Clinical Trials Register

Summary
EudraCT Number:	2015-005124-25
Sponsor's Protocol Code Number:	No0001-C201
National Competent Authority:	Bulgarian Drug Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2016-05-13
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Bulgarian Drug Agency

A.2

EudraCT number

2015-005124-25

A.3

Full title of the trial

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.

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

A study in women with endometriosis performed in several centers to
assess the blood levels after injection of two subcutaneous implants
containing 3.6 mg goserelin

A.4.1

Sponsor's protocol code number

No0001-C201

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Novalon S.A.
B.1.3.4	Country	Belgium
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Novalon S.A.
B.4.2	Country	Belgium
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Novalon S.A.
B.5.2	Functional name of contact point	Clinical Project Leader
B.5.3	Address:
B.5.3.1	Street Address	Rue Saint Georges 5-7
B.5.3.2	Town/ city	Liège
B.5.3.3	Post code	4000
B.5.3.4	Country	Belgium
B.5.4	Telephone number	+32(0)43492822
B.5.5	Fax number	+32(0)43492821
B.5.6	E-mail	gwinnen@mithra.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Zoreline 3.6 mg implant
D.3.4	Pharmaceutical form	Implant in pre-filled syringe
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	GOSERELIN
D.3.9.1	CAS number	65807-02-5
D.3.9.4	EV Substance Code	SUB07962MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	3.6
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Comparator
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Zoladex® 3.6 mg implant
D.2.1.1.2	Name of the Marketing Authorisation holder	AstraZeneca UK Limited
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.4	Pharmaceutical form	Implant in pre-filled syringe
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	GOSERELIN
D.3.9.1	CAS number	65807-02-5
D.3.9.4	EV Substance Code	SUB07962MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	3.6
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

endometriosis

E.1.1.1

Medical condition in easily understood language

endometriosis

E.1.1.2

Therapeutic area

Diseases [C] - Female diseases of the urinary and reproductive systems and pregancy complications [C13]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	PT
E.1.2	Classification code	10014778
E.1.2	Term	Endometriosis
E.1.2	System Organ Class	10038604 - Reproductive system and breast disorders

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To characterize the goserelin plasma concentration profile based on primary pharmacokinetic endpoints 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 2 consecutive injections with Zoreline 3.6 mg or Zoladex® 3.6 mg subcutaneous implant in female subjects with confirmed endometriosis.

E.2.2

Secondary objectives of the trial

-To characterize additional PK parameters: gosereline plasma concentration at the end of the first treatment cycle[CDay29 of Period 1] and 17 days post-second implant injection [CDay17 of Period 2]; time to reach Cmax [tmax].
-To assess the general safety and acceptability of the drug in both groups.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Women aged between 18 and 45 years (inclusive), who are not menopausal.
2. Clinical diagnosis of endometriosis, within the last 5 years indicated for treatment with hormone therapy as judged by the investigator.
Note: As per clinical guidelines: Clinical diagnosis is be based on clinical symptoms of endometriosis (such as chronic pelvic pain, dyspareunia, cyclic intestinal pain (bloating/diarrhoea/constipation), uterine cramping in young females, severe dysmenorrhea, dyspareunia, ovulation pain, cyclical/menstrual symptoms with or without abnormal bleeding, infertility, chronic fatigue) confirmed by laparoscopy (with or without histology) and/or transvaginal/rectal ultrasound (bladder, ovarian or rectum locations) and/or enema studies (for deeply infiltrating endometriosis).
3. Good physical and mental health as judged by the investigator determined by medical history, physical examination, clinical laboratory and vital signs.
4. Willing to give informed consent in writing.
5. Willing to use non-hormonal anti-conception from screening visit till the end of treatment (Day 29 of Period 2).
6. Willing and able to attend the scheduled study visits and to comply with the study procedures.
7. Body Mass Index (BMI) between 18 and 32 kg/m2 inclusive.

E.4

Principal exclusion criteria

1. Previous or current hormonal treatment for endometriosis: including usage of GnRH receptor agonists or GnRH receptor antagonists within 6 months prior to the screening visit.
2. Use of treatments that interfere with estradiol plasma level within one week (or 5 half-lives, whichever is longer) before drug administration.
3. Endometriosis surgery scheduled in the period between screening and end of study.
4. Alanine aminotransferase (ALT)/ serum glutamic-pyruvic transaminase (SGPT) or aspartate transaminase (AST) / serum glutamic oxaloacetic transaminase (SGOT) levels ≥ 2x upper limit of normal (ULN) or GGT ≥ 2.5 x upper limit of normal.
5. Evidence (including clinically significant abnormal bilirubin and/or albumin values) or history for chronic hepatic disease. Gilbert’s disease however is allowed.
6. Moderate or severe chronic kidney disease with an estimated glomerular filtration rate (eGFR), calculated by using the modification of diet in renal disease (MDRD) equation, < 60 mL/min/1,73m2.
7. Use of implanted long-acting progestin treatments like nexplanon or implanon at less than 1 month before the screening visit.
8. Receipt of an investigational drug within the last 28 days before the Screening visit (or 5 times the half-life of the drug, whichever is longer), if considered by the investigator to possibly influencing the outcome of this trial.
9. An unstable medical condition or chronic disease (including history of neurological [including cognitive and untreated depression], cardiovascular [including uncontrolled hypertension], gastrointestinal, pulmonary, bone, metabolic or endocrine disease), or malignancy that could confound interpretation of the study at investigator’s discretion.
10. History of severe uncontrolled asthma, anaphylactic reactions, or severe urticarial and/or angioedema, and particularly, history of hypersensitivity towards any components of the study drug.
11. History or presence of any malignancy other than treated squamous cell/basal cell carcinoma within the last 5 years.
12. Loss in bone mass that could affect the patient's health.
13. Prolonged QTc interval defined as mean QTcF > 450 ms at Screening or on Day 1 of Period 1 as measured by triplicate ECG.
Note: If the mean value of the QTcF interval from the three measurements is above 450 ms, another triplicate ECG should
be recorded once.
14. Family history for prolonged QT interval including history of arrhythmia, sudden unexplained death at a young age (before 40 years) in a first-degree relative.
15. Patients with unstable angina pectoris or stable angina pectoris classified higher than Canadian Cardiovascular Society Class II, or a myocardial infarction, or stroke within 6 months before Visit 1 ( Screening visit ).
16. History of hospitalization within 12 months before Visit 1 (Screening visit) caused by heart failure or a diagnosis of heart failure higher than New York Heart Association Class II.
17. Patient with decompensated diabetes mellitus.
18. Other abnormal laboratory results, which according to the investigator would affect the patient's health or the outcome of the trial.
19. Pregnancy (or willingness to become pregnant during the study) or breast-feeding.
20. Intellectual incapacity or inability to comprehend, precluding adequate understanding or co-operation.
21. Any contraindications for goserelin administration.

E.5 End points

E.5.1

Primary end point(s)

- Maximum measured goserelin plasma concentration in both groups (Cmax).
- Area under the goserelin plasma concentration curve from administration to the last measurable concentration at time t in both groups (AUC0-t).
- Area under the goserelin plasma concentration curve from administration to the last common measurable concentration time-point within all patients in both groups (AUC0-tcom).

E.5.1.1

Timepoint(s) of evaluation of this end point

The timepoints of evaluation of these endpoints are described in table
8.1-1 of the protocol.

E.5.2

Secondary end point(s)

Pharmacokinetics (PK):
- Time to reach the maximum goserelin plasma concentration (t max).
- Goserelin plasma concentration at the end of the first dosing interval (CDay29 of Period 1) and 17 days after second implant injection (CDay17 of Period 2).
Pharmacodynamics (PD):
- Maximum measured estradiol plasma concentration in both groups (Cmax).
- Area under the estradiol plasma concentration curve from administration to the last measurable concentration at time t in both groups (AUC0-t).
Safety:
- Occurrence of serious and non-serious adverse events including
clinically significant abnormalities in ECGs, vital signs, physical examination, and safety laboratory parameters.

E.5.2.1

Timepoint(s) of evaluation of this end point

The timepoints of evaluation of the PK and PD endpoints are described in
table 8.1-1 of the protocol.
The timepoints of evaluation of safety are described in table 5.3-1 of the protocol.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Yes

E.8.2.2

Placebo

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LPLV

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.2

In the whole clinical trial

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

None.

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2016-06-24

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-10-19

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2017-10-26

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