| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Premenstrual dysphoric disorder (PMDD) affects 3% to 5% of menstruating women. PMDD is defined by markedly depressed mood, anxiety, and/or affective lability during the last week of the late luteal phase with absence of these symptoms in the postmenses week. These symptoms markedly interfere with work or school or with usual social activities and relationships with others. Suppression of ovarian cyclicity is known to alleviate symptoms of PMDD. |
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| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
There are 4 co-primary endpoints, each of which is based on comparison between the LNG/EE continuous regimen and placebo groups of the mean change from the baseline efficacy period in average daily DRSP 21-item total daily scores.
The 4 comparisons of primary interest are the changes between baseline and:
(1) the cycle 1 efficacy period
(2) the worst 5 days during cycle 1
(3) the last on-therapy efficacy period, and
(4) the worst 5 days during the last on-therapy estimated cycle.
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| E.2.2 | Secondary objectives of the trial |
To evaluate the effect of treatment with LNG/EE administered in a continuous daily regimen versus placebo on the following:
- Analysis of DRSP score averaged over the study
- Responder/remitter analyses based on CGI-S scores, percentage improvement in DRSP scores and PMDD criteria
- Clinical Global Impression scale-Severity of Illness item (CGI-S) scores
- Change from baseline in mean clinically defined DRSP cluster (symptom subgroup) scores.
- Change from baseline in Work Limitations Questionnaire (WLQ).
- Area under the curve (AUC) analysis of DRSP scores for the entire 112-day period.
- Subject global evaluation mean scores.
- Change in weight. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Generally healthy women aged 18 to 49 years who meet Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV), criteria for PMDD and who are willing to take a combination OC.
2.Subjects must have symptoms consistent with PMDD by history over the past year.
3.Subjects must prospectively meet the following criteria using the DRSP instrument and worksheet : a. Subjects must have an average (across 5 days) daily follicular phase (days 8 to 12 after the first day of menses) score < 3 on each of the 21 items during both the pretreatment screening cycle 2 and placebo run-in cycle 3. b.Subjects must have each qualifying symptom on at least 4 of 7 efficacy period days (the 6 days before menses through day 1 of menses [7 days total]):
- At least moderate (> or = 4) for at least 2 days
- At least mild (> or = 3) for at least 2 of the remaining days on 5 or more of the 11 PMDD symptoms during both the pretreatment screening cycle 2 and placebo run-in cycle 3, with at least 1 of the symptoms being either items 1 (a, b or c), (2), 3 (a or b), or 4 (a or b). c.Subjects must have an average daily efficacy period (the 6 days before menses through day 1 of menses [7 days total]) score > or = 50 with a > or = 50% increase from the previous average daily total follicular phase score to the efficacy period score during both the pretreatment screening cycle 2 and placebo run-in cycle 3.d.Subjects must have an efficacy period (the 6 days before menses through day 1 of menses [7 days total]) score of at least moderate (> or = 4) for at least 2 days on any of the 3 functional impairment items during both the pretreatment screening cycle 2 and placebo run-in cycle 3.
4.Subjects must not be at risk for pregnancy during the study, or they must be using an effective, nonhormonal method of birth control (eg, diaphragm, condom with spermicide, sterilization, or nonhormonal intrauterine device [IUD]) or must be practicing complete abstinence.
5. Subjects must have had regular (21- to 35-day) menstrual cycles by history for the2-month period preceding the pretreatment screening cycle 1 (visit 1).
6. Subjects must have a cervical cytological smear report of negative forintraepithelial lesion or malignancy. If atypical squamous cells of undeterminedsignificance (ASCUS) is reported, the subject must have a negative test for humanpapilloma virus (HPV). The cervical cytological smear must be performed atpretreatment screening cycle 1 (visit 1) or within 6 months of pretreatmentscreening cycle 1 (visit 1) provided that a copy of the report is available. |
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| E.4 | Principal exclusion criteria |
1. The presence or history of the following will prevent enrollment:
Thrombophlebitis, thrombosis, thromboembolic disorders, deep vein thrombosis, pulmonary embolism, or known coagulopathy.
Ischemic heart disease or myocardial infarction.
Cerebrovascular disease, cardiovascular disease, or thrombogenic valvular heart disease.
Headaches with focal neurological symptoms in the 90 days before visit 1.
Known or suspected estrogen-dependent neoplasia, known or suspected carcinoma of the breast, or ovarian carcinoma.
Undiagnosed abnormal genital bleeding within the past 180 days of pretreatment screening cycle 1 (visit 1).
Major depressive disorder requiring antidepressant treatment or hospitalization, or associated with suicide attempt or risk for suicide within the last 3 years before pretreatment screening cycle 1 (visit 1).
Known hypersensitivity to estrogens, progestins, or any components of the study medication.
Use of depot medroxyprogesterone acetate (ie, Depo-Provera) within 6 months of pretreatment screening cycle 1 (visit 1) and for the duration of the study.
Use of monthly hormonal contraceptive injections, a hormonal IUD, implantable contraceptive hormones, oral contraceptives, estrogens, progestins, androgens, or gonadotropin-releasing hormone (GnRH) analogs within 60 days of pretreatment screening cycle 1 (visit 1) and for the duration of the study.
Use of any experimental drug or device or participation in another research study within 10 days of pretreatment screening cycle 1 (visit 1) and for the duration of the study.
Use of antidepressants/anxiolytics including but not limited to, tricyclic antidepressants, selective serotonin reuptake inhibitors (excluding fluoxetine), selective serotonin and norepinephrine reuptake inhibitors (eg, venlafaxine), serotonin agonists, monoamine oxidase inhibitors, benzodiazepines, bupropion, nefazadone, mirtazipine, and herbal preparations (eg, St. John’s wort, kava) within 10 days of pretreatment screening cycle 1 (visit 1) and for the duration of the study.
Use of fluoxetine within the 30 days of pretreatment screening cycle 1 (visit 1) and for the duration of the study.
2. The presence of any of the following will prevent enrollment:
Hamilton Depression Rating Scale (HAM-D17) score >11 administered during pretreatment screening cycle 2, days 8 to 12 (visit 2).
Diagnosis of a current Axis I psychiatric disorder, based on the Mini International Neuropsychiatric regarding major depressive episode criteria administered during pretreatment screening cycle 2, days 8 to 12 (visit 2).
Seasonal affective disorder, bipolar depression, psychotic disorder, somatoform disorder, dysthymic disorder, schizophrenia, obsessive-compulsive disorder, or antisocial/borderline/schizotypal personality disorder.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
There are 4 co-primary endpoints, each of which is based on comparison between the LNG/EE continuous regimen and placebo groups of the mean change from the baseline efficacy period in average daily DRSP 21-item total daily scores.
The four comparisons of primary interest are the changes between baseline and
(1) the cycle 1 efficacy period
(2) the worst 5 days during cycle 1
(3) the last on-therapy efficacy period and
(4) the worst 5 days during the last on-therapy estimated cycle
Each subject will be asked to complete the DRSP questionnaire during pretreatment screening cycle 2, during placebo run-in cycle 3, and during each of the four 28-day pill packs of double-blind treatment. For each subject, the baseline DRSP 21-item score will be the mean of the scores determined during the pretreatment screening cycle 2 and placebo run-in cycle 3, using data from the average of the 5 most symptomatic days (highest daily 21-item scores) of the efficacy period of those cycles. The subject's baseline mean score will be compared with data from the average of the 5 most symptomatic days of the efficacy period (the “estimated” 6 days before menses through “estimated” day 1 of menses [7 days total]) of subsequent double-blind treatment cycles. The efficacy period for each on-therapy cycle will be defined on an individual subject basis. Each subject’s average cycle length will be calculated using the pretreatment screening cycle 2 and placebo run-in cycle 3 data. The efficacy period for the subsequent double-blind treatment cycles will be defined based on the individual subject’s average pretreatment cycle length. Day 1 of the study is defined as the first day of menses after the placebo run-in period. For example, if a subject's baseline average cycle length is 24 days, then the efficacy period would be 19 to 25, 43 to 49, 67 to 73, and 91 to 97. For 25 days, the efficacy period would be 20 to 26, 45 to 51, 70 to 76, and 95 to 101. For 26 days, the efficacy period would be 21 to 27, 47 to 53, 73 to 79, and 99 to 105. For 27 days, the efficacy period would be 22 to 28, 49 to 55, 76 to 82, and 103 to 109. For 28 days, the efficacy period would be 23 to 29, 51 to 57, 79 to 85, and 107 to 113, and so on. If a subject’s last on-therapy efficacy period ends on day 113 or 114, this phase can still be used provided that at least 5 on-therapy days have data to use in each DRSP analysis. Because the double-blind study medication is to be taken for 112 days, subjects with an average baseline cycle length of 29 or more days will only have 3 efficacy periods (and “estimated” cycles) defined. Subjects with an average baseline cycle length of 21 or 22 days will have 5 efficacy periods (and “estimated” cycles) defined. Each subject’s last on-therapy efficacy period (or “estimated” cycle) can be the first through the fifth, depending on her average baseline cycle length and the number of days she took double-blind study medication. |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Information not present in EudraCT |
| E.6.2 | Prophylaxis | Information not present in EudraCT |
| E.6.3 | Therapy | Information not present in EudraCT |
| E.6.4 | Safety | Information not present in EudraCT |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Information not present in EudraCT |
| E.6.7 | Pharmacodynamic | Information not present in EudraCT |
| E.6.8 | Bioequivalence | Information not present in EudraCT |
| E.6.9 | Dose response | Information not present in EudraCT |
| E.6.10 | Pharmacogenetic | Information not present in EudraCT |
| E.6.11 | Pharmacogenomic | Information not present in EudraCT |
| E.6.12 | Pharmacoeconomic | Information not present in EudraCT |
| E.6.13 | Others | Information not present in EudraCT |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | Yes |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 30 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| End of the trial is last visit of last subject undergoing the trial. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 26 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 26 |
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