Dysmenorrhea
Conditions
Brief summary
The study investigates four vaginal ring groups with respect to relief of primary dysmenorrhea, and should identify at least one vaginal ring that shows clinically relevant treatment efficacy in relief of primary dysmenorrhea.
Detailed description
The study investigates four vaginal ring groups with respect to relief of primary dysmenorrhea, and should identify at least one vaginal ring that shows clinically relevant treatment efficacy in relief of primary dysmenorrhea. The intake of ibuprofen rescue medication and the impact on daily life is investigated: change from baseline data of these two variables will be compared between each of the four active ring groups, separately, and the placebo ring group. Furthermore, the study assesses the measurement characteristics and psychometric properties of a newly developed Dysmenorrhea Daily Dairy. Vaginal bleeding pattern and general safety and tolerability will also be evaluated.
Interventions
DRUGNomegestrol acetate contraceptive vaginal ring (NOMAC-CVR)
Either 700 or 900 mcg NOMAC and 300 mcg E2 intravaginal ring for two 28-day cycles
DRUGEtonogestrel containing contraceptive vaginal ring (ENG-CVR)
Either 100 or 125 mcg ENG and 300 mcg E2, intravaginally for two 28-day cycles
DRUGPlacebo
Placebo to match vaginal ring, intravaginally for two 28-day cycles
DRUGIbuprofen
Ibuprofen 400 mg will be dispensed throughout the entire study as needed as rescue medication for treating menstrual cramping pain. The maximum daily ibuprofen dose is 3200 mg (8 tablets)
Sponsors
Organon and Co
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 50 Years
Healthy volunteers
No
Inclusion criteria
* Body mass index (BMI) ≥18 and ≤35 * Established diagnosis of primary dysmenorrhea * If of child-bearing potential must agree to use condoms for contraception during the entire screening period, treatment period, and post-treatment period until the final study visit, unless she or her partner are surgically sterilized * Agree to stop using hormonal contraceptive (combined or progestin-only), or a non hormonal intrauterine device (IUD) * Regular menstrual cycles ranging from 24 to 35 days in length
Exclusion criteria
* Any of the following contraindications to the use of contraceptive steroids including: presence or a history of venous or arterial thrombotic/thromboembolic events or cerebrovascular accident (stroke, history of migraine with focal neurological symptoms, diabetes mellitus with vascular involvement, severe or multiple risk factor(s) for venous or arterial thrombosis, severe dyslipoproteinemia, severe hypertension, pancreatitis or a history thereof if associated with severe hypertriglyceridaemia, presence or history of severe hepatic (liver) disease, including benign or malignant tumors, known or suspected sex steroid-influenced malignancies, and/or undiagnosed vaginal bleeding * Pregnant or breastfeeding * Secondary dysmenorrhea * Has not had spontaneous menstruation following a delivery or abortion * Participated in an investigational drug study within 30 days * History of malignancy ≤5 years * Documented abnormal cervical smear result within 6 months * Use of recreational or illicit drugs * Consumes \>2 alcoholic drinks per day or \>14 alcoholic drinks per week, or engages in binge drinking * Allergy/sensitivity to ibuprofen, or any contraindication to its use, or has experienced asthma, urticaria, or allergic-type reactions after taking aspirin, or other nonsteroidal anti inflammatory drugs * Has been sterilized using a fallopian tube occlusion device * Is receiving, or has received sex hormones for any purpose other than contraception within 2 months or injectable hormonal contraception within 6 months
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Mean Menstrual Cramping Pain Score Through Cycle 2 | Baseline and Day 29 to 56 (Cycle 2) | The Mean Menstrual Cramping Pain score was calculated as the average of the three highest daily menstrual cramping scores (item #3 of the Menstrual Distress Questionnaire: Cramps) in the baseline cycle and treatment Cycle 2, respectively. The daily menstrual cramping pain score was based on five pain categories: none (0); mild (1); moderate (2); strong (3); and severe (4). In case of absence of withdrawal bleeding, or onset of menstruation, the mean of the three highest menstrual cramping pain scores recorded within Days 21-28 was used for analysis. The Mean Menstrual Cramping Pain Score in the baseline or subsequent cycles could range from 0 (none) to 4 (severe). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Total Mean Impact Score Through Cycle 2 | Baseline and Day 29 to 56 (Cycle 2) | Total Mean Impact Score is the mean of the sum of the daily responses to questions 6, 8, 9, and 10 in the Dysmenorrhea Daily e-Dairy, as recorded within the menstrual cramping pain analysis window. These questions assessed how much interference there was from pelvic cramping pain on work/school activities (Q6), physical activities (Q8), social/leisure activities (Q9) and sleep (Q10). Each question was rated on a 5-point (0-4) scale, with 0 being not at all, 1 slightly, 2 moderately, 3 quite a bit and 4 extremely. The total mean impact score could thus range from 0 (lowest possible impact) to 16 (highest possible impact). |
| Change From Baseline in Number of Ibuprofen Tablets Taken Through Cycle 2 | Baseline and Day 29 to 56 (Cycle 2) | Participants were provided with ibuprofen 400 mg tablets at the screening visit to be taken throughout the study as needed as rescue medication for treating menstrual cramping pain. The maximum daily ibuprofen dose was 3200 mg (8 tablets). Participants were instructed to take the provided ibuprofen, and no other medications, for the relief of menstrual cramping pain, and to record their ibuprofen usage in their e-Diaries. |
| Change From Baseline in Number of Days of Ibuprofen Intake Through Cycle 2 | Baseline and Day 29 to 56 (Cycle 2) | Participants were provided with ibuprofen 400 mg tablets at the screening visit to be taken throughout the study as needed as rescue medication for treating menstrual cramping pain. The maximum daily ibuprofen dose was 3200 mg (8 tablets). Participants were instructed to take the provided ibuprofen, and no other medications, for the relief of menstrual cramping pain, and to record their ibuprofen usage in their e-Diaries. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| NOMAC-E2 700/300 mcg NOMAC-E2 700/300 mcg was administered for two 28-day treatment periods, each period (cycle) consisting of 21 days of vaginal ring use followed by 7 vaginal ring-free days. | 86 |
| NOMAC-E2 900/300 mcg NOMAC-E2 900/300 mcg administered for two 28-day treatment periods, each period (cycle) consisting of 21 days of vaginal ring use followed by 7 vaginal ring-free days. | 91 |
| ENG-E2 100/300 mcg ENG-E2 100/300 mcg was administered for two 28-day treatment periods, each period (cycle) consisting of 21 days of vaginal ring use followed by 7 vaginal ring-free days. | 87 |
| ENG-E2 125/300 mcg ENG-E2 125/300 mcg was administered for two 28-day treatment periods, each period (cycle) consisting of 21 days of vaginal ring use followed by 7 vaginal ring-free days. | 85 |
| Placebo Placebo was administered for two 28-day treatment periods, each period (cycle) consisting of 21 days of vaginal ring use followed by 7 vaginal ring-free days. | 90 |
| Total | 439 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 2 | 2 | 2 | 3 | 3 |
| Overall Study | Lost to Follow-up | 0 | 0 | 0 | 0 | 3 |
| Overall Study | Non-compliance with protocol | 0 | 3 | 1 | 1 | 2 |
| Overall Study | Non-compliance with study drug | 0 | 0 | 3 | 0 | 1 |
| Overall Study | Pregnancy | 0 | 0 | 0 | 0 | 1 |
| Overall Study | Subject moved | 0 | 0 | 0 | 1 | 0 |
| Overall Study | Subject withdrew consent | 0 | 1 | 2 | 1 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | NOMAC-E2 700/300 mcg | NOMAC-E2 900/300 mcg | ENG-E2 100/300 mcg | ENG-E2 125/300 mcg | Placebo | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 28.7 Years STANDARD_DEVIATION 7.5 | 28.7 Years STANDARD_DEVIATION 8.1 | 29.0 Years STANDARD_DEVIATION 7.7 | 28.3 Years STANDARD_DEVIATION 7.8 | 28.4 Years STANDARD_DEVIATION 8.2 | 28.6 Years STANDARD_DEVIATION 7.8 |
| Sex: Female, Male Female | 86 Participants | 91 Participants | 87 Participants | 85 Participants | 90 Participants | 439 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 12 / 86 | 11 / 91 | 14 / 86 | 7 / 85 | 11 / 90 |
| serious Total, serious adverse events | 0 / 86 | 1 / 91 | 0 / 86 | 1 / 85 | 0 / 90 |
Outcome results
Primary
Change From Baseline in Mean Menstrual Cramping Pain Score Through Cycle 2
The Mean Menstrual Cramping Pain score was calculated as the average of the three highest daily menstrual cramping scores (item #3 of the Menstrual Distress Questionnaire: Cramps) in the baseline cycle and treatment Cycle 2, respectively. The daily menstrual cramping pain score was based on five pain categories: none (0); mild (1); moderate (2); strong (3); and severe (4). In case of absence of withdrawal bleeding, or onset of menstruation, the mean of the three highest menstrual cramping pain scores recorded within Days 21-28 was used for analysis. The Mean Menstrual Cramping Pain Score in the baseline or subsequent cycles could range from 0 (none) to 4 (severe).
Time frame: Baseline and Day 29 to 56 (Cycle 2)
Population: All randomized participants in whom a vaginal ring was inserted and who had at least one baseline or one post-baseline value for Menstrual Cramping Pain Score
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| NOMAC-E2 700/300 mcg | Change From Baseline in Mean Menstrual Cramping Pain Score Through Cycle 2 | -1.7 Units on a scale |
| NOMAC-E2 900/300 mcg | Change From Baseline in Mean Menstrual Cramping Pain Score Through Cycle 2 | -1.7 Units on a scale |
| ENG-E2 100/300 mcg | Change From Baseline in Mean Menstrual Cramping Pain Score Through Cycle 2 | -1.9 Units on a scale |
| ENG-E2 125/300 mcg | Change From Baseline in Mean Menstrual Cramping Pain Score Through Cycle 2 | -1.7 Units on a scale |
| Placebo | Change From Baseline in Mean Menstrual Cramping Pain Score Through Cycle 2 | -1.2 Units on a scale |
p-value: <0.00195% CI: [-1, -0.2]cLDA
p-value: <0.00195% CI: [-0.9, -0.2]cLDA
p-value: <0.00195% CI: [-1.1, -0.4]cLDA
p-value: <0.00195% CI: [-0.9, -0.2]cLDA
Secondary
Change From Baseline in Number of Days of Ibuprofen Intake Through Cycle 2
Participants were provided with ibuprofen 400 mg tablets at the screening visit to be taken throughout the study as needed as rescue medication for treating menstrual cramping pain. The maximum daily ibuprofen dose was 3200 mg (8 tablets). Participants were instructed to take the provided ibuprofen, and no other medications, for the relief of menstrual cramping pain, and to record their ibuprofen usage in their e-Diaries.
Time frame: Baseline and Day 29 to 56 (Cycle 2)
Population: All randomized participants in whom a vaginal ring was inserted and who had at least one baseline or one post-baseline value for Number of Days of Ibuprofen Intake
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| NOMAC-E2 700/300 mcg | Change From Baseline in Number of Days of Ibuprofen Intake Through Cycle 2 | -1.3 Days of ibuprofen intake |
| NOMAC-E2 900/300 mcg | Change From Baseline in Number of Days of Ibuprofen Intake Through Cycle 2 | -1.7 Days of ibuprofen intake |
| ENG-E2 100/300 mcg | Change From Baseline in Number of Days of Ibuprofen Intake Through Cycle 2 | -1.7 Days of ibuprofen intake |
| ENG-E2 125/300 mcg | Change From Baseline in Number of Days of Ibuprofen Intake Through Cycle 2 | -1.4 Days of ibuprofen intake |
| Placebo | Change From Baseline in Number of Days of Ibuprofen Intake Through Cycle 2 | -1.1 Days of ibuprofen intake |
p-value: =0.44795% CI: [-0.6, 0.3]cLDA
p-value: =0.00395% CI: [-1, -0.1]cLDA
p-value: =0.00395% CI: [-1, -0.1]cLDA
p-value: =0.15695% CI: [-0.7, 0.2]cLDA
Secondary
Change From Baseline in Number of Ibuprofen Tablets Taken Through Cycle 2
Participants were provided with ibuprofen 400 mg tablets at the screening visit to be taken throughout the study as needed as rescue medication for treating menstrual cramping pain. The maximum daily ibuprofen dose was 3200 mg (8 tablets). Participants were instructed to take the provided ibuprofen, and no other medications, for the relief of menstrual cramping pain, and to record their ibuprofen usage in their e-Diaries.
Time frame: Baseline and Day 29 to 56 (Cycle 2)
Population: All randomized participants in whom a vaginal ring was inserted and who had at least one baseline or one post-baseline value for Number of Ibuprofen Tablets Taken
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| NOMAC-E2 700/300 mcg | Change From Baseline in Number of Ibuprofen Tablets Taken Through Cycle 2 | -6.4 Ibuprofen tablets |
| NOMAC-E2 900/300 mcg | Change From Baseline in Number of Ibuprofen Tablets Taken Through Cycle 2 | -6.3 Ibuprofen tablets |
| ENG-E2 100/300 mcg | Change From Baseline in Number of Ibuprofen Tablets Taken Through Cycle 2 | -7.1 Ibuprofen tablets |
| ENG-E2 125/300 mcg | Change From Baseline in Number of Ibuprofen Tablets Taken Through Cycle 2 | -6.0 Ibuprofen tablets |
| Placebo | Change From Baseline in Number of Ibuprofen Tablets Taken Through Cycle 2 | -4.8 Ibuprofen tablets |
p-value: =0.02695% CI: [-3.4, 0.2]cLDA
p-value: =0.03695% CI: [-3.3, 0.2]cLDA
p-value: =0.00295% CI: [-4.1, -0.5]cLDA
p-value: =0.195% CI: [-3, 0.6]cLDA
Secondary
Change From Baseline in Total Mean Impact Score Through Cycle 2
Total Mean Impact Score is the mean of the sum of the daily responses to questions 6, 8, 9, and 10 in the Dysmenorrhea Daily e-Dairy, as recorded within the menstrual cramping pain analysis window. These questions assessed how much interference there was from pelvic cramping pain on work/school activities (Q6), physical activities (Q8), social/leisure activities (Q9) and sleep (Q10). Each question was rated on a 5-point (0-4) scale, with 0 being not at all, 1 slightly, 2 moderately, 3 quite a bit and 4 extremely. The total mean impact score could thus range from 0 (lowest possible impact) to 16 (highest possible impact).
Time frame: Baseline and Day 29 to 56 (Cycle 2)
Population: All randomized participants in whom a vaginal ring was inserted and who had at least one baseline or one post-baseline value for Total Mean Impact Score
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| NOMAC-E2 700/300 mcg | Change From Baseline in Total Mean Impact Score Through Cycle 2 | -4.8 Units on a scale |
| NOMAC-E2 900/300 mcg | Change From Baseline in Total Mean Impact Score Through Cycle 2 | -5.0 Units on a scale |
| ENG-E2 100/300 mcg | Change From Baseline in Total Mean Impact Score Through Cycle 2 | -4.7 Units on a scale |
| ENG-E2 125/300 mcg | Change From Baseline in Total Mean Impact Score Through Cycle 2 | -4.3 Units on a scale |
| Placebo | Change From Baseline in Total Mean Impact Score Through Cycle 2 | -3.1 Units on a scale |
p-value: =0.00295% CI: [-3, -0.4]cLDA
p-value: <0.00195% CI: [-3.1, -0.6]cLDA
p-value: =0.00395% CI: [-2.9, -0.3]cLDA
p-value: =0.02495% CI: [-2.5, 0.1]cLDA