PrimaryObjective 1: To evaluate the effects of ENG and E2 on ovarian function (pharmacodynamics) when the ENG-E2 vaginal ring (MK-8342B) is used for an extended period of time (i.e., 35 days) in healthy young adult female subjects.Objective 2: To…
ID
Source
Brief title
Condition
- Other condition
Synonym
Health condition
hormonal contraception and primary dysmenorrhea in women
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Pharmacodynamics
The largest follicular diameter, endometrial thickness, and serum
concentrations of P and SHBG will be measured at various time points. Summary
statistics will be provided by time point and Max P and Max FD for the period
will be determined.
Pharmacokinetics
The following pharmacokinetic parameters will be calculated for ENG, E2, and E1
in serum, as appropriate: AUC1-22, AUC1-36, AUC1-44, AUC36-44, Cmin, Cmax,
Tmax, and apparent terminal t*. When multiple time points occur on the same
day, AUC (indicated in study days) are converted into study hours as follows:
* Day 1, Hour 0 is the time of ENG-E2 vaginal ring insertion
* Day 36, Hour 840 is 840 hours post ENG-E2 vaginal ring insertion and the time
of ring removal
Safety:
Safety endpoints will include adverse events, physical examinations,
gynecological examination, vital signs (heart rate and blood pressure), and
clinical laboratory tests (hematology, serum chemistry, and urinalysis).
Secondary outcome
-
Background summary
Therapeutic effect of combined oral contraceptives is based on the hormonal
activity of a progestogen and an estrogen. Contraceptives that employ the oral
route of administration have a disadvantage in that the drug substance passes
through the gastrointestinal tract, possibly resulting in diminished uptake of
drug due to interactions with food, degradation, diarrhea, and/or vomiting. In
addition, the drug substance will be subject to hepatic first-pass
metabolism, requiring a higher dose to achieve the intended effect. This
increased daily intake of hormones results in daily peak concentrations that
may potentially result in unwanted side effects. Vaginal administration of
progestogen/estrogen combinations, as compared to oral administration, is
expected to result in more efficient drug delivery (high absolute
bioavailability), a controlled release steady pharmacokinetic profile (i.e.,
absence of daily peaks and troughs), as well as a pharmacodynamic (including
metabolic) profile that more closely resembles the physiological state in a
fertile female. Vaginal administration is therefore considered a feasible and
attractive hormonal contraceptive option.
MK-8342B is a vaginal ring containing a progestogen, ENG, and the estrogen
estradiol, E2, referred to in this protocol as ENG-E2. The ring is placed in
the vagina and remains in place for 21 days, followed by a 7-day ring-free
interval. During use, the ENG-E2 vaginal ring continuously releases ENG and E2.
The vaginal delivery system is made of an ethylene vinylacetate copolymer,
similar to the marketed contraceptive vaginal ring NuvaRing®, which contains
ENG in combination with ethinylestradiol (EE). ENG-E2 is being developed for
contraception and treatment of primary dysmenorrhea.
Study objective
Primary
Objective 1: To evaluate the effects of ENG and E2 on ovarian function
(pharmacodynamics) when the ENG-E2 vaginal ring (MK-8342B) is used for an
extended period of time (i.e., 35 days) in healthy young adult female subjects.
Objective 2: To characterize the pharmacokinetics of ENG and E2 when the ENG-E2
vaginal ring (MK-8342B) is used for an extended period of time (i.e., 35 days)
in healthy young adult female subjects.
Estimation: The effects of extended use (i.e., 35 days) of the ENG-E2 vaginal
ring (MK-8342B) on ovarian function and pharmacokinetics of ENG and E2 in
healthy young adult female subjects will be estimated.
Secondary
Objective 1: To assess the safety and tolerability of the ENG-E2 vaginal ring
(MK-8342B) when used for an extended period of time (i.e., 35 days) in healthy
young adult female subjects.
Objective 2: To determine when ovulation occurs post-treatment (i.e., return to
ovulation) after the ENG-E2 vaginal ring (MK-8342B) has been used for an
extended period of time (i.e., 35 days) in healthy young adult female subjects.
Planned exploratory applicator use
Objective: To obtain further clinical experience with the use of the applicator
for placement of the ENG-E2 vaginal ring (MK-8342B) in healthy young adult
female subjects.
Planned exploratory biomarker
Objective: To explore the relationship between genetic variation and response
to the treatment administered. Variation across the human genome will be
analyzed for association with clinical data collected in this study.
Study design
This is an open-label, single-center study in young adult female subjects to
evaluate the pharmacodynamics and pharmacokinetics of the ENG-E2 vaginal ring.
Twenty (20), healthy, adult, female subjects between 18 and 35 years of age
(inclusive) will be dosed. To meet this sample size target, approximately 30
subjects will enter the pre-treatment screening period.
Screening of subjects will occur within 10 weeks prior to start of the study
treatment period (ENG-E2 vaginal ring insertion). As part of the screening
procedures, all potential subjects will be evaluated using vaginal ultrasound
scans and P measurement to establish that they have the ability to ovulate.
Prior to the start of the pre-treatment screening period, all forms of hormonal
contraception will be withdrawn. All subjects must agree not to use hormonal
contraception (other than the study drug) through the duration of the study.
On Day 1 of the study, subjects will receive a single ENG-E2 vaginal ring which
will be used for an extended treatment period of 35 days. Pharmacodynamic and
pharmacokinetic assessments will be obtained throughout the ENG-E2 vaginal ring
treatment period until Day 44 post ENG-E2 vaginal ring insertion (i.e., 8 days
after ring removal). Subjects who completed the 35-day ring use period will be
followed to ensure return of ovulation via
vaginal ultrasound scan and P measurement until confirmed ovulation or until
Day 71 (± 1 day) post ENG-E2 vaginal ring insertion (i.e., 35 days after ring
removal), whichever occurs first.
Subjects who have started the ENG-E2 vaginal ring treatment but discontinued
prior to ENG-E2 vaginal ring removal (Day 36) will not be followed for return
of ovulation. Subjects who have started the ENG-E2 vaginal ring treatment but
discontinued the study for any reason will be asked to return to the study site
for end-of-study procedures approximately 14 days after ENG-E2 vaginal ring
removal and to determine if any adverse events have occurred since the last
visit. Safety and tolerability will be assessed prior to, during, and following
the treatment period with ENG-E2 vaginal ring.
Subjects may be replaced at the discretion of the Sponsor.
Intervention
The Study Events Flow Chart (Section 6 of the protocol) summarizes the clinical
procedures to be performed at each visit. I. Additional evaluations/testing may
be deemed necessary by the Investigator and/or the Sponsor for reasons related
to subject safety.
For this study, Max FD, endometrial thickness, and blood collection for P,
SHBG, ENG, E2, and E1 are the critical parameters. Blood samples need to be
collected as close to the exact time point as possible. All other procedures
should be completed as close to the prescribed/scheduled time as possible but
can be performed prior or after the prescribed/scheduled time.
Any nonscheduled procedures required for urgent evaluation of safety concerns
take precedence over all routine scheduled procedures.
Study burden and risks
The ENG-E2 (125/300 *g/day) vaginal ring administered in this study is not
anticipated to induce any potential risk, other than the adverse events
associated with the use of hormonal contraceptives, as it is a dose formulation
found to be well tolerated in Phase 1 and Phase 2B studies. There will be no
direct health benefit for study participants from receipt of the ENG-E2 vaginal
ring. An indirect health benefit to the healthy subjects enrolled in this study
is the free medical tests received at screening and during the study.
Details about specific benefits and risks of the ENG-E2 vaginal ring and
applicator may be found in the accompanying IB and informed consent documents.
The safety monitoring practices employed by this protocol (i.e., vital signs,
clinical laboratory tests, adverse event questioning, gynecological
examination, and physical examination) are adequate to protect the subjects*
safety and should detect all expected treatment-emergent adverse events.
One Merck Drive P.O. Box 100
Whitehouse Station NJ, 08889-0100
US
One Merck Drive P.O. Box 100
Whitehouse Station NJ, 08889-0100
US
Listed location countries
Age
Inclusion criteria
1. Healthy adult female subjects, 18-35 years of age, inclusive, at screening.
2. Continuous non-smokers who have not used nicotine-containing products for at least
3 months prior to ENG-E2 vaginal ring insertion.
3. Body mass index (BMI) * 18.5 and * 30.0 kg/m2, at screening and prior to ENG-E2 vaginal ring insertion.
4. Has good visibility of both ovaries upon ultrasonography at screening.
5. Subjects not using hormonal contraceptives should have regular menstrual cycles ranging from * 21 to * 35 days in length in the 3 months prior to screening.
6. Has ability to ovulate as determined by vaginal ultrasound scan measurements (i.e., measurement of Max FD and double-layer endometrial thickness) during the pre-treatment screening period. Vaginal ultrasound scan measurements will be performed 9 days (± 1) after the start of the last menstruation or withdrawal bleeding and every 3 days ± 1 day onwards until ovulation is observed, during the pre-treatment screening period. After ovulation, the subject must have P levels > 16 nmol/L on two subsequent occasions within 5 days (time of ovulation determined by vaginal ultrasound scan measurement).
7. Medically healthy with no clinically significant abnormalities in medical history, physical and gynecological examination, laboratory profiles, or vital signs, as judged by the Investigator.
8. If sexually active, subject should use a non-hormonal IUD or if she or her partner is not surgically sterilized, agrees to have her male partner use a male condom without spermicide from the time of screening and throughout completion of the study (including the follow-up period).
9. A normal cervical Pap (Papanicolaou) test (Pap <3) within 24 months of screening (first visit) should be documented at the time of screening (first visit); subjects who do not have documentation of normal cervical Pap test within 24 months of screening (first visit) must have a cervical Pap test performed at screening with a normal result. 10. Subject must understand the study procedures in the informed consent form (ICF) and be willing and able to comply with the protocol and provides written informed consent for the trial, including for Future Biomedical Research.
Exclusion criteria
1. Subject is 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 opinion of the Investigator, 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 screening.
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); headaches with focal neurological symptoms or migraine headaches with aura; 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 or progestogen dependent neoplasia; cervical cancer.
7. Positive pregnancy test or lactating.
8. Abnormal cervical Pap test within 24 months prior to screening (first visit).
9. Within the past 6 months prior to screening, 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 prolapsed 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 gynecological examination 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 breathalyzer screen at screening or on Day 1.
14. Drink alcohol in excess of 14 units per week, with one unit = 125 mL of wine or 284 mL of beer or 25 mL of 45% alcohol.
15. Positive urine cotinine at screening and Day 1 (threshold >100 ng/mL). Note: subjects may be retested 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 treatment listed in Table 1 of the protocol
18. Hemoglobin level below 11 g/dL at screening.
19. Blood or plasma donation (* 500 mL) within 60 days prior to screening.
20. Donation of bone marrow within the last 6 months prior to screening.
21. Is working at or has an immediate family member (spouse or children) who works at the investigational site or is a Sponsor staff member directly involved with this trial.
22. Participation in another clinical trial within 30 days prior to screening. The 30-day window will be derived from the date of the last blood collection or last dosing, whichever is later, in the previous study to the screening visit of the current study.
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2016-000693-38-NL |
| CCMO | NL57712.056.16 |