Paroxetine for Women With Menopausal Vasomotor Symptoms
Paroxetine for Women With Menopausal Vasomotor Symptoms
Detailed descriptions of the two multicenter, randomized, double-blind, placebo-controlled phase 3 studies, including inclusion and exclusion criteria and VMS efficacy endpoints, have been published previously. The treatment period was 12 weeks in the first study (ClinicalTrials.gov identifier NCT01361308) and 24 weeks in the second study (ClinicalTrials.gov identifier NCT01101841). Otherwise, the two studies were similar in screening, placebo run-in period, population enrolled, and treatment regimens.
In brief, participants in both studies were postmenopausal women aged at least 40 years at screening who met one of the following criteria for menopause: spontaneous amenorrhea for 12 consecutive months or more; amenorrhea for 6 months or more, with follicle-stimulating hormone levels higher than 40 mIU/mL; or bilateral salpingo-oophorectomy, with or without hysterectomy, 6 weeks or more before screening. A key inclusion criterion was an average of more than 7 to 8 moderate to severe hot flashes/day or 50 to 60 moderate to severe hot flashes/week reported for 30 days or more before screening. Psychotropic drugs, including all sedative and hypnotic medications (with the exception of zolpidem, zaleplon, eszopiclone, and diphenhydramine), were prohibited during the study. Use of nightly zolpidem, zaleplon, eszopiclone, and diphenhydramine was minimal, and no analysis was performed with respect to the use of these medications. Participants taking psychotropic drugs or estrogen/progestin-containing products were required to undergo prespecified washout periods before the run-in visit. Key exclusion criteria were as follows: known nonresponse of VMS to previous SSRI or serotonin-norepinephrine reuptake inhibitor treatment, untreated hypertension, impaired liver or kidney function, unstable cardiac disease, pregnancy, history of self-injurious behavior, history of clinical diagnosis or treatment of depression or any other psychiatric disorder (including substance abuse or alcohol disorders), and any other ongoing medical condition. No sleep-specific inclusion or exclusion criteria (such as presence of sleep apnea or restless legs) were applied.
Each study began with a single-blind, placebo run-in period of up to 12 days, during which eligible participants received placebo once daily at bedtime and used electronic daily diaries to record the number and severity of VMS and the number of nighttime awakenings that they attributed to VMS. A double-blind treatment period followed, during which participants were randomly assigned 1:1 to receive paroxetine 7.5 mg or an identical capsule of placebo once daily at bedtime for 12 or 24 weeks. Randomization was applied centrally across all sites using an interactive voice response system, and all personnel were blinded to study medication until study completion and database lock.
Participants recorded VMS daily using a real-time interactive voice or Web response system that was accessible 24 hours/day; primary VMS efficacy endpoints have been reported elsewhere. Sleep parameters included change from baseline in the total number of nighttime awakenings attributed to VMS (where participants were asked to self-record all nighttime awakenings that they attributed to VMS in the electronic sleep diary the following morning between 6AM and 11AM; Appendix) and other sleep-related measurements (sleep-onset latency and hours of sleep per night; Appendix). Data were recorded throughout the study period and were collected for analysis in both studies on day 1 (study start), day 28 (week 4), and day 85 (week 12; end of 12-wk study) and for the 24-week study on day 169 (week 24; end of 24-wk study).
In addition, the extent to which VMS interfered with sleep was measured on weeks 4, 12, and 24 using the sleep interference item from the 10-item validated Hot Flash–Related Daily Interference Scale (HFRDIS), with scores ranging from 0 (no interference with sleep associated with hot flashes) to 10 (interference with sleep associated with hot flashes to the worst possible extent). This HFRDIS item was defined as a secondary endpoint a priori. The proportion of women with moderate to severe difficulty sleeping was also assessed using the validated 21-item Greene Climacteric Scale (GCS), which includes a question on "difficulty in sleeping" (0, none; 1, mild; 2, moderate; 3, severe).
Safety was assessed by evaluating TEAEs and potential discontinuation AEs. The Discontinuation-Emergent Signs and Symptoms scale, which includes the symptoms "trouble sleeping/insomnia" and "increased dreaming or nightmares," was administered within a mean (SD) of 7 (3) days of the last dose of study medication, regardless of when the participant exited the study. Sleep-related TEAEs and discontinuation AEs are presented herein.
(Enlarge Image)
Appendix.
Sleep diary.
The principal population for analysis of secondary endpoints was the modified intent-to-treat population (all consenting and randomly assigned participants with valid baseline daily VMS diary data who had taken one or more doses of study medication and had one or more days of on-treatment daily VMS diary data). The safety population comprised all participants who received one or more doses of study medication and who had one or more postdose safety measurements.
In this prospective analysis of sleep-related predefined secondary endpoints, data from the two phase 3 studies were pooled for weeks 1 to 12. Data for weeks 13 to 24 represent the 24-week study only. The two studies were similarly designed and involved comparable populations, allowing pooling of data, which enables evaluation of information from more than 1,100 participants and makes the data set and analysis more robust.
Prespecified analyses were used to assess the impact of paroxetine 7.5 mg on the number of nighttime awakenings attributed to VMS, sleep-onset latency, sleep duration, and sleep scores (HFRDIS and GCS). For each participant, total nighttime awakenings attributed to VMS at baseline were calculated as the average during the run-in period before randomization. Nighttime awakenings during the double-blind treatment period were calculated as the average for each study week. Sleep-onset latency and duration of sleep were calculated as change from baseline in number of minutes at each postbaseline time point evaluated.
Methods
Participants and Study Design
Detailed descriptions of the two multicenter, randomized, double-blind, placebo-controlled phase 3 studies, including inclusion and exclusion criteria and VMS efficacy endpoints, have been published previously. The treatment period was 12 weeks in the first study (ClinicalTrials.gov identifier NCT01361308) and 24 weeks in the second study (ClinicalTrials.gov identifier NCT01101841). Otherwise, the two studies were similar in screening, placebo run-in period, population enrolled, and treatment regimens.
In brief, participants in both studies were postmenopausal women aged at least 40 years at screening who met one of the following criteria for menopause: spontaneous amenorrhea for 12 consecutive months or more; amenorrhea for 6 months or more, with follicle-stimulating hormone levels higher than 40 mIU/mL; or bilateral salpingo-oophorectomy, with or without hysterectomy, 6 weeks or more before screening. A key inclusion criterion was an average of more than 7 to 8 moderate to severe hot flashes/day or 50 to 60 moderate to severe hot flashes/week reported for 30 days or more before screening. Psychotropic drugs, including all sedative and hypnotic medications (with the exception of zolpidem, zaleplon, eszopiclone, and diphenhydramine), were prohibited during the study. Use of nightly zolpidem, zaleplon, eszopiclone, and diphenhydramine was minimal, and no analysis was performed with respect to the use of these medications. Participants taking psychotropic drugs or estrogen/progestin-containing products were required to undergo prespecified washout periods before the run-in visit. Key exclusion criteria were as follows: known nonresponse of VMS to previous SSRI or serotonin-norepinephrine reuptake inhibitor treatment, untreated hypertension, impaired liver or kidney function, unstable cardiac disease, pregnancy, history of self-injurious behavior, history of clinical diagnosis or treatment of depression or any other psychiatric disorder (including substance abuse or alcohol disorders), and any other ongoing medical condition. No sleep-specific inclusion or exclusion criteria (such as presence of sleep apnea or restless legs) were applied.
Each study began with a single-blind, placebo run-in period of up to 12 days, during which eligible participants received placebo once daily at bedtime and used electronic daily diaries to record the number and severity of VMS and the number of nighttime awakenings that they attributed to VMS. A double-blind treatment period followed, during which participants were randomly assigned 1:1 to receive paroxetine 7.5 mg or an identical capsule of placebo once daily at bedtime for 12 or 24 weeks. Randomization was applied centrally across all sites using an interactive voice response system, and all personnel were blinded to study medication until study completion and database lock.
Study Assessments
Participants recorded VMS daily using a real-time interactive voice or Web response system that was accessible 24 hours/day; primary VMS efficacy endpoints have been reported elsewhere. Sleep parameters included change from baseline in the total number of nighttime awakenings attributed to VMS (where participants were asked to self-record all nighttime awakenings that they attributed to VMS in the electronic sleep diary the following morning between 6AM and 11AM; Appendix) and other sleep-related measurements (sleep-onset latency and hours of sleep per night; Appendix). Data were recorded throughout the study period and were collected for analysis in both studies on day 1 (study start), day 28 (week 4), and day 85 (week 12; end of 12-wk study) and for the 24-week study on day 169 (week 24; end of 24-wk study).
In addition, the extent to which VMS interfered with sleep was measured on weeks 4, 12, and 24 using the sleep interference item from the 10-item validated Hot Flash–Related Daily Interference Scale (HFRDIS), with scores ranging from 0 (no interference with sleep associated with hot flashes) to 10 (interference with sleep associated with hot flashes to the worst possible extent). This HFRDIS item was defined as a secondary endpoint a priori. The proportion of women with moderate to severe difficulty sleeping was also assessed using the validated 21-item Greene Climacteric Scale (GCS), which includes a question on "difficulty in sleeping" (0, none; 1, mild; 2, moderate; 3, severe).
Safety was assessed by evaluating TEAEs and potential discontinuation AEs. The Discontinuation-Emergent Signs and Symptoms scale, which includes the symptoms "trouble sleeping/insomnia" and "increased dreaming or nightmares," was administered within a mean (SD) of 7 (3) days of the last dose of study medication, regardless of when the participant exited the study. Sleep-related TEAEs and discontinuation AEs are presented herein.
(Enlarge Image)
Appendix.
Sleep diary.
Statistical Analyses
The principal population for analysis of secondary endpoints was the modified intent-to-treat population (all consenting and randomly assigned participants with valid baseline daily VMS diary data who had taken one or more doses of study medication and had one or more days of on-treatment daily VMS diary data). The safety population comprised all participants who received one or more doses of study medication and who had one or more postdose safety measurements.
In this prospective analysis of sleep-related predefined secondary endpoints, data from the two phase 3 studies were pooled for weeks 1 to 12. Data for weeks 13 to 24 represent the 24-week study only. The two studies were similarly designed and involved comparable populations, allowing pooling of data, which enables evaluation of information from more than 1,100 participants and makes the data set and analysis more robust.
Prespecified analyses were used to assess the impact of paroxetine 7.5 mg on the number of nighttime awakenings attributed to VMS, sleep-onset latency, sleep duration, and sleep scores (HFRDIS and GCS). For each participant, total nighttime awakenings attributed to VMS at baseline were calculated as the average during the run-in period before randomization. Nighttime awakenings during the double-blind treatment period were calculated as the average for each study week. Sleep-onset latency and duration of sleep were calculated as change from baseline in number of minutes at each postbaseline time point evaluated.