Continuous Oral Contraceptive Treatment in Premenstrual Dysphoric Disorder (PMDD)
Study Details
Study Description
Brief Summary
The purpose of this study is to compare a low dose oral contraceptive (OC) given continuously (every day for three months) with the same low dose oral contraceptive given in an interrupted regimen (one week of inactive placebo pills each month) and with continuous placebo (inactive placebo given every day for three months). The primary hypothesis is that continuous OC will be significantly more effective in reducing premenstrual symptoms compared with either the interrupted OC or continuous placebo.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 4 |
Detailed Description
Premenstrual Dysphoric Disorder (PMDD) describes the cyclic appearance of affective symptoms and resultant impairment during the luteal phase of the menstrual cycle. The objective of this trial is to determine if extended oral contraceptive (OC) regimens with eliminated pill-free intervals will successfully prevent the expression of PMDD symptoms. The central hypothesis of this application is that continuous administration of OCs will minimize the destabilizing effects of changing reproductive steroid levels and prevent PMDD symptom emergence. The cause of PMDD is unknown, the morbidity substantial, and the identified treatments limited in their effectiveness, since 40% of PMDD women are non-responders to elective serotonin re-uptake inhibitors (SSRIs). Earlier controlled studies of OCs to treat PMDD failed to find OCs superior to placebo using the traditional 21/7 platform (21 active pills followed by a 7 day pill-free interval (PFI)). Two recent trials of a low dose OC using a 24/4 platform did report greater reductions in premenstrual symptoms relative to placebo, presumably due to the shortened PFI. Despite the apparent efficacy of the 3-day extended dosing of this OC, the placebo response rate was substantial in these studies, resulting in a low effect size. Moreover, no steroid hormone levels were examined in these prior studies. In the absence of hormonal data, inferences about the mechanism of efficacy of extended OCs must remain speculative and untested.
Our proposed research will addresses the critical role of hormonal change in the precipitation of PMDD symptoms before and after treatment with a continuous OC regimen, an interrupted OC regimen (21/7 platform) and continuous placebo. This study will also permit us to examine the role of neurosteroids in PMDD. While acting acutely as anxiolytic positive modulators of the gamma-aminobutyric acid A (GABAA) receptor, these neurosteroids may paradoxically reduce the response of the GABAA receptor and cause irritability (in rats) following either extended exposure or withdrawal. Further, our prior research suggests that elevated levels of or changes in peripheral neurosteroid levels are associated with dysphoric mood symptoms in women with PMDD. Our hypothesis is that changes in neurosteroids modulate symptom severity rather than appearance in PMDD. The results of our study will suggest therapeutic targets and will inform future studies of both PMDD and related affective disorders.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Active Comparator: Continuous OC (EE/DROS) Continuous daily oral drospirenone (DROS; 3mg) + ethinyl estradiol (EE; 20ug) |
Drug: Continuous OC (EE/DROS)
Continuous EE(20ug)+DROS(3mg) daily for 3 months
Other Names:
|
| Active Comparator: Intermittent OC (EE/DROS) Interrupted (21 days active - 7 days placebo) oral DROS (20ug)/EE(3mg) |
Drug: Intermittent OC (EE/DROS)
Intermittent EE(20ug)+DROS(3mg) daily for 21 days each month
Other Names:
|
| Placebo Comparator: Placebo Continuous daily oral placebo |
Drug: placebo
daily placebo
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Pre-Post Change in Premenstrual Symptom Severity [monthly]
Pre-post change (pre minus post) in mean premenstrual week severity of the worst emotional symptom as measured using the Daily Record of Severity of Problems items 1-8. Worst symptom for each individual was defined as the symptom in the baseline month demonstrating the highest mean severity during the premenstrual week. Mean premenstrual week severity scores were calculated to correspond to mean ratings; therefore, the mean premenstrual severity values ranged as follows: 1=Not at All, 2=Minimal, 3=Mild, 4=Moderate, 5=Severe, 6=Extreme. The change variable presented here is calculated as follows: "mean rating on the individual's worst symptom during the premenstrual week at baseline" minus "mean rating during the premenstrual week during the last on-treatment cycle". Therefore, higher values on this outcome variable correspond to greater reductions in premenstrual symptoms across the trial.
Eligibility Criteria
Criteria
Inclusion Criteria:
-
meets prospective criteria for PMDD, AND
-
English speaking and reading skills.
Exclusion Criteria:
-
current psychiatric disorder other than PMDD,
-
history of venous thromboembolism,
-
over 35 years of age and obese,
-
uncontrolled hypertension or end-organ vascular disease,
-
diabetes,
-
migraine headache with aura,
-
breastfeeding or pregnant,
-
cigarette smoking,
-
family history of premenopausal breast cancer or breast cancer in more than one first degree relative,
-
elevated serum potassium levels, use of prescription medications (except stable thyroid supplementation),
-
irregular menstrual cycles, OR
-
history of: endometriosis, hepatic disease, breast carcinoma, pulmonary embolism or phlebothrombosis, malignant melanoma, cholecystitis or pancreatitis.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | University of North Carolina | Chapel Hill | North Carolina | United States | 27599 |
Sponsors and Collaborators
- University of North Carolina, Chapel Hill
- National Institute of Mental Health (NIMH)
Investigators
- Principal Investigator: Susan Girdler, PhD, University of North Carolina, Chapel Hill
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- MH081837
- R01MH081837
Study Results
Participant Flow
| Recruitment Details | |
|---|---|
| Pre-assignment Detail |
| Arm/Group Title | Continuous Low Dose Oral Contraceptive | Interrupted Low Dose Oral Contraceptive (21/7 Platform) | Continuous Placebo |
|---|---|---|---|
| Arm/Group Description | continuous low dose oral contraceptive low dose oral contraceptive (20 ug ethinyl estradiol + 3 mg drospirenone): daily for three months | interrupted low dose oral contraceptive (21/7 platform) 20 ug ethinyl estradiol + 3 mg drospirenone: daily for 21 days each month | continuous placebo placebo: daily |
| Period Title: Overall Study | |||
| STARTED | 22 | 21 | 24 |
| COMPLETED | 16 | 17 | 22 |
| NOT COMPLETED | 6 | 4 | 2 |
Baseline Characteristics
| Arm/Group Title | Continuous Low Dose Oral Contraceptive | Interrupted Low Dose Oral Contraceptive (21/7 Platform) | Continuous Placebo | Total |
|---|---|---|---|---|
| Arm/Group Description | continuous low dose oral contraceptive low dose oral contraceptive (20 ug ethinyl estradiol + 3 mg drospirenone): daily for three months | interrupted low dose oral contraceptive (21/7 platform) 20 ug ethinyl estradiol + 3 mg drospirenone: daily for 21 days each month | continuous placebo placebo: daily | Total of all reporting groups |
| Overall Participants | 22 | 21 | 24 | 67 |
| Age (years) [Mean (Standard Deviation) ] | ||||
| Mean (Standard Deviation) [years] |
33.2
(8.1)
|
32.2
(8.6)
|
32.1
(6.7)
|
32.5
(7.7)
|
| Sex: Female, Male (Count of Participants) | ||||
| Female |
22
100%
|
21
100%
|
24
100%
|
67
100%
|
| Male |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Region of Enrollment (participants) [Number] | ||||
| United States |
22
100%
|
21
100%
|
24
100%
|
67
100%
|
Outcome Measures
| Title | Pre-Post Change in Premenstrual Symptom Severity |
|---|---|
| Description | Pre-post change (pre minus post) in mean premenstrual week severity of the worst emotional symptom as measured using the Daily Record of Severity of Problems items 1-8. Worst symptom for each individual was defined as the symptom in the baseline month demonstrating the highest mean severity during the premenstrual week. Mean premenstrual week severity scores were calculated to correspond to mean ratings; therefore, the mean premenstrual severity values ranged as follows: 1=Not at All, 2=Minimal, 3=Mild, 4=Moderate, 5=Severe, 6=Extreme. The change variable presented here is calculated as follows: "mean rating on the individual's worst symptom during the premenstrual week at baseline" minus "mean rating during the premenstrual week during the last on-treatment cycle". Therefore, higher values on this outcome variable correspond to greater reductions in premenstrual symptoms across the trial. |
| Time Frame | monthly |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Continuous Low Dose Oral Contraceptive | Interrupted Low Dose Oral Contraceptive (21/7 Platform) | Continuous Placebo |
|---|---|---|---|
| Arm/Group Description | continuous low dose oral contraceptive low dose oral contraceptive (20 ug ethinyl estradiol + 3 mg drospirenone): daily for three months | interrupted low dose oral contraceptive (21/7 platform) 20 ug ethinyl estradiol + 3 mg drospirenone: daily for 21 days each month | continuous placebo placebo: daily |
| Measure Participants | 16 | 17 | 21 |
| Mean (Standard Deviation) [units on a scale] |
1.93
(.22)
|
1.73
(.22)
|
1.64
(.19)
|
Adverse Events
| Time Frame | ||||||
|---|---|---|---|---|---|---|
| Adverse Event Reporting Description | ||||||
| Arm/Group Title | Continuous Low Dose Oral Contraceptive | Interrupted Low Dose Oral Contraceptive (21/7 Platform) | Continuous Placebo | |||
| Arm/Group Description | continuous low dose oral contraceptive low dose oral contraceptive (20 ug ethinyl estradiol + 3 mg drospirenone): daily for three months | interrupted low dose oral contraceptive (21/7 platform) 20 ug ethinyl estradiol + 3 mg drospirenone: daily for 21 days each month | continuous placebo placebo: daily | |||
All Cause Mortality |
||||||
| Continuous Low Dose Oral Contraceptive | Interrupted Low Dose Oral Contraceptive (21/7 Platform) | Continuous Placebo | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | / (NaN) | / (NaN) | / (NaN) | |||
Serious Adverse Events |
||||||
| Continuous Low Dose Oral Contraceptive | Interrupted Low Dose Oral Contraceptive (21/7 Platform) | Continuous Placebo | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/22 (0%) | 0/21 (0%) | 0/24 (0%) | |||
Other (Not Including Serious) Adverse Events |
||||||
| Continuous Low Dose Oral Contraceptive | Interrupted Low Dose Oral Contraceptive (21/7 Platform) | Continuous Placebo | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 22/22 (100%) | 21/21 (100%) | 24/24 (100%) | |||
| Gastrointestinal disorders | ||||||
| GI Symptoms | 13/22 (59.1%) | 13 | 16/21 (76.2%) | 16 | 13/24 (54.2%) | 13 |
| Bloating | 4/22 (18.2%) | 4 | 11/21 (52.4%) | 11 | 10/24 (41.7%) | 10 |
| Heartburn or Reflux | 0/22 (0%) | 0 | 1/21 (4.8%) | 1 | 0/24 (0%) | 0 |
| General disorders | ||||||
| Fatigue | 14/22 (63.6%) | 14 | 17/21 (81%) | 17 | 15/24 (62.5%) | 15 |
| Infections and infestations | ||||||
| Yeast Infection | 2/22 (9.1%) | 2 | 1/21 (4.8%) | 1 | 2/24 (8.3%) | 2 |
| Musculoskeletal and connective tissue disorders | ||||||
| Leg or Calf Discomfort | 10/22 (45.5%) | 10 | 13/21 (61.9%) | 13 | 9/24 (37.5%) | 9 |
| Nervous system disorders | ||||||
| Headache, Not Migraine | 10/22 (45.5%) | 10 | 16/21 (76.2%) | 16 | 20/24 (83.3%) | 20 |
| Headache, Migraine, No Aura | 5/22 (22.7%) | 5 | 3/21 (14.3%) | 3 | 3/24 (12.5%) | 3 |
| Headache, Migraine, with Aura | 0/22 (0%) | 0 | 1/21 (4.8%) | 1 | 0/24 (0%) | 0 |
| Psychiatric disorders | ||||||
| Low Mood | 17/22 (77.3%) | 17 | 13/21 (61.9%) | 13 | 17/24 (70.8%) | 17 |
| Irritability | 14/22 (63.6%) | 14 | 14/21 (66.7%) | 14 | 15/24 (62.5%) | 15 |
| Anxious Symptoms | 8/22 (36.4%) | 8 | 8/21 (38.1%) | 8 | 15/24 (62.5%) | 15 |
| Suicidality | 4/22 (18.2%) | 4 | 2/21 (9.5%) | 2 | 1/24 (4.2%) | 1 |
| Reproductive system and breast disorders | ||||||
| Breast Tenderness | 15/22 (68.2%) | 15 | 15/21 (71.4%) | 15 | 18/24 (75%) | 18 |
| Spotting | 11/22 (50%) | 11 | 10/21 (47.6%) | 10 | 4/24 (16.7%) | 4 |
| Changing Bleeding Pattern - Prolonged Bleeding | 7/22 (31.8%) | 7 | 4/21 (19%) | 4 | 2/24 (8.3%) | 2 |
| Change in Bleeding Pattern | 2/22 (9.1%) | 2 | 2/21 (9.5%) | 2 | 3/24 (12.5%) | 3 |
| Respiratory, thoracic and mediastinal disorders | ||||||
| Shortness of Breath or Chest Pain | 3/22 (13.6%) | 3 | 3/21 (14.3%) | 3 | 2/24 (8.3%) | 2 |
Limitations/Caveats
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
| Name/Title | Dr. Susan Girdler |
|---|---|
| Organization | University of North Carolina at Chapel Hill |
| Phone | 919-966-2179 |
| susan_girdler@med.unc.edu |
- MH081837
- R01MH081837