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Clinical Trial Results:
Open-label, multi-center, randomized parallel group study to assess the pharmacokinetic (PK) profile of Zoreline 3.6 mg goserelin subcutaneous implant (test product, Novalon S.A.) and of Zoladex® 3.6 mg goserelin subcutaneous implant (reference product, AstraZeneca UK Limited), in women with confirmed endometriosis

Summary
EudraCT number	2015-005124-25
Trial protocol	BG
Global end of trial date	26 Oct 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
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

No0001-C201

ISRCTN number

US NCT number

WHO universal trial number (UTN)

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

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

10 Jul 2018

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

26 Oct 2017

Was the trial ended prematurely?

Main objective of the trial

Characterize the goserelin plasma concentration pharmacokinetic profile from Day 1 to 29 of Period 1 and Day 1 (coinciding with Day 29 of Period 1) to Day 17 of Period 2 (2 treatment cycles whereas Day 29 of Period 2 represents the end of treatment), after injection with Zoreline 3.6 mg or Zoladex® 3.6 mg subcutaneous implant in female subjects with confirmed endometriosis. The study was required for a marketing authorization application. Zoreline was developed as a generic version of Zoladex® 3.6 mg goserelin SC implant (AstraZeneca, UK). The active pharmaceutical ingredient and excipients in Zoreline and Zoladex® are identical. Goserelin is a type of hormone therapy called luteinising hormone blocker. Goserelin stops the release of luteinising hormone (LH) from the pituitary gland and follicle stimulating hormone (FSH) secretion leading to a fall in serum estradiol concentrations. High levels of estradiol can affect uterine tissue and trigger endometriosis.

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 in all trial related documents.

Background therapy

Not applicable. Please note: The trial was originally designed to investigate pharmacokinetic (PK) parameters after a single injection of the study products (i.e., one Treatment Period). In an amendment to the protocol during the trial, a second Treatment Period was added to provide further data and improve comparability with the reference product. The study consisted of one (Cohort 1; before protocol amendment) or two (Cohort 2; after protocol amendment) consecutive 28-day Treatment Periods. Day 1 of Treatment Period 2 coincided with Day 29 of Treatment Period 1. An End of Study visit was performed on Day 29 of Treatment Period 1 for Cohort 1 and on Day 29 of Treatment Period 2 for Cohort 2. Results of the study are presented separately for the two cohorts, whenever relevant.

Evidence for comparator

Not applicable LIST OF ABBREVIATIONS USED IN THIS STUDY ENTRY AE=Adverse event; ANCOVA=Analysis of covariance; AUC(0-t)=Area under the plasma concentration-time curve, calculated to the last quantifiable data point; AUC(0-tcom)=Area under the plasma concentration-time curve from administration to the last common measurable concentration time-point within all patients in both groups; Cmax=Maximum measured plasma concentration; Cmin=Minimum post-dose plasma concentration; GLSM=Geometric least square mean; LC-MS/MS=Liquid chromatography with tandem mass spectrometry; LH=Luteinizing hormone; LHRH=Luteinizing hormone releasing hormone; PD=Pharmacodynamic; PK=Pharmacokinetic; PP=Per Protocol. The Per Protocol population included all patients who completed the treatment period, excluding patients with major protocol deviations, i.e. deviations that have major impact on the assessments of goserelin or estradiol plasma concentrations. These included but were not limited to predefined disallowed concomitant medications and delayed visit schedules. TEAEs=treatment-emergent adverse events; Tmax=Time until the maximum measured plasma concentration

Actual start date of recruitment

26 Sep 2016

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Bulgaria: 68

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Female adult subjects (age between 18 and 45 years inclusive, white /Caucasian) with confirmed endometriosis were screened according to the study inclusion and exclusion criteria. Overall, 68 subjects were randomized (N=34 subjects in the test treatment group and N=34 subjects in the reference group).

Screening details

At the screening visit (up to 14 days before first study treatment administration), 68 subjects meeting all the eligibility criteria were randomized 1:1 to receive either the test or reference product. All subjects signed an Informed Consent Form before the first study-related procedure was performed.

Period 1 title

Treatment (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Blinding implementation details

This was an open-label study. Blinding was only applied to laboratory staff performing the bioanalysis (i.e., they were not provided with the randomization codes).

Are arms mutually exclusive

Yes

Zoreline (Test product)

Arm description

Test product was administered either once (Cohort 1, before protocol amendment) or twice (Cohort 2; after protocol amendment), on Day 1 of each 28-day treatment period. Day 1 of Treatment Period 2 coincided with Day 29 of Treatment Period 1. The maximum study duration was approximately 43 days for Cohort 1 (one injection) and 71 days for Cohort 2 (two injections), including the screening period. Test product was administered subcutaneously into the anterior abdominal wall below the navel line using an aseptic technique by a trained member of the clinical team.

Arm type

Experimental

Investigational medicinal product name

Zoreline

Investigational medicinal product code

Other name

Test product

Pharmaceutical forms

Implant

Routes of administration

Implantation

Dosage and administration details

Test product name : Zoreline (Test product) Formulation : Goserelin acetate Strength of dosage form : 3.6 mg subcutaneous implant Zoreline 3.6 mg subcutaneous implant was formulated as a sterile implant, in a pre-filled, single-use, disposable syringe device. Test product was administered either once (Cohort 1) or twice (Cohort 2), on Day 1 of each 28-day treatment period. Day 1 of Treatment Period 2 coincided with Day 29 of Treatment Period 1. Test product was administered subcutaneously 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 anesthetic was allowed if this was part of local practice.

Zoladex (Reference product)

Arm description

Reference product was administered either once (Cohort 1; before protocol amendment) or twice (Cohort 2; after protocol amendment), on Day 1 of each 28-day treatment period. Day 1 of Treatment Period 2 coincided with Day 29 of Treatment Period 1. The maximum study duration was approximately 43 days for Cohort 1 (one injection) and 71 days for Cohort 2 (two injections), including the screening period. Test product was administered subcutaneously into the anterior abdominal wall below the navel line using an aseptic technique by a trained member of the clinical team.

Arm type

Active comparator

Investigational medicinal product name

Zoladex®

Investigational medicinal product code

Other name

Reference product

Pharmaceutical forms

Implant

Routes of administration

Implantation

Dosage and administration details

Reference product name : Zoladex® Formulation : Goserelin acetate Strength of dosage form : 3.6 mg subcutaneous implant, Marketing Authorization Holder : AstraZeneca UK Limited Zoladex® 3.6 mg subcutaneous implant was supplied as a sterile implant, in a pre-filled disposable syringe device. Reference product was administered either once (Cohort 1) or twice (Cohort 2), on Day 1 of each 28-day treatment period. Day 1 of Treatment Period 2 coincided with Day 29 of Treatment Period 1. Reference product was administered subcutaneously 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 anesthetic was allowed if this was part of local practice.

Number of subjects in period 1	Zoreline (Test product)	Zoladex (Reference product)
Started	34	34
Completed	31	30
Not completed	3	4
Consent withdrawn by subject	3	4

Baseline characteristics

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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	34	34	68
Age categorical
Cohort 1: Patients receiving one treatment period (recruited before protocol amendment) Cohort 2: Patients receiving two treatment periods (recruited after protocol amendment) Safety Population
Units: Subjects
Adults (18-64 years)	34	34	68
Age continuous
Cohort 1: Patients receiving one treatment period (recruited before protocol amendment) Cohort 2: Patients receiving two treatment periods (recruited after protocol amendment) Safety Population
Units: years
arithmetic mean (standard deviation)	31.83 ( 4.94 )	30.97 ( 5.79 )	-
Gender categorical
Cohort 1: Patients receiving one treatment period (recruited before protocol amendment) Cohort 2: Patients receiving two treatment periods (recruited after protocol amendment) Safety Population
Units: Subjects
Female	34	34	68
Male	0	0	0
Race
Cohort 1: Patients receiving one treatment period (recruited before protocol amendment) Cohort 2: Patients receiving two treatment periods (recruited after protocol amendment) Safety Population
Units: Subjects
White/Caucasian	34	34	68
Body mass index (BMI)
Cohort 1: Patients receiving one treatment period (recruited before protocol amendment) Cohort 2: Patients receiving two treatment periods (recruited after protocol amendment) Safety Population
Units: kg/m^2
arithmetic mean (standard deviation)	25.06 ( 3.88 )	24.49 ( 3.54 )	-

Subject analysis set title

Cohort 1 - Test product

Subject analysis set type

Safety analysis

Subject analysis set description

Cohort 1: Patients receiving one treatment period of Test product (recruited before protocol amendment)

Subject analysis set title

Cohort 2 - Test product

Subject analysis set type

Safety analysis

Subject analysis set description

Cohort 2: Patients receiving two treatment periods of Test product (recruited after protocol amendment)

Subject analysis set title

Cohort 1 - Reference product

Subject analysis set type

Safety analysis

Subject analysis set description

Cohort 1: Patients receiving one treatment period of Reference product (recruited before protocol amendment)

Subject analysis set title

Cohort 2 - Reference product

Subject analysis set type

Safety analysis

Subject analysis set description

Cohort 2: Patients receiving two treatment periods of Reference product (recruited after protocol amendment)

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), and completed the treatment period, excluding patients with major protocol deviations, i.e. deviations that have major impact on the assessments of goserelin or estradiol plasma concentrations. These included but were not limited to predefined disallowed 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), and completed the treatment period, excluding patients with major protocol deviations, i.e. deviations that have major impact on the assessments of goserelin or estradiol plasma concentrations. These included but were not limited to predefined disallowed concomitant medications and delayed visit schedules.

Subject analysis sets values	Cohort 1 - Test product	Cohort 2 - Test product	Cohort 1 - Reference product	Cohort 2 - Reference product	Zoreline (Test product) - PP set	Zoladex (Reference product) - PP set
Number of subjects	24	10	24	10	29	29
Age categorical
Cohort 1: Patients receiving one treatment period (recruited before protocol amendment) Cohort 2: Patients receiving two treatment periods (recruited after protocol amendment) Safety Population
Units: Subjects
Adults (18-64 years)	24	10	24	10	29	29
Age continuous
Cohort 1: Patients receiving one treatment period (recruited before protocol amendment) Cohort 2: Patients receiving two treatment periods (recruited after protocol amendment) Safety Population
Units: years
arithmetic mean (standard deviation)	31.38 ( 4.64 )	32.90 ( 5.72 )	31.04 ( 5.61 )	30.80 ( 6.51 )	31.76 ( 5.05 )	31.07 ( 5.54 )
Gender categorical
Cohort 1: Patients receiving one treatment period (recruited before protocol amendment) Cohort 2: Patients receiving two treatment periods (recruited after protocol amendment) Safety Population
Units: Subjects
Female	24	10	24	10	29	29
Male	0	0	0	0
Race
Cohort 1: Patients receiving one treatment period (recruited before protocol amendment) Cohort 2: Patients receiving two treatment periods (recruited after protocol amendment) Safety Population
Units: Subjects
White/Caucasian	24	10	24	10	29	29
Body mass index (BMI)
Cohort 1: Patients receiving one treatment period (recruited before protocol amendment) Cohort 2: Patients receiving two treatment periods (recruited after protocol amendment) Safety Population
Units: kg/m^2
arithmetic mean (standard deviation)	25.26 ( 4.02 )	24.57 ( 3.69 )	24.35 ( 3.42 )	24.83 ( 3.99 )	25.09 ( 3.94 )	24.75 ( 3.58 )

End points

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Reporting group title

Zoreline (Test product)

Reporting group description

Reporting group title

Zoladex (Reference product)

Reporting group description

Subject analysis set title

Cohort 1 - Test product

Subject analysis set type

Safety analysis

Subject analysis set description

Cohort 1: Patients receiving one treatment period of Test product (recruited before protocol amendment)

Subject analysis set title

Cohort 2 - Test product

Subject analysis set type

Safety analysis

Subject analysis set description

Cohort 2: Patients receiving two treatment periods of Test product (recruited after protocol amendment)

Subject analysis set title

Cohort 1 - Reference product

Subject analysis set type

Safety analysis

Subject analysis set description

Cohort 1: Patients receiving one treatment period of Reference product (recruited before protocol amendment)

Subject analysis set title

Cohort 2 - Reference product

Subject analysis set type

Safety analysis

Subject analysis set description

Cohort 2: Patients receiving two treatment periods of Reference product (recruited after protocol amendment)

Subject analysis set title

Zoreline (Test product) - PP set

Subject analysis set type

Per protocol

Subject analysis set description

Subject analysis set title

Zoladex (Reference product) - PP set

Subject analysis set type

Per protocol

Subject analysis set description

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. Plasma concentration of goserelin was measured using validated liquid chromatography with tandem mass spectrometry (LC-MS/MS). For pharmacokinetic (PK) parameters, results are presented for the per protocol (PP) population i.e. all patients completing the treatment period, excluding those with major protocol deviations wrt. goserelin or estradiol plasma concentration. Timeframe Cohort 1 Pre-dose and at 4h, 8h, and 12h post-dose (Day 1), at 24h (Day 2), 48h (Day 3), and 72h (Day 4), and at Day 6, 8, 9, 11, 12, 13, 14, 15, 16, 17, 18, 19, 22, and 29. Cohort 2 Treatment Period 1: Pre-dose (Day 1) and then on Days 11, 13, 14, 15, 16, 18, 19, and 22. Treatment Period 2: Pre-dose (Day 1 coinciding with Day 29 of Treatment Period 1), 4h, 8h,

End point type

Primary

End point timeframe

Timeframe for blood sampling, used for the evaluation of PK parameters of goserelin are shown for Cohort 1 and Cohort 2 in the field -- 'End point description'.

End point values	Cohort 1 - Test product	Cohort 2 - Test product	Cohort 1 - Reference product	Cohort 2 - Reference product
Number of subjects analysed	20 ^[1]	9	22	7
Units: ng/mL
arithmetic mean (standard deviation)	2.81675 ( 1.162417 )	2.41296 ( 0.666803 )	2.27258 ( 1.649437 )	1.19651 ( 0.471987 )

Notes
[1] - Per Protocol Population was used for all groups analysed.

1_Cmax -- Cohort 1

Statistical analysis description

Analysis of covariance (ANCOVA) was performed on the log-transformed PK parameters AUC(0-t), AUC(0-tcom), and Cmax, by cohort. The ANCOVA model included the treatment and body weight (assessed at screening visit) as fixed effects.

Comparison groups

Cohort 1 - Reference product v Cohort 1 - Test product

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[2]

Method

ANCOVA

Parameter type

Ratio of GLSM

Point estimate

1.32

Confidence interval

level

90%

sides

2-sided

lower limit

0.93

upper limit

1.86

Notes
[2] - From each ANCOVA, the geometric least square means (GLSM) adjusted for body weight with its 95% Confidence Intervals (95%) was 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. The ratio of GLSM (test product versus reference product) and its 90% CI was calculated by taking the anti-log of the difference of least square means (LSMs).

2_Cmax -- Cohort 2

Statistical analysis description

For further details - please see the 'Analysis description' shown for end point 1 - statistical analysis 1.

Comparison groups

Cohort 2 - Test product v Cohort 2 - Reference product

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[3]

Method

ANCOVA

Parameter type

Ratio of GLSM

Point estimate

2.08

Confidence interval

level

90%

sides

2-sided

lower limit

1.5

upper limit

2.89

Notes
[3] - For further details - please see the field 'Analysis type comment' shown for end point 1 - statistical analysis 1.

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

PK -- AUC (0-t) -- Area under the goserelin plasma concentration curve -- To the last measurable concentration Timeframe Cohort 1 Pre-dose and at 4h, 8h and 12h post-dose (Day 1), at 24h (Day 2), 48h (Day 3), and 72h (Day 4), and at Day 6, 8, 9, 11, 12, 13, 14, 15, 16, 17, 18, 19, 22, and 29. Cohort 2 Treatment Period 1: Pre-dose (Day 1) and then on Days 11, 13, 14, 15, 16, 18, 19, and 22. Treatment Period 2: Pre-dose (Day 1 coinciding with Day 29 of Treatment Period 1), 4h, 8h and 12h post-dose (Day 1), at 24h (Day 2), 48h (Day 3), and 72h (Day 4), and at Days 6, 8, 9, 11, 12, 13, 14, 15, and 17.

End point type

Primary

End point timeframe

Timeframe for blood sampling, used for the evaluation of PK parameters of goserelin are shown for Cohort 1 and Cohort 2 in the field -- 'End point description'.

End point values	Cohort 1 - Test product	Cohort 2 - Test product	Cohort 1 - Reference product	Cohort 2 - Reference product
Number of subjects analysed	20 ^[4]	9	22	7
Units: ng.h/mL
arithmetic mean (standard deviation)	331.865 ( 167.2125 )	218.192 ( 27.6298 )	319.167 ( 160.1637 )	157.915 ( 38.2840 )

Notes
[4] - Per Protocol Population was used for all groups analysed.

1_AUC (0-t) -- Cohort 1

Statistical analysis description

For further details - please see the 'Analysis description' shown for end point 1 - statistical analysis 1.

Comparison groups

Cohort 1 - Test product v Cohort 1 - Reference product

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[5]

Method

ANCOVA

Parameter type

Ratio of GLSM

Point estimate

0.94

Confidence interval

level

90%

sides

2-sided

lower limit

0.68

upper limit

1.31

Notes
[5] - For further details - please see the field 'Analysis type comment' shown for end point 1 - statistical analysis 1.

2_AUC (0-t) -- Cohort 2

Comparison groups

Cohort 2 - Test product v Cohort 2 - Reference product

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

Method

ANCOVA

Parameter type

Ratio of GLSM

Point estimate

1.4

Confidence interval

level

90%

sides

2-sided

lower limit

1.15

upper limit

1.7

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

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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 the group

End point description

AUC (0-tcom) -- Area under the goserelin plasma concentration curve from administration to the last common measurable concentration time-point within all patients in both groups. Timeframe Cohort 1 Pre-dose and at 4h, 8h and 12h post-dose (Day 1), at 24h (Day 2), 48h (Day 3), and 72h (Day 4), and at Day 6, 8, 9, 11, 12, 13, 14, 15, 16, 17, 18, 19, 22, and 29. Cohort 2 Treatment Period 1: Pre-dose (Day 1) and then on Days 11, 13, 14, 15, 16, 18, 19, and 22. Treatment Period 2: Pre-dose (Day 1 coinciding with Day 29 of Treatment Period 1), 4h, 8h and 12h post-dose (Day 1), at 24h (Day 2), 48h (Day 3), and 72h (Day 4), and at Days 6, 8, 9, 11, 12, 13, 14, 15, and 17.

End point type

Primary

End point timeframe

Timeframe for blood sampling, used for the evaluation of PK parameters of goserelin are shown for Cohort 1 and Cohort 2 in the field -- 'End point description'.

End point values	Cohort 1 - Test product	Cohort 2 - Test product	Cohort 1 - Reference product	Cohort 2 - Reference product
Number of subjects analysed	20 ^[6]	9	22	7
Units: ng.h/mL
arithmetic mean (standard deviation)	290.674 ( 149.6395 )	218.192 ( 27.6298 )	261.173 ( 134.6129 )	157.915 ( 38.2840 )

Notes
[6] - Per Protocol Population was used for all groups analysed.

1_AUC (0-tcom) -- Cohort 1

Statistical analysis description

For further details - please see the 'Analysis description' shown for end point 1 - statistical analysis 1.

Comparison groups

Cohort 1 - Test product v Cohort 1 - Reference product

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[7]

Method

ANCOVA

Parameter type

Ratio of GLSM

Point estimate

1.01

Confidence interval

level

90%

sides

2-sided

lower limit

0.72

upper limit

1.41

Notes
[7] - For further details - please see the field 'Analysis type comment' shown for end point 1 - statistical analysis 1.

2_AUC (0-tcom) -- Cohort 2

Statistical analysis description

For further details - please see the 'Analysis description' shown for end point 1 - statistical analysis 1.

Comparison groups

Cohort 2 - Test product v Cohort 2 - Reference product

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[8]

Method

ANCOVA

Parameter type

Ratio of GLSM

Point estimate

1.4

Confidence interval

level

90%

sides

2-sided

lower limit

1.15

upper limit

1.7

Notes
[8] - For further details - please see the field 'Analysis type comment' shown for end point 1 - statistical analysis 1.

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

4_PK -- tmax -- Time until the maximum measured goserelin plasma concentration Timeframe: Cohort 1 Pre-dose and at 4h, 8h and 12h post-dose (Day 1), at 24h (Day 2), 48h (Day 3), and 72h (Day 4), and at Day 6, 8, 9, 11, 12, 13, 14, 15, 16, 17, 18, 19, 22, and 29 Cohort 2 Treatment Period 1: Pre-dose (Day 1) and then on Days 11, 13, 14, 15, 16, 18, 19, and 22 Treatment Period 2: Pre-dose (Day 1 coinciding with Day 29 of Treatment Period 1), 4h, 8h and 12h post-dose (Day 1), at 24h (Day 2), 48h (Day 3), and 72h (Day 4), and at Days 6, 8, 9, 11, 12, 13, 14, 15, and 17.

End point type

Secondary

End point timeframe

Timeframe for blood sampling used for the evaluation of PK parameters of goserelin are shown for Cohort 1 and Cohort 2 in the field -- 'End point description'.

End point values	Cohort 1 - Test product	Cohort 2 - Test product	Cohort 1 - Reference product	Cohort 2 - Reference product
Number of subjects analysed	20 ^[9]	9	22	7
Units: hour
median (full range (min-max))	4.00 (4.00 to 8.00)	4.00 (4.00 to 8.00)	311.88 (4.00 to 407.37)	313.10 (287.35 to 383.87)

Notes
[9] - Per Protocol Population was used for all groups analysed.

No statistical analyses for this end point

Secondary: 5_PK -- C(Day29, Period 1) -- Goserelin plasma concentration -- At the end of the treatment

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End point title

5_PK -- C(Day29, Period 1) -- Goserelin plasma concentration -- At the end of the treatment

End point description

CDay29 of Period 1 -- Goserelin plasma concentration at the end of the first dosing interval Cohort 1 Pre-dose and at 4h, 8h and 12h post-dose (Day 1), at 24h (Day 2), 48h (Day 3), and 72h (Day 4), and at Day 6, 8, 9, 11, 12, 13, 14, 15, 16, 17, 18, 19, 22, and 29 Cohort 2 Treatment Period 1: Pre-dose (Day 1) and then on Days 11, 13, 14, 15, 16, 18, 19, and 22 Treatment Period 2: Pre-dose (Day 1 coinciding with Day 29 of Treatment Period 1), 4h, 8h and 12h post-dose (Day 1), at 24h (Day 2), 48h (Day 3), and 72h (Day 4), and at Days 6, 8, 9, 11, 12, 13, 14, 15, and 17.

End point type

Secondary

End point timeframe

Timeframe for blood sampling used for the evaluation of PK parameters of goserelin are shown for Cohort 1 and Cohort 2 in the field -- 'End point description'.

End point values	Cohort 1 - Test product	Cohort 2 - Test product	Cohort 1 - Reference product	Cohort 2 - Reference product
Number of subjects analysed	20 ^[10]	9	22	7
Units: ng/mL
arithmetic mean (standard deviation)
CDay29 of Period 1	0.12421 ( 0.072045 )	0.14726 ( 0.091587 )	0.22813 ( 0.120940 )	0.17374 ( 0.054663 )

Notes
[10] - Per Protocol Population was used for all groups analysed.

No statistical analyses for this end point

Secondary: 6_PK -- C(Day17 of Period 2) -- Goserelin plasma concentration -- At the end of the treatment

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End point title

6_PK -- C(Day17 of Period 2) -- Goserelin plasma concentration -- At the end of the treatment

End point description

CDay17 of Period 2 -- Goserelin plasma concentration at the end of the 17 days post second implant injection. Cohort 1 Pre-dose and at 4h, 8h and 12h post-dose (Day 1), at 24h (Day 2), 48h (Day 3), and 72h (Day 4), and at Day 6, 8, 9, 11, 12, 13, 14, 15, 16, 17, 18, 19, 22, and 29 Cohort 2 Treatment Period 1: Pre-dose (Day 1) and then on Days 11, 13, 14, 15, 16, 18, 19, and 22 Treatment Period 2: Pre-dose (Day 1 coinciding with Day 29 of Treatment Period 1), 4h, 8h and 12h post-dose (Day 1), at 24h (Day 2), 48h (Day 3), and 72h (Day 4), and at Days 6, 8, 9, 11, 12, 13, 14, 15, and 17.

End point type

Secondary

End point timeframe

Timeframe for blood sampling used for the evaluation of PK parameters of goserelin are shown for Cohort 1 and Cohort 2 in the field -- 'End point description'.

End point values	Cohort 2 - Test product	Cohort 2 - Reference product
Number of subjects analysed	9 ^[11]	7
Units: ng/mL
arithmetic mean (standard deviation)
CDay17 of Period 2	0.38084 ( 0.095024 )	0.63150 ( 0.194419 )

Notes
[11] - Per Protocol Population was used for all groups analysed.

No statistical analyses for this end point

Secondary: 7_PD -- Cmax -- Plasma estradiol

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End point title

7_PD -- Cmax -- Plasma estradiol

End point description

PD -- Cmax -- Plasma estradiol Plasma concentration of estradiol was measured using validated liquid chromatography with tandem mass spectrometry (LC-MS/MS). Timeframe: Cohort 1 Pre-dose and at 24h (Day 2), 48h (Day 3), and 72h (Day 4), and at Day 6, 8, 9, 11, 12, 13, 14, 15, 16, 17, 18, 19, 22, and 29 Cohort 2 Treatment Period 1: Pre-dose (Day 1) and then on Days 11, 13, 14, 15, 16, 18, 19, and 22 Treatment Period 2: Pre-dose (Day 1 coinciding with Day 29 of Treatment Period 1), and at 24h (Day 2), 48h (Day 3), and 72h (Day 4), and at Days 6, 8, 9, 11, 12, 13, 14, 15, and 17.

End point type

Secondary

End point timeframe

Timeframe for blood sampling used for the evaluation of PD parameters of estradiol are shown for Cohort 1 and Cohort 2 in the field -- 'End point description'.

End point values	Cohort 1 - Test product	Cohort 2 - Test product	Cohort 1 - Reference product	Cohort 2 - Reference product
Number of subjects analysed	20 ^[12]	9	22	7
Units: ng/mL
arithmetic mean (standard deviation)	0.23977 ( 0.131051 )	0.00625 ( 0.005407 )	0.32211 ( 0.387875 )	0.01499 ( 0.016481 )

Notes
[12] - Per Protocol Population was used for all groups analysed.

No statistical analyses for this end point

Secondary: 8_PD -- Cmin -- Plasma estradiol

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End point title

8_PD -- Cmin -- Plasma estradiol

End point description

PD -- Cmin -- Plasma estradiol Timeframe: Cohort 1 Pre-dose and at 24h (Day 2), 48h (Day 3), and 72h (Day 4), and at Day 6, 8, 9, 11, 12, 13, 14, 15, 16, 17, 18, 19, 22, and 29 Cohort 2 Treatment Period 1: Pre-dose (Day 1) and then on Days 11, 13, 14, 15, 16, 18, 19, and 22 Treatment Period 2: Pre-dose (Day 1 coinciding with Day 29 of Treatment Period 1), and at 24h (Day 2), 48h (Day 3), and 72h (Day 4), and at Days 6, 8, 9, 11, 12, 13, 14, 15, and 17.

End point type

Secondary

End point timeframe

Timeframe for blood sampling used for the evaluation of PD parameters of estradiol are shown for Cohort 1 and Cohort 2 in the field -- 'End point description'.

End point values	Cohort 1 - Test product	Cohort 2 - Test product	Cohort 1 - Reference product	Cohort 2 - Reference product
Number of subjects analysed	20 ^[13]	9	22	7
Units: ng/mL
median (full range (min-max))	0.0026 (0.0026 to 0.0077)	0.0026 (0.0026 to 0.0064)	0.0026 (0.0026 to 0.0074)	0.0026 (0.0026 to 0.0026)

Notes
[13] - Per Protocol Population was used for all groups analysed.

No statistical analyses for this end point

Secondary: 9_PD -- AUC (0-t) -- Plasma estradiol

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End point title

9_PD -- AUC (0-t) -- Plasma estradiol

End point description

PD -- AUC (0-t) -- Plasma estradiol AUC(0-t): Area under the estradiol plasma concentration curve from administration to the last measurable concentration at time t in both groups Timeframe: Cohort 1 Pre-dose and at 24h (Day 2), 48h (Day 3), and 72h (Day 4), and at Day 6, 8, 9, 11, 12, 13, 14, 15, 16, 17, 18, 19, 22, and 29 Cohort 2 Treatment Period 1: Pre-dose (Day 1) and then on Days 11, 13, 14, 15, 16, 18, 19, and 22 Treatment Period 2: Pre-dose (Day 1 coinciding with Day 29 of Treatment Period 1), and at 24h (Day 2), 48h (Day 3), and 72h (Day 4), and at Days 6, 8, 9, 11, 12, 13, 14, 15, and 17.

End point type

Secondary

End point timeframe

Timeframe for blood sampling used for the evaluation of PD parameters of estradiol are shown for Cohort 1 and Cohort 2 in the field -- 'End point description'.

End point values	Cohort 1 - Test product	Cohort 2 - Test product	Cohort 1 - Reference product	Cohort 2 - Reference product
Number of subjects analysed	20 ^[14]	9	22	7
Units: ng.h/mL
arithmetic mean (standard deviation)	33.799 ( 30.6097 )	0.791 ( 1.2864 )	54.462 ( 67.6323 )	1.626 ( 1.5389 )

Notes
[14] - Per Protocol Population was used for all groups analysed.

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Adverse events (AE) 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). The safety population was used for the analysis of AEs. Safety population included all subjects who were randomized and received study drug.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

15.1

Reporting group title

Zoreline (Test)

Reporting group description

Test product was administered either once (Cohort 1) or twice (Cohort 2), on Day 1 of each 28-day treatment period. Day 1 of Treatment Period 2 coincided with Day 29 of Treatment Period 1. Test product was administered subcutaneously into the anterior abdominal wall below the navel line using an aseptic technique by a trained member of the clinical team.

Reporting group title

Zoladex (Reference)

Reporting group description

Reference product was administered either once (Cohort 1) or twice (Cohort 2), on Day 1 of each 28-day treatment period. Day 1 of Treatment Period 2 coincided with Day 29 of Treatment Period 1. Test product was administered subcutaneously into the anterior abdominal wall below the navel line using an aseptic technique by a trained member of the clinical team.

Serious adverse events	Zoreline (Test)	Zoladex (Reference)
Total subjects affected by serious adverse events
subjects affected / exposed	0 / 34 (0.00%)	0 / 34 (0.00%)
number of deaths (all causes)	0	0
number of deaths resulting from adverse events

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	9 / 34 (26.47%)	7 / 34 (20.59%)
Investigations
Weight increased
subjects affected / exposed	1 / 34 (2.94%)	0 / 34 (0.00%)
occurrences all number	1	0
Vascular disorders
Hot flush
subjects affected / exposed	2 / 34 (5.88%)	3 / 34 (8.82%)
occurrences all number	2	3
Nervous system disorders
Headache
subjects affected / exposed	5 / 34 (14.71%)	3 / 34 (8.82%)
occurrences all number	5	4
Somnolence
subjects affected / exposed	1 / 34 (2.94%)	0 / 34 (0.00%)
occurrences all number	1	0
General disorders and administration site conditions
Chest pain
subjects affected / exposed	0 / 34 (0.00%)	1 / 34 (2.94%)
occurrences all number	0	1
Discomfort
subjects affected / exposed	1 / 34 (2.94%)	0 / 34 (0.00%)
occurrences all number	1	0
Fatigue
subjects affected / exposed	1 / 34 (2.94%)	0 / 34 (0.00%)
occurrences all number	1	0
Pyrexia
subjects affected / exposed	0 / 34 (0.00%)	1 / 34 (2.94%)
occurrences all number	0	1
Gastrointestinal disorders
Abdominal distension
subjects affected / exposed	1 / 34 (2.94%)	0 / 34 (0.00%)
occurrences all number	1	0
Nausea
subjects affected / exposed	0 / 34 (0.00%)	1 / 34 (2.94%)
occurrences all number	0	1
Vomiting
subjects affected / exposed	0 / 34 (0.00%)	1 / 34 (2.94%)
occurrences all number	0	1
Reproductive system and breast disorders
Breast swelling
subjects affected / exposed	1 / 34 (2.94%)	0 / 34 (0.00%)
occurrences all number	1	0
Oligomenorrhoea
subjects affected / exposed	1 / 34 (2.94%)	0 / 34 (0.00%)
occurrences all number	1	0

More information

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Were there any global substantial amendments to the protocol? Yes

25 May 2017

An amendment was issued on 25 May 2017 to add a second period of treatment to improve PK and PD profile comparability with the reference product. A second dose of treatment was therefore scheduled at Day 29 of the first treatment period. The protocol amendment also involved a change to the blood sampling schedule for Treatment Period 1 and new sampling time points for Treatment Period 2. Patients recruited before and after protocol amendment were referred to as Cohort 1 and Cohort 2, respectively.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None.

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Clinical trials

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

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

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

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

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

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

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

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

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

Secondary: 5_PK -- C(Day29, Period 1) -- Goserelin plasma concentration -- At the end of the treatment

Secondary: 5_PK -- C(Day29, Period 1) -- Goserelin plasma concentration -- At the end of the treatment

Secondary: 6_PK -- C(Day17 of Period 2) -- Goserelin plasma concentration -- At the end of the treatment

Secondary: 6_PK -- C(Day17 of Period 2) -- Goserelin plasma concentration -- At the end of the treatment

Secondary: 7_PD -- Cmax -- Plasma estradiol

Secondary: 7_PD -- Cmax -- Plasma estradiol

Secondary: 8_PD -- Cmin -- Plasma estradiol

Secondary: 8_PD -- Cmin -- Plasma estradiol

Secondary: 9_PD -- AUC (0-t) -- Plasma estradiol

Secondary: 9_PD -- AUC (0-t) -- Plasma estradiol

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

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