Endometriosis
Conditions
Brief summary
Purpose of the study is to test efficacy and safety of BAY98-7196 intravaginal ring as a new treatment option for patients with endometriosis-associated pelvic pain
Interventions
DRUGLevonorgestrel
Levonorgestrel 40 µg/d intravaginal ring (treatment for 84 days, 28 days wearing period for each ring) and Placebo 3-months depot intramuscular injection
DRUGAnastrozole
Participants received Anastrozole 300 µg/d or 600 µg/d or 1050 µg/d + Levonorgestrel 40 µg/d intravaginal ring (treatment for 84 days, 28 days wearing period for each ring) and Placebo 3-months depot intramuscular injection
DRUGPlacebo
Placebo intravaginal ring (treatment for 84 days, 28 days wearing period for each ring) and Placebo 3-months depot intramuscular injection
DRUGLupron / Leuprolide acetate
Placebo intravaginal ring (treatment for 84 days, 28 days wearing period for each ring) and Lupron / Leuprolide acetate 11.25 mg 3-months depot intramuscular injection
Sponsors
Bayer
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Premenopausal women18 years and above at the time of screening. * Women with endometriosis confirmed by laparoscopy or laparotomy within the last ten years but not less than 8 weeks before the screening visit In Japan, diagnosis based on imaging (transvaginal ultrasound or MRI) also qualifies for inclusion. * Moderate to severe endometriosis-associated pelvic pain (EAPP) of ≥5 in the last 28 days before screening visit 1 measured on the numeric rating scale (NRS; i.e. 4-week recall period). * At randomization: Adherence to the study procedures during the screening period, at least 24 diary entries of ESD item 1 during the last 28 consecutive days before the randomization visit, and a sum of the available ESD item 1 ('worst pain' on the daily NRS) entries during this period of at least 98 (corresponding to an average score of ≥ 3.5). * Willingness to use only ibuprofen as rescue pain medication for EAPP, if needed according to investigator's instruction. * Use of a non-hormonal barrier method (i.e. spermicide-coated condoms) for contraception from screening visit until the end of the study. This is not required if adequate contraception is achieved by vasectomy of the partner
Exclusion criteria
* Pregnancy or lactation (less than three months since delivery, abortion, or lactation before start of treatment) * Any diseases or conditions that can compromise the function of the body systems and could result in altered absorption, excessive accumulation, impaired metabolism, or altered excretion of the study drug * Any diseases or conditions that might interfere with the conduct of the study or the interpretation of the results. * Any disease or condition that may worsen under hormonal treatment according to the assessment and opinion of the investigator. * Undiagnosed abnormal genital bleeding * Wish for pregnancy during the study * Regular use of pain medication due to other underlying diseases * Non-responsiveness of endometriosis associated pelvic pain (EAPP) to GnRH-a or surgery (partial response is not exclusionary).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Absolute Change in Mean Pain of the 7 Days With Worst EAPP From Baseline (Last 28 Days Before Randomization) to End of Treatment (Last 28 Days of Treatment Period, Days 57-84) as Measured on NRS by Question 1 of ESD | Baseline (last 28 days before randomization), end of treatment (Treatment 3) (last 28 days of the treatment period, Day 57-84) | Pain intensity was assessed on 11-point (0-10) NRS by question 1. In question 1, participants were asked to rate the pain in the target area during the past 24 hours, where 0= no pain and 10= worst imaginable pain and responses were recorded in ESD. The mean pain of the 7 days with worst EAPP within a 28-day window was calculated as the sum of ESD item 1 on 7 days with worst EAPP within that 28-day window divided by 7. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Absolute Change in Mean Pain From Baseline (Last 28 Days Before Randomization) to First Cycle Under Study Treatment(Day1-28), Second Cycle Under Study Treatment(Day29-56),Third Cycle Under Study Treatment (Day57-84) as Measured on NRS by Question1 of ESD | Baseline (last 28 days before randomization), first cycle (Treatment 1) (Day 1-28), second cycle (Treatment 2) (Day 29-56), and third cycle (Treatment 3) (last 28 days of the treatment period, Day 57-84) | Pain intensity was assessed on 11-point (0-10) NRS by question 1. In question 1, subjects were asked to rate the pain in the target area during the past 24 hours, where 0= no pain and 10= worst imaginable pain and responses were recorded in ESD. The mean pain within a 28-day window was calculated as the sum of ESD item 1 within that 28-day window divided by the number with non-missing days within that 28-day window. Here, number of subjects 'n' signifies evaluable subjects for the respective category. |
| Percentage of Days During Baseline (Last 28 Days Before Randomization) and Cycles 1, 2, and 3 With Pain Greater Than or Equal to (>=) 7 as Measured on NRS by Question 1 of ESD as Measured on NRS by Question 1 of ESD | Baseline (last 28 days before randomization), Cycle 1 (Treatment 1), Cycle 2 (Treatment 2), and Cycle 3 (Treatment 3) | Pain intensity was assessed on 11-point (0-10) NRS by question 1. In question 1, subjects were asked to rate the pain in the target area during the past 24 hours, where 0= no pain and 10= worst imaginable pain and responses were recorded in ESD. The percentage of days with pain \>=7 within a 28-day window was calculated as 100 divided by the number of non-missing days within that 28-day window multiplied by the number of days within that 28-day window where item 1 of the ESD was \>=7. |
| Absolute Change in Mean Pain of the 7 Days With Worst EAPP From Baseline (Last 28 Days Before Randomization) to First Cycle Under Study Treatment (Day 1-28) and to Second Cycle Under Study Treatment (Day 29-56) as Measured on NRS by Question 1 of ESD | Baseline (last 28 days before randomization), first cycle (Treatment 1) (Day 1-28), second cycle (Treatment 2) (Day 29-56) | Pain intensity was assessed on 11-point (0-10) NRS by question 1. In question 1, subjects were asked to rate the pain in the target area during the past 24 hours, where 0= no pain and 10= worst imaginable pain and responses were recorded in ESD. The mean pain of the 7 days with worst EAPP within a 28-day window was calculated as the sum of ESD item 1 on 7 days with worst EAPP within that 28-day window divided by 7. |
| Percentage of Days During Baseline (Last 28 Days Before Randomization) and Cycles 1, 2, and 3 With Pain >=4 as Measured on NRS by Question 1 of ESD | Baseline (last 28 days before randomization), Cycle 1 (Treatment 1), Cycle 2 (Treatment 2), and Cycle 3 (Treatment 3) | Pain intensity was assessed on 11-point (0-10) NRS by question 1. In question 1, subjects were asked to rate the pain in the target area during the past 24 hours, where 0= no pain and 10= worst imaginable pain and responses were recorded in ESD. The percentage of days with pain \>=4 within a 28-day window was calculated as 100 divided by the number of non-missing days within that 28-day window multiplied by the number of days within that window where Item 1 of the ESD was \>=4. Here, number of subjects 'n' signifies evaluable subjects for the respective category. |
| Change From Baseline (Last 28 Days Before Randomization) to Cycle 1, 2, and 3 in Percentage of Days With Pain >=4 as Measured on NRS by Question 1 of ESD | Baseline (last 28 days before randomization), Cycle 1 (Treatment 1), Cycle 2 (Treatment 2), and Cycle 3 (Treatment 3) | Pain intensity was assessed on 11-point (0-10) NRS by question 1. In question 1, subjects were asked to rate the pain in the target area during the past 24 hours, where 0= no pain and 10= worst imaginable pain and responses were recorded in ESD. The percentage of days with pain \>=4 within a 28-day window was calculated as 100 divided by the number of non-missing days within that 28-day window multiplied by the number of days within that window where Item 1 of the ESD was \>=4. Here, number of subjects 'n' signifies evaluable subjects for the respective category. |
| Change From Baseline (Last 28 Days Before Randomization) to Cycle 1, 2, and 3 in Percentage of Days With Pain >=7 as Measured on NRS by Question 1 of ESD | Baseline (last 28 days before randomization), Cycle 1 (Treatment 1), Cycle 2 (Treatment 2), and Cycle 3 (Treatment 3) | Pain intensity was assessed on 11-point (0-10) NRS by question 1. In question 1, subjects were asked to rate the pain in the target area during the past 24 hours, where 0= no pain and 10= worst imaginable pain and responses were recorded in ESD. The percentage of days with pain \>=7 within a 28-day window was calculated as 100 divided by the number of non-missing days within that 28-day window multiplied by the number of days within that 28-day window where item 1 of the ESD was \>=7. Here, number of subjects 'n' signifies evaluable subjects for the respective category. |
Countries
Austria, Belgium, Canada, Czechia, Denmark, Finland, Germany, Japan, Netherlands, Norway, Poland, Spain, Switzerland, United States
Participant flow
Recruitment details
Study was conducted in fourteen countries in Austria, Belgium, Canada, Czech Republic, Denmark, Finland, Germany, Japan, Netherlands, Norway, Poland, Spain, Switzerland, United States, between 16 October 2014 (first participant first visit) and 24 October 2016 (last participant last visit).
Pre-assignment details
Overall, 605 participants were screened, of them 286 failed screening, remaining 319 participants were randomized and allocated to treatment, of them 14 participants did not receive study treatment for various reasons, remaining 305 participants were treated and 272 participants completed study treatment.
Participants by arm
| Arm | Count |
|---|---|
| LNG 40 mcg IVR + Placebo Injection Participants wore an intra-vaginal ring (IVR) of Levonorgestrel (LNG) 40 microgram (mcg) continuously for 84 days, with exchange of the IVR every 28 days and participants were administered a single dose of placebo matched to leuprorelin intramuscular (i.m.) injection (3 month depot) on the first day of study treatment. | 52 |
| ATZ 300 mcg / LNG 40 mcg IVR + Placebo Injection Participants wore IVR of Anastrozole (ATZ) 300 mcg and LNG 40 mcg (BAY98-7196) continuously for 84 days, with exchange of the IVR every 28 days and participants were administered a single dose of placebo matched to leuprorelin i.m. injection (3 month depot) on the first day of study treatment. | 53 |
| ATZ 600 mcg / LNG 40 mcg IVR + Placebo Injection Participants wore IVR of ATZ 600 mcg and LNG 40 mcg (BAY98-7196) continuously for 84 days, with exchange of the IVR every 28 days and participants were administered a single dose of placebo matched to leuprorelin i.m. injection (3 month depot) on the first day of study treatment. | 55 |
| ATZ 1050 mcg / LNG 40 mcg IVR + Placebo Injection Participants wore IVR of ATZ 1050 mcg and LNG 40 mcg (BAY98-7196) continuously for 84 days, with exchange of the IVR every 28 days and participants were administered a single dose of placebo matched to leuprorelin i.m. injection (3 month depot) on the first day of study treatment. | 53 |
| Placebo IVR + Leuprorelin Injection Participants wore IVR of placebo matched to BAY98-7196 continuously for 84 days, with exchange of the IVR every 28 days and participants were administered a single dose of 11.25 milligram (mg) leuprorelin i.m. injection (3 month depot) on the first day of study treatment. | 53 |
| Placebo IVR + Placebo Injection Participants wore IVR of placebo matched to BAY98-7196 continuously for 84 days, with exchange of the IVR every 28 days and participants were administered a single dose of placebo matched to leuprorelin i.m. injection (3 month depot) on the first day of study treatment. | 53 |
| Total | 319 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 4 | 8 | 3 | 4 | 3 | 3 |
| Overall Study | Lack of Efficacy | 0 | 2 | 1 | 0 | 0 | 1 |
| Overall Study | Lost to Follow-up | 0 | 0 | 0 | 0 | 1 | 0 |
| Overall Study | Other Reasons | 1 | 2 | 0 | 2 | 0 | 0 |
| Overall Study | Pregnancy | 1 | 0 | 0 | 0 | 2 | 0 |
| Overall Study | Protocol Violation | 0 | 2 | 0 | 1 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 0 | 1 | 0 | 0 | 3 |
Baseline characteristics
| Characteristic | LNG 40 mcg IVR + Placebo Injection | ATZ 300 mcg / LNG 40 mcg IVR + Placebo Injection | ATZ 600 mcg / LNG 40 mcg IVR + Placebo Injection | ATZ 1050 mcg / LNG 40 mcg IVR + Placebo Injection | Placebo IVR + Leuprorelin Injection | Placebo IVR + Placebo Injection | Total |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 33.27 years STANDARD_DEVIATION 7.4 | 32.96 years STANDARD_DEVIATION 8.79 | 33.96 years STANDARD_DEVIATION 5.73 | 33.72 years STANDARD_DEVIATION 7.85 | 33.7 years STANDARD_DEVIATION 6.29 | 34.89 years STANDARD_DEVIATION 7.13 | 33.75 years STANDARD_DEVIATION 7.23 |
| Body Mass Index (BMI) | 24.19 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 4.52 | 26.07 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 6.71 | 23.84 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 6.15 | 25.47 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 5.68 | 25.47 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 5.51 | 24.43 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 5.08 | 24.91 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 5.67 |
| Mean Pain of the 7 Days With Worst Endometriosis Associated Pelvic Pain (EAPP) | 7.8205 units on a scale STANDARD_DEVIATION 1.171 | 7.4664 units on a scale STANDARD_DEVIATION 0.9893 | 8.1905 units on a scale STANDARD_DEVIATION 1.068 | 7.5429 units on a scale STANDARD_DEVIATION 1.2568 | 7.8964 units on a scale STANDARD_DEVIATION 1.1952 | 7.6886 units on a scale STANDARD_DEVIATION 1.2389 | 7.7842 units on a scale STANDARD_DEVIATION 1.1702 |
| Percentage of Days With Pain >=4 | 86.0058 percentage of days STANDARD_DEVIATION 19.3136 | 84.7239 percentage of days STANDARD_DEVIATION 18.1713 | 89.029 percentage of days STANDARD_DEVIATION 16.3667 | 85.8451 percentage of days STANDARD_DEVIATION 17.9466 | 92.9141 percentage of days STANDARD_DEVIATION 11.6008 | 80.4397 percentage of days STANDARD_DEVIATION 20.1004 | 86.6042 percentage of days STANDARD_DEVIATION 17.6568 |
| Percentage of Days With Pain Greater Than or Equal to (>=) 7 | 50.094 percentage of days STANDARD_DEVIATION 35.5201 | 40.1521 percentage of days STANDARD_DEVIATION 29.8714 | 55.1155 percentage of days STANDARD_DEVIATION 33.7625 | 37.3044 percentage of days STANDARD_DEVIATION 30.2894 | 48.7001 percentage of days STANDARD_DEVIATION 33.6685 | 41.1847 percentage of days STANDARD_DEVIATION 33.0479 | 45.8234 percentage of days STANDARD_DEVIATION 33.1247 |
| Sex: Female, Male Female | 52 Participants | 53 Participants | 55 Participants | 53 Participants | 53 Participants | 53 Participants | 319 Participants |
| Sex: Female, Male Male | 0 Participants | 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 | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 38 / 49 | 40 / 50 | 40 / 54 | 35 / 49 | 35 / 50 | 38 / 53 |
| serious Total, serious adverse events | 2 / 49 | 0 / 50 | 0 / 54 | 2 / 49 | 3 / 50 | 4 / 53 |
Outcome results
Primary
Absolute Change in Mean Pain of the 7 Days With Worst EAPP From Baseline (Last 28 Days Before Randomization) to End of Treatment (Last 28 Days of Treatment Period, Days 57-84) as Measured on NRS by Question 1 of ESD
Pain intensity was assessed on 11-point (0-10) NRS by question 1. In question 1, participants were asked to rate the pain in the target area during the past 24 hours, where 0= no pain and 10= worst imaginable pain and responses were recorded in ESD. The mean pain of the 7 days with worst EAPP within a 28-day window was calculated as the sum of ESD item 1 on 7 days with worst EAPP within that 28-day window divided by 7.
Time frame: Baseline (last 28 days before randomization), end of treatment (Treatment 3) (last 28 days of the treatment period, Day 57-84)
Population: The dose-response analysis was performed using the MCP-Mod method with groups containing LNG, ATZ + LNG, and Placebo. It was analyzed using the per-protocol set (PPS) with evaluable participants for this endpoint.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| LNG 40 mcg IVR + Placebo Injection | Absolute Change in Mean Pain of the 7 Days With Worst EAPP From Baseline (Last 28 Days Before Randomization) to End of Treatment (Last 28 Days of Treatment Period, Days 57-84) as Measured on NRS by Question 1 of ESD | -1.8974 units on a scale | Standard Deviation 1.6416 |
| ATZ 300 mcg / LNG 40 mcg IVR + Placebo Injection | Absolute Change in Mean Pain of the 7 Days With Worst EAPP From Baseline (Last 28 Days Before Randomization) to End of Treatment (Last 28 Days of Treatment Period, Days 57-84) as Measured on NRS by Question 1 of ESD | -1.6061 units on a scale | Standard Deviation 1.6652 |
| ATZ 600 mcg / LNG 40 mcg IVR + Placebo Injection | Absolute Change in Mean Pain of the 7 Days With Worst EAPP From Baseline (Last 28 Days Before Randomization) to End of Treatment (Last 28 Days of Treatment Period, Days 57-84) as Measured on NRS by Question 1 of ESD | -2.4014 units on a scale | Standard Deviation 2.1833 |
| ATZ 1050 mcg / LNG 40 mcg IVR + Placebo Injection | Absolute Change in Mean Pain of the 7 Days With Worst EAPP From Baseline (Last 28 Days Before Randomization) to End of Treatment (Last 28 Days of Treatment Period, Days 57-84) as Measured on NRS by Question 1 of ESD | -2.2653 units on a scale | Standard Deviation 1.5972 |
| Placebo IVR + Leuprorelin Injection | Absolute Change in Mean Pain of the 7 Days With Worst EAPP From Baseline (Last 28 Days Before Randomization) to End of Treatment (Last 28 Days of Treatment Period, Days 57-84) as Measured on NRS by Question 1 of ESD | -3.7679 units on a scale | Standard Deviation 2.3507 |
| Placebo IVR + Placebo Injection | Absolute Change in Mean Pain of the 7 Days With Worst EAPP From Baseline (Last 28 Days Before Randomization) to End of Treatment (Last 28 Days of Treatment Period, Days 57-84) as Measured on NRS by Question 1 of ESD | -2.293 units on a scale | Standard Deviation 1.8247 |
Comparison: The analysis was performed by using MCP-Mod method using pre-defined candidate dose-response model.p-value: 0.3875Contrast tests for dose-response model
Comparison: The analysis was performed by using MCP-Mod method using pre-defined candidate dose-response model.p-value: 0.2676Contrast tests for dose-response model
Comparison: The analysis was performed by using MCP-Mod method using pre-defined candidate dose-response model.p-value: 0.3211Contrast tests for dose-response model
Comparison: The analysis was performed by using MCP-Mod method using pre-defined candidate dose-response model.p-value: 0.1721Contrast tests for dose-response model
Secondary
Absolute Change in Mean Pain From Baseline (Last 28 Days Before Randomization) to First Cycle Under Study Treatment(Day1-28), Second Cycle Under Study Treatment(Day29-56),Third Cycle Under Study Treatment (Day57-84) as Measured on NRS by Question1 of ESD
Pain intensity was assessed on 11-point (0-10) NRS by question 1. In question 1, subjects were asked to rate the pain in the target area during the past 24 hours, where 0= no pain and 10= worst imaginable pain and responses were recorded in ESD. The mean pain within a 28-day window was calculated as the sum of ESD item 1 within that 28-day window divided by the number with non-missing days within that 28-day window. Here, number of subjects 'n' signifies evaluable subjects for the respective category.
Time frame: Baseline (last 28 days before randomization), first cycle (Treatment 1) (Day 1-28), second cycle (Treatment 2) (Day 29-56), and third cycle (Treatment 3) (last 28 days of the treatment period, Day 57-84)
Population: It was analyzed using the per-protocol set (PPS) with evaluable participants for this endpoint.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LNG 40 mcg IVR + Placebo Injection | Absolute Change in Mean Pain From Baseline (Last 28 Days Before Randomization) to First Cycle Under Study Treatment(Day1-28), Second Cycle Under Study Treatment(Day29-56),Third Cycle Under Study Treatment (Day57-84) as Measured on NRS by Question1 of ESD | Baseline | 6.0938 units on a scale | Standard Deviation 1.5314 |
| LNG 40 mcg IVR + Placebo Injection | Absolute Change in Mean Pain From Baseline (Last 28 Days Before Randomization) to First Cycle Under Study Treatment(Day1-28), Second Cycle Under Study Treatment(Day29-56),Third Cycle Under Study Treatment (Day57-84) as Measured on NRS by Question1 of ESD | Change at Treatment 1 | -0.8472 units on a scale | Standard Deviation 1.1905 |
| LNG 40 mcg IVR + Placebo Injection | Absolute Change in Mean Pain From Baseline (Last 28 Days Before Randomization) to First Cycle Under Study Treatment(Day1-28), Second Cycle Under Study Treatment(Day29-56),Third Cycle Under Study Treatment (Day57-84) as Measured on NRS by Question1 of ESD | Change at Treatment 2 | -1.5774 units on a scale | Standard Deviation 1.6278 |
| LNG 40 mcg IVR + Placebo Injection | Absolute Change in Mean Pain From Baseline (Last 28 Days Before Randomization) to First Cycle Under Study Treatment(Day1-28), Second Cycle Under Study Treatment(Day29-56),Third Cycle Under Study Treatment (Day57-84) as Measured on NRS by Question1 of ESD | Change at Treatment 3 | -1.8001 units on a scale | Standard Deviation 1.7687 |
| ATZ 300 mcg / LNG 40 mcg IVR + Placebo Injection | Absolute Change in Mean Pain From Baseline (Last 28 Days Before Randomization) to First Cycle Under Study Treatment(Day1-28), Second Cycle Under Study Treatment(Day29-56),Third Cycle Under Study Treatment (Day57-84) as Measured on NRS by Question1 of ESD | Change at Treatment 2 | -1.5068 units on a scale | Standard Deviation 1.8707 |
| ATZ 300 mcg / LNG 40 mcg IVR + Placebo Injection | Absolute Change in Mean Pain From Baseline (Last 28 Days Before Randomization) to First Cycle Under Study Treatment(Day1-28), Second Cycle Under Study Treatment(Day29-56),Third Cycle Under Study Treatment (Day57-84) as Measured on NRS by Question1 of ESD | Change at Treatment 1 | -0.9009 units on a scale | Standard Deviation 1.3434 |
| ATZ 300 mcg / LNG 40 mcg IVR + Placebo Injection | Absolute Change in Mean Pain From Baseline (Last 28 Days Before Randomization) to First Cycle Under Study Treatment(Day1-28), Second Cycle Under Study Treatment(Day29-56),Third Cycle Under Study Treatment (Day57-84) as Measured on NRS by Question1 of ESD | Baseline | 5.7409 units on a scale | Standard Deviation 1.3044 |
| ATZ 300 mcg / LNG 40 mcg IVR + Placebo Injection | Absolute Change in Mean Pain From Baseline (Last 28 Days Before Randomization) to First Cycle Under Study Treatment(Day1-28), Second Cycle Under Study Treatment(Day29-56),Third Cycle Under Study Treatment (Day57-84) as Measured on NRS by Question1 of ESD | Change at Treatment 3 | -1.6411 units on a scale | Standard Deviation 1.8071 |
| ATZ 600 mcg / LNG 40 mcg IVR + Placebo Injection | Absolute Change in Mean Pain From Baseline (Last 28 Days Before Randomization) to First Cycle Under Study Treatment(Day1-28), Second Cycle Under Study Treatment(Day29-56),Third Cycle Under Study Treatment (Day57-84) as Measured on NRS by Question1 of ESD | Change at Treatment 3 | -2.0112 units on a scale | Standard Deviation 1.9575 |
| ATZ 600 mcg / LNG 40 mcg IVR + Placebo Injection | Absolute Change in Mean Pain From Baseline (Last 28 Days Before Randomization) to First Cycle Under Study Treatment(Day1-28), Second Cycle Under Study Treatment(Day29-56),Third Cycle Under Study Treatment (Day57-84) as Measured on NRS by Question1 of ESD | Change at Treatment 2 | -1.7349 units on a scale | Standard Deviation 1.9403 |
| ATZ 600 mcg / LNG 40 mcg IVR + Placebo Injection | Absolute Change in Mean Pain From Baseline (Last 28 Days Before Randomization) to First Cycle Under Study Treatment(Day1-28), Second Cycle Under Study Treatment(Day29-56),Third Cycle Under Study Treatment (Day57-84) as Measured on NRS by Question1 of ESD | Change at Treatment 1 | -1.0931 units on a scale | Standard Deviation 1.4002 |
| ATZ 600 mcg / LNG 40 mcg IVR + Placebo Injection | Absolute Change in Mean Pain From Baseline (Last 28 Days Before Randomization) to First Cycle Under Study Treatment(Day1-28), Second Cycle Under Study Treatment(Day29-56),Third Cycle Under Study Treatment (Day57-84) as Measured on NRS by Question1 of ESD | Baseline | 6.3694 units on a scale | Standard Deviation 1.53 |
| ATZ 1050 mcg / LNG 40 mcg IVR + Placebo Injection | Absolute Change in Mean Pain From Baseline (Last 28 Days Before Randomization) to First Cycle Under Study Treatment(Day1-28), Second Cycle Under Study Treatment(Day29-56),Third Cycle Under Study Treatment (Day57-84) as Measured on NRS by Question1 of ESD | Baseline | 5.7128 units on a scale | Standard Deviation 1.4415 |
| ATZ 1050 mcg / LNG 40 mcg IVR + Placebo Injection | Absolute Change in Mean Pain From Baseline (Last 28 Days Before Randomization) to First Cycle Under Study Treatment(Day1-28), Second Cycle Under Study Treatment(Day29-56),Third Cycle Under Study Treatment (Day57-84) as Measured on NRS by Question1 of ESD | Change at Treatment 3 | -2.1268 units on a scale | Standard Deviation 1.6877 |
| ATZ 1050 mcg / LNG 40 mcg IVR + Placebo Injection | Absolute Change in Mean Pain From Baseline (Last 28 Days Before Randomization) to First Cycle Under Study Treatment(Day1-28), Second Cycle Under Study Treatment(Day29-56),Third Cycle Under Study Treatment (Day57-84) as Measured on NRS by Question1 of ESD | Change at Treatment 1 | -1.1257 units on a scale | Standard Deviation 1.3317 |
| ATZ 1050 mcg / LNG 40 mcg IVR + Placebo Injection | Absolute Change in Mean Pain From Baseline (Last 28 Days Before Randomization) to First Cycle Under Study Treatment(Day1-28), Second Cycle Under Study Treatment(Day29-56),Third Cycle Under Study Treatment (Day57-84) as Measured on NRS by Question1 of ESD | Change at Treatment 2 | -1.9615 units on a scale | Standard Deviation 1.3966 |
| Placebo IVR + Leuprorelin Injection | Absolute Change in Mean Pain From Baseline (Last 28 Days Before Randomization) to First Cycle Under Study Treatment(Day1-28), Second Cycle Under Study Treatment(Day29-56),Third Cycle Under Study Treatment (Day57-84) as Measured on NRS by Question1 of ESD | Change at Treatment 2 | -2.6855 units on a scale | Standard Deviation 2.0601 |
| Placebo IVR + Leuprorelin Injection | Absolute Change in Mean Pain From Baseline (Last 28 Days Before Randomization) to First Cycle Under Study Treatment(Day1-28), Second Cycle Under Study Treatment(Day29-56),Third Cycle Under Study Treatment (Day57-84) as Measured on NRS by Question1 of ESD | Change at Treatment 3 | -3.502 units on a scale | Standard Deviation 2.3096 |
| Placebo IVR + Leuprorelin Injection | Absolute Change in Mean Pain From Baseline (Last 28 Days Before Randomization) to First Cycle Under Study Treatment(Day1-28), Second Cycle Under Study Treatment(Day29-56),Third Cycle Under Study Treatment (Day57-84) as Measured on NRS by Question1 of ESD | Change at Treatment 1 | -1.5315 units on a scale | Standard Deviation 1.4809 |
| Placebo IVR + Leuprorelin Injection | Absolute Change in Mean Pain From Baseline (Last 28 Days Before Randomization) to First Cycle Under Study Treatment(Day1-28), Second Cycle Under Study Treatment(Day29-56),Third Cycle Under Study Treatment (Day57-84) as Measured on NRS by Question1 of ESD | Baseline | 6.3962 units on a scale | Standard Deviation 1.4575 |
| Placebo IVR + Placebo Injection | Absolute Change in Mean Pain From Baseline (Last 28 Days Before Randomization) to First Cycle Under Study Treatment(Day1-28), Second Cycle Under Study Treatment(Day29-56),Third Cycle Under Study Treatment (Day57-84) as Measured on NRS by Question1 of ESD | Change at Treatment 1 | -0.9777 units on a scale | Standard Deviation 1.068 |
| Placebo IVR + Placebo Injection | Absolute Change in Mean Pain From Baseline (Last 28 Days Before Randomization) to First Cycle Under Study Treatment(Day1-28), Second Cycle Under Study Treatment(Day29-56),Third Cycle Under Study Treatment (Day57-84) as Measured on NRS by Question1 of ESD | Change at Treatment 2 | -1.8994 units on a scale | Standard Deviation 1.3069 |
| Placebo IVR + Placebo Injection | Absolute Change in Mean Pain From Baseline (Last 28 Days Before Randomization) to First Cycle Under Study Treatment(Day1-28), Second Cycle Under Study Treatment(Day29-56),Third Cycle Under Study Treatment (Day57-84) as Measured on NRS by Question1 of ESD | Change at Treatment 3 | -2.2228 units on a scale | Standard Deviation 1.4957 |
| Placebo IVR + Placebo Injection | Absolute Change in Mean Pain From Baseline (Last 28 Days Before Randomization) to First Cycle Under Study Treatment(Day1-28), Second Cycle Under Study Treatment(Day29-56),Third Cycle Under Study Treatment (Day57-84) as Measured on NRS by Question1 of ESD | Baseline | 5.6399 units on a scale | Standard Deviation 1.5312 |
Comparison: The analysis was performed by using MCP-Mod method using pre-defined candidate dose-response model.p-value: 0.5794Contrast tests for dose-response model
Comparison: The analysis was performed by using MCP-Mod method using pre-defined candidate dose-response model.p-value: 0.4301Contrast tests for dose-response model
Comparison: The analysis was performed by using MCP-Mod method using pre-defined candidate dose-response model.p-value: 0.5337Contrast tests for dose-response model
Comparison: The analysis was performed by using MCP-Mod method using pre-defined candidate dose-response model.p-value: 0.3396Contrast tests for dose-response model
Secondary
Absolute Change in Mean Pain of the 7 Days With Worst EAPP From Baseline (Last 28 Days Before Randomization) to First Cycle Under Study Treatment (Day 1-28) and to Second Cycle Under Study Treatment (Day 29-56) as Measured on NRS by Question 1 of ESD
Pain intensity was assessed on 11-point (0-10) NRS by question 1. In question 1, subjects were asked to rate the pain in the target area during the past 24 hours, where 0= no pain and 10= worst imaginable pain and responses were recorded in ESD. The mean pain of the 7 days with worst EAPP within a 28-day window was calculated as the sum of ESD item 1 on 7 days with worst EAPP within that 28-day window divided by 7.
Time frame: Baseline (last 28 days before randomization), first cycle (Treatment 1) (Day 1-28), second cycle (Treatment 2) (Day 29-56)
Population: It was analyzed using the per-protocol set (PPS) with evaluable participants for this endpoint.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LNG 40 mcg IVR + Placebo Injection | Absolute Change in Mean Pain of the 7 Days With Worst EAPP From Baseline (Last 28 Days Before Randomization) to First Cycle Under Study Treatment (Day 1-28) and to Second Cycle Under Study Treatment (Day 29-56) as Measured on NRS by Question 1 of ESD | Change at Treatment 1 | -0.7582 units on a scale | Standard Deviation 1.1518 |
| LNG 40 mcg IVR + Placebo Injection | Absolute Change in Mean Pain of the 7 Days With Worst EAPP From Baseline (Last 28 Days Before Randomization) to First Cycle Under Study Treatment (Day 1-28) and to Second Cycle Under Study Treatment (Day 29-56) as Measured on NRS by Question 1 of ESD | Change at Treatment 2 | -1.6447 units on a scale | Standard Deviation 1.4831 |
| ATZ 300 mcg / LNG 40 mcg IVR + Placebo Injection | Absolute Change in Mean Pain of the 7 Days With Worst EAPP From Baseline (Last 28 Days Before Randomization) to First Cycle Under Study Treatment (Day 1-28) and to Second Cycle Under Study Treatment (Day 29-56) as Measured on NRS by Question 1 of ESD | Change at Treatment 1 | -0.6849 units on a scale | Standard Deviation 1.3832 |
| ATZ 300 mcg / LNG 40 mcg IVR + Placebo Injection | Absolute Change in Mean Pain of the 7 Days With Worst EAPP From Baseline (Last 28 Days Before Randomization) to First Cycle Under Study Treatment (Day 1-28) and to Second Cycle Under Study Treatment (Day 29-56) as Measured on NRS by Question 1 of ESD | Change at Treatment 2 | -1.5126 units on a scale | Standard Deviation 2.0161 |
| ATZ 600 mcg / LNG 40 mcg IVR + Placebo Injection | Absolute Change in Mean Pain of the 7 Days With Worst EAPP From Baseline (Last 28 Days Before Randomization) to First Cycle Under Study Treatment (Day 1-28) and to Second Cycle Under Study Treatment (Day 29-56) as Measured on NRS by Question 1 of ESD | Change at Treatment 1 | -1.1463 units on a scale | Standard Deviation 1.3992 |
| ATZ 600 mcg / LNG 40 mcg IVR + Placebo Injection | Absolute Change in Mean Pain of the 7 Days With Worst EAPP From Baseline (Last 28 Days Before Randomization) to First Cycle Under Study Treatment (Day 1-28) and to Second Cycle Under Study Treatment (Day 29-56) as Measured on NRS by Question 1 of ESD | Change at Treatment 2 | -2.1224 units on a scale | Standard Deviation 2.2791 |
| ATZ 1050 mcg / LNG 40 mcg IVR + Placebo Injection | Absolute Change in Mean Pain of the 7 Days With Worst EAPP From Baseline (Last 28 Days Before Randomization) to First Cycle Under Study Treatment (Day 1-28) and to Second Cycle Under Study Treatment (Day 29-56) as Measured on NRS by Question 1 of ESD | Change at Treatment 1 | -1.0000 units on a scale | Standard Deviation 1.2579 |
| ATZ 1050 mcg / LNG 40 mcg IVR + Placebo Injection | Absolute Change in Mean Pain of the 7 Days With Worst EAPP From Baseline (Last 28 Days Before Randomization) to First Cycle Under Study Treatment (Day 1-28) and to Second Cycle Under Study Treatment (Day 29-56) as Measured on NRS by Question 1 of ESD | Change at Treatment 2 | -1.9959 units on a scale | Standard Deviation 1.3978 |
| Placebo IVR + Leuprorelin Injection | Absolute Change in Mean Pain of the 7 Days With Worst EAPP From Baseline (Last 28 Days Before Randomization) to First Cycle Under Study Treatment (Day 1-28) and to Second Cycle Under Study Treatment (Day 29-56) as Measured on NRS by Question 1 of ESD | Change at Treatment 1 | -1.2071 units on a scale | Standard Deviation 1.1978 |
| Placebo IVR + Leuprorelin Injection | Absolute Change in Mean Pain of the 7 Days With Worst EAPP From Baseline (Last 28 Days Before Randomization) to First Cycle Under Study Treatment (Day 1-28) and to Second Cycle Under Study Treatment (Day 29-56) as Measured on NRS by Question 1 of ESD | Change at Treatment 2 | -2.8607 units on a scale | Standard Deviation 2.0665 |
| Placebo IVR + Placebo Injection | Absolute Change in Mean Pain of the 7 Days With Worst EAPP From Baseline (Last 28 Days Before Randomization) to First Cycle Under Study Treatment (Day 1-28) and to Second Cycle Under Study Treatment (Day 29-56) as Measured on NRS by Question 1 of ESD | Change at Treatment 1 | -0.9048 units on a scale | Standard Deviation 1.1686 |
| Placebo IVR + Placebo Injection | Absolute Change in Mean Pain of the 7 Days With Worst EAPP From Baseline (Last 28 Days Before Randomization) to First Cycle Under Study Treatment (Day 1-28) and to Second Cycle Under Study Treatment (Day 29-56) as Measured on NRS by Question 1 of ESD | Change at Treatment 2 | -1.8022 units on a scale | Standard Deviation 1.5131 |
Comparison: The analysis was performed by using MCP-Mod method using pre-defined candidate dose-response model.p-value: 0.231Contrast tests for dose-response model
Comparison: The analysis was performed by using MCP-Mod method using pre-defined candidate dose-response model.p-value: 0.1865Contrast tests for dose-response model
Comparison: The analysis was performed by using MCP-Mod method using pre-defined candidate dose-response model.p-value: 0.1955Contrast tests for dose-response model
Comparison: The analysis was performed by using MCP-Mod method using pre-defined candidate dose-response model.p-value: 0.1416Contrast tests for dose-response model
Secondary
Change From Baseline (Last 28 Days Before Randomization) to Cycle 1, 2, and 3 in Percentage of Days With Pain >=4 as Measured on NRS by Question 1 of ESD
Pain intensity was assessed on 11-point (0-10) NRS by question 1. In question 1, subjects were asked to rate the pain in the target area during the past 24 hours, where 0= no pain and 10= worst imaginable pain and responses were recorded in ESD. The percentage of days with pain \>=4 within a 28-day window was calculated as 100 divided by the number of non-missing days within that 28-day window multiplied by the number of days within that window where Item 1 of the ESD was \>=4. Here, number of subjects 'n' signifies evaluable subjects for the respective category.
Time frame: Baseline (last 28 days before randomization), Cycle 1 (Treatment 1), Cycle 2 (Treatment 2), and Cycle 3 (Treatment 3)
Population: It was analyzed using the per-protocol set (PPS) with evaluable participants for this endpoint.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LNG 40 mcg IVR + Placebo Injection | Change From Baseline (Last 28 Days Before Randomization) to Cycle 1, 2, and 3 in Percentage of Days With Pain >=4 as Measured on NRS by Question 1 of ESD | Change at Treatment 1 | -12.8228 percentage of days | Standard Deviation 20.433 |
| LNG 40 mcg IVR + Placebo Injection | Change From Baseline (Last 28 Days Before Randomization) to Cycle 1, 2, and 3 in Percentage of Days With Pain >=4 as Measured on NRS by Question 1 of ESD | Change at Treatment 2 | -22.4950 percentage of days | Standard Deviation 28.1535 |
| LNG 40 mcg IVR + Placebo Injection | Change From Baseline (Last 28 Days Before Randomization) to Cycle 1, 2, and 3 in Percentage of Days With Pain >=4 as Measured on NRS by Question 1 of ESD | Change at Treatment 3 | -23.5498 percentage of days | Standard Deviation 30.2853 |
| ATZ 300 mcg / LNG 40 mcg IVR + Placebo Injection | Change From Baseline (Last 28 Days Before Randomization) to Cycle 1, 2, and 3 in Percentage of Days With Pain >=4 as Measured on NRS by Question 1 of ESD | Change at Treatment 2 | -26.8462 percentage of days | Standard Deviation 32.6194 |
| ATZ 300 mcg / LNG 40 mcg IVR + Placebo Injection | Change From Baseline (Last 28 Days Before Randomization) to Cycle 1, 2, and 3 in Percentage of Days With Pain >=4 as Measured on NRS by Question 1 of ESD | Change at Treatment 1 | -15.4147 percentage of days | Standard Deviation 24.0608 |
| ATZ 300 mcg / LNG 40 mcg IVR + Placebo Injection | Change From Baseline (Last 28 Days Before Randomization) to Cycle 1, 2, and 3 in Percentage of Days With Pain >=4 as Measured on NRS by Question 1 of ESD | Change at Treatment 3 | -27.4770 percentage of days | Standard Deviation 34.2051 |
| ATZ 600 mcg / LNG 40 mcg IVR + Placebo Injection | Change From Baseline (Last 28 Days Before Randomization) to Cycle 1, 2, and 3 in Percentage of Days With Pain >=4 as Measured on NRS by Question 1 of ESD | Change at Treatment 2 | -26.4468 percentage of days | Standard Deviation 34.4661 |
| ATZ 600 mcg / LNG 40 mcg IVR + Placebo Injection | Change From Baseline (Last 28 Days Before Randomization) to Cycle 1, 2, and 3 in Percentage of Days With Pain >=4 as Measured on NRS by Question 1 of ESD | Change at Treatment 1 | -15.1334 percentage of days | Standard Deviation 22.5347 |
| ATZ 600 mcg / LNG 40 mcg IVR + Placebo Injection | Change From Baseline (Last 28 Days Before Randomization) to Cycle 1, 2, and 3 in Percentage of Days With Pain >=4 as Measured on NRS by Question 1 of ESD | Change at Treatment 3 | -32.2600 percentage of days | Standard Deviation 37.4997 |
| ATZ 1050 mcg / LNG 40 mcg IVR + Placebo Injection | Change From Baseline (Last 28 Days Before Randomization) to Cycle 1, 2, and 3 in Percentage of Days With Pain >=4 as Measured on NRS by Question 1 of ESD | Change at Treatment 2 | -33.2423 percentage of days | Standard Deviation 27.3686 |
| ATZ 1050 mcg / LNG 40 mcg IVR + Placebo Injection | Change From Baseline (Last 28 Days Before Randomization) to Cycle 1, 2, and 3 in Percentage of Days With Pain >=4 as Measured on NRS by Question 1 of ESD | Change at Treatment 1 | -15.1947 percentage of days | Standard Deviation 21.174 |
| ATZ 1050 mcg / LNG 40 mcg IVR + Placebo Injection | Change From Baseline (Last 28 Days Before Randomization) to Cycle 1, 2, and 3 in Percentage of Days With Pain >=4 as Measured on NRS by Question 1 of ESD | Change at Treatment 3 | -35.1119 percentage of days | Standard Deviation 30.9316 |
| Placebo IVR + Leuprorelin Injection | Change From Baseline (Last 28 Days Before Randomization) to Cycle 1, 2, and 3 in Percentage of Days With Pain >=4 as Measured on NRS by Question 1 of ESD | Change at Treatment 2 | -37.7330 percentage of days | Standard Deviation 36.9484 |
| Placebo IVR + Leuprorelin Injection | Change From Baseline (Last 28 Days Before Randomization) to Cycle 1, 2, and 3 in Percentage of Days With Pain >=4 as Measured on NRS by Question 1 of ESD | Change at Treatment 1 | -21.4331 percentage of days | Standard Deviation 23.4546 |
| Placebo IVR + Leuprorelin Injection | Change From Baseline (Last 28 Days Before Randomization) to Cycle 1, 2, and 3 in Percentage of Days With Pain >=4 as Measured on NRS by Question 1 of ESD | Change at Treatment 3 | -53.4266 percentage of days | Standard Deviation 38.8452 |
| Placebo IVR + Placebo Injection | Change From Baseline (Last 28 Days Before Randomization) to Cycle 1, 2, and 3 in Percentage of Days With Pain >=4 as Measured on NRS by Question 1 of ESD | Change at Treatment 1 | -14.5323 percentage of days | Standard Deviation 20.967 |
| Placebo IVR + Placebo Injection | Change From Baseline (Last 28 Days Before Randomization) to Cycle 1, 2, and 3 in Percentage of Days With Pain >=4 as Measured on NRS by Question 1 of ESD | Change at Treatment 3 | -33.3421 percentage of days | Standard Deviation 25.7105 |
| Placebo IVR + Placebo Injection | Change From Baseline (Last 28 Days Before Randomization) to Cycle 1, 2, and 3 in Percentage of Days With Pain >=4 as Measured on NRS by Question 1 of ESD | Change at Treatment 2 | -30.9527 percentage of days | Standard Deviation 25.4665 |
Secondary
Change From Baseline (Last 28 Days Before Randomization) to Cycle 1, 2, and 3 in Percentage of Days With Pain >=7 as Measured on NRS by Question 1 of ESD
Pain intensity was assessed on 11-point (0-10) NRS by question 1. In question 1, subjects were asked to rate the pain in the target area during the past 24 hours, where 0= no pain and 10= worst imaginable pain and responses were recorded in ESD. The percentage of days with pain \>=7 within a 28-day window was calculated as 100 divided by the number of non-missing days within that 28-day window multiplied by the number of days within that 28-day window where item 1 of the ESD was \>=7. Here, number of subjects 'n' signifies evaluable subjects for the respective category.
Time frame: Baseline (last 28 days before randomization), Cycle 1 (Treatment 1), Cycle 2 (Treatment 2), and Cycle 3 (Treatment 3)
Population: It was analyzed using the per-protocol set (PPS) with evaluable participants for this endpoint.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LNG 40 mcg IVR + Placebo Injection | Change From Baseline (Last 28 Days Before Randomization) to Cycle 1, 2, and 3 in Percentage of Days With Pain >=7 as Measured on NRS by Question 1 of ESD | Change at Treatment 2 | -24.1404 percentage of days | Standard Deviation 28.5082 |
| LNG 40 mcg IVR + Placebo Injection | Change From Baseline (Last 28 Days Before Randomization) to Cycle 1, 2, and 3 in Percentage of Days With Pain >=7 as Measured on NRS by Question 1 of ESD | Change at Treatment 1 | -13.6756 percentage of days | Standard Deviation 22.6822 |
| LNG 40 mcg IVR + Placebo Injection | Change From Baseline (Last 28 Days Before Randomization) to Cycle 1, 2, and 3 in Percentage of Days With Pain >=7 as Measured on NRS by Question 1 of ESD | Change at Treatment 3 | -26.4197 percentage of days | Standard Deviation 31.4648 |
| ATZ 300 mcg / LNG 40 mcg IVR + Placebo Injection | Change From Baseline (Last 28 Days Before Randomization) to Cycle 1, 2, and 3 in Percentage of Days With Pain >=7 as Measured on NRS by Question 1 of ESD | Change at Treatment 3 | -20.8529 percentage of days | Standard Deviation 28.3939 |
| ATZ 300 mcg / LNG 40 mcg IVR + Placebo Injection | Change From Baseline (Last 28 Days Before Randomization) to Cycle 1, 2, and 3 in Percentage of Days With Pain >=7 as Measured on NRS by Question 1 of ESD | Change at Treatment 2 | -17.2826 percentage of days | Standard Deviation 29.0007 |
| ATZ 300 mcg / LNG 40 mcg IVR + Placebo Injection | Change From Baseline (Last 28 Days Before Randomization) to Cycle 1, 2, and 3 in Percentage of Days With Pain >=7 as Measured on NRS by Question 1 of ESD | Change at Treatment 1 | -12.5862 percentage of days | Standard Deviation 21.4336 |
| ATZ 600 mcg / LNG 40 mcg IVR + Placebo Injection | Change From Baseline (Last 28 Days Before Randomization) to Cycle 1, 2, and 3 in Percentage of Days With Pain >=7 as Measured on NRS by Question 1 of ESD | Change at Treatment 3 | -25.3052 percentage of days | Standard Deviation 33.5497 |
| ATZ 600 mcg / LNG 40 mcg IVR + Placebo Injection | Change From Baseline (Last 28 Days Before Randomization) to Cycle 1, 2, and 3 in Percentage of Days With Pain >=7 as Measured on NRS by Question 1 of ESD | Change at Treatment 1 | -15.0341 percentage of days | Standard Deviation 21.0071 |
| ATZ 600 mcg / LNG 40 mcg IVR + Placebo Injection | Change From Baseline (Last 28 Days Before Randomization) to Cycle 1, 2, and 3 in Percentage of Days With Pain >=7 as Measured on NRS by Question 1 of ESD | Change at Treatment 2 | -20.6791 percentage of days | Standard Deviation 30.2152 |
| ATZ 1050 mcg / LNG 40 mcg IVR + Placebo Injection | Change From Baseline (Last 28 Days Before Randomization) to Cycle 1, 2, and 3 in Percentage of Days With Pain >=7 as Measured on NRS by Question 1 of ESD | Change at Treatment 3 | -22.9682 percentage of days | Standard Deviation 28.8677 |
| ATZ 1050 mcg / LNG 40 mcg IVR + Placebo Injection | Change From Baseline (Last 28 Days Before Randomization) to Cycle 1, 2, and 3 in Percentage of Days With Pain >=7 as Measured on NRS by Question 1 of ESD | Change at Treatment 2 | -22.3713 percentage of days | Standard Deviation 24.4098 |
| ATZ 1050 mcg / LNG 40 mcg IVR + Placebo Injection | Change From Baseline (Last 28 Days Before Randomization) to Cycle 1, 2, and 3 in Percentage of Days With Pain >=7 as Measured on NRS by Question 1 of ESD | Change at Treatment 1 | -13.3722 percentage of days | Standard Deviation 19.6416 |
| Placebo IVR + Leuprorelin Injection | Change From Baseline (Last 28 Days Before Randomization) to Cycle 1, 2, and 3 in Percentage of Days With Pain >=7 as Measured on NRS by Question 1 of ESD | Change at Treatment 3 | -39.9516 percentage of days | Standard Deviation 33.8277 |
| Placebo IVR + Leuprorelin Injection | Change From Baseline (Last 28 Days Before Randomization) to Cycle 1, 2, and 3 in Percentage of Days With Pain >=7 as Measured on NRS by Question 1 of ESD | Change at Treatment 2 | -36.3540 percentage of days | Standard Deviation 34.9706 |
| Placebo IVR + Leuprorelin Injection | Change From Baseline (Last 28 Days Before Randomization) to Cycle 1, 2, and 3 in Percentage of Days With Pain >=7 as Measured on NRS by Question 1 of ESD | Change at Treatment 1 | -19.8898 percentage of days | Standard Deviation 25.9273 |
| Placebo IVR + Placebo Injection | Change From Baseline (Last 28 Days Before Randomization) to Cycle 1, 2, and 3 in Percentage of Days With Pain >=7 as Measured on NRS by Question 1 of ESD | Change at Treatment 2 | -26.9979 percentage of days | Standard Deviation 24.9493 |
| Placebo IVR + Placebo Injection | Change From Baseline (Last 28 Days Before Randomization) to Cycle 1, 2, and 3 in Percentage of Days With Pain >=7 as Measured on NRS by Question 1 of ESD | Change at Treatment 1 | -16.0105 percentage of days | Standard Deviation 19.019 |
| Placebo IVR + Placebo Injection | Change From Baseline (Last 28 Days Before Randomization) to Cycle 1, 2, and 3 in Percentage of Days With Pain >=7 as Measured on NRS by Question 1 of ESD | Change at Treatment 3 | -28.4273 percentage of days | Standard Deviation 29.6186 |
Secondary
Percentage of Days During Baseline (Last 28 Days Before Randomization) and Cycles 1, 2, and 3 With Pain >=4 as Measured on NRS by Question 1 of ESD
Pain intensity was assessed on 11-point (0-10) NRS by question 1. In question 1, subjects were asked to rate the pain in the target area during the past 24 hours, where 0= no pain and 10= worst imaginable pain and responses were recorded in ESD. The percentage of days with pain \>=4 within a 28-day window was calculated as 100 divided by the number of non-missing days within that 28-day window multiplied by the number of days within that window where Item 1 of the ESD was \>=4. Here, number of subjects 'n' signifies evaluable subjects for the respective category.
Time frame: Baseline (last 28 days before randomization), Cycle 1 (Treatment 1), Cycle 2 (Treatment 2), and Cycle 3 (Treatment 3)
Population: It was analyzed using the per-protocol set (PPS) with evaluable participants for this endpoint.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LNG 40 mcg IVR + Placebo Injection | Percentage of Days During Baseline (Last 28 Days Before Randomization) and Cycles 1, 2, and 3 With Pain >=4 as Measured on NRS by Question 1 of ESD | Treatment 2 | 61.8199 percentage of days | Standard Deviation 37.1217 |
| LNG 40 mcg IVR + Placebo Injection | Percentage of Days During Baseline (Last 28 Days Before Randomization) and Cycles 1, 2, and 3 With Pain >=4 as Measured on NRS by Question 1 of ESD | Treatment 1 | 71.8037 percentage of days | Standard Deviation 32.3658 |
| LNG 40 mcg IVR + Placebo Injection | Percentage of Days During Baseline (Last 28 Days Before Randomization) and Cycles 1, 2, and 3 With Pain >=4 as Measured on NRS by Question 1 of ESD | Treatment 3 | 60.2902 percentage of days | Standard Deviation 37.8585 |
| ATZ 300 mcg / LNG 40 mcg IVR + Placebo Injection | Percentage of Days During Baseline (Last 28 Days Before Randomization) and Cycles 1, 2, and 3 With Pain >=4 as Measured on NRS by Question 1 of ESD | Treatment 2 | 57.8777 percentage of days | Standard Deviation 34.7429 |
| ATZ 300 mcg / LNG 40 mcg IVR + Placebo Injection | Percentage of Days During Baseline (Last 28 Days Before Randomization) and Cycles 1, 2, and 3 With Pain >=4 as Measured on NRS by Question 1 of ESD | Treatment 1 | 69.3092 percentage of days | Standard Deviation 27.8642 |
| ATZ 300 mcg / LNG 40 mcg IVR + Placebo Injection | Percentage of Days During Baseline (Last 28 Days Before Randomization) and Cycles 1, 2, and 3 With Pain >=4 as Measured on NRS by Question 1 of ESD | Treatment 3 | 57.0171 percentage of days | Standard Deviation 34.3642 |
| ATZ 600 mcg / LNG 40 mcg IVR + Placebo Injection | Percentage of Days During Baseline (Last 28 Days Before Randomization) and Cycles 1, 2, and 3 With Pain >=4 as Measured on NRS by Question 1 of ESD | Treatment 2 | 62.5822 percentage of days | Standard Deviation 37.6989 |
| ATZ 600 mcg / LNG 40 mcg IVR + Placebo Injection | Percentage of Days During Baseline (Last 28 Days Before Randomization) and Cycles 1, 2, and 3 With Pain >=4 as Measured on NRS by Question 1 of ESD | Treatment 1 | 73.8956 percentage of days | Standard Deviation 31.6868 |
| ATZ 600 mcg / LNG 40 mcg IVR + Placebo Injection | Percentage of Days During Baseline (Last 28 Days Before Randomization) and Cycles 1, 2, and 3 With Pain >=4 as Measured on NRS by Question 1 of ESD | Treatment 3 | 56.7691 percentage of days | Standard Deviation 40.3803 |
| ATZ 1050 mcg / LNG 40 mcg IVR + Placebo Injection | Percentage of Days During Baseline (Last 28 Days Before Randomization) and Cycles 1, 2, and 3 With Pain >=4 as Measured on NRS by Question 1 of ESD | Treatment 2 | 52.6028 percentage of days | Standard Deviation 35.6106 |
| ATZ 1050 mcg / LNG 40 mcg IVR + Placebo Injection | Percentage of Days During Baseline (Last 28 Days Before Randomization) and Cycles 1, 2, and 3 With Pain >=4 as Measured on NRS by Question 1 of ESD | Treatment 1 | 70.6504 percentage of days | Standard Deviation 27.8528 |
| ATZ 1050 mcg / LNG 40 mcg IVR + Placebo Injection | Percentage of Days During Baseline (Last 28 Days Before Randomization) and Cycles 1, 2, and 3 With Pain >=4 as Measured on NRS by Question 1 of ESD | Treatment 3 | 50.7332 percentage of days | Standard Deviation 36.2903 |
| Placebo IVR + Leuprorelin Injection | Percentage of Days During Baseline (Last 28 Days Before Randomization) and Cycles 1, 2, and 3 With Pain >=4 as Measured on NRS by Question 1 of ESD | Treatment 1 | 70.2066 percentage of days | Standard Deviation 28.9333 |
| Placebo IVR + Leuprorelin Injection | Percentage of Days During Baseline (Last 28 Days Before Randomization) and Cycles 1, 2, and 3 With Pain >=4 as Measured on NRS by Question 1 of ESD | Treatment 3 | 38.6986 percentage of days | Standard Deviation 39.6045 |
| Placebo IVR + Leuprorelin Injection | Percentage of Days During Baseline (Last 28 Days Before Randomization) and Cycles 1, 2, and 3 With Pain >=4 as Measured on NRS by Question 1 of ESD | Treatment 2 | 54.0965 percentage of days | Standard Deviation 38.9629 |
| Placebo IVR + Placebo Injection | Percentage of Days During Baseline (Last 28 Days Before Randomization) and Cycles 1, 2, and 3 With Pain >=4 as Measured on NRS by Question 1 of ESD | Treatment 2 | 49.487 percentage of days | Standard Deviation 31.3566 |
| Placebo IVR + Placebo Injection | Percentage of Days During Baseline (Last 28 Days Before Randomization) and Cycles 1, 2, and 3 With Pain >=4 as Measured on NRS by Question 1 of ESD | Treatment 3 | 47.0976 percentage of days | Standard Deviation 35.3227 |
| Placebo IVR + Placebo Injection | Percentage of Days During Baseline (Last 28 Days Before Randomization) and Cycles 1, 2, and 3 With Pain >=4 as Measured on NRS by Question 1 of ESD | Treatment 1 | 65.9074 percentage of days | Standard Deviation 30.0166 |
Secondary
Percentage of Days During Baseline (Last 28 Days Before Randomization) and Cycles 1, 2, and 3 With Pain Greater Than or Equal to (>=) 7 as Measured on NRS by Question 1 of ESD as Measured on NRS by Question 1 of ESD
Pain intensity was assessed on 11-point (0-10) NRS by question 1. In question 1, subjects were asked to rate the pain in the target area during the past 24 hours, where 0= no pain and 10= worst imaginable pain and responses were recorded in ESD. The percentage of days with pain \>=7 within a 28-day window was calculated as 100 divided by the number of non-missing days within that 28-day window multiplied by the number of days within that 28-day window where item 1 of the ESD was \>=7.
Time frame: Baseline (last 28 days before randomization), Cycle 1 (Treatment 1), Cycle 2 (Treatment 2), and Cycle 3 (Treatment 3)
Population: It was analyzed using the per-protocol set (PPS) with evaluable participants for this endpoint.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LNG 40 mcg IVR + Placebo Injection | Percentage of Days During Baseline (Last 28 Days Before Randomization) and Cycles 1, 2, and 3 With Pain Greater Than or Equal to (>=) 7 as Measured on NRS by Question 1 of ESD as Measured on NRS by Question 1 of ESD | Treatment 2 | 25.6257 percentage of days | Standard Deviation 33.9315 |
| LNG 40 mcg IVR + Placebo Injection | Percentage of Days During Baseline (Last 28 Days Before Randomization) and Cycles 1, 2, and 3 With Pain Greater Than or Equal to (>=) 7 as Measured on NRS by Question 1 of ESD as Measured on NRS by Question 1 of ESD | Treatment 1 | 35.6034 percentage of days | Standard Deviation 34.3126 |
| LNG 40 mcg IVR + Placebo Injection | Percentage of Days During Baseline (Last 28 Days Before Randomization) and Cycles 1, 2, and 3 With Pain Greater Than or Equal to (>=) 7 as Measured on NRS by Question 1 of ESD as Measured on NRS by Question 1 of ESD | Treatment 3 | 23.1293 percentage of days | Standard Deviation 33.9451 |
| ATZ 300 mcg / LNG 40 mcg IVR + Placebo Injection | Percentage of Days During Baseline (Last 28 Days Before Randomization) and Cycles 1, 2, and 3 With Pain Greater Than or Equal to (>=) 7 as Measured on NRS by Question 1 of ESD as Measured on NRS by Question 1 of ESD | Treatment 2 | 22.8695 percentage of days | Standard Deviation 28.3443 |
| ATZ 300 mcg / LNG 40 mcg IVR + Placebo Injection | Percentage of Days During Baseline (Last 28 Days Before Randomization) and Cycles 1, 2, and 3 With Pain Greater Than or Equal to (>=) 7 as Measured on NRS by Question 1 of ESD as Measured on NRS by Question 1 of ESD | Treatment 1 | 27.5659 percentage of days | Standard Deviation 27.6426 |
| ATZ 300 mcg / LNG 40 mcg IVR + Placebo Injection | Percentage of Days During Baseline (Last 28 Days Before Randomization) and Cycles 1, 2, and 3 With Pain Greater Than or Equal to (>=) 7 as Measured on NRS by Question 1 of ESD as Measured on NRS by Question 1 of ESD | Treatment 3 | 19.9332 percentage of days | Standard Deviation 26.054 |
| ATZ 600 mcg / LNG 40 mcg IVR + Placebo Injection | Percentage of Days During Baseline (Last 28 Days Before Randomization) and Cycles 1, 2, and 3 With Pain Greater Than or Equal to (>=) 7 as Measured on NRS by Question 1 of ESD as Measured on NRS by Question 1 of ESD | Treatment 2 | 34.4364 percentage of days | Standard Deviation 40.5623 |
| ATZ 600 mcg / LNG 40 mcg IVR + Placebo Injection | Percentage of Days During Baseline (Last 28 Days Before Randomization) and Cycles 1, 2, and 3 With Pain Greater Than or Equal to (>=) 7 as Measured on NRS by Question 1 of ESD as Measured on NRS by Question 1 of ESD | Treatment 1 | 40.0813 percentage of days | Standard Deviation 37.2694 |
| ATZ 600 mcg / LNG 40 mcg IVR + Placebo Injection | Percentage of Days During Baseline (Last 28 Days Before Randomization) and Cycles 1, 2, and 3 With Pain Greater Than or Equal to (>=) 7 as Measured on NRS by Question 1 of ESD as Measured on NRS by Question 1 of ESD | Treatment 3 | 29.8103 percentage of days | Standard Deviation 39.0434 |
| ATZ 1050 mcg / LNG 40 mcg IVR + Placebo Injection | Percentage of Days During Baseline (Last 28 Days Before Randomization) and Cycles 1, 2, and 3 With Pain Greater Than or Equal to (>=) 7 as Measured on NRS by Question 1 of ESD as Measured on NRS by Question 1 of ESD | Treatment 2 | 14.9331 percentage of days | Standard Deviation 23.8028 |
| ATZ 1050 mcg / LNG 40 mcg IVR + Placebo Injection | Percentage of Days During Baseline (Last 28 Days Before Randomization) and Cycles 1, 2, and 3 With Pain Greater Than or Equal to (>=) 7 as Measured on NRS by Question 1 of ESD as Measured on NRS by Question 1 of ESD | Treatment 1 | 23.9322 percentage of days | Standard Deviation 28.6234 |
| ATZ 1050 mcg / LNG 40 mcg IVR + Placebo Injection | Percentage of Days During Baseline (Last 28 Days Before Randomization) and Cycles 1, 2, and 3 With Pain Greater Than or Equal to (>=) 7 as Measured on NRS by Question 1 of ESD as Measured on NRS by Question 1 of ESD | Treatment 3 | 14.3362 percentage of days | Standard Deviation 25.677 |
| Placebo IVR + Leuprorelin Injection | Percentage of Days During Baseline (Last 28 Days Before Randomization) and Cycles 1, 2, and 3 With Pain Greater Than or Equal to (>=) 7 as Measured on NRS by Question 1 of ESD as Measured on NRS by Question 1 of ESD | Treatment 2 | 12.1320 percentage of days | Standard Deviation 25.1638 |
| Placebo IVR + Leuprorelin Injection | Percentage of Days During Baseline (Last 28 Days Before Randomization) and Cycles 1, 2, and 3 With Pain Greater Than or Equal to (>=) 7 as Measured on NRS by Question 1 of ESD as Measured on NRS by Question 1 of ESD | Treatment 1 | 28.2015 percentage of days | Standard Deviation 28.843 |
| Placebo IVR + Leuprorelin Injection | Percentage of Days During Baseline (Last 28 Days Before Randomization) and Cycles 1, 2, and 3 With Pain Greater Than or Equal to (>=) 7 as Measured on NRS by Question 1 of ESD as Measured on NRS by Question 1 of ESD | Treatment 3 | 8.5351 percentage of days | Standard Deviation 20.7819 |
| Placebo IVR + Placebo Injection | Percentage of Days During Baseline (Last 28 Days Before Randomization) and Cycles 1, 2, and 3 With Pain Greater Than or Equal to (>=) 7 as Measured on NRS by Question 1 of ESD as Measured on NRS by Question 1 of ESD | Treatment 1 | 25.1742 percentage of days | Standard Deviation 24.2811 |
| Placebo IVR + Placebo Injection | Percentage of Days During Baseline (Last 28 Days Before Randomization) and Cycles 1, 2, and 3 With Pain Greater Than or Equal to (>=) 7 as Measured on NRS by Question 1 of ESD as Measured on NRS by Question 1 of ESD | Treatment 3 | 12.7574 percentage of days | Standard Deviation 18.5154 |
| Placebo IVR + Placebo Injection | Percentage of Days During Baseline (Last 28 Days Before Randomization) and Cycles 1, 2, and 3 With Pain Greater Than or Equal to (>=) 7 as Measured on NRS by Question 1 of ESD as Measured on NRS by Question 1 of ESD | Treatment 2 | 14.1869 percentage of days | Standard Deviation 17.7364 |