Premenstrual Syndrome
Conditions
Keywords
Premenstrual Dysphoric Disorder, PMDD, PMS
Brief summary
This study will evaluate the effectiveness of flutamide in reducing symptoms of premenstrual dysphoric disorder.
Detailed description
Premenstrual dysphoric disorder (PMDD) is a condition that affects about 5% of menstruating women. Women with PMDD experience serious emotional and physical disturbances, which may include depression, tension, irritability, anger, anxiety, and sleep and appetite problems. Symptoms of PMDD are directly linked with the menstrual cycle, generally beginning in the latter half of the cycle and ending around the start of the next cycle. If left unmanaged, PMDD may interfere with a woman's ability to carry out normal day-to-day functioning. Current treatments for PMDD include medications, psychotherapy, and nutritional modifications. Flutamide, a medication that blocks the action of testosterone and other mood-influencing hormones, may be helpful in alleviating symptoms of PMDD. This study will evaluate the effectiveness of flutamide in reducing symptoms of premenstrual dysphoric disorder. This two-phase study will last a total of 4 months and will include 7 study visits. Phase 1 will last 2 months and will include Visits 1 through 3. During Phase 1, participants will keep a daily record of symptoms, participate in a diagnostic interview, and undergo a medical history review, a physical exam, and screening laboratory tests. Eligible participants will then enter Phase 2, the treatment phase of the study. During the treatment phase, participants will be randomly assigned to take flutamide or placebo for 2 months. Study visits will occur every 2 weeks and will include Visits 4 through 7. These visits will include discussion of side effects, symptom rating, and laboratory tests to check for pregnancy and any side effects related to liver function, blood counts, or blood chemistry. At the end of treatment with flutamide or placebo, participants will have the option of receiving treatment with sertraline, an antidepressant known to be effective for many women with PMDD. Sertraline will be given during the 2 premenstrual weeks for two cycles. If participants have already unsuccessfully tried sertraline for PMDD treatment, an alternative treatment can be attempted.
Interventions
DRUGFlutamide
Participants will take one 125-mg flutamide capsule twice a day for two menstrual cycles. If a participant is unable to tolerate a twice-daily dose due to side effects, the dose will be reduced to one capsule per day.
DRUGPlacebo
Participants will take a lactose capsule twice a day for two menstrual cycles. If a participant is unable to tolerate a twice-daily dose due to side effects, the dose will be reduced to one capsule per day.
Sponsors
National Institute of Mental Health (NIMH)
Weill Medical College of Cornell University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 48 Years
Healthy volunteers
No
Inclusion criteria
* Meets DSM-IV criteria for PMDD by history * Regular menstrual cycles that are 25 to 35 days in length during the year prior to study entry * Willing to use barrier methods of birth control during the study if sexually active * If engaged in psychotherapy for at least 3 months before study entry, participation will be allowed if the intensity of psychotherapy remains the same during the study * Normal PAP and physical exam, including pelvic exam, within the 1 year prior to study entry
Exclusion criteria
* Use of oral contraceptives or other exogenous hormone preparations within the 3 months prior to study entry * Suicide attempt or severe suicidal ideation within the 2 years prior to study entry * History of any psychotic disorder or bipolar disorder * Substance abuse, except nicotine, within the 6 months prior to study entry * Use of pharmacological treatment for PMDD symptoms (e.g., antidepressants, hormones, gonadotropin-releasing hormone agonists, anxiolytics, calcium, herbal preparations, diuretics) within the 3 months prior to study entry * Daily use of psychotropic or anticonvulsant medications within the 3 months prior to study entry * Use of sleeping pills more than once per week * Consumption of more than 50 ounces of alcohol per week * Pregnant or breastfeeding * Hepatic, renal, autoimmune, or chronic inflammatory disease * Seizure disorder * Inability to read or follow instructions in English
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Premenstrual Symptoms as Measured by the Premenstrual Tension Scale (PMTS) | Measured at Months 1and 2 | Low score on PMTS scale is 0 and high score is 40. Change score is calculated as PMTS score at month 1 or month 2 minus baseline PMTS score. Negative change score is a reduction in symptoms during treatment and positive change score is an increase in symptoms during treatment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Premenstrual Symptoms as Measured by the Daily Rating of Severity of Problems (DRSP) Scale | Measured at Months 1 and 2 | DRSP low score is 21 high score is 126. High score indicates more severe symptoms. Average score for the 4 days preceding menses was calculated for each subject in each cycle. Change score is calculated as DRSP score at month 1 or month 2 minus baseline DRSP score. Negative change score is a reduction in symptoms during treatment and positive change score is an increase in symptoms during treatment. |
| Side Effect Burden Measured by Side Effect Questionnaire | Measured at Months 1 and 2 | The Side Effects Questionnaire is a measure of combined side effect burden, including a score for frequency (0-6), intensity (0-6) and interference with function (0-6). Low score is 0, high score is 18, High score represents greater severe side effect burden |
| Premenstrual Symptoms as Measured by the Clinical Global Improvement Scale at Month 1 and Month 2 | Measured at Months 1 and 2 | Scale range in 1-7. 1 is very much improved compared to baseline, 4 is no change compared to baseline, and 7 is very much worse compared to baseline. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change in Clinical Global Severity Scale | Measured at Month 1 and Month 2 | Scale range in 1-7. 1 is not at all ill, 4 is moderately ill, and 6 is severely ill and 7 is among the most extremely ill patients. Change score is calculated as Clinical Global Severity Scale score at the end of treatment month 1 or treatment month 2 minus baseline score. Negative change score is a reduction in symptoms during treatment and a positive change score is an increase in symptoms during treatment. |
| Change in Premenstrual Symptoms as Measured by the Patient Global Premenstrual Symptoms as Measured by the Patient Global Improvement Scale at Month 1 and Month 2 | Measured at Month 1 and Month 2 | Scale range in 1-7. 1 is very much improved, 4 is no change, and 7 is very much worse. |
Participant flow
Pre-assignment details
115 subjects enrolled in the screening phase of the study. 27 subjects qualified for randomization and 25 of those agreed to participate in the treatment study.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants will take placebo flutamide
Placebo: Participants will take a lactose capsule twice a day for two menstrual cycles. If a participant is unable to tolerate a twice-daily dose due to side effects, the dose will be reduced to one capsule per day. | 12 |
| Flutamide Participants will take flutamide
Flutamide: Participants will take one 125-mg flutamide capsule twice a day for two menstrual cycles. If a participant is unable to tolerate a twice-daily dose due to side effects, the dose will be reduced to one capsule per day. | 13 |
| Total | 25 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 2 | 2 |
Baseline characteristics
| Characteristic | Flutamide | Total | Placebo |
|---|---|---|---|
| Age, Continuous | 36.3 years | 35.3 years | 34.3 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants | 6 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 8 Participants | 19 Participants | 11 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 12 Participants | 22 Participants | 10 Participants |
| Sex: Female, Male Female | 13 Participants | 25 Participants | 12 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 11 | 0 / 13 |
| other Total, other adverse events | 7 / 11 | 11 / 13 |
| serious Total, serious adverse events | 0 / 11 | 0 / 13 |
Outcome results
Primary
Change in Premenstrual Symptoms as Measured by the Premenstrual Tension Scale (PMTS)
Low score on PMTS scale is 0 and high score is 40. Change score is calculated as PMTS score at month 1 or month 2 minus baseline PMTS score. Negative change score is a reduction in symptoms during treatment and positive change score is an increase in symptoms during treatment.
Time frame: Measured at Months 1and 2
Population: 12 subjects were randomized to placebo and 13 randomized to flutamide. At the one month visit 11 subjects taking placebo and 13 subjects taking flutamide provided PMTS ratings. At the two month visit 10 subjects taking placebo and 11subjects randomized to flutamide provided PMTS ratings
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change in Premenstrual Symptoms as Measured by the Premenstrual Tension Scale (PMTS) | Month 1 | -6.9 score on a scale | Standard Error 2.3 |
| Placebo | Change in Premenstrual Symptoms as Measured by the Premenstrual Tension Scale (PMTS) | Month 2 | -5.5 score on a scale | Standard Error 2.2 |
| Flutamide | Change in Premenstrual Symptoms as Measured by the Premenstrual Tension Scale (PMTS) | Month 1 | -5.5 score on a scale | Standard Error 2.1 |
| Flutamide | Change in Premenstrual Symptoms as Measured by the Premenstrual Tension Scale (PMTS) | Month 2 | -8.3 score on a scale | Standard Error 2.1 |
Comparison: paired t-test analysis comparing change from baseline PMTS score at month 1 between flutamide and placebo groupsp-value: =0.57t-test, 2 sided
Comparison: paired t-test analysis comparing change from baseline PMTS score at month 2 between flutamide and placebo groups.p-value: =0.27t-test, 2 sided
Secondary
Change in Premenstrual Symptoms as Measured by the Daily Rating of Severity of Problems (DRSP) Scale
DRSP low score is 21 high score is 126. High score indicates more severe symptoms. Average score for the 4 days preceding menses was calculated for each subject in each cycle. Change score is calculated as DRSP score at month 1 or month 2 minus baseline DRSP score. Negative change score is a reduction in symptoms during treatment and positive change score is an increase in symptoms during treatment.
Time frame: Measured at Months 1 and 2
Population: 12 subjects were randomized to placebo and 13 randomized to flutamide. At the one month visit 10 subjects taking placebo and 12 subjects taking flutamide provided DRSP ratings. At the two month visit 10 subjects taking placebo and 12 subjects randomized to flutamide provided DRSP ratings
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change in Premenstrual Symptoms as Measured by the Daily Rating of Severity of Problems (DRSP) Scale | Month 1 | -21.3 score on a scale | Standard Error 5.3 |
| Placebo | Change in Premenstrual Symptoms as Measured by the Daily Rating of Severity of Problems (DRSP) Scale | Month 2 | -22.2 score on a scale | Standard Error 7.5 |
| Flutamide | Change in Premenstrual Symptoms as Measured by the Daily Rating of Severity of Problems (DRSP) Scale | Month 1 | -26.0 score on a scale | Standard Error 4.9 |
| Flutamide | Change in Premenstrual Symptoms as Measured by the Daily Rating of Severity of Problems (DRSP) Scale | Month 2 | -35.6 score on a scale | Standard Error 6.8 |
Comparison: paired t-test comparing change in DRSP scores from baseline to Month 1 of treatment Larger positive change score indicates a greater reduction in symptoms from baseline.p-value: =0.52t-test, 2 sided
Comparison: paired t-test comparing change in DRSP scores from baseline to Month 2 of treatment Larger positive change score indicates a greater reduction in symptoms from baseline.p-value: =0.2t-test, 2 sided
Secondary
Premenstrual Symptoms as Measured by the Clinical Global Improvement Scale at Month 1 and Month 2
Scale range in 1-7. 1 is very much improved compared to baseline, 4 is no change compared to baseline, and 7 is very much worse compared to baseline.
Time frame: Measured at Months 1 and 2
Population: 12 subjects were randomized to placebo and 13 randomized to flutamide. At the one month visit 11 subjects taking placebo and 13 subjects taking flutamide had CGI-improvement ratings. At the two month visit 10 subjects taking placebo and 12 subjects randomized to flutamide had CGI-improvement ratings
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Premenstrual Symptoms as Measured by the Clinical Global Improvement Scale at Month 1 and Month 2 | Month 1 | 3.2 score on a scale | Standard Error 0.3 |
| Placebo | Premenstrual Symptoms as Measured by the Clinical Global Improvement Scale at Month 1 and Month 2 | Month 2 | 3.1 score on a scale | Standard Error 0.3 |
| Flutamide | Premenstrual Symptoms as Measured by the Clinical Global Improvement Scale at Month 1 and Month 2 | Month 1 | 2.5 score on a scale | Standard Error 0.3 |
| Flutamide | Premenstrual Symptoms as Measured by the Clinical Global Improvement Scale at Month 1 and Month 2 | Month 2 | 2.2 score on a scale | Standard Error 0.3 |
Comparison: paired t-test was performed comparing the Clinical Global Improvement score at month 1 between placebo and flutamide groupsp-value: =0.15t-test, 2 sided
Comparison: t-test was performed comparing the Clinical Global Improvement score at month 2 between placebo and flutamide groupsp-value: =0.05t-test, 2 sided
Secondary
Side Effect Burden Measured by Side Effect Questionnaire
The Side Effects Questionnaire is a measure of combined side effect burden, including a score for frequency (0-6), intensity (0-6) and interference with function (0-6). Low score is 0, high score is 18, High score represents greater severe side effect burden
Time frame: Measured at Months 1 and 2
Population: 12 subjects were randomized to placebo and 13 randomized to flutamide. At the one month visit 11 subjects taking placebo and 13 subjects taking flutamide provided side effect ratings. At the two month visit 10 subjects taking placebo and 10 subjects randomized to flutamide provided side effect ratings
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Side Effect Burden Measured by Side Effect Questionnaire | Month 1 | 3.9 score on a scale | Standard Error 1.4 |
| Placebo | Side Effect Burden Measured by Side Effect Questionnaire | Month 2 | 2.2 score on a scale | Standard Error 1.2 |
| Flutamide | Side Effect Burden Measured by Side Effect Questionnaire | Month 1 | 3.5 score on a scale | Standard Error 1.3 |
| Flutamide | Side Effect Burden Measured by Side Effect Questionnaire | Month 2 | 5.1 score on a scale | Standard Error 1.2 |
p-value: =0.8t-test, 2 sided
p-value: =0.1t-test, 2 sided
Other Pre-specified
Change in Clinical Global Severity Scale
Scale range in 1-7. 1 is not at all ill, 4 is moderately ill, and 6 is severely ill and 7 is among the most extremely ill patients. Change score is calculated as Clinical Global Severity Scale score at the end of treatment month 1 or treatment month 2 minus baseline score. Negative change score is a reduction in symptoms during treatment and a positive change score is an increase in symptoms during treatment.
Time frame: Measured at Month 1 and Month 2
Population: 12 subjects were randomized to placebo and 13 randomized to flutamide. At the one month visit 11 subjects taking placebo and 13 subjects taking flutamide provided CGI severity ratings. At the two month visit 10 subjects taking placebo and 11subjects randomized to flutamide provided CGI severity ratings
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change in Clinical Global Severity Scale | Month 1 | -0.9 score on a scale | Standard Error 0.4 |
| Placebo | Change in Clinical Global Severity Scale | Month 2 | -0.5 score on a scale | Standard Error 0.4 |
| Flutamide | Change in Clinical Global Severity Scale | Month 1 | -1.2 score on a scale | Standard Error 0.4 |
| Flutamide | Change in Clinical Global Severity Scale | Month 2 | -1.7 score on a scale | Standard Error 0.4 |
p-value: =0.5t-test, 2 sided
p-value: <0.04t-test, 2 sided
Other Pre-specified
Change in Premenstrual Symptoms as Measured by the Patient Global Premenstrual Symptoms as Measured by the Patient Global Improvement Scale at Month 1 and Month 2
Scale range in 1-7. 1 is very much improved, 4 is no change, and 7 is very much worse.
Time frame: Measured at Month 1 and Month 2
Population: 12 subjects were randomized to placebo and 13 randomized to flutamide. At the one month visit 11 subjects taking placebo and 12 subjects taking flutamide had Patient Global Improvement Scale ratings. At the two month visit 10 subjects taking placebo and 11 subjects randomized to flutamide had Patient Global Improvement Scale ratings
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change in Premenstrual Symptoms as Measured by the Patient Global Premenstrual Symptoms as Measured by the Patient Global Improvement Scale at Month 1 and Month 2 | Month 1 | 3.0 score on a scale | Standard Error 0.3 |
| Placebo | Change in Premenstrual Symptoms as Measured by the Patient Global Premenstrual Symptoms as Measured by the Patient Global Improvement Scale at Month 1 and Month 2 | Month 2 | 2.2 score on a scale | Standard Error 0.3 |
| Flutamide | Change in Premenstrual Symptoms as Measured by the Patient Global Premenstrual Symptoms as Measured by the Patient Global Improvement Scale at Month 1 and Month 2 | Month 1 | 2.4 score on a scale | Standard Error 0.3 |
| Flutamide | Change in Premenstrual Symptoms as Measured by the Patient Global Premenstrual Symptoms as Measured by the Patient Global Improvement Scale at Month 1 and Month 2 | Month 2 | 3.1 score on a scale | Standard Error 0.3 |
Comparison: paired t-test was performed comparing the Patient Global Improvement score at month 1 between placebo and flutamide groupsp-value: =0.2t-test, 2 sided
p-value: =0.06t-test, 2 sided