Treatment of Menstrually Related Disorders With Continuous v. Interrupted Oral Contraceptives

• ClinicalTrials.gov Identifier: NCT00089414
• Recruitment Status: Terminated
• First Posted: August 5, 2004
• Results First Posted: January 2, 2017
• Last Update Posted: August 25, 2017
• Sponsor: National Institute of Mental Health (NIMH)
• Information provided by (Responsible Party): National Institutes of Health Clinical Center (CC) ( National Institute of Mental Health (NIMH) )

Tracking Information

• First Submitted Date: August 4, 2004
• First Posted Date: August 5, 2004
• Results First Submitted Date: January 14, 2013
• Results First Posted Date: January 2, 2017
• Last Update Posted Date: August 25, 2017
• Study Start Date: July 2004
• Actual Primary Completion Date: June 2010 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: November 2, 2016)

Change in Premenstrual Tension Syndrome Scale (PMTS) Factors Associated With Premenstrual Symptoms. [ Time Frame: Every 2 weeks for 3 months ]

The PMTS observer scales assess symptoms in ten different domains including irritability-hostility; tension; efficiency; dysphoria; moodiness; motor coordination; mental-cognitive functioning; eating habits; sexual drive and activity; physical symptoms and social impairment. They have been used to measure premenstrual symptom severity and response to treatment in several clinical trials and prevalence studies. Score ranges from no symptoms to severe symptoms on a scale of 0 to 6, with 0 being no symptoms and 6 being severely symptomatic.

• Original Primary Outcome Measures: Not Provided

Current Secondary Outcome Measures (submitted: November 2, 2016)

• Change in Clinical Global Impression Scale (CGI) Factors Associated With Premenstrual Symptoms. [ Time Frame: Every 2 wks for 3 months ]
  The CGI was developed for use in NIMH-sponsored clinical trials to provide a brief, stand-alone assessment of the clinician's view of the patient's global functioning prior to and after initiating a study medication.1 The CGI provides an overall clinician-determined summary measure that takes into account all available information, including a knowledge of the patient's history, psychosocial circumstances, symptoms, behavior, and the impact of the symptoms on the patient's ability to function. The CGI actually comprises two companion one-item measures evaluating the following: (a) severity of psychopathology from 1 to 7 and (b) change from the initiation of treatment on a similar seven-point scale, with 1 being normal/more improved and 7 being severe/worse.
• Change in Beck Depression Inventory (BDI) Factors Associated With Premenstrual Symptoms [ Time Frame: Every 2 weeks for 3 months ]
  The Beck Depression Inventory (BDI)is a 21-question multiple-choice self-report inventory, one of the most widely used instruments for measuring the severity of depression. Total scores are interpreted per these ranges: 0-9: indicates minimal depression 10-18: indicates mild depression 19-29: indicates moderate depression 30-63: indicates severe depression.

• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Treatment of Menstrually Related Disorders With Continuous v. Interrupted Oral Contraceptives
• Official Title: The Treatment of Menstrually-Related Mood Disorders With Extended Versus Interrupted Oral Contraceptives

Brief Summary

This study will determine whether uninterrupted treatment with birth control pills over several menstrual cycles prevents severe premenstrual syndrome (PMDD).

Previous studies have shown that the hormones estrogen and progesterone regulate mood in women with MRMD. This study will use various treatment regimens with birth control pills and placebo (sugar pill) to clarify the relationships among estrogen and progesterone, the menstrual cycle, and mood.

Healthy women between 18 and 45 years of age who menstruate may be eligible for this 15-week study. Candidates are screened with a physical examination, blood and urine tests, an electrocardiogram, and 3 months of symptoms ratings to confirm MRMD.

Participants are randomly assigned to one of three treatment groups. Group 1 takes a birth control pill every day and on three occasions takes a placebo capsule. Group 2 takes a birth control pill most but not all days and on three occasions takes a placebo capsule. Group 3 takes a birth control pill every day and on three occasions takes another medication called CDB-2914 that causes menstrual bleeding to occur.

Participants come to the NIH clinic every other week for blood tests and measurement of vital signs (blood pressure, pulse, and temperature) and to complete symptoms ratings scales. Subjects who develop breakthrough bleeding (menstruation earlier than expected) will have a transvaginal ultrasound. For this procedure, a probe is inserted into the vagina for about 10 minutes. The probe gives off and receives sound waves that can be used to form a picture of the endometrium (lining of the uterus).

...

• Detailed Description: Results from previous protocols (#90-M-0088 and 92-M-0174) have demonstrated that women with menstrually-related mood disorder (MRMD), but not women lacking this disorder, experience mood deterioration within approximately one to two weeks after exposure to either estradiol or progesterone in the context of gonadal suppression (induced by use of the depot gonadotropin releasing hormone agonist leuprolide acetate). Preliminary results of protocol 00-M-0103 suggest that this hormone-induced depression occurs consequent to changes in gonadal steroid levels and not to simple exposure to basal levels above a critical threshold. Additionally, continued administration of hormone for three months resulted in no further symptoms subsequent to the initial precipitated episode. These data suggest the potential therapeutic benefit of extended oral contraceptive (OC) regimens with reduced pill-free intervals in MRMD to minimize the mood destabilizing effects of changing hormone levels. In this protocol we examine whether the effects of 15 weeks of continuous oral contraceptive administration causes a remission of symptoms in women with MRMD.
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment

Condition

• Premenstrual Syndrome
• PMS
• Premenstrual Dysphoric Disorder
• PMDD
• Depression

Intervention

• Drug: Ethinyl Estradiol/Drospirenone
  Drug administered dependent upon arm.
  Other Name: Yasmin
• Drug: Placebo
• Drug: CDB 2914
  Other Name: Progesterone antagonist

Study Arms

• Experimental: 1
  Treatment arm # 1 consists of the continuous administration of Yasmin oral contraceptive (a combination of 30 µg of ethinyl estradiol and 3 mg of drospirenone) for 15 weeks starting on day 2 to 5 of the first menstrual cycle.
  Intervention: Drug: Ethinyl Estradiol/Drospirenone
• Active Comparator: 2
  Treatment arm # 2 (interrupted Yasmin administration) will be identical to arm # 1 with the exception that the continuous administration of Yasmin will be interrupted by the substitution of placebo for Yasmin for one week during weeks 3, 8, and 14 of the study. The women participating in this treatment arm will experience episodes of menstruation after Yasmin withdrawal (when they are on placebo).
  Interventions:

  • Drug: Ethinyl Estradiol/Drospirenone
  • Drug: Placebo
• Active Comparator: 3
  Yasmin oral contraceptive; CDB 2914 progesterone antagonist. Treatment arm # 3 is identical to treatment arm # 1 with the exception that the continuous administration of Yasmin will also include the administration of progesterone antagonist CDB-2914 during weeks 3, 8, and 14. Menses is anticipated to occur within 2-3 days of CDB-2914 administration. Women in treatment arms # 3 and # 1 will be exposed to continuous levels of Yasmin, but due to the local effects of the progesterone antagonist on the endometrium, women in arm # 3 will experience menses.
  Interventions:

  • Drug: Ethinyl Estradiol/Drospirenone
  • Drug: CDB 2914

Publications *

• Bäckström T, Sanders D, Leask R, Davidson D, Warner P, Bancroft J. Mood, sexuality, hormones, and the menstrual cycle. II. Hormone levels and their relationship to the premenstrual syndrome. Psychosom Med. 1983 Dec;45(6):503-7.
• Schmidt PJ, Nieman LK, Grover GN, Muller KL, Merriam GR, Rubinow DR. Lack of effect of induced menses on symptoms in women with premenstrual syndrome. N Engl J Med. 1991 Apr 25;324(17):1174-9.
• Muse KN, Cetel NS, Futterman LA, Yen SC. The premenstrual syndrome. Effects of "medical ovariectomy". N Engl J Med. 1984 Nov 22;311(21):1345-9.

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: July 3, 2010): 5
• Original Enrollment (submitted: June 23, 2005): 54
• Actual Study Completion Date: June 2010
• Actual Primary Completion Date: June 2010 (Final data collection date for primary outcome measure)

Eligibility Criteria

• INCLUSION CRITERIA (are from protocol 81-M-0126 and are as follows):
• Subjects who meet criteria for MRMD are healthy (by physical exam, normal pelvic exam and pap smear, and normal lab values) and medication free will be included in this study.
• Oral contraceptives (and CDB-2914 in arm #3) will not be administered to any subject with significant clinical or laboratory abnormalities.

EXCLUSION CRITERIA:

Any patient with a current axis I psychiatric diagnosis will be excluded from participating in this protocol.

Subjects taking psychotropic agents (e.g. antidepressants, anxiolytics or mood stabilizers) will likewise be excluded from the study.

Women who have received glucocorticoid or megestrol therapy within the last year (and thus may experience residual suppression of the compensatory HPA axis response to CDB-2914-induced glucocorticoid receptor antagonism) will be also excluded, albeit almost entirely on theoretical grounds.

Women who have any chronic medical conditions or are taking medications will be excluded.

Women who have a medical condition or are taking any chronic medications that may increase serum potassium levels will also be excluded.

Those patients who would be uncomfortable with extending the length of their menstrual cycles will not be enrolled in this study and will either be offered participation in another study or an outside referral for treatment in the community.

The following conditions will constitute contraindications to treatment with continuous oral contraception or the use of the progesterone antagonist, CDB-2914, and will preclude a patient's participating in this protocol:

• history of endometriosis, or recent, rapid growth of uterine fibroid tumors (defined as doubling in size in six month period);
• diagnosis of ill-defined, obscure pelvic lesions, particularly undiagnosed ovarian enlargement;
• hepatic disease as manifested by abnormal liver function tests;
• history of breast carcinoma;
• history of pulmonary embolism or phlebothrombosis;
• undiagnosed vaginal bleeding;
• porphyria;
• history of malignant melanoma;
• history of cholecystitis or pancreatitis;
• history of hypercholesterolemia, hypertension, diabetes, or renal disease;
• recurrent migraine headaches (greater than or equal to 3 per year) in women 35 or older;
• pregnancy or lactation;
• cigarette smoking in women 35 or older, or more than 10 cigarettes per day in women under 35; or
• use of oral, injectable, or inhaled glucocorticoids or megestrol within the last year.

Sex/Gender

• Sexes Eligible for Study: Female

• Ages: 18 Years to 45 Years (Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT00089414
• Other Study ID Numbers: 040221; 04-M-0221
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: National Institutes of Health Clinical Center (CC) ( National Institute of Mental Health (NIMH) )
• Study Sponsor: National Institute of Mental Health (NIMH)
• Collaborators: Not Provided

Investigators

• Principal Investigator: Pedro E Martinez, M.D.; National Institute of Mental Health (NIMH)

• PRS Account: National Institutes of Health Clinical Center (CC)
• Verification Date: July 2017