Clinical Trials Register

Summary
EudraCT Number:	2011-004085-15
Sponsor's Protocol Code Number:	CF111/203
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2011-09-20
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

Germany - BfArM

A.2

EudraCT number

2011-004085-15

A.3

Full title of the trial

Open-Label, Randomized Study to Evaluate the Influence on the Hormonal and Ovarian Activity of Two Different Dosages of Drospirenone (either 4.0 mg for 24 Days or 2.8 mg Daily for 28 Days) Over Two Treatment Cycles in 50 Healthy, Young Females

A.4.1

Sponsor's protocol code number

CF111/203

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	Laboratories León Farma S.A
B.1.3.4	Country	Spain
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	Laboratories León Farma S.A.
B.4.2	Country	Spain
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Chemo France
B.5.2	Functional name of contact point	Directeur du Dèveloppement
B.5.3	Address:
B.5.3.1	Street Address	7 rue Victor Hugo
B.5.3.2	Town/ city	Sèvres
B.5.3.3	Post code	92310
B.5.3.4	Country	France
B.5.4	Telephone number	0033149662226
B.5.5	Fax number	0033141149917
B.5.6	E-mail	dominique.drouin@chemofrance.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	Drospirenone
D.3.2	Product code	LF111
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.1	CAS number	67392-87-4
D.3.9.2	Current sponsor code	LF111
D.3.9.3	Other descriptive name	DROSPIRENONE
D.3.9.4	EV Substance Code	SUB06413MIG
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	4
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	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	Drospirenone
D.3.2	Product code	LF111
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.1	CAS number	67392-87-4
D.3.9.2	Current sponsor code	LF111
D.3.9.3	Other descriptive name	DROSPIRENONE
D.3.9.4	EV Substance Code	SUB06413MIG
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	2.8
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
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Film-coated tablet
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Evaluation of the influence of Drosperinone on the hormonal and ovarian activity, the bleeding pattern and the endometrial thickness.

E.1.1.1

Medical condition in easily understood language

Evaluating the contraceptive efficacy by measuring the hormonal and ovarian activity, the bleeding pattern and the thickness of the uterus.

E.1.1.2

Therapeutic area

Body processes [G] - Metabolic Phenomena [G03]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.0
E.1.2	Level	PT
E.1.2	Classification code	10030970
E.1.2	Term	Oral contraception
E.1.2	System Organ Class	10042613 - Surgical and medical procedures

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 assess the ovulation inhibition potential reflected by the hormonal and ovarian activity of two different dosages and intake regimens of drospirenone (DRSP) in 50 healthy women.
Subjects will be assigned to one of two treatment regimens after stratification for the ovulation day in the precycle.

E.2.2

Secondary objectives of the trial

• To evaluate the hormonal pituitary feed-back by LH and FSH analyses

• To assess the influence on the bleeding pattern and the endometrial thickness

• To evaluate the safety and tolerability of 4.0 mg drospirenone o.d. over 24 days and 2.8 mg o.d. over 28 days given over 2 treatment cycles

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Healthy premenopausal females of any ethnic origin (18 to 35 years of age), inclusive;
(smokers not older than 30 years, inclusive; smokers ≤ 30 years up to 10 cigarettes daily)

• Body Mass Index (BMI) of 18-30 kg/m2, inclusive

•Subjects must have a history of regular cycles

•Subjects must consent to use reliable non-hormonal contraceptive methods (spermicide-coated condoms, diaphragm, female or male sterilization or sexual abstinence) throughout the study

• Subjects must be in good physical and mental health as determined by vital signs, medical history (no history of a cervical smear PAP ≥3 within the last year) and gynaecological examination

• Subjects must have a blood pressure after resting for 5 minutes between 90-140 mmHg (systolic) and 50-90 mmHg (diastolic)

• Subjects must have a pulse rate after resting for 5 minutes between 48 and 100 beats per minute (bpm)

• Signed informed consent prior to study participation in accordance with the legal requirements and oral confirmation of the volunteer’s health insurance coverage

• Status at least 3 months after a delivery, abortion, or lactation before screening

E.4

Principal exclusion criteria

• Pregnancy, a repeatedly positive urine pregnancy test or lactation

• Known or suspected malign tumours or history thereof; subjects with cervical cytological smear classified higher than PAP II according to Papanicolaou grading scale I – IV have to be excluded (PAP II K can be controlled after an anti-inflammatory therapy up to 1 week after ending of this therapy)

• History of thrombophlebitis, venous or arterial thromboembolic diseases (thrombosis, pulmonary embolism, stroke or myocardial infarction)

• Any known severe neurological, gastrointestinal, hepatical or other disease that might interfere with the intake of an investigational drug or any study condition

• Clinical relevant findings from serum biochemistry and haematology and HBsAg/HCV/HIV serology as evaluated by the investigator

• Additional contraindications related to the antimineralocorticoid activity of drospirenone (conditions that predispose to hyperkalaemia): renal or adrenal insufficiency or hepatic dysfunction

• Anovulatory precycle, or no ovulation by day 19 of the precycle, or sonographical pecularities concerning the ovarian status (e.g. ovarian cyst formation, that have not disappeared during the precycle)

• Alcohol, drug, or medicine abuse or suspicion thereof

• Participation in a further clinical trial at the same time or intake of an investigational medicinal product within 4 weeks prior to screening

• Volunteer is a dependent person, e.g. a relative, family member, or member of the investigator’s or sponsor’s staff

• Volunteer is in custody or submitted to an institution due to a judicial order

• Donation of blood or plasmapheresis after signing the informed consent

• Known allergy to any ingredient of the investigational drug

• Regular intake or use of the following medication:
o any drugs that might interfere with the investigational drug
o any hormonal preparation from start of the precycle until the end of treatment cyles (except for the investigational drug)
o especially any drugs known to induce liver enzymes (e.g. rifampicin, dexamethasone, barbiturates, anticonvulsants, St. John’s wort)
o and any drugs known to inhibit CYP 3A4 (e.g. ketoconazole, verapamil, cimetidine, macrolides)
o any broad-spectrum antibiotics
o long-acting injectable or implant hormonal therapy within 6 months prior to the start of the precycle
o use of hormonal implants or IUDs within 1 month prior to the start of screening

E.5 End points

E.5.1

Primary end point(s)

To determine the hormonal and ovarian activity.

Demonstration of a spontaneous ovulatory precycle by sonographic measurements of the leading follicle initially every 3rd day starting on day 9 (± 1 day) of the precycle. If on day 12 (± 1 day) no follicle with a maximum diameter of ≥ 13 mm could be detected, subjects will be excluded. Starting from a follicle diameter of 15 mm daily visits with sonographic measurements will take place. If no ovulation could be observed by day 19, subjects will be excluded. Ovulation day will be recorded and confirmed by a serum progesterone measurement 3 (± 1) or 6 (± 1) days later (if required).

Based on the cycle day when ovulation could be sonographically detected, a stratification of the subjects will be done before randomization and subjects will be assigned to both treatment groups in similar rates. Randomization will take place on day 6 (± 1) or day 9 (± 1) after ovulation.

In treatment cycles 1 and 2 Hoogland Score evaluation (established by Hoogland and Skouby)[1] will be conducted. The Hoogland score reflects the ovarian status and will be assessed per cycle based on data from multiple serum analyses of estradiol and proges-terone and by multiple ovarian follicle size measurements by transvaginal ultrasound (TVUS) at the following visits:
o cycle 1 and 2: day 3, 6, 9, 12, 15, 18, 21, 24, 27 (all ±1day).

E.5.1.1

Timepoint(s) of evaluation of this end point

The primary endpoint is scheduled to be evaluated at the end of the trial (2012)

E.5.2

Secondary end point(s)

• The pituitary hormones LH and FSH will be analyzed in order to interprete the hormonal feed-back during the cycle courses

• Endometrium thickness will be followed throughout all cycles by TVUS in order to evaluate the conditions for a possible nidation

• The bleeding pattern will be evaluated by means of daily diary entries by the subjects in order to evaluate the cycle control and occurrence of intermediate bleedings

• Safety examinations will be done by inquiry of adverse events, vital signs measurements and pregnancy tests, a gynaecological examination (including cervical smear at screening and a basis sonographical examination at screening and final examination), as well as laboratory examinations in blood and urine

E.5.2.1

Timepoint(s) of evaluation of this end point

The secondary endpoints are scheduled to be evaluated at the end of the trial (2012).

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

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

influence on the bleeding pattern, the endometrial thickness, the hormones LH and FSH

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)

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

DRSP will be evaluated using two different dosages: 4.0 mg and 2.8 mg

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

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

See protocol section 10: Termination of trial. The end of the trial is defined as the date of the last visit of the last patient.

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

Yes

F.3.2

Patients

F.3.3

Specific vulnerable populations

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.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)

If needed, the physician will discuss furhter contraceptive methods with the subject. The subject will be referred to a gynaecologist, if applicable.

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

2011-11-04

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2011-10-12

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2012-04-17

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