Moderate to Severe Primary Dysmenorrhea
Conditions
Brief summary
The purpose of this study is to assess the etonogestrel (ENG) + 17β-estradiol (E2) vaginal ring's efficacy compared to a placebo vaginal ring in the treatment of dysmenorrhea at Treatment Cycle 2. In addition, this study will assess the safety and tolerability of the ENG-E2 vaginal rings. Primary hypothesis: Relative to the placebo ring, the ENG-E2 vaginal ring results in a greater proportion of participants with a ≥3 point reduction in peak pelvic pain score and no increase in the number of rescue pain relief (ibuprofen) tablets taken at Treatment Cycle 2 as compared to baseline.
Interventions
DRUGEtonogestrel (ENG) 125 μg + 17β-estradiol (E2) 300 μg vaginal ring
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.
Up to 4 cycles (or 6 cycles if also participating in the extension) of placebo administered intravaginally. Each cycle will consist of 21 days of placebo vaginal ring use followed by 7 ring-free days.
DRUGIbuprofen
Ibuprofen tablets, to be taken orally, will be provided for use as rescue medication for dysmenorrhea treatment throughout the study. Participants may take 400 mg every 4 hours as needed for pelvic pain/cramping, or as instructed by their physician according to local labeling for relief of menstrual pain.
Sponsors
Organon and Co
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
FEMALE
Age
No minimum to 50 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. | Baseline 4-day cramping window and Treatment Cycle 2 4-day cramping window, as determined by committee for each participant | 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. |
| Number of Participants Who Experienced an Adverse Event (AE) | Up to approximately 158 days | 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. |
| Number of Participants Who Discontinued Treatment Due to an AE | Up to approximately 128 days | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 | Baseline 4-day cramping window and Treatment Cycle 2 4-day cramping window, as determined by committee for each participant | 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. |
| Change From Baseline in Peak Pelvic Pain Score at Treatment Cycle 2 | Baseline 4-day cramping window and Treatment Cycle 2 4-day cramping window, as determined by committee for each participant | 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. |
| Change From Baseline in Mean Pelvic Pain Score at Treatment Cycle 2 | Baseline 4-day cramping window and Treatment Cycle 2 4-day cramping window, as determined by committee for each participant | 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. |
| 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 | Baseline 4-day cramping window and Treatment Cycle 2 4-day cramping window, as determined by committee for each participant | 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. |
| Percentage of Participants With Pelvic Pain Score of 0 or 1 and no Use of Ibuprofen Tablets at Treatment Cycle 2 | Treatment Cycle 2 4-day cramping window, as determined by committee for each participant | 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. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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. | 13 |
| 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. | 12 |
| Total | 25 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Pregnancy | 0 | 1 |
| Overall Study | Protocol Violation | 2 | 1 |
| Overall Study | Study terminated by sponsor | 9 | 10 |
| Overall Study | Subject moved | 1 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | ENG-E2 125 μg/300 μg | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 27 Years STANDARD_DEVIATION 7 | 29 Years STANDARD_DEVIATION 6 | 28 Years STANDARD_DEVIATION 6 |
| Sex: Female, Male Female | 13 Participants | 12 Participants | 25 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 1 / 13 | 2 / 11 |
| serious Total, serious adverse events | 0 / 13 | 0 / 11 |
Outcome results
Primary
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.
Time frame: Up to approximately 128 days
Population: All randomized participants in whom a vaginal ring was inserted.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ENG-E2 125 μg/300 μg | Number of Participants Who Discontinued Treatment Due to an AE | 0 Participants |
| Placebo | Number of Participants Who Discontinued Treatment Due to an AE | 0 Participants |
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.
Time frame: Up to approximately 158 days
Population: All randomized participants in whom a vaginal ring was inserted.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ENG-E2 125 μg/300 μg | Number of Participants Who Experienced an Adverse Event (AE) | 1 Participants |
| Placebo | Number of Participants Who Experienced an Adverse Event (AE) | 2 Participants |
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.
Time frame: Baseline 4-day cramping window and Treatment Cycle 2 4-day cramping window, as determined by committee for each participant
Population: 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.
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.
Time frame: Baseline 4-day cramping window and Treatment Cycle 2 4-day cramping window, as determined by committee for each participant
Population: 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.
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.
Time frame: Baseline 4-day cramping window and Treatment Cycle 2 4-day cramping window, as determined by committee for each participant
Population: 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.
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.
Time frame: Baseline 4-day cramping window and Treatment Cycle 2 4-day cramping window, as determined by committee for each participant
Population: 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.
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.
Time frame: Baseline 4-day cramping window and Treatment Cycle 2 4-day cramping window, as determined by committee for each participant
Population: 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.
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.
Time frame: Treatment Cycle 2 4-day cramping window, as determined by committee for each participant
Population: 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.