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Continuous Oral Contraceptive Treatment in Premenstrual Dysphoric Disorder (PMDD) (PMDD)

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ClinicalTrials.gov Identifier: NCT00927095
Recruitment Status : Completed
First Posted : June 24, 2009
Results First Posted : August 24, 2016
Last Update Posted : August 24, 2016
Sponsor:
Collaborator:
National Institute of Mental Health (NIMH)
Information provided by (Responsible Party):
Susan Girdler, PhD, University of North Carolina, Chapel Hill

Tracking Information
First Submitted Date  ICMJE June 22, 2009
First Posted Date  ICMJE June 24, 2009
Results First Submitted Date  ICMJE April 25, 2016
Results First Posted Date  ICMJE August 24, 2016
Last Update Posted Date August 24, 2016
Study Start Date  ICMJE July 2008
Actual Primary Completion Date July 2014   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 13, 2016)
Pre-Post Change in Premenstrual Symptom Severity [ Time Frame: 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.
Original Primary Outcome Measures  ICMJE
 (submitted: June 23, 2009)
premenstrual symptom severity [ Time Frame: monthly ]
Change History Complete list of historical versions of study NCT00927095 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Continuous Oral Contraceptive Treatment in Premenstrual Dysphoric Disorder (PMDD)
Official Title  ICMJE Continuous OC Treatment in PMDD: Steroid Hormone Mechanisms
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.
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 Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Premenstrual Dysphoric Disorder
Intervention  ICMJE
  • Drug: Continuous OC (EE/DROS)
    Continuous EE(20ug)+DROS(3mg) daily for 3 months
    Other Name: Yaz
  • Drug: Intermittent OC (EE/DROS)
    Intermittent EE(20ug)+DROS(3mg) daily for 21 days each month
    Other Name: Yaz
  • Drug: placebo
    daily placebo
    Other Name: oral placebo
Study Arms  ICMJE
  • Active Comparator: Continuous OC (EE/DROS)
    Continuous daily oral drospirenone (DROS; 3mg) + ethinyl estradiol (EE; 20ug)
    Intervention: Drug: Continuous OC (EE/DROS)
  • Active Comparator: Intermittent OC (EE/DROS)
    Interrupted (21 days active - 7 days placebo) oral DROS (20ug)/EE(3mg)
    Intervention: Drug: Intermittent OC (EE/DROS)
  • Placebo Comparator: Placebo
    Continuous daily oral placebo
    Intervention: Drug: placebo
Publications * Eisenlohr-Moul TA, Girdler SS, Johnson JL, Schmidt PJ, Rubinow DR. Treatment of premenstrual dysphoria with continuous versus intermittent dosing of oral contraceptives: Results of a three-arm randomized controlled trial. Depress Anxiety. 2017 Oct;34(10):908-917. doi: 10.1002/da.22673. Epub 2017 Jul 17.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: July 13, 2016)
67
Original Estimated Enrollment  ICMJE
 (submitted: June 23, 2009)
120
Actual Study Completion Date  ICMJE July 2014
Actual Primary Completion Date July 2014   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: Female
Ages  ICMJE 18 Years to 52 Years   (Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00927095
Other Study ID Numbers  ICMJE MH081837
R01MH081837 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Responsible Party Susan Girdler, PhD, University of North Carolina, Chapel Hill
Study Sponsor  ICMJE University of North Carolina, Chapel Hill
Collaborators  ICMJE National Institute of Mental Health (NIMH)
Investigators  ICMJE
Principal Investigator: Susan Girdler, PhD University of North Carolina, Chapel Hill
PRS Account University of North Carolina, Chapel Hill
Verification Date July 2016

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP