Differential Effects of Clomiphene Citrate in Women Undergoing Superovulation

• Sponsor: University of Utah (Other)
• Overall Status: Completed
• CT.gov ID: NCT01291056
• Collaborator: (none)
• Enrollment: 20
• Location: 1
• Arms: 2
• Duration (Months): 15.9
• Patients Per Site Per Month: 1.3

Study Details

Study Description

Brief Summary

Clomiphene citrate is commonly used for ovulation induction in women with anovulation, correction of luteal phase deficiency or for superovulation as empiric therapy for unexplained infertility. Superovulation using clomiphene, usually with intrauterine insemination, is usually regarded as first line therapy for unexplained infertility, infertility due to mild endometriosis, or infertility with mild or moderate compromise of the male factor. The side effect profile reported by some women using clomiphene citrate is similar to symptoms of premenstrual dysphoric disorder (PMDD), including tension, irritability, depressed mood, affective lability, lack of energy, difficulty concentrating, and physical symptoms such as breast tenderness, bloating, headache joint and muscle pain. Few studies have been performed to examine the relationship between clomiphene citrate and mood symptoms; however, these studies have been limited by their small sample size, potential for recall bias and lack of randomization. Moreover, the experience of infertility is dysphoric in and of itself. Therefore, a rigorous evaluation of whether, when in the cycle, and how often clomiphene is associated with mood changes is needed. Such a study would add to the body of literature on this topic in three important ways: 1) use of prospective data collection to more accurately identify commonly reported symptoms, 2) characterize the timing of symptom occurrence relative to treatment cycle, and 3) provide information relevant to planning of future studies involving targeted treatment of clomiphene citrate induced symptoms. If clomiphene use is shown to affect mood, the results would point to an important avenue for psychopharmacologic insight into relationships between mood and sex steroids.

OBJECTIVES:

Specific Aim #1: To identify psychological and physical symptoms experienced by women taking clomiphene citrate for superovulation in a prospective, placebo controlled trial setting.

Specific Aim #2: To determine whether measures of the emotional and physical state prior to the administration of clomiphene, predict the occurrence of mood changes during the five days of clomiphene administration and in the late follicular and luteal phases of the cycle in which clomiphene was administered.

Condition or Disease	Intervention/Treatment	Phase
Mood	Other: Placebo; Drug: Clomiphene	N/A

Detailed Description

The aim of this study is to identify psychological and physical symptoms experienced by women taking clomiphene citrate for superovulation in a prospective setting.

Clomiphene citrate is commonly used for ovulation induction in women with anovulation, correction of luteal phase deficiency or for superovulation as empiric therapy for unexplained infertility1. While clomiphene citrate is generally well tolerated, common side effects have been reported including vasomotor flushes, breast tenderness, pelvic discomfort, and mood swings. Visual changes, such as palenopsia are rarely reported2. The side effect profile reported by some women using clomiphene citrate is similar to symptoms of premenstrual dysphoric disorder (PMDD). Symptoms of PMDD include tension, irritability, depressed mood, affective lability, lack of energy, difficulty concentrating, and physical symptoms such as breast tenderness, bloating, headache joint and muscle pain. Several validated scales have been used to record symptom occurrences and to characterize the timing of symptom occurrence relative to the menstrual cycle3.

The psychological and mood side effects of clomiphene citrate in women undergoing infertility treatment have been studied to a limited degree. One study reported mood swings in 9 out of 14 women surveyed4. Another small study found a higher frequency of irritability, mood swings, feeling down and bloating in women undergoing fertility treatment who were taking clomiphene citrate compared to no medication.

Study Design

• Study Type: Interventional
• Actual Enrollment: 20 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Double (Participant, Investigator)
• Official Title: Differential Effects of Clomiphene Citrate in Women Undergoing Superovulation: A Double-blind, Placebo-controlled, Crossover Study
• Study Start Date: Jan 1, 2010
• Actual Primary Completion Date: May 1, 2011
• Actual Study Completion Date: May 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Clomphine Each participant will take assigned medication (clomiphene citrate 50mg or placebo) on days 3-7 of her menstrual cycle.	Drug: Clomiphene; Each participant will take assigned medication (clomiphene citrate 50mg or placebo) on days 3-7 of her menstrual cycle.
Placebo Comparator: Placebo Each participant will take assigned medication (clomiphene citrate 50mg or placebo) on days 3-7 of her menstrual cycle.	Other: Placebo; Each participant will take assigned medication (clomiphene citrate 50mg or placebo) on days 3-7 of her menstrual cycle.

Outcome Measures

Primary Outcome Measures

1. Follicular Cycle Total Behavioral Score for Calendar of Premenstrual Experiences (COPE) Self Assessment [1 year]

   To identify behavioral symptoms experienced by women taking clomiphene citrate versus placebo for superovulation in a prospective setting.

2. Follicular Cycle Total Physical Score for Calendar of Premenstrual Experiences (COPE) Self Assessment [1 Year]

   To identify physical symptoms experienced by women taking clomiphene citrate versus placebo for superovulation in a prospective setting.

3. Luteal Cycle Total Behavioral Score for Calendar of Premenstrual Experiences (COPE) Self Assessment [1 year]

   To identify behavioral symptoms experienced by women taking clomiphene citrate versus placebo for superovulation in a prospective setting.

4. Luteal Cycle Total Physical Score for Calendar of Premenstrual Experiences (COPE) Self Assessment [1 year]

   To identify physical symptoms experienced by women taking clomiphene citrate versus placebo for superovulation in a prospective setting.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 25 Years to 40 Years
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Menstruating women, ages 25-40, with regular menstrual cycles 23-35 days in length who elect to treat unexplained infertility using clomiphene citrate for superovulation combined with intrauterine insemination will be eligible for participation in this study.

• Eligible participants will be identified by physicians at the Utah Center for Reproductive Medicine at the University of Utah and will be provided written informed consent before being randomized to treatment groups.

• Male partner's semen analysis must show a sperm density of at least 10 million per ml, and motility of 20% or greater and normal morphology using World Health Organization (WHO) criteria.

Exclusion Criteria:

• Women with a history of depression or anxiety disorder requiring hospitalization or treatment lasting more than six months and women who currently or have received treatment during the previous six months for anxiety, depression or other psychiatric disorders listed in the 4th Edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) will be excluded.

• Women who have previously received treatment with clomiphene citrate will also be excluded from the study.

• Women using tobacco or illicit drugs will be excluded from study participation.

• Because the measurement tool used to measure symptoms has been validated only in women who can read and speak English, women who cannot speak and read English will not be eligible to participate in the study.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Utah	Salt Lake City	Utah	United States	84108

Sponsors and Collaborators

• University of Utah

Investigators

• Principal Investigator: Jessica Pittman, M.D., University of Utah

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Jessica Pittman, M.D., University of Utah
• ClinicalTrials.gov Identifier: NCT01291056
• Other Study ID Numbers: 00038807
• First Posted: Feb 7, 2011
• Last Update Posted: Jun 28, 2016
• Last Verified: May 1, 2016

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Jessica Pittman, M.D., University of Utah: Clomiphene citrate; Mood symptoms; Infertility; Superovulation; Effects of clomiphene on mood
• Additional relevant MeSH terms: Clomiphene

Study Results

Participant Flow

Recruitment Details	Eligible participants were identified by physicians at the Utah Center for Reproductive Medicine at the University of Utah and provided written informed consent before being randomized to treatment groups.

Arm/Group Title	Clomiphene Citrate, Then Placebo	Placebo, Then Clomiphene Citrate
Arm/Group Description	Clomiphene Citrate 50 milligrams daily, then Placebo daily	Placebo, then Clomiphene Citrate 50 milligrams daily
Period Title: Intervention One (Menstraution Day 3-7)
STARTED	10	10
COMPLETED	10	10
NOT COMPLETED	0	0
Period Title: Intervention One (Menstraution Day 3-7)
STARTED	10	10
COMPLETED	10	10
NOT COMPLETED	0	0
Period Title: Intervention One (Menstraution Day 3-7)
STARTED	10	10
COMPLETED	10	10
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Clomiphene Citrate, Then Placebo	Placebo, Then Clomiphene Citrate	Total
Arm/Group Description	Clomiphene Citrate 50 milligrams daily, then Placebo daily	Placebo, then Clomiphene Citrate 50 milligrams daily	Total of all reporting groups
Overall Participants	10	10	20
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	10 100%	10 100%	20 100%
>=65 years	0 0%	0 0%	0 0%
Sex: Female, Male (Count of Participants)
Female	10 100%	10 100%	20 100%
Male	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	Follicular Cycle Total Behavioral Score for Calendar of Premenstrual Experiences (COPE) Self Assessment
Description	To identify behavioral symptoms experienced by women taking clomiphene citrate versus placebo for superovulation in a prospective setting.
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

The scale incorporates physical, behavioral and mental symptoms. Each participant will rate the symptom(s) from zero to three based off severity. Symptoms with zero means that no symptoms are present. Symptoms with three means that the symptoms are severe. Range 0 -75 per cycle day.

Arm/Group Title	Clomiphene Citrate	Placebo
Arm/Group Description	Clomiphene Citrate 50 milligrams daily	Placebo
Measure Participants	20	20
Median (Full Range) [units on a scale]	3	5

2. Primary Outcome

Title	Follicular Cycle Total Physical Score for Calendar of Premenstrual Experiences (COPE) Self Assessment
Description	To identify physical symptoms experienced by women taking clomiphene citrate versus placebo for superovulation in a prospective setting.
Time Frame	1 Year

Outcome Measure Data

Analysis Population Description

The scale incorporates physical, behavioral and mental symptoms. Each participant will rate the symptom(s) from zero to three based off severity. Symptoms with zero means that no symptoms are present. Symptoms with three means that the symptoms are severe. Range 0 -75 per cycle day.

Arm/Group Title	Clomiphene Citrate	Placebo
Arm/Group Description	Clomiphene Citrate 50 milligrams daily	Placebo
Measure Participants	20	20
Median (Full Range) [units on a scale]	10	8

3. Primary Outcome

Title	Luteal Cycle Total Behavioral Score for Calendar of Premenstrual Experiences (COPE) Self Assessment
Description	To identify behavioral symptoms experienced by women taking clomiphene citrate versus placebo for superovulation in a prospective setting.
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

The scale incorporates physical, behavioral and mental symptoms. Each participant will rate the symptom(s) from zero to three based off severity. Symptoms with zero means that no symptoms are present. Symptoms with three means that the symptoms are severe. Range 0 -75 per cycle day.

Arm/Group Title	Clomiphene Citrate	Placebo
Arm/Group Description	Clomiphene Citrate 50 milligrams daily	Placebo
Measure Participants	20	20
Median (Full Range) [units on a scale]	5	2

4. Primary Outcome

Title	Luteal Cycle Total Physical Score for Calendar of Premenstrual Experiences (COPE) Self Assessment
Description	To identify physical symptoms experienced by women taking clomiphene citrate versus placebo for superovulation in a prospective setting.
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

The scale incorporates physical, behavioral and mental symptoms. Each participant will rate the symptom(s) from zero to three based off severity. Symptoms with zero means that no symptoms are present. Symptoms with three means that the symptoms are severe. Physical symptoms were calculated to give the total score. Range 0 -75 per cycle day.

Arm/Group Title	Clomiphene Citrate	Placebo
Arm/Group Description	Clomiphene Citrate 50 milligrams daily	Placebo
Measure Participants	20	20
Median (Full Range) [units on a scale]	9	9

Adverse Events

Arm/Group Title	Clomiphene Citrate, Then Placebo		Placebo, Then Clomiphene Citrate
Arm/Group Description	Clomiphene Citrate 50 milligrams daily, then Placebo daily		Placebo daily, then Clomiphene Citrate 50 milligrams daily
All Cause Mortality
	Clomiphene Citrate, Then Placebo		Placebo, Then Clomiphene Citrate
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Clomiphene Citrate, Then Placebo		Placebo, Then Clomiphene Citrate
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/10 (0%)		0/10 (0%)
Other (Not Including Serious) Adverse Events
	Clomiphene Citrate, Then Placebo		Placebo, Then Clomiphene Citrate
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/10 (0%)		0/10 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE 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.