: Day 1 -30 min (Baseline), and after implant injection on Day 1 at 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12 h; and on Day 2, 3, 4, 8, 15, 22, 29, 36, 43, 50, 57, 71, 78, 85 (per 24h)
    End point values
    		 Zoreline (Test product) Zoladex (Reference product)
    Number of subjects analysed
    27 [4]
    24 [5]
    Units: µg.h/L
        arithmetic mean (standard deviation)
    904.400 ( 350.9048 )
    954.980 ( 322.8665 )
    Notes
    [4] - Per Protocol Population
    [5] - Per Protocol Population
    Statistical analysis title
    		 AUC(0-t)
    Statistical analysis description
    Please see description for statistical analysis in end point 1.
    Comparison groups
    Zoreline (Test product) v Zoladex (Reference product)
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 other [6]
    Method
    		 ANCOVA
    Parameter type
    		 Ratio of GLSM
    Point estimate
    0.92
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.77
         upper limit
    		 1.12
    Notes
    [6] - This study in male patient with prostate cancer does not aim to demonstrate the PK bioequivalence, but to further support the safety comparison between of Zoreline 10.8 mg and Zoladex® LA 10.8 mg, as part of regulatory documentation.

    Primary: 3_PK -- AUC(0-tcom) -- Area under the goserelin plasma concentration curve -- Last common measurable time-point for all patients in both groups

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    End point title
    		 3_PK -- AUC(0-tcom) -- Area under the goserelin plasma concentration curve -- Last common measurable time-point for all patients in both groups
    End point description
    AUC(0-tcom): Area under the goserelin plasma concentration curve from administration to the last common measurable time-point within all patients in both groups.
    End point type
    Primary
    End point timeframe
    Blood sampling for evaluation of PK parameters of goserelin was performed: Day 1 -30 min (Baseline), and after implant injection on Day 1 at 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12 h; and on Day 2, 3, 4, 8, 15, 22, 29, 36, 43, 50, 57, 71, 78, 85 (per 24h)
    End point values
    		 Zoreline (Test product) Zoladex (Reference product)
    Number of subjects analysed
    27 [7]
    24 [8]
    Units: µg.h/L
        arithmetic mean (standard deviation)
    904.400 ( 350.9048 )
    954.980 ( 322.8665 )
    Notes
    [7] - Per Protocol Population
    [8] - Per Protocol Population
    Statistical analysis title
    		 AUC(0-tcom)
    Statistical analysis description
    Please see description for statistical analysis in end point 1.
    Comparison groups
    Zoladex (Reference product) v Zoreline (Test product)
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 other [9]
    Method
    		 ANCOVA
    Parameter type
    		 Ratio of GLSM
    Point estimate
    0.92
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.77
         upper limit
    		 1.12
    Notes
    [9] - This study in male patient with prostate cancer does not aim to demonstrate the PK bioequivalence, but to further support the safety comparison between of Zoreline 10.8 mg and Zoladex® LA 10.8 mg, as part of regulatory documentation

    Secondary: 4_PK -- tmax -- Time until the maximum measured goserelin plasma concentration

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    End point title
    		 4_PK -- tmax -- Time until the maximum measured goserelin plasma concentration
    End point description
    tmax: Time until the maximum measured goserelin plasma concentration is reached.
    End point type
    Secondary
    End point timeframe
    Blood sampling for evaluation of PK parameters of goserelin was performed: Day 1 -30 min (Baseline), and after implant injection on Day 1 at 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12 h; and on Day 2, 3, 4, 8, 15, 22, 29, 36, 43, 50, 57, 71, 78, 85 (per 24h)
    End point values
    		 Zoreline (Test product) Zoladex (Reference product)
    Number of subjects analysed
    27 [10]
    24 [11]
    Units: hour
        median (full range (min-max))
    2.50 (1.42 to 8.00)
    4.00 (1.45 to 12.00)
    Notes
    [10] - Per Protocol Population
    [11] - Per Protocol Population
    No statistical analyses for this end point

    Secondary: 5_PK -- C(Day85) -- Goserelin plasma concentration -- At the end of the treatment

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    End point title
    		 5_PK -- C(Day85) -- Goserelin plasma concentration -- At the end of the treatment
    End point description
    C(day85): Goserelin plasma concentration at the end of the treatment period.
    End point type
    Secondary
    End point timeframe
    Blood sampling for evaluation of PK parameters of goserelin was performed: Day 1 -30 min (Baseline), and after implant injection on Day 1 at 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12 h; and on Day 2, 3, 4, 8, 15, 22, 29, 36, 43, 50, 57, 71, 78, 85 (per 24h)
    End point values
    		 Zoreline (Test product) Zoladex (Reference product)
    Number of subjects analysed
    27 [12]
    24 [13]
    Units: µg/L
        arithmetic mean (standard deviation)
    0.105 ( 0.0928 )
    0.161 ( 0.1030 )
    Notes
    [12] - Per Protocol Population
    [13] - Per Protocol Population
    No statistical analyses for this end point

    Secondary: 6_PK -- Cmin -- Minimum post-dose goserelin plasma concentration

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    End point title
    		 6_PK -- Cmin -- Minimum post-dose goserelin plasma concentration
    End point description
    Cmin: Minimum post-dose goserelin plasma concentration.
    End point type
    Secondary
    End point timeframe
    Blood sampling for evaluation of PK parameters of goserelin was performed: Day 1 -30 min (Baseline), and after implant injection on Day 1 at 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12 h; and on Day 2, 3, 4, 8, 15, 22, 29, 36, 43, 50, 57, 71, 78, 85 (per 24h)
    End point values
    		 Zoreline (Test product) Zoladex (Reference product)
    Number of subjects analysed
    27 [14]
    24 [15]
    Units: µg/L
        arithmetic mean (standard deviation)
    0.043 ( 0.0345 )
    0.102 ( 0.0647 )
    Notes
    [14] - Per Protocol Population
    [15] - Per Protocol Population
    No statistical analyses for this end point

    Secondary: 7_PD -- Cmax -- Plasma Testosterone

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    End point title
    		 7_PD -- Cmax -- Plasma Testosterone
    End point description
    Cmax -- Plasma Testosterone -- Maximum measured testosterone plasma concentration. The administered medication (Goserelin) is used to suppress production of the sex hormones, including testosterone and is used particularly in the treatment of prostate cancer. Total testosterone was measured in plasma, using ultra-performance liquid chromatography method with triple quadrupole tandem mass spectrometric detection (UPLC-MS/MS). For all pharmacodynamic (PD) parameters, the results are presented for the per protocol (PP) population.
    End point type
    Secondary
    End point timeframe
    Blood sampling for evaluation of PD parameters of testosterone was performed at: Day 1 -30 min (Baseline), and after implant injection on Day 1 after 12 h; on Day 2, 3, 4, 8, 15, 22, 29, 36, 43, 50, 57, 71, 78, 85 (per 24h interval).
    End point values
    		 Zoreline (Test product) Zoladex (Reference product)
    Number of subjects analysed
    27 [16]
    24 [17]
    Units: µg/L
        arithmetic mean (standard deviation)
    7.839 ( 2.4317 )
    7.063 ( 2.5346 )
    Notes
    [16] - Per Protocol Population
    [17] - Per Protocol Population
    No statistical analyses for this end point

    Secondary: 8_PD -- Cmin -- Plasma Testosterone

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    End point title
    		 8_PD -- Cmin -- Plasma Testosterone
    End point description
    Cmin -- Plasma Testosterone -- Minimum measured testosterone plasma concentration. For further information, please see the description in end point 7.
    End point type
    Secondary
    End point timeframe
    Blood sampling for evaluation of PD parameters of testosterone was performed at: Day 1 -30 min (Baseline), and after implant injection on Day 1 after 12 h; on Day 2, 3, 4, 8, 15, 22, 29, 36, 43, 50, 57, 71, 78, 85 (per 24h interval).
    End point values
    		 Zoreline (Test product) Zoladex (Reference product)
    Number of subjects analysed
    27 [18]
    24 [19]
    Units: µg/L
        arithmetic mean (standard deviation)
    0.112 ( 0.0856 )
    0.095 ( 0.0534 )
    Notes
    [18] - Per Protocol Population
    [19] - Per Protocol Population
    No statistical analyses for this end point

    Secondary: 9_PD -- AUC(0-t) -- Testosterone

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    End point title
    		 9_PD -- AUC(0-t) -- Testosterone
    End point description
    AUC(0-t) -- Testosterone -- Area under the testosterone plasma concentration curve from administration to the last measurable concentration at time t in both groups. For further information, please see the description in end point 7.
    End point type
    Secondary
    End point timeframe
    Blood sampling for evaluation of PD parameters of testosterone was performed at: Day 1 -30 min (Baseline), and after implant injection on Day 1 after 12 h; on Day 2, 3, 4, 8, 15, 22, 29, 36, 43, 50, 57, 71, 78, 85 (per 24h interval).
    End point values
    		 Zoreline (Test product) Zoladex (Reference product)
    Number of subjects analysed
    27 [20]
    24 [21]
    Units: µg.h/L
        arithmetic mean (standard deviation)
    2411.927 ( 1348.5835 )
    1739.898 ( 516.1524 )
    Notes
    [20] - Per Protocol Population
    [21] - Per Protocol Population
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were reported from the time of patient informed consent signature to study completion or discontinuation.
    Adverse event reporting additional description
    All AEs starting on or after the time study drug implantation were classified as treatment-emergent adverse events (TEAEs).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15.1
    Reporting groups
    Reporting group title
    Zoreline (Test)
    Reporting group description
    		 -

    Reporting group title
    Zoladex (Reference)
    Reporting group description
    		 -

    Serious adverse events
    		 Zoreline (Test) Zoladex (Reference)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 29 (3.45%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Nervous system disorders
    ischemic stroke
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Zoreline (Test) Zoladex (Reference)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    18 / 29 (62.07%)
    12 / 29 (41.38%)
    Investigations
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 29 (3.45%)
         occurrences all number
    0
    1
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 29 (3.45%)
         occurrences all number
    0
    1
    Body temperature increased
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 29 (3.45%)
         occurrences all number
    0
    1
    C-reactive protein increased
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 29 (3.45%)
         occurrences all number
    0
    1
    Injury, poisoning and procedural complications
    Arthropod bite
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 29 (3.45%)
         occurrences all number
    0
    1
    Vascular disorders
    Hot flush
         subjects affected / exposed
    8 / 29 (27.59%)
    5 / 29 (17.24%)
         occurrences all number
    8
    5
    Hypertension
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 29 (3.45%)
    1 / 29 (3.45%)
         occurrences all number
    1
    2
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    Pyrexia
         subjects affected / exposed
    2 / 29 (6.90%)
    1 / 29 (3.45%)
         occurrences all number
    2
    1
    Eye disorders
    Eye haemorrhage
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 29 (3.45%)
         occurrences all number
    0
    1
    Diarrhoea
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Nasal congestion
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 29 (3.45%)
         occurrences all number
    0
    1
    Oropharyngeal pain
         subjects affected / exposed
    3 / 29 (10.34%)
    2 / 29 (6.90%)
         occurrences all number
    3
    2
    Skin and subcutaneous tissue disorders
    Erythema
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 29 (3.45%)
         occurrences all number
    0
    1
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    3 / 29 (10.34%)
    0 / 29 (0.00%)
         occurrences all number
    4
    0
    Haematuria
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Joint swelling
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 29 (3.45%)
         occurrences all number
    0
    1
    Pain in extremity
         subjects affected / exposed
    1 / 29 (3.45%)
    1 / 29 (3.45%)
         occurrences all number
    1
    1
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 29 (3.45%)
         occurrences all number
    0
    1
    Sinusitis
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 29 (3.45%)
         occurrences all number
    0
    1
    Viral infection
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0

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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? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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