Hot Flashes, Menopause, Vasomotor Disturbance
Conditions
Brief summary
The broad goal of this study is to obtain pilot data to determine the tolerability and preliminary efficacy of the non-hormonal agent gabapentin for insomnia symptoms and nighttime vasomotor Symptoms (VMS) when open-label gabapentin is administered at low dose and only at night in peri- and postmenopausal women. We hypothesize that the majority of participants will be able to increase and tolerate treatment, and insomnia symptoms and the frequency of nighttime VMS will improve on low-dose gabapentin dosed at bedtime.
Detailed description
Thirty-two peri- and postmenopausal women at the Boston sites (MGH and BWH) were enrolled into this open-label pilot study. The study was a 7-week intervention study using open-label gabapentin at bedtime with a scheduled dose titration from 100-mg for one week, followed by 300-mg for 3 weeks, and then 600-mg for 3 weeks. The intervention study followed a 3-week screening period to establish a stable baseline for insomnia symptoms and VMS and to determine the safety of administering gabapentin in study participants. Tolerability and treatment response (insomnia symptoms, nighttime VMS) were assessed systematically at each study visit. The dose titration schedule was followed in all participants unless there are dose-limiting toxicities.
Interventions
DRUGGabapentin
The study is a 7-week intervention study using open-label gabapentin at bedtime with a scheduled dose titration from 100-mg for one week, followed by 300-mg for 3 weeks, and then 600-mg for 3 weeks.
Sponsors
Brigham and Women's Hospital
National Institute on Aging (NIA)
Massachusetts General Hospital
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
40 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
1. Females aged 40-65 years 2. Postmenopausal or perimenopausal 3. Having bothersome hot flashes 4. Having some bothersome hot flashes during the night 5. Insomnia or problems sleeping 6. In general, good health 7. Signed informed consent
Exclusion criteria
1. Recent use of hormone therapy or hormonal contraceptives (with the exception of the Mirena IUD) 2. Recent use of any prescribed therapy that is taken specifically for hot flashes 3. Recent use of any over-the-counter or herbal therapies that are taken specifically for hot flashes 4. Recent use of any prescribed medications with known hot flash efficacy 5. Known hypersensitivity or contraindications (reasons not to take) to gabapentin 6. Not using a medically approved method of birth control, if sexually active and not 12 or more months since last menstrual period 7. Recent drug or alcohol abuse 8. Lifetime diagnosis of psychosis or bipolar disorder 9. Suicide attempt in the past 3 years or any current suicidal ideation 10. Current major depression (assessed during screening) 11. Pregnancy, intending pregnancy, or breast feeding 12. History of: 1. Renal insufficiency or a kidney disorder 2. Sleep disorder diagnosis of sleep apnea, restless legs syndrome, periodic limb movement disorder, or narcolepsy 13. Any unstable medical condition 14. Working a night/rotating shift 15. Abnormal screening blood tests 16. Current participation in another drug trial or intervention study 17. Inability or unwillingness to complete the study procedures
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Sleep Quality and Disturbances Over Past Month | Baseline, study completion at 7 weeks | Sleep quality and disturbances during the past month were assessed with the Pittsburgh Sleep Quality Index (PSQI). The PSQI also incorporates daytime functioning into the total score. In scoring the PSQI, seven component scores are derived, each scored 0 (no difficulty) to 3 (severe difficulty). The component scores are summed to produce a global score (range 0 to 21). Higher scores indicate worse sleep quality. |
| Vasomotor Symptoms (VMS) Frequency, Severity, and Bothersomeness During Nighttime | Baseline, study completion at 7 weeks | Vasomotor symptoms (VMS) were tracked and quantified prospectively using a daily hot flash diary. The hot flash diary was adapted from a 7-day self-report tool for vasomotor symptoms originally developed by the North Central Cancer Treatment Group (NCCTG). The diary asks for the subject to log number of hot flashes during the day and night, severity of hot flashes during day and night, and how bothersome the hot flashes were during day and night. Vasomotor symptoms were also systematically assessed at baseline, week 4, and week 7 using the Hot Flash-Related Daily Interference Scale (HFRDIS), a 10-item self-report questionnaire to determine perceived hot flash interference with quality of life and daily activities. |
| Severity of Insomnia | Baseline, study completion at 7 weeks | Severity of insomnia was measured throughout the study using the Insomnia Severity Index (ISI) .The ISI is a 7-item scale that evaluates the severity of insomnia retrospectively over the past week. The scale is more specific to insomnia symptoms than the Pittsburgh scale (PSQI), which focuses more broadly on overall sleep quality. The ISI score ranges from a minimum of 0 to 28. A score of 0-7=no clinically significant insomnia, 8-14=subthreshold insomnia, 5-21=clinical insomnia (moderate severity), 22-28=clinical insomnia (severe), with higher values indicating more severe insomnia. |
| Tolerability of Gabapentin | Baseline, Week 4 visit, and study completion at 7 weeks | Tolerability of gabapentin was assessed by self-report at the week 1, week 4 and week 7 contacts by asking participants to complete the SAFTEE-SI and CPFQ questionnaires and prompting subjects to report any adverse events at each study visit. Tolerability of gabapentin is defined as the proportion of participants that is able to increase the dose from 300-mg to 600-mg and to remain on the higher dose for the duration of the trial. |
| Reason for Non-tolerability and Discontinuation of Gabapentin | Baseline, Week 4 Visit, and study completion at 7 weeks | Reason why subjects who initiated treatment with gabapentin chose to discontinue before study completion |
| Vasomotor Symptoms (VMS) Frequency, Severity, and Bothersomeness During Daytime | Baseline, study completion at 7 weeks | Vasomotor symptoms (VMS) were tracked and quantified prospectively using a daily hot flash diary. The hot flash diary was adapted from a 7-day self-report tool for vasomotor symptoms originally developed by the North Central Cancer Treatment Group (NCCTG). The diary asks for the subject to log number of hot flashes during the day and night, severity of hot flashes during day and night, and how bothersome the hot flashes were during day and night. Vasomotor symptoms were also systematically assessed at baseline, week 4, and week 7 using the Hot Flash-Related Daily Interference Scale (HFRDIS), a 10-item self-report questionnaire to determine perceived hot flash interference with quality of life and daily activities. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Quality of Life-Menopause Specific | Baseline, study completion at 7 weeks | The Quality of life-Menopause specific is assessed by the Menopause Specific Quality of Life (MENQOL). The MENQOL is self-administered and consists of a total of 29 items in a Likert-scale format. Each item assesses the impact of one of four domains of menopausal symptoms, as experienced over the last month: vasomotor (items 1-3), psychosocial (items 4-10), physical (items 11-26), and sexual (items 27-29). Items pertaining to a specific symptom are rated as present or not present, and if present, how bothersome on a zero (not bothersome) to six (extremely bothersome) scale. Means are computed for each subscale by dividing the sum of the domain's items by the number of items within that domain. Non-endorsement of an item is scored a 1 and endorsement a 2, plus the number of the particular rating, so that the possible score on any item ranges from 1-8. Total score also ranges from 1-8. |
| Quality of Life-Overall | Baseline, study completion at 7 weeks | Quality of life-Overall was assessed with the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q). The Q-LES-Q is a 16-item self-report questionnaire that assesses enjoyment of and satisfaction with life. The scoring of the Q-LES-Q-SF involves summing only the first 14 items to yield a raw total score. The last two items are not included in the total score but are standalone items. The raw total score ranges from 14 to 70 with higher scores indicating higher quality of life enjoyment and satisfaction. |
Countries
United States
Participant flow
Recruitment details
Women were recruited from the Boston area and enrolled at either the Massachusetts General Hospital Center for Women's Mental Health or the Brigham and Women's Hospital Women's Hormones and Aging Research Program.
Participants by arm
| Arm | Count |
|---|---|
| Open-label Gabapentin Dose titration of 100mg for 1 week, 300mg for 3 weeks, and 600mg for 3 weeks.
Gabapentin: The study is a 7-week intervention study using open-label gabapentin at bedtime with a scheduled dose titration from 100-mg for one week, followed by 300-mg for 3 weeks, and then 600-mg for 3 weeks. | 26 |
| Total | 26 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 4 |
| Overall Study | Lost to Follow-up | 1 |
| Overall Study | Physician Decision | 4 |
| Overall Study | Withdrawal by Subject | 3 |
Baseline characteristics
| Characteristic | Open-label Gabapentin |
|---|---|
| Age, Continuous | 55.31 years STANDARD_DEVIATION 4.5 |
| Baseline BMI | 29.4 kg/m^2 STANDARD_DEVIATION 6.6 |
| Employment Disabled, Unable to work, on Medical Leave | 4 Participants |
| Employment Employed Full-Time | 8 Participants |
| Employment Employed Part-Time | 6 Participants |
| Employment Retired or Unemployed | 8 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 24 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Gynecological History Naturally Postmenopausal | 18 Participants |
| Gynecological History Perimenopausal | 5 Participants |
| Gynecological History Surgically Postmenopausal | 3 Participants |
| Highest Level of Education College Graduate/Baccalaureate Degree | 4 Participants |
| Highest Level of Education Graduate Degree | 4 Participants |
| Highest Level of Education Less than College Graduate | 18 Participants |
| Marital Status Divorced or Separated | 5 Participants |
| Marital Status Never Married | 7 Participants |
| Marital Status Presently Married or Living with Partner | 12 Participants |
| Marital Status Widowed | 2 Participants |
| Number of Children 1 to 4 Children | 14 Participants |
| Number of Children No Children | 12 Participants |
| Provider Status Does not have Doctor/Nurse Providing Regular Care | 1 Participants |
| Provider Status Has Doctor/Nurse Providing Regular Care | 25 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 10 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 16 Participants |
| Region of Enrollment United States | 26 Participants |
| Sex: Female, Male Female | 26 Participants |
| Sex: Female, Male Male | 0 Participants |
| Smoking History Current Smoker | 4 Participants |
| Smoking History Non-Current Smoker | 22 Participants |
| Years since last menstrual period (LMP) 1-5 Years | 13 Participants |
| Years since last menstrual period (LMP) <1 Years | 5 Participants |
| Years since last menstrual period (LMP) >5 Years | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 11 / 26 |
| serious Total, serious adverse events | 0 / 26 |
Outcome results
Primary
Reason for Non-tolerability and Discontinuation of Gabapentin
Reason why subjects who initiated treatment with gabapentin chose to discontinue before study completion
Time frame: Baseline, Week 4 Visit, and study completion at 7 weeks
Population: Four subjects initiated treatment with gabapentin but discontinued prior to study completion due to side effects.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Open-label Gabapentin | Reason for Non-tolerability and Discontinuation of Gabapentin | Morning sickness and Nausea | 3 Participants |
| Open-label Gabapentin | Reason for Non-tolerability and Discontinuation of Gabapentin | Mild Rash | 1 Participants |
Primary
Severity of Insomnia
Severity of insomnia was measured throughout the study using the Insomnia Severity Index (ISI) .The ISI is a 7-item scale that evaluates the severity of insomnia retrospectively over the past week. The scale is more specific to insomnia symptoms than the Pittsburgh scale (PSQI), which focuses more broadly on overall sleep quality. The ISI score ranges from a minimum of 0 to 28. A score of 0-7=no clinically significant insomnia, 8-14=subthreshold insomnia, 5-21=clinical insomnia (moderate severity), 22-28=clinical insomnia (severe), with higher values indicating more severe insomnia.
Time frame: Baseline, study completion at 7 weeks
Population: Analyzable population includes all 20 completers of the study, since all 20 completers of the study had ISI data at baseline and study completion.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Open-label Gabapentin | Severity of Insomnia | mean ISI score at baseline | 15.6 scores on a scale |
| Open-label Gabapentin | Severity of Insomnia | mean ISI score at study completion | 6.0 scores on a scale |
Primary
Sleep Quality and Disturbances Over Past Month
Sleep quality and disturbances during the past month were assessed with the Pittsburgh Sleep Quality Index (PSQI). The PSQI also incorporates daytime functioning into the total score. In scoring the PSQI, seven component scores are derived, each scored 0 (no difficulty) to 3 (severe difficulty). The component scores are summed to produce a global score (range 0 to 21). Higher scores indicate worse sleep quality.
Time frame: Baseline, study completion at 7 weeks
Population: Analyzable population includes all 20 completers of the study, since all 20 completers of the study had PSQI data at baseline and study completion.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Open-label Gabapentin | Sleep Quality and Disturbances Over Past Month | PSQI total score at baseline | 9.6 scores on a scale |
| Open-label Gabapentin | Sleep Quality and Disturbances Over Past Month | PSQI total score at study completion | 4.9 scores on a scale |
Primary
Tolerability of Gabapentin
Tolerability of gabapentin was assessed by self-report at the week 1, week 4 and week 7 contacts by asking participants to complete the SAFTEE-SI and CPFQ questionnaires and prompting subjects to report any adverse events at each study visit. Tolerability of gabapentin is defined as the proportion of participants that is able to increase the dose from 300-mg to 600-mg and to remain on the higher dose for the duration of the trial.
Time frame: Baseline, Week 4 visit, and study completion at 7 weeks
Population: All 26 participants who initiated treatment with gabapentin were included in this analysis.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Open-label Gabapentin | Tolerability of Gabapentin | # of subjects who tolerated gabapentin | 22 Participants |
| Open-label Gabapentin | Tolerability of Gabapentin | # of subjects who did not tolerate gabapentin | 4 Participants |
Primary
Vasomotor Symptoms (VMS) Frequency, Severity, and Bothersomeness During Daytime
Vasomotor symptoms (VMS) were tracked and quantified prospectively using a daily hot flash diary. The hot flash diary was adapted from a 7-day self-report tool for vasomotor symptoms originally developed by the North Central Cancer Treatment Group (NCCTG). The diary asks for the subject to log number of hot flashes during the day and night, severity of hot flashes during day and night, and how bothersome the hot flashes were during day and night. Vasomotor symptoms were also systematically assessed at baseline, week 4, and week 7 using the Hot Flash-Related Daily Interference Scale (HFRDIS), a 10-item self-report questionnaire to determine perceived hot flash interference with quality of life and daily activities.
Time frame: Baseline, study completion at 7 weeks
Population: Though 20 participants completed the study, the analyzable population includes only the 19 completers who have VMS data for both baseline and the final visit.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Open-label Gabapentin | Vasomotor Symptoms (VMS) Frequency, Severity, and Bothersomeness During Daytime | mean VMS per day at baseline | 4.1 vasomotor symptoms (VMS) per day |
| Open-label Gabapentin | Vasomotor Symptoms (VMS) Frequency, Severity, and Bothersomeness During Daytime | mean VMS per day at study completion | 2.2 vasomotor symptoms (VMS) per day |
Primary
Vasomotor Symptoms (VMS) Frequency, Severity, and Bothersomeness During Nighttime
Vasomotor symptoms (VMS) were tracked and quantified prospectively using a daily hot flash diary. The hot flash diary was adapted from a 7-day self-report tool for vasomotor symptoms originally developed by the North Central Cancer Treatment Group (NCCTG). The diary asks for the subject to log number of hot flashes during the day and night, severity of hot flashes during day and night, and how bothersome the hot flashes were during day and night. Vasomotor symptoms were also systematically assessed at baseline, week 4, and week 7 using the Hot Flash-Related Daily Interference Scale (HFRDIS), a 10-item self-report questionnaire to determine perceived hot flash interference with quality of life and daily activities.
Time frame: Baseline, study completion at 7 weeks
Population: Though 20 participants completed the study, the analyzable population includes only the 19 completers who have VMS data for both baseline and the final visit.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Open-label Gabapentin | Vasomotor Symptoms (VMS) Frequency, Severity, and Bothersomeness During Nighttime | mean VMS per night at baseline | 3.5 vasomotor symptoms (VMS) per night |
| Open-label Gabapentin | Vasomotor Symptoms (VMS) Frequency, Severity, and Bothersomeness During Nighttime | mean VMS per night at study completion | 1.1 vasomotor symptoms (VMS) per night |
Other Pre-specified
Quality of Life-Menopause Specific
The Quality of life-Menopause specific is assessed by the Menopause Specific Quality of Life (MENQOL). The MENQOL is self-administered and consists of a total of 29 items in a Likert-scale format. Each item assesses the impact of one of four domains of menopausal symptoms, as experienced over the last month: vasomotor (items 1-3), psychosocial (items 4-10), physical (items 11-26), and sexual (items 27-29). Items pertaining to a specific symptom are rated as present or not present, and if present, how bothersome on a zero (not bothersome) to six (extremely bothersome) scale. Means are computed for each subscale by dividing the sum of the domain's items by the number of items within that domain. Non-endorsement of an item is scored a 1 and endorsement a 2, plus the number of the particular rating, so that the possible score on any item ranges from 1-8. Total score also ranges from 1-8.
Time frame: Baseline, study completion at 7 weeks
Population: Analyzable population includes all 20 completers of the study, since all 20 completers of the study had MENQOL data at baseline and study completion.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Open-label Gabapentin | Quality of Life-Menopause Specific | MENQOL scores at baseline | 3.2 scores on a scale |
| Open-label Gabapentin | Quality of Life-Menopause Specific | MENQOL scores at study completion | 1.9 scores on a scale |
Other Pre-specified
Quality of Life-Overall
Quality of life-Overall was assessed with the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q). The Q-LES-Q is a 16-item self-report questionnaire that assesses enjoyment of and satisfaction with life. The scoring of the Q-LES-Q-SF involves summing only the first 14 items to yield a raw total score. The last two items are not included in the total score but are standalone items. The raw total score ranges from 14 to 70 with higher scores indicating higher quality of life enjoyment and satisfaction.
Time frame: Baseline, study completion at 7 weeks
Population: Analyzable population includes all 20 completers of the study, since all 20 completers of the study had Q-LES-Q data at baseline and study completion.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Open-label Gabapentin | Quality of Life-Overall | Q-LES-Q scores at baseline | 60.3 scores on a scale |
| Open-label Gabapentin | Quality of Life-Overall | Q-LES-Q scores at study completion | 61.7 scores on a scale |