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) )

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
• Conditions: Premenstrual Syndrome; PMS; Premenstrual Dysphoric Disorder; PMDD; Depression
• Interventions: Drug: Ethinyl Estradiol/Drospirenone; Drug: Placebo; Drug: CDB 2914
• Enrollment: 5

Participant Flow

Recruitment Details
Pre-assignment Details

Arm/Group Title	Continuous Yasmin	Interrupted Yasmin	Continuous Yasmin Plus Progesterone Antagonist
Arm/Group Description	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.	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).	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.
Period Title: Overall Study
Started	2	1	2
Completed	2	1	2
Not Completed	0	0	0

Baseline Characteristics

Arm/Group Title		Continuous OCP Plus Placebo	Interrupted OC	Continuous OC Plus PR Antagonist	Total
Arm/Group Description		Treatment arm # 1 (extended ethinyl estradiol and progestin [EE/P]) consists of the continuous administration of 30 µg of ethinyl estradiol and 3 mg of drospirenone (Yasmin) for 15 weeks starting on day 2 to 5 of the first menstrual cycle.	Treatment arm # 2 (interrupted EE/P administration) will be identical to arm # 1 with the exception that the continuous administration of EE/P will be interrupted by the substitution of placebo for EE/P 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 EE/P withdrawal (placebo).	Yasmin oral contraceptive; CDB 2914 progesterone antagonist. Treatment arm # 3 (extended EE/P with menses) is identical to treatment arm # 1 except the progesterone antagonist CDB-2914 will be administered during weeks 3, 8, and 14. Menses is anticipated to occur within 2-3 days of CDB-2914 administration. As such, menses will occur in these women at approximately the same interval as experienced by those women in treatment arm # 2 due to the local effects of the progesterone receptor antagonist on the endometrium (lining of the uterus). Thus, women in treatment arms # 3 and # 1 will be exposed to continuous levels of ethinyl estradiol and progestin, but due to the local effects of the progesterone antagonist on the endometrium, women in arm # 3 will experience menses.	Total of all reporting groups
Overall Number of Baseline Participants		2	1	2	5
Baseline Analysis Population Description		[Not Specified]
Age, Categorical; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	2 participants	1 participants	2 participants	5 participants
	<=18 years	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	Between 18 and 65 years	2 100.0%	1 100.0%	2 100.0%	5 100.0%
	>=65 years	0 0.0%	0 0.0%	0 0.0%	0 0.0%
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	2 participants	1 participants	2 participants	5 participants
		31.5 (6.364)	41 (0)	34.5 (2.121)	34.6 (3.8794)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	2 participants	1 participants	2 participants	5 participants
	Female	2 100.0%	1 100.0%	2 100.0%	5 100.0%
	Male	0 0.0%	0 0.0%	0 0.0%	0 0.0%
Region of Enrollment; Measure Type: Number; Unit of measure: Participants
United States	Number Analyzed	2 participants	1 participants	2 participants	5 participants
		2	1	2	5

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

This study was terminated early due to confounding factors in design. Protocol terminated after receiving information from manufacturer (Pharma) that CDB-2914 crosses the blood-brain barrier, invalidating Arm #3 due to potential Central Nervous System effect of the compound on behavior.

Arm/Group Title	Continuous Yasmin	Interrupted Yasmin	Continuous Yasmin Plus Progesterone Antagonist
Arm/Group Description:	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.	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).	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.
Overall Number of Participants Analyzed	0	0	0

No data displayed because Outcome Measure has zero total analyzed.

2. Secondary Outcome

Title	Change in Clinical Global Impression Scale (CGI) Factors Associated With Premenstrual Symptoms.
Description	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.
Time Frame	Every 2 wks for 3 months

Outcome Measure Data

Analysis Population Description

This study was terminated early due to confounding factors in design. Protocol terminated after receiving information from manufacturer (Pharma) that CDB-2914 crosses the blood-brain barrier, invalidating Arm #3 due to potential Central Nervous System effect of the compound on behavior.

Arm/Group Title	Continuous Yasmin	Interrupted Yasmin	Continuous Yasmin Plus Progesterone Antagonist
Arm/Group Description:	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.	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).	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.
Overall Number of Participants Analyzed	0	0	0

No data displayed because Outcome Measure has zero total analyzed.

3. Secondary Outcome

Title	Change in Beck Depression Inventory (BDI) Factors Associated With Premenstrual Symptoms
Description	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.
Time Frame	Every 2 weeks for 3 months

Outcome Measure Data

Analysis Population Description

This study was terminated early due to confounding factors in design. Protocol terminated after receiving information from manufacturer (Pharma) that CDB-2914 crosses the blood-brain barrier, invalidating Arm #3 due to potential Central Nervous System effect of the compound on behavior.

Arm/Group Title	Continuous Yasmin	Interrupted Yasmin	Continuous Yasmin Plus Progesterone Antagonist
Arm/Group Description:	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.	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).	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.
Overall Number of Participants Analyzed	0	0	0

No data displayed because Outcome Measure has zero total analyzed.

Adverse Events

Time Frame	[Not Specified]
Adverse Event Reporting Description	[Not Specified]
Arm/Group Title	Continuous OCP Plus Placebo	Interrupted OC	Continuous OC Plus PR Antagonist
Arm/Group Description	Treatment arm # 1 (extended ethinyl estradiol and progestin [EE/P]) consists of the continuous administration of 30 µg of ethinyl estradiol and 3 mg of drospirenone (Yasmin) for 15 weeks starting on day 2 to 5 of the first menstrual cycle.	Treatment arm # 2 (interrupted EE/P administration) will be identical to arm # 1 with the exception that the continuous administration of EE/P will be interrupted by the substitution of placebo for EE/P 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 EE/P withdrawal (placebo).	Yasmin oral contraceptive; CDB 2914 progesterone antagonist. Treatment arm # 3 (extended EE/P with menses) is identical to treatment arm # 1 except the progesterone antagonist CDB-2914 will be administered during weeks 3, 8, and 14. Menses is anticipated to occur within 2-3 days of CDB-2914 administration. As such, menses will occur in these women at approximately the same interval as experienced by those women in treatment arm # 2 due to the local effects of the progesterone receptor antagonist on the endometrium (lining of the uterus). Thus, women in treatment arms # 3 and # 1 will be exposed to continuous levels of ethinyl estradiol and progestin, but due to the local effects of the progesterone antagonist on the endometrium, women in arm # 3 will experience menses.
All-Cause Mortality
	Continuous OCP Plus Placebo	Interrupted OC	Continuous OC Plus PR Antagonist
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	--/--	--/--	--/--
Serious Adverse Events
	Continuous OCP Plus Placebo	Interrupted OC	Continuous OC Plus PR Antagonist
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	0/2 (0.00%)	0/1 (0.00%)	0/2 (0.00%)
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	1%
	Continuous OCP Plus Placebo	Interrupted OC	Continuous OC Plus PR Antagonist
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	0/2 (0.00%)	0/1 (0.00%)	0/2 (0.00%)

Limitations and Caveats

Protocol terminated after receiving information from manufacturer (Pharma) that CDB-2914 crosses the blood-brain barrier, invalidating Arm #3 due to potential CNS effect of the compound on behavior.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

Results Point of Contact

• Name/Title: Pedro E. Martinez, M.D., Principal Investigator
• Organization: Behavioral Endocrinology Branch/National Institute of Mental Health/NIH
• Phone: 301-402-0615
• EMail: martinep@mail.nih.gov

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.

• Responsible Party: National Institutes of Health Clinical Center (CC) ( National Institute of Mental Health (NIMH) )
• ClinicalTrials.gov Identifier: NCT00089414
• Other Study ID Numbers: 040221; 04-M-0221
• First Submitted: August 4, 2004
• First Posted: August 5, 2004
• Results First Submitted: January 14, 2013
• Results First Posted: January 2, 2017
• Last Update Posted: August 25, 2017