Clinical Trials Register

Summary
EudraCT Number:	2015-005284-16
Sponsor's Protocol Code Number:	MK-8342B-072
National Competent Authority:	Austria - BASG
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2016-04-20
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

Austria - BASG

A.2

EudraCT number

2015-005284-16

A.3

Full title of the trial

A Phase I, Open-Label Study to Investigate the Pharmacokinetics and Pharmacodynamics of Etonogestrel (ENG) and 17ß-Estradiol (E2) in Healthy female Postmenarcheal Adolescents and Healthy Female Adults Following Administration of MK-8342B (ENG-E2, 125/300 µg/day) Vaginal Ring

Eine offene Phase I Studie zur Untersuchung der pharmakokinetischen und pharmakodynamischen Eigenschaften von Etonogestrel (ENG) und 17ß-Estradiol (E2) in gesunden weiblichen jugendlichen nach Auftreten der ersten Menstruation und gesunden weiblichen Erwachsenen nach Verabreichung von MK-8342B (ENG-E2, 125/300 µg/Tag) Vaginalring

A.3.1

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

Research done in healthy human volunteers to Investigate how the MK-8342B (ENG-E2, 125/300 µg/day) Vaginal Ring behaves in and influences the body of female Postmenarcheal Adolescents and Healthy Female Adults.

Forschung an gesunden Freiwilligen zu untersuchen, wie MK - 8342B (ENG E2, 125/300 g / Tag) Vaginalring sich verhält und den weiblichen Körper von Jugendlichen Mädchen (welche die Periode haben) und gesunder weiblicher Erwachsene beeinflusst .

A.4.1

Sponsor's protocol code number

MK-8342B-072

A.7

Trial is part of a Paediatric Investigation Plan

Yes

A.8

EMA Decision number of Paediatric Investigation Plan

P/028/2016

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
B.1.3.4	Country	United States
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	Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Assign Clinical Research GmbH
B.5.2	Functional name of contact point	Project Management and Monitoring
B.5.3	Address:
B.5.3.1	Street Address	Hainburger Strasse 33
B.5.3.2	Town/ city	Vienna
B.5.3.3	Post code	1030
B.5.3.4	Country	Austria
B.5.4	Telephone number	+431403380544
B.5.5	Fax number	+431403380566
B.5.6	E-mail	carina.anger@assigngroup.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	Etonogestrel/Estradiol
D.3.2	Product code	MK-8342B
D.3.4	Pharmaceutical form	Vaginal delivery system
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Vaginal use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Etonogestrel
D.3.9.1	CAS number	54048-10-1
D.3.9.2	Current sponsor code	MK-8342
D.3.9.3	Other descriptive name	ETONOGESTREL, ENG, SCH900342, Org 3236
D.3.9.4	EV Substance Code	SUB07335MIG
D.3.10	Strength
D.3.10.1	Concentration unit	µg microgram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	125
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Estradiol
D.3.9.1	CAS number	50-28-2
D.3.9.2	Current sponsor code	MK-9271
D.3.9.3	Other descriptive name	ESTRADIOL, E2, SCH 900618, Org 2317
D.3.9.4	EV Substance Code	SUB07242MIG
D.3.10	Strength
D.3.10.1	Concentration unit	µg microgram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	300
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	Yes
D.3.11.13.1	Other medicinal product type	combined hormonal contraceptive vaginal ring

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

Hormonal contraception and primary dysmenorrhea in woman seeking contraception.

Hormonale Verhütung und Minderung der Regelschmerzen bei Frauen welche eine Verhütung benötigen

E.1.1.1

Medical condition in easily understood language

Contraceptive method and treatment of painful periods with abdominal cramps.

Verhütungsmethode und Therapie für schmerzhafte Regelschmerzen

E.1.1.2

Therapeutic area

Body processes [G] - Reproductive physiologi cal processes [G08]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	19.0
E.1.2	Level	LLT
E.1.2	Classification code	10073728
E.1.2	Term	Hormonal contraception
E.1.2	System Organ Class	100000004865

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Objective 1: To investigate the pharmacokinetics of ENG, E2 and E1 (estrone) following administration of MK-8342B (ENG-E2, 125/300 μg/day) vaginal ring in healthy female postmenarcheal adolescents (≥12 to <18 years of age) and in healthy female adults (≥18 to ≤36 years of age).
Objective 2: To evaluate the pharmacodynamic effects (on progesterone [P], luteinizing hormone [LH], follicle-stimulating hormone [FSH], and Sex hormonal binding globulin [SHBG] following administration of MK-8342B (ENG-E2, 125/300 μg/day) vaginal ring in healthy female postmenarcheal adolescents (≥12 to <18 years of age) and in healthy female adults (≥18 to ≤36 years of age).
Objective 3: To investigate the safety and tolerability following administration of MK-8342B (ENG-E2, 125/300 μg/day) vaginal ring in healthy female postmenarcheal adolescents (≥12 to <18 years of age) and in healthy female adults (≥18 to ≤36 years of age).

1. Ziel: Untersuchung der pharmakokinetischen und pharmakodynamischen Eigenschaften von ENG, E2 und E1 nach Verabreichung von MK-8342B Vaginalring (ENG-E2 125/300 μg/Tag) in gesunden weiblichen jugendlichen nach Auftreten der ersten Menstruation (≥12 bis <18 Jahre) und gesunden weiblichen Erwachsenen (≥18 bis ≤36 Jahre).
2. Ziel: Untersuchung der der pharmakodynamischen Effekte auf Progesteron, luternisierendes Hormon, follikelstimulierende Hormon und Sexualhormon-bindendes-Globulin nach Verabreichung von MK-8342B Vaginalring (ENG-E2 125/300 μg/Tag) in gesunden weiblichen jugendlichen nach Auftreten der ersten Menstruation (≥12 bis <18 Jahre) und gesunden weiblichen Erwachsenen (≥18 bis ≤36 Jahre).
3. Ziel: Untersuchung des Sicherheitsprofils und der Verträglichkeit von MK-8342B nach Verabreichung von MK-8342B Vaginalring (ENG-E2 125/300 μg/Tag) in gesunden weiblichen jugendlichen nach Auftreten der ersten Menstruation und gesunden weiblichen Erwachsenen

E.2.2

Secondary objectives of the trial

Not applicable

nicht zutreffend

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Healthy female either postmenarcheal adolescents ≥12 to <18 years of age at screening or adults of childbearing potential between ≥18 to ≤36 years of age at screening.
2. Regular menstrual cycles ≥ 21 to ≤ 35 days in length in the 3 months prior to screening
3. Continuous non smokers who have not used nicotine containing products for at least 3 months prior to the first vaginal ring insertion.
4. BMI ≥ 17.5 and ≤ 29.0kg/m2 at screening.
5. Medically healthy with no clinically significant medical history, physical examination, clinical laboratory profiles, vital signs, or ECGs, as deemed by the Investigator.
6. Able and willing to stop hormonal contraceptive, including oral contraceptives, transdermal contraceptive patches, implants and intrauterine device (IUD) - if used 28 days prior to first viginal ring cycle; or depot injections - if used 90 days prior to the first vaginal ring cycle.
7. If sexually active agrees to use condom without spermicide during the screening phase and the follow-up phase of the study/during the entire duration of the study.
8. If ≥ 18 years old at study entry or turning 18 during study participation - normal cervical Pap test within 24 months documented at the time of screening. If not - Pap test must be performed at screening with normal result.
9. Able to understand and willing to comply with the protocol. Able to understand and willing to sign the informed consent form. For adolescent subjects, a parental ICF is also required.

E.4

Principal exclusion criteria

1. Mentally or legally incapacitated or has significant emotional problems at the time of the screening visit or expected during the conduct of the study
2. History or presence of clinically significant medical or psychiatric condition or disease in the opinion of the Investigator
3. History of any illness that, in the Investigator's opinion, might confound the results of the study or poses an additional risk to the subject by their participation in the study
4. History or presence of alcoholism or drug abuse within the past 2 years, prior to vaginal ring insertion
5. History or presence of hypersensitivity or idiosyncratic reaction to the study drug or related compounds
6. History or presence of: venous thromboembolic events (VTE), arterial thromboembolic events (ATE), and other major adverse cardiovascular events (MACE) (e.g., myocardial infarction, cerebral vascular accident); migraines or severe headaches; breast cancer or undiagnosed breast nodules; hypertension; transient ischemic attacks; liver tumors or liver disease; jaundice with previous use of oral contraceptives or past pregnancy; diabetes; pancreatitis or severe hypertriglyceridemia; carcinoma of the endometrium or other known or suspected estrogen dependent neoplasia;
family history of 1st degree relative with breast or ovarian cancer; cervical cancer, or cervical procedures including loop electrosurgical excision procedure or conization (i.e., cold knife cone biopsy from the mucous membrane of the cervix); any condition that would contraindicate the use of hormonal contraceptives
7. Positive pregnancy test or lactating
8. Abnormal cervical Pap test within 1 year prior to screening.
9. Within the past 6 months of first vaginal ring insertion, has had undiagnosed (unexplained) abnormal vaginal bleeding or any abnormal bleeding that is expected to recur during the study (e.g., bleeding from cervical polyp, bleeding after sex).
10. Has stage 4 pelvic organ prolapse (1 cm beyond introitus) or lesser degrees of prolapse with a history of difficulty retaining tampons, vaginal rings, or other products within the vagina
11. Clinically significant abnormalities of the genital organs as determined by a gynecologist and based on the Investigator’s judgment
12. Has gonorrhea, chlamydia, or trichomonas or symptomatic vaginitis/cervicitis. Subjects may be rescreened 3 weeks after completing treatment for these conditions
13. Positive results for the urine drug and/or alcohol screen at screening or each check in
14. Drink alcohol in excess of 14 glasses/units per week (1 unit = 125 mL of wine or 284 mL of beer or 25 mL of 45% alcohol)
15. Positive urine cotinine at screening (threshold >10 ng/mL). Note: subjects may be retested at screening if positive.
16. Positive results at screening for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), or hepatitis C virus (HCV)
17. Unable to refrain from or anticipates the use of:
• Any drug, including prescription and non prescription medications, herbal remedies, or vitamin supplements beginning 14 days prior to the first vaginal ring cycle and throughout the study. Paracetamol (up to 2 g per 24 hours) may be permitted for minor ailments (e.g., in case of menstrual pain, sunburn, fever).
• Any drugs known to be significant inducers of CYP enzymes and/or P gp, including St. John’s wort, for 28 days prior to the first vaginal ring cycle and throughout the study. Appropriate sources will be consulted by the Investigator or designee to confirm lack of pharmacokinetic/pharmacodynamic interaction with the study drugs.
• Any drugs known to increase or decrease levels of SHBG (e.g., opiates, statins, and antiepileptic drugs), transdermal contraceptive patches, implants and hormonal replacement therapy, within 28 days prior to the first vaginal ring cycle and throughout the study
• An IUD or vaginal ring within 28 days prior to the first vaginal ring cycle and throughout the study
• Injection of medroxy progesterone acetate (e.g., Depo Provera®) within 90 days prior to the first vaginal ring cycle and throughout the study.
18. Hemoglobin level below 11 g/dL at screening
19. Blood or plasma donation within 90 days prior to the first vaginal ring cycle
20. Donation of bone marrow within the last 6 months prior to the first vaginal ring cycle.
21. Working at or having an immediate family member (spouse or children) who works at the investigational site or is a Sponsor staff directly involved with this trial.
22. Participation in another clinical trial within 90 days prior to the first insertion of study drug. The 90-day window will be derived from the date of the last blood collection or last dosing, whichever is later, in the previous study to Day 1 of Cycle 1 of the current study

E.5 End points

E.5.1

Primary end point(s)

1. Pharmacokinetic:
• Tmax - Time to maximum observed serum drug concentration
• Cmax - Maximum observed serum concentration
• AUC1-29 - Area under the concentration versus time curve, from Day 1 (0 hour) to Day 29 (672 hours) after vaginal ring insertion
• AUC1-22 - Area under the concentration versus time curve, from Day 1 (0 hour) to Day 22 (504 hours) after vaginal ring insertion
• Cmin - Minimum observed/measured non-zero concentration
• Cavg1-29 - Ratio of AUC1-29 to the corresponding time interval (Day 1 [0 hour] to Day 29 [672 hours after vaginal ring insertion])
• Cavg1-22 - Ratio of AUC1-22 to the corresponding time interval (Day 1 [0 hour] to Day 22 [504 hours after vaginal ring insertion])
• apparent t1/2 - Apparent terminal half life
for ENG, E2, and E1 in Cycle 2 in serum, as appropriate.
2. Pharmacodynamic:
Raw and percent change from baseline (Hour 0 of cycle 2) values for serum hormone concentrations for P, LH, FSH, and SHBG will be presented at each time point. Summary statistics will be provided by time point. Additionally, concentration versus time profiles will be presented.
3. Safety:
• adverse events
• physical examinations
• vital signs (heart rate and blood pressure)
• clinical laboratory tests (hematology, serum chemistry, and urinalysis)

E.5.1.1

Timepoint(s) of evaluation of this end point

1. Pharmacokinetic - Day 1-22 and day 1-29 of cycle 2
2. Pharmacodynamic - At each time point up to day 27 of cycle 2
3. Safety - Screening to day 29 of Cycle 2 and 14 days after the last vaginal ring removal for AEs

E.5.2

Secondary end point(s)

not applicable

E.5.2.1

Timepoint(s) of evaluation of this end point

not applicable

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)

Yes

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

Yes

E.7.1.3.1

Other trial type description

First use in postmenarcheal adolescent females.

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

E.8.1.1

Randomised

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

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

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

This study will be completed when the last subject completes EOS and any assessment associated with this visit has been documented and followed-up appropriately by the Investigator.

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

Yes

F.1.1

Number of subjects for this age range:

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)

Yes

F.1.1.6.1

Number of subjects for this age range:

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

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.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
G.4 Investigator Network to be involved in the Trial: 1

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2016-05-30

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-06-07

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2016-07-14

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