Efficacy and Safety of Etonogestrel + 17β-Estradiol Vagin... | NCT02668783

ID	Type	Description	Link
2015-004325-14	EudraCT Number

Label	Type	Description	Intervention Names
ENG-E2 125 μg/300 μg	Experimental	Participants will receive 4 cycles (or 6 cycles if also participating in the extension) of ENG-E2 125 μg/300 μg. Each cycle will consist of 21 days of vaginal ring use followed by 7 ring-free days.	Drug: Etonogestrel (ENG) 125 μg + 17β-estradiol (E2) 300 μg vaginal ring Drug: Ibuprofen
Placebo	Placebo Comparator	Participants will receive 4 cycles (or 6 cycles if also participating in the extension) of placebo. Each cycle will consist of 21 days of placebo vaginal ring use followed by 7 ring-free days.	Drug: Placebo vaginal ring Drug: Ibuprofen

Name	Type	Description	Arm Group Labels	Other Names
Etonogestrel (ENG) 125 μg + 17β-estradiol (E2) 300 μg vaginal ring	Drug	Up to 4 cycles (or 6 cycles if also participating in the extension) of ENG-E2 125 μg/300 μg administered intravaginally. Each cycle will consist of 21 days of vaginal ring use followed by 7 ring-free days.

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Percentage of Participants With ≥3 Point Reduction in Peak Pelvic Pain Score and no Increase in Number of Ibuprofen Tablets Taken at Treatment Cycle 2, Compared to Baseline.	Participants were asked to rate their worst pain or cramps in the past 24 hours on a scale of 0 to 10 (0=No pain or cramps to 10=Extreme pain or cramps) and to indicate the number of ibuprofen tablets they took during the 4-day cramping window. The peak pelvic pain score was to be calculated as the highest (daily) pelvic pain score observed within the cramping window of the cycle and the total number of ibuprofen tablets taken was to be based on the 4-day cramping window. The baseline peak pelvic pain score and number of ibuprofen tablets taken were to be defined as the mean value of the 2 peak pelvic pain scores and the mean value of the total number of ibuprofen tablets taken during the cramping window of each of the 2 menstruations during the screening period, respectively. The percentage of participants with a reduction in peak pelvic pain score of ≥3 points and no increase in the use of ibuprofen at Treatment Cycle 2 as compared to baseline was to be presented.	Baseline 4-day cramping window and Treatment Cycle 2 4-day cramping window, as determined by committee for each participant
Number of Participants Who Experienced an Adverse Event (AE)	An AE was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the study treatment, whether or not considered related to the use of study treatment. The number of participants who experienced an AE is presented.	Up to approximately 158 days
Number of Participants Who Discontinued Treatment Due to an AE	An AE was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the study treatment, whether or not considered related to the use of study treatment. The number of participants who discontinued study treatment due to an AE is presented.	Up to approximately 128 days

Secondary Outcomes

Measure	Description	Time Frame
Change From Baseline in Peak Pelvic Pain Score at Treatment Cycle 2	Participants were asked to rate their worst pain or cramps in the past 24 hours on a scale of 0 to 10 (0=No pain or cramps to 10=Extreme pain or cramps). The peak pelvic pain score was to be calculated as the highest (daily) pelvic pain score observed within the 4-day cramping window of the cycle. The baseline peak pelvic pain score was to be defined as the mean value of the 2 peak pelvic pain scores during the cramping window of each of the 2 menstruations during the screening period. The change from baseline in peak pelvic pain score at Treatment Cycle 2 was to be presented.

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

Post-menarcheal female, age ≤50 years, in good physical and mental health.
History of moderate to severe primary dysmenorrhea for the past 3 months or longer, and no history of recurrent non-menstrual pelvic pain intermittently or continuously throughout the month, and no history of dysmenorrhea secondary to structural pelvic pathology.
Body mass index (BMI) of ≥18 and <38 kg/m^2.
History of regular menstrual cycles with a cycle length between 24 and 32 days (inclusive) for the past three months.
Willing to adhere to use of the vaginal ring and to all required trial procedures, and not planning to relocate during the study.
Willing to use the rescue medication ibuprofen at the study recommended dose and no other pain medication for treatment of dysmenorrhea.

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.
Gynecologic conditions: surgically sterilized, has used hormonal contraceptives (pill, patch, ring, implant, intrauterine system) within the past 3 months, or currently uses non-hormonal intrauterine device (IUD); within past 6 months has had undiagnosed (unexplained) abnormal vaginal bleeding or any abnormal vaginal bleeding expected to recur during study; has gonorrhea, chlamydia, or trichomonas or symptomatic vaginitis/cervicitis; has abnormal cervical smear or positive high-risk human papillomavirus (HPV) test at screening or documented within 3 years of screening; 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.
Gastrointestinal and urologic disorders, including history of pancreatitis associated with severe hypertriglyceridemia; clinically significant liver disease, including active viral hepatitis or cirrhosis; or a history of the gastrointestinal or urologic tract which may cause pelvic pain.
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; known allergy/sensitivity or contraindication to ibuprofen, or has experienced asthma, urticaria, or allergic-type reactions after taking aspirin, or other nonsteroidal anti-inflammatory drugs; history of drug or alcohol abuse or dependence.
Known or suspected pregnancy, or had been pregnant or breastfeeding within past 2 months.
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

ID	Title	Description
FG000	ENG-E2 125 μg/300 μg	Participants received 4 (or 6 cycles if also participating in the extension) of ENG-E2 125 μg/300 μg. Each cycle consisted of 21 days of vaginal ring use followed by 7 ring-free days.
FG001	Placebo

ID	Title	Description
BG000	ENG-E2 125 μg/300 μg	Participants received 4 (or 6 cycles if also participating in the extension) of ENG-E2 125 μg/300 μg. Each cycle consisted of 21 days of vaginal ring use followed by 7 ring-free days.
BG001	Placebo	Participants received 4 (or 6 cycles if also participating in the extension) of placebo. Each cycle consisted of 21 days of placebo vaginal ring use followed by 7 ring-free days.
BG002	Total	Total of all reporting groups

Units	Counts
Participants	BG00013 BG00112 BG00225

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

Percentage of Participants With ≥3 Point Reduction in Peak Pelvic Pain Score and no Increase in Number of Ibuprofen Tablets Taken at Treatment Cycle 2, Compared to Baseline.

Participants were asked to rate their worst pain or cramps in the past 24 hours on a scale of 0 to 10 (0=No pain or cramps to 10=Extreme pain or cramps) and to indicate the number of ibuprofen tablets they took during the 4-day cramping window. The peak pelvic pain score was to be calculated as the highest (daily) pelvic pain score observed within the cramping window of the cycle and the total number of ibuprofen tablets taken was to be based on the 4-day cramping window. The baseline peak pelvic pain score and number of ibuprofen tablets taken were to be defined as the mean value of the 2 peak pelvic pain scores and the mean value of the total number of ibuprofen tablets taken during the cramping window of each of the 2 menstruations during the screening period, respectively. The percentage of participants with a reduction in peak pelvic pain score of ≥3 points and no increase in the use of ibuprofen at Treatment Cycle 2 as compared to baseline was to be presented.

Population was to consist of all participants in whom vaginal ring was inserted & who had ≥1 day of diary entry each within a 4-day cramping window during a baseline cycle & a treatment cycle. Due to termination, committee to determine cramping windows was not assembled, cramping windows were not determined & efficacy data could not be analyzed.

Posted

Baseline 4-day cramping window and Treatment Cycle 2 4-day cramping window, as determined by committee for each participant

ID	Title	Description
OG000	ENG-E2 125 μg/300 μg	Participants received 4 (or 6 cycles if also participating in the extension) of ENG-E2 125 μg/300 μg. Each cycle consisted of 21 days of vaginal ring use followed by 7 ring-free days.
OG001	Placebo	Participants received 4 (or 6 cycles if also participating in the extension) of placebo. Each cycle consisted of 21 days of placebo vaginal ring use followed by 7 ring-free days.

Units	Counts
Participants	OG0000 OG0010

Primary

Number of Participants Who Experienced an Adverse Event (AE)

An AE was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the study treatment, whether or not considered related to the use of study treatment. The number of participants who experienced an AE is presented.

All randomized participants in whom a vaginal ring was inserted.

Posted

Number

Participants

Up to approximately 158 days

ID	Title	Description
OG000	ENG-E2 125 μg/300 μg	Participants received 4 (or 6 cycles if also participating in the extension) of ENG-E2 125 μg/300 μg. Each cycle consisted of 21 days of vaginal ring use followed by 7 ring-free days.
OG001	Placebo	Participants received 4 (or 6 cycles if also participating in the extension) of placebo. Each cycle consisted of 21 days of placebo vaginal ring use followed by 7 ring-free days.

Units	Counts
Participants

Primary

Number of Participants Who Discontinued Treatment Due to an AE

All randomized participants in whom a vaginal ring was inserted.

Posted

Number

Participants

Up to approximately 128 days

ID	Title	Description
OG000	ENG-E2 125 μg/300 μg	Participants received 4 (or 6 cycles if also participating in the extension) of ENG-E2 125 μg/300 μg. Each cycle consisted of 21 days of vaginal ring use followed by 7 ring-free days.
OG001	Placebo	Participants received 4 (or 6 cycles if also participating in the extension) of placebo. Each cycle consisted of 21 days of placebo vaginal ring use followed by 7 ring-free days.

Units	Counts
Participants

Secondary

Change From Baseline in Peak Pelvic Pain Score at Treatment Cycle 2

Participants were asked to rate their worst pain or cramps in the past 24 hours on a scale of 0 to 10 (0=No pain or cramps to 10=Extreme pain or cramps).

The peak pelvic pain score was to be calculated as the highest (daily) pelvic pain score observed within the 4-day cramping window of the cycle. The baseline peak pelvic pain score was to be defined as the mean value of the 2 peak pelvic pain scores during the cramping window of each of the 2 menstruations during the screening period. The change from baseline in peak pelvic pain score at Treatment Cycle 2 was to be presented.

Population was to consist of all participants in whom a vaginal ring was inserted & who had ≥1 day of diary entry each within 4-day cramping window during a baseline cycle & a treatment cycle. Due to termination, committee to determine cramping windows was not assembled, cramping windows were not determined & efficacy data could not be analyzed.

Posted

Baseline 4-day cramping window and Treatment Cycle 2 4-day cramping window, as determined by committee for each participant

ID	Title	Description
OG000	ENG-E2 125 μg/300 μg	Participants received 4 (or 6 cycles if also participating in the extension) of ENG-E2 125 μg/300 μg. Each cycle consisted of 21 days of vaginal ring use followed by 7 ring-free days.
OG001	Placebo	Participants received 4 (or 6 cycles if also participating in the extension) of placebo. Each cycle consisted of 21 days of placebo vaginal ring use followed by 7 ring-free days.

Secondary

Change From Baseline in the Number of Days With no Impact on Items of Physical, Work/School and Social/Leisure Activities at Treatment Cycle 2

Participants were asked to indicate how much pain or cramps limited their physical, work/school and social/leisure activities and over the previous 24 hours. The level of negative impact of dysmenorrhea on daily life was scored on a 5-point scale (0=Not at all to 4=Extremely impacted). For each of the 3 impact items, the baseline score was to be defined as the mean value obtained from the 2 menstruations during the screening period. The change from baseline to Treatment Cycle 2 in the number of days during the cramping window with no impact of dysmenorrhea (score = 0) on each of the following items was to be presented: work/school, physical activities and leisure/social activities.

Population was to consist of all participants in whom a vaginal ring was inserted & who had ≥1 day of diary entry each within a 4-day cramping window during a baseline cycle & a treatment cycle. Due to termination, committee to determine cramping windows was not assembled, cramping windows were not determined & efficacy data could not be analyzed.

Posted

Baseline 4-day cramping window and Treatment Cycle 2 4-day cramping window, as determined by committee for each participant

ID	Title	Description
OG000	ENG-E2 125 μg/300 μg	Participants received 4 (or 6 cycles if also participating in the extension) of ENG-E2 125 μg/300 μg. Each cycle consisted of 21 days of vaginal ring use followed by 7 ring-free days.
OG001	Placebo

Secondary

Percentage of Participants With Pelvic Pain Score of "0" or "1" and no Use of Ibuprofen Tablets at Treatment Cycle 2

Participants were asked to rate their worst pain or cramps on a scale of 0 to 10 (0=No pain or cramps to 10=Extreme pain or cramps) and to indicate the number of ibuprofen tablets they took during the 4-day cramping window. The percentage of participants with no or minimal pelvic pain (score of "0" or "1") and no use of ibuprofen at Treatment Cycle 2 was to be presented.

Population was to consist of all participants in whom a vaginal ring was inserted & who had ≥1 day of diary entry each within a 4-day cramping window during Treatment Cycle 2. Due to termination, committee to determine cramping windows was not assembled, cramping windows were not determined & efficacy data could not be analyzed.

Posted

Treatment Cycle 2 4-day cramping window, as determined by committee for each participant

ID	Title	Description
OG000	ENG-E2 125 μg/300 μg	Participants received 4 (or 6 cycles if also participating in the extension) of ENG-E2 125 μg/300 μg. Each cycle consisted of 21 days of vaginal ring use followed by 7 ring-free days.
OG001	Placebo	Participants received 4 (or 6 cycles if also participating in the extension) of placebo. Each cycle consisted of 21 days of placebo vaginal ring use followed by 7 ring-free days.

Secondary

Percentage of Participants With ≥3 Point Reduction in Peak Pelvic Pain Score and a Decrease in Ibuprofen Tablet Intake at Treatment Cycle 2, Compared to Baseline

Participants were asked to rate their worst pain or cramps in the past 24 hours on a scale of 0 to 10 (0=No pain or cramps to 10=Extreme pain or cramps) and to indicate the number of ibuprofen tablets they took during the 4-day cramping window. The baseline peak pelvic pain score and number of ibuprofen tablets taken were to be defined as the mean value of the 2 peak pelvic pain scores and the mean value of the total number of ibuprofen tablets taken during the cramping window of each of the 2 menstruations during the screening period, respectively. The percentage of participants with a reduction in peak pelvic pain score of ≥3 points and a decrease in the use of ibuprofen at Treatment Cycle 2 as compared to baseline was to be presented.

Posted

Baseline 4-day cramping window and Treatment Cycle 2 4-day cramping window, as determined by committee for each participant

ID	Title	Description
OG000	ENG-E2 125 μg/300 μg	Participants received 4 (or 6 cycles if also participating in the extension) of ENG-E2 125 μg/300 μg. Each cycle consisted of 21 days of vaginal ring use followed by 7 ring-free days.

Secondary

Change From Baseline in Mean Pelvic Pain Score at Treatment Cycle 2

The mean pelvic pain score was to be calculated as the mean of the highest scores for pelvic pain observed within the 4-day cramping window of the screening or treatment cycle. The baseline mean pelvic pain score was to be defined as the mean value of the 2 mean pelvic pain scores of the 2 menstruations during the screening period. The change from baseline in mean pelvic pain score at Treatment Cycle 2 was to be presented.

Posted

Baseline 4-day cramping window and Treatment Cycle 2 4-day cramping window, as determined by committee for each participant

ID	Title	Description
OG000	ENG-E2 125 μg/300 μg	Participants received 4 (or 6 cycles if also participating in the extension) of ENG-E2 125 μg/300 μg. Each cycle consisted of 21 days of vaginal ring use followed by 7 ring-free days.
OG001	Placebo	Participants received 4 (or 6 cycles if also participating in the extension) of placebo. Each cycle consisted of 21 days of placebo vaginal ring use followed by 7 ring-free days.

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Vomiting in pregnancy	Pregnancy, puerperium and perinatal conditions	MedDRA 19.0	Systematic Assessment	EG0000 events0 affected13 at risk EG0011 events1 affected11 at risk
Mood swings	Psychiatric disorders	MedDRA 19.0	Systematic Assessment	EG0001 events1 affected13 at risk EG0010 events0 affected11 at risk
Vulvovaginal discomfort	Reproductive system and breast disorders	MedDRA 19.0	Systematic Assessment	EG0000 events0 affected13 at risk EG0011 events1 affected11 at risk

ID	Term
C044815	etonogestrel
D000071063	Endoglin
D004958	Estradiol
D003274	Contraceptive Devices, Female
D007052	Ibuprofen

ID	Term
D011956	Receptors, Cell Surface
D008565	Membrane Proteins
D011506	Proteins
D000602	Amino Acids, Peptides, and Proteins
D004963	Estrenes
D004962	Estranes
D013256	Steroids
D000072473	Fused-Ring Compounds
D011083	Polycyclic Compounds
D045166	Estradiol Congeners
D012739	Gonadal Steroid Hormones
D042341	Gonadal Hormones
D006728	Hormones
D006730	Hormones, Hormone Substitutes, and Hormone Antagonists
D003273	Contraceptive Devices
D004864	Equipment and Supplies
D010666	Phenylpropionates
D000146	Acids, Carbocyclic
D002264	Carboxylic Acids
D009930	Organic Chemicals

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 Microgram/300 Microgram	Participants received 4 (or 6 cycles if also participating in the extension) of ENG-E2 125 μg/300 μg. Each cycle consisted of 21 days of vaginal ring use followed by 7 ring-free days.			0	13	1	13
EG001	Placebo	Participants received 4 (or 6 cycles if also participating in the extension) of placebo. Each cycle consisted of 21 days of placebo vaginal ring use followed by 7 ring-free days.			0	11	2	11