Efficacy and Safety of Etonogestrel + 17β-Estradiol Vagin... | NCT02616146

ID	Type	Description	Link
2014-002208-26	EudraCT Number
MK-1029-006	Other Identifier	Merck Protocol Number

Label	Type	Description	Intervention Names
ENG-E2 125 μg/300 μg	Experimental	Participants will receive up to 13 cycles of ENG-E2 125 μg/300 μg. Each cycle will consist of 21 days of vaginal ring use followed by 7 vaginal ring-free days.	Drug: ENG-E2 125 μg/300 μg vaginal ring
LNG-EE 150 μg/30 μg	Active Comparator	Participants will receive up to 13 cycles of LNG-EE 150 μg/30 μg. Each cycle will consist of one tablet per day for 21 days, followed a 7-day tablet-free interval.	Drug: LNG-EE 150 μg/30 μg COC

Name	Type	Description	Arm Group Labels	Other Names
ENG-E2 125 μg/300 μg vaginal ring	Drug	Up to 13 cycles of ENG-E2 125 μg/300 μg administered intravaginally, each cycle consisting of 21 days of vaginal ring use followed by 7 vaginal ring-free days.

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Number of In-Treatment Pregnancies Per 100 Woman-Years of Exposure in Participants 18-35 Years of Age (Pearl Index)	The Primary Efficacy Outcome Measure for this study was contraceptive efficacy, or the prevention of in-treatment pregnancy. The total incidence of in-treatment pregnancies was expressed as the Pearl Index, which is defined as the number of in-treatment pregnancies per 100 woman-years of exposure (one woman-year defined as a period of 365.25 days). NOTE: Due to early termination of this study, the ENG-E2 reporting group received only up to 10 cycles of treatment, and the LNG-EE reporting group received only up to 9 cycles of treatment.	Up to 1 year (13 28-day cycles)
Number of Participants Who Experienced an Adverse Event (AE)	An AE is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an AE. NOTE: Due to early termination of this study, the ENG-E2 reporting group received only up to 10 cycles of treatment, and the LNG-EE reporting group received only up to 9 cycles of treatment.	Up to 1 year
Number of Participants Who Discontinued Treatment Due to an AE	An AE is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an AE. NOTE: Due to early termination of this study, the ENG-E2 reporting group received only up to 10 cycles of treatment, and the LNG-EE reporting group received only up to 9 cycles of treatment.

Secondary Outcomes

Measure	Description	Time Frame
Number of Participants With Breakthrough Bleeding/Spotting (BTB-S), by Cycle	BTB-S was considered any bleeding/spotting that occurred during expected non-bleeding interval that was neither early nor continued withdrawal bleeding. BTB-S was classified as follows: Bleeding = any bloody vaginal discharge that required one or more sanitary pads or tampons per day; Spotting = any bloody vaginal discharge that required no sanitary pads or tampons per day. NOTE: Due to early termination of this study, the ENG-E2 reporting group received only up to 10 cycles of treatment, and the LNG-EE reporting group received only up to 9 cycles of treatment.

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

Premenopausal female at risk for pregnancy and seeking contraception.
Willing to use a hormonal contraceptive vaginal ring for up to 13 treatment cycles, and not intending to use any other form of contraception.
Body mass index (BMI) of ≥18 and <38 kg/m^2.
In good physical and mental health, based upon the medical judgment of the investigator.
Willing to adhere to use of vaginal ring and all required trial procedures.

Exclusion Criteria:

Cardiovascular risks and disorders, including history of venous thromboembolic [VTE] events, arterial thrombotic or thromboembolic [ATE] events, transient ischemic attack, angina pectoris, or claudication; at higher risk of VTE events due to recent prolonged immobilization, plans for surgery requiring prolonged immobilization, or a hereditary or acquired predisposition or elevated risk for venous or arterial thrombosis; currently smoking or uses tobacco/nicotine containing products and is ≥35 years of age; uncontrolled or severe hypertension; history of severe dyslipoproteinemia; <35 years of age with a history of migraine with aura or focal neurological symptoms or ≥35 years of age with a history of migraines with or without aura or focal neurologic symptoms; diabetes mellitus with end-organ involvement or >20 years duration; multiple cardiovascular risk factors such as ≥35 years of age, obesity, inadequately controlled hypertension, use of tobacco/ nicotine products, or inadequately controlled diabetes.
Gastrointestinal disorders, including history of pancreatitis associated with severe hypertriglyceridemia; clinically significant liver disease, including active viral hepatitis or cirrhosis; history of malabsorptive bariatric surgery.
Other medical disorders, including history of malignancy ≤5 years prior to signing informed consent except for adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer; any disease that may worsen under hormonal treatment such as disturbances in bile flow, systemic lupus erythematosus, pemphigoid gestationis or idiopathic icterus during previous pregnancy, middle-ear deafness, Sydenham chorea, or porphyria; known allergy/sensitivity or contraindication to the investigational products or their excipients; history of drug or alcohol abuse or dependence.
Recent, current, or suspected pregnancy; or has not had at least 2 menstrual cycles or has not completed two 28-day cycles of a hormonal contraceptive following a recent pregnancy; or is breastfeeding.
Gynecologic conditions: has gonorrhea, chlamydia, or trichomonas or symptomatic vaginitis/cervicitis; has abnormal cervical Pap test or positive high-risk human papillomavirus (HPV) test at screening or documented within 3 years of screening; currently using an intrauterine device/intrauterine system (IUD/IUS) or contraceptive implant; within past 6 months has had undiagnosed (unexplained) abnormal vaginal bleeding or any abnormal vaginal bleeding expected to recur during trial; has stage 4 pelvic organ prolapse (1 cm beyond introitus) or lesser degrees of prolapse with history of difficulty retaining tampons, vaginal rings, or other products within vagina.
Has used investigational drug and/or participated in other clinical trial within past 8 weeks.

Name	Affiliation	Role
Medical Director	Merck Sharp & Dohme LLC	Study Director

Facility	Status	City	State	ZIP	Country	Contacts
MSD Osterreich GmbH		Vienna			Austria
Merck Sharp & Dohme

ID	Title	Description
FG000	ENG-E2 125 μg/300 μg	Participants were to receive up to 13 cycles of etonogestrel + 17β-estradiol (ENG-E2) 125 μg/300 μg. Each cycle was to consist of 21 days of vaginal ring use followed by 7 vaginal ring-free days.
FG001	LNG-EE 150 μg/30 μg

ID	Title	Description
BG000	ENG-E2 125 μg/300 μg	Participants were to receive up to 13 cycles of ENG-E2 125 μg/300 μg. Each cycle was to consist of 21 days of vaginal ring use followed by 7 vaginal ring-free days.
BG001	LNG-EE 150 μg/30 μg	Participants were to receive up to 13 cycles of LNG-EE 150 μg/30 μg. Each cycle was to consist of one tablet per day for 21 days, followed a 7-day tablet-free interval.
BG002	Total	Total of all reporting groups

Units	Counts
Participants	BG0001512 BG001504 BG0022016

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Number of In-Treatment Pregnancies Per 100 Woman-Years of Exposure in Participants 18-35 Years of Age (Pearl Index)

The Primary Efficacy Outcome Measure for this study was contraceptive efficacy, or the prevention of in-treatment pregnancy. The total incidence of in-treatment pregnancies was expressed as the Pearl Index, which is defined as the number of in-treatment pregnancies per 100 woman-years of exposure (one woman-year defined as a period of 365.25 days). NOTE: Due to early termination of this study, the ENG-E2 reporting group received only up to 10 cycles of treatment, and the LNG-EE reporting group received only up to 9 cycles of treatment.

restricted Full Analysis Set (rFAS) population, defined as the population of women with at least one "at risk" treatment cycle without documented use of hormonal or nonhormonal backup contraception during the cycle, or participants with a treatment cycle (at risk or not) in which a pregnancy has occurred.

Posted

Number

Pregnancies per 100 woman years

Up to 1 year (13 28-day cycles)

ID	Title	Description
OG000	ENG-E2 125 μg/300 μg	Participants were to receive up to 13 cycles of ENG-E2 125 μg/300 μg. Each cycle was to consist of 21 days of vaginal ring use followed by 7 vaginal ring-free days.
OG001	LNG-EE 150 μg/30 μg	Participants were to receive up to 13 cycles of LNG-EE 150 μg/30 μg. Each cycle was to consist of one tablet per day for 21 days, followed a 7-day tablet-free interval.

Units	Counts
Participants	OG0001266 OG001404

Title

Denominators

Categories

Title	Measurements
	OG0001.54 OG0012.93

Primary

Number of Participants Who Experienced an Adverse Event (AE)

An AE is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an AE. NOTE: Due to early termination of this study, the ENG-E2 reporting group received only up to 10 cycles of treatment, and the LNG-EE reporting group received only up to 9 cycles of treatment.

This primary endpoint was based on all randomized participants in whom at least one vaginal ring was inserted or one comparator tablet was ingested.

Posted

Count of Participants

Participants

Up to 1 year

ID	Title	Description
OG000	ENG-E2 125 μg/300 μg	Participants were to receive up to 13 cycles of ENG-E2 125 μg/300 μg. Each cycle was to consist of 21 days of vaginal ring use followed by 7 vaginal ring-free days.
OG001	LNG-EE 150 μg/30 μg	Participants were to receive up to 13 cycles of LNG-EE 150 μg/30 μg. Each cycle was to consist of one tablet per day for 21 days, followed a 7-day tablet-free interval.

Primary

Number of Participants Who Discontinued Treatment Due to an AE

This primary endpoint was based on all randomized participants in whom at least one vaginal ring was inserted or one comparator tablet was ingested.

Posted

Count of Participants

Participants

Up to 1 year

ID	Title	Description
OG000	ENG-E2 125 μg/300 μg	Participants were to receive up to 13 cycles of ENG-E2 125 μg/300 μg. Each cycle was to consist of 21 days of vaginal ring use followed by 7 vaginal ring-free days.
OG001	LNG-EE 150 μg/30 μg	Participants were to receive up to 13 cycles of LNG-EE 150 μg/30 μg. Each cycle was to consist of one tablet per day for 21 days, followed a 7-day tablet-free interval.

Secondary

Number of Participants With Breakthrough Bleeding/Spotting (BTB-S), by Cycle

BTB-S was considered any bleeding/spotting that occurred during expected non-bleeding interval that was neither early nor continued withdrawal bleeding. BTB-S was classified as follows: Bleeding = any bloody vaginal discharge that required one or more sanitary pads or tampons per day; Spotting = any bloody vaginal discharge that required no sanitary pads or tampons per day. NOTE: Due to early termination of this study, the ENG-E2 reporting group received only up to 10 cycles of treatment, and the LNG-EE reporting group received only up to 9 cycles of treatment.

FAS Evaluable population, defined as a subset of FAS population that met the following criteria: a) No more than 2 consecutive days with missing bleeding data on Daily Diary unless there was at least one day with BTB-S during the ring-use interval; and b) treatment cycle length (including hormone-free interval) is between 22 and 35 days, inclusive.

Posted

Count of Participants

Participants

Up to 1 year

ID	Title	Description
OG000	ENG-E2 125 μg/300 μg	Participants were to receive up to 13 cycles of ENG-E2 125 μg/300 μg. Each cycle was to consist of 21 days of vaginal ring use followed by 7 vaginal ring-free days.
OG001	LNG-EE 150 μg/30 μg	Participants were to receive up to 13 cycles of LNG-EE 150 μg/30 μg. Each cycle was to consist of one tablet per day for 21 days, followed a 7-day tablet-free interval.

Secondary

Number of Participants With Absence of Withdrawal Bleeding (AWB), by Cycle

Participants were asked to keep a daily diary to record vaginal bleeding events. AWB was defined as no bleeding/spotting during the expected bleeding period. NOTE: Due to early termination of this study, the ENG-E2 reporting group received only up to 10 cycles of treatment, and the LNG-EE reporting group received only up to 9 cycles of treatment.

Posted

Count of Participants

Participants

Up to 1 year

ID	Title	Description
OG000	ENG-E2 125 μg/300 μg	Participants were to receive up to 13 cycles of ENG-E2 125 μg/300 μg. Each cycle was to consist of 21 days of vaginal ring use followed by 7 vaginal ring-free days.
OG001	LNG-EE 150 μg/30 μg	Participants were to receive up to 13 cycles of LNG-EE 150 μg/30 μg. Each cycle was to consist of one tablet per day for 21 days, followed a 7-day tablet-free interval.

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Visual acuity reduced	Eye disorders	MedDRA 19.0	Systematic Assessment	EG0000 events0 affected1,504 at risk EG0011 events1 affected492 at risk
Dengue fever	Infections and infestations	MedDRA 19.0	Systematic Assessment	EG0001 events1 affected1,504 at risk EG0010 events0 affected492 at risk
Gastrointestinal infection	Infections and infestations	MedDRA 19.0	Systematic Assessment	EG0001 events1 affected1,504 at risk EG0010 events0 affected492 at risk
Influenza	Infections and infestations	MedDRA 19.0	Systematic Assessment	EG0000 events0 affected1,504 at risk EG0011 events1 affected492 at risk
Urinary tract infection	Infections and infestations	MedDRA 19.0	Systematic Assessment	EG0001 events1 affected1,504 at risk EG0010 events0 affected492 at risk
Foreign body	Injury, poisoning and procedural complications	MedDRA 19.0	Systematic Assessment	EG0001 events1 affected1,504 at risk EG0010 events0 affected492 at risk
Epilepsy	Nervous system disorders	MedDRA 19.0	Systematic Assessment	EG0001 events1 affected1,504 at risk EG0010 events0 affected492 at risk
Syncope	Nervous system disorders	MedDRA 19.0	Systematic Assessment	EG0001 events1 affected1,504 at risk EG0010 events0 affected492 at risk
Device deployment issue	Product Issues	MedDRA 19.0	Systematic Assessment	EG0001 events1 affected1,504 at risk EG0010 events0 affected492 at risk
Cystitis haemorrhagic	Renal and urinary disorders	MedDRA 19.0	Systematic Assessment	EG0001 events1 affected1,504 at risk EG0010 events0 affected492 at risk
Pulmonary embolism	Respiratory, thoracic and mediastinal disorders	MedDRA 19.0	Systematic Assessment	EG0000 events0 affected1,504 at risk EG0011 events1 affected492 at risk
Deep vein thrombosis	Vascular disorders	MedDRA 19.0	Systematic Assessment	EG0000 events0 affected1,504 at risk EG0011 events1 affected492 at risk

ID	Term
D003273	Contraceptive Devices
D004864	Equipment and Supplies

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	ENG-E2 125 μg/300 μg	Participants were to receive up to 13 cycles of ENG-E2 125 μg/300 μg. Each cycle was to consist of 21 days of vaginal ring use followed by 7 vaginal ring-free days.			8	1,504	116	1,504
EG001	LNG-EE 150 μg/30 μg	Participants were to receive up to 13 cycles of LNG-EE 150 μg/30 μg. Each cycle was to consist of one tablet per day for 21 days, followed a 7-day tablet-free interval.			3	492	40	492