Comparison of Fluoxetine, Calcium and Placebo for the Treatment of Moderate to Severe Premenstrual Syndrome (PMS)

• Sponsor: Donaghue Medical Research Foundation (Other)
• Overall Status: Completed
• CT.gov ID: NCT00965562
• Collaborator: Yale University (Other)
• Enrollment: 49
• Location: 1
• Arms: 3
• Duration (Months): 121
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

The purpose of this study is to compare the efficacy of calcium carbonate to fluoxetine in the treatment of moderate to severe PMS. Second, to compare each active agent to a placebo control. Third, to evaluate the efficacy of each treatment for specific symptom clusters (i.e. affective and somatic). Fourth, to determine whether the addition of calcium to on going fluoxetine treatment leads to additional therapeutic benefit.

Condition or Disease	Intervention/Treatment	Phase
Premenstrual Syndrome	Drug: Fluoxetine; Drug: Calcium; Drug: Placebo	N/A

Detailed Description

This is a double blind, randomized, placebo controlled, parallel study that will randomize 60 women at the Yale site into treatment. Participants will be screened at various collaborating ob-gyn centers for possible PMS symptoms, and direct referrals from the community will also be accepted. Subject participation length is about 7 months with 6 scheduled study visits.

Methodology: After successfully completing the screening and qualification phase, participants will be randomized to treatment at Visit 1 for 5 cycles of double-blind treatment. Participants will be evaluated monthly during the randomization phase for adverse events, concurrent medication, and primary and secondary efficacy variables.

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Study Design

• Study Type: Interventional
• Actual Enrollment: 49 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Double-blind, Parallel Comparison of Fluoxetine, Calcium and Placebo for the Treatment of Moderate to Severe Premenstrual Syndrome (PMS)
• Study Start Date: Sep 1, 2000
• Actual Primary Completion Date: Jun 1, 2010
• Actual Study Completion Date: Oct 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: I Fluoxetine	Drug: Fluoxetine; Fluoxetine 20 mg per day for 4 menstrual cycles. For the fifth menstrual cycle, all women will receive calcium. Women on Fluoxetine will continue taking it in addition to 1200mg of calcium.; Other Names: Prozac
Active Comparator: II Calcium	Drug: Calcium; 1200 mg of calcium to be taken for 5 menstrual cycles.
Placebo Comparator: III	Drug: Placebo; For 5 cycles, women will receive placebo. At the end of the fourth cycle, all women will receive 1200 mg of calcium in addition to the placebo medication.

Outcome Measures

Primary Outcome Measures

1. Comparison of the Change in IDS Symptom Scores Among Groups [over duration of treatment, 4 menstrual cycles averaging 4 months after baseline visit]

   IDS = Inventory of Depressive Symptomatology: measures depressive symptoms during the previous premenstrual phase with high internal consistency: sum of responses to 28 of 30 possible items each scored 0 to 3 points with total scoring (0=no symptoms, 84=most severe). This outcome is a measure of effect size between the two trial groups and the placebo group, with the placebo effect size value used as a reference.

2. Comparison of the Change in PMTS Symptom Scores Among Groups [over duration of treatment, 4 menstrual cycles averaging 4 months after baseline visit]

   PMTS = Premenstrual Tension Syndrome (Observer Rating) Scale: a clinician-administered retrospective scale developed for the study of PMS, a sum of responses to 10 items each with 4 points (0=no symptoms, 40=most severe). This outcome is a measure of effect size between the two trial groups and the placebo group, with the placebo effect size value used as a reference.

3. Comparison of the Change in CGI-S Symptom Scores Among Groups [over duration of treatment, 4 menstrual cycles averaging 4 months after baseline visit]

   CGI-S = Clinical Global Impression-Severity: a severity scale widely used in psychopharmacology research (1=normal not at all ill, 7=among most extremely ill). This outcome is a measure of effect size between the two trial groups and the placebo group, with the placebo effect size value used as a reference.

4. Comparison of the Change in DRSP Symptom Scores Among Groups [over duration of treatment, 4 menstrual cycles averaging 4 months after baseline visit]

   DRSP = Daily Record of Severity of Problems, which combines responses to 21 items each with scale: 1=no symptoms, 6=extreme. This outcome is a measure of effect size between the two trial groups and the placebo group, with the placebo effect size value used as a reference.

5. Comparison of the Change in CGI Improvement Scores Among Groups [over duration of treatment, 4 menstrual cycles averaging 4 months after baseline visit]

   CGI-I = Clinical Global Impression Improvement: the improvement subscale of CGI measuring change at each visit as compared to visit 1 (1=very much improved, 7=very much worse). This outcome is a measure of effect size between the two trial groups and the placebo group, with the placebo effect size value used as a reference.

Secondary Outcome Measures

1. Proportion of Participants With DRSP LOCF Response to Treatment (50% Improvement) [over duration of treatment, 4 menstrual cycles averaging 4 months after baseline visit]

   DRSP: Daily Record of Severity of Problems, which combines responses to 21 items each with scale: 1=no symptoms, 6=extreme. LOCF: the last observation carried forward.

2. Proportion of Participants With IDS LOCF Response to Treatment (50% Improvement) [over duration of treatment, 4 menstrual cycles averaging 4 months after baseline visit]

   IDS: Inventory of Depressive Symptomatology: measures depressive symptoms during the previous premenstrual phase with high internal consistency: sum of responses to 28 of 30 possible items each scored 0 to 3 points with total scoring (0=least severe, 84=most severe). LOCF: last observation carried forward.

3. Proportion of Participants With PMTS LOCF Response to Treatment (50% Improvement) [over duration of treatment, 4 menstrual cycles averaging 4 months after baseline visit]

   PMTS: Premenstrual Tension Syndrome (Observer Rating) Scale: a clinician-administered retrospective scale developed for the study of PMS, a sum of responses to 10 items each with 4 points (0=no symptoms, 40=most severe). LOCF: last observation carried forward.

4. Proportion of Participants With DRSP Visit-wise Response to Treatment (50% Improvement) [over duration of treatment from baseline to visit 5, including 4 menstrual cycles averaging 4 months after baseline visit]

   Visit-wise response considers participants who remained in the study until Visit 5 and provided data for the visit. DRSP = Daily Record of Severity of Problems, which combines responses to 21 items each with scale: 1=no symptoms, 6=extreme.

5. Proportion of Patients With IDS Visit-wise Response to Treatment (50% Improvement) [over duration of treatment from baseline to visit 5, including 4 menstrual cycles averaging 4 months after baseline visit]

   Visit-wise response considers participants who remained in the study until Visit 5 and provided data for the visit. IDS = Inventory of Depressive Symptomatology: measures depressive symptoms during the previous premenstrual phase with high internal consistency, sum of responses to 28 of 30 possible items each scored 0 to 3 points with total scoring (0=no symptoms, 84=most severe).

6. Proportion of Patients With PMTS Visit-wise Response to Treatment (50% Improvement) [over duration of treatment from baseline to visit 5, including 4 menstrual cycles averaging 4 months after baseline visit]

   Visit-wise response considers participants who remained in the study until Visit 5 and provided data for the visit. PMTS = Premenstrual Tension Syndrome (Observer Rating) Scale: a clinician-administered retrospective scale developed for the study of PMS, a sum of responses to 10 items each with 4 points (0=no symptoms, 40=most severe).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 48 Years
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Female outpatients between the ages of 18 and 48 who are:

• Menstruating

• Meet criteria for moderate to severe PMS

• Report PMS symptoms for at least 9 our of the 12 months prior to screening; 4) *Are using an adequate method of birth control.

Exclusion Criteria:

• Any candidate who:

• Fulfills MINI (DSM-IV) criteria for a serious AXIS 1 disorder

• Fulfills DSM-IV criteria during the charting phase consistent with a diagnosis of psychotic disorder, bipolar disorder or major depressive disorder

• Has a severe, co-existing condition that, in the investigator's opinion, renders the patient unsuitable for the study

• Poses a significant risk of suicide

• Takes ongoing medication that could treat PMS symptoms

• Has a history of hypersensitivity or adverse reaction to fluoxetine or calcium

• Is lactating, pregnant or is planning to become pregnant during the course of the study.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Yale School of Medicine	New Haven	Connecticut	United States	06510

Sponsors and Collaborators

• Donaghue Medical Research Foundation
• Yale University

Investigators

• Principal Investigator: Kimberly A Yonkers, MD, Yale School of Medicine

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Kimberly Yonkers, Professor, Yale University
• ClinicalTrials.gov Identifier: NCT00965562
• Other Study ID Numbers: 0001011511; NCT00683605
• First Posted: Aug 25, 2009
• Last Update Posted: Mar 23, 2015
• Last Verified: Feb 1, 2015

• Keywords provided by Kimberly Yonkers, Professor, Yale University: Premenstrual syndrome; PMS; calcium
• Additional relevant MeSH terms: Syndrome; Premenstrual Syndrome; Fluoxetine; Calcium

Study Results

Participant Flow

Recruitment Details	Recruitment occurred through on-site screening in private gynecological practices and community advertisements. Recruitment occurred between 2001-2005 in Providence, Rhode Island and between 2001-2009 in New Haven, Connecticut. Potential subjects provided consent for screening and assessment.

Arm/Group Title	I: Fluoxetine	II: Calcium	III: Placebo
Arm/Group Description	Fluoxetine : Fluoxetine 20 mg per day for 4 menstrual cycles.	Calcium : 1200 mg of calcium to be taken for 4 menstrual cycles.	Placebo : For 4 cycles, women will receive placebo.
Period Title: Overall Study
STARTED	16	17	16
Women With at Least 2 Follow up Visits	13	13	13
Women Who Participated Full Follow up	6	10	11
COMPLETED	13	13	13
NOT COMPLETED	3	4	3

Baseline Characteristics

Arm/Group Title	I: Fluoxetine	II: Calcium	III: Placebo	Total
Arm/Group Description	Fluoxetine : Fluoxetine 20 mg per day for 4 menstrual cycles.	Calcium : 1200 mg of calcium to be taken for 4 menstrual cycles.	Placebo : For 4 cycles, women will receive placebo.	Total of all reporting groups
Overall Participants	13	13	13	39
Age, Customized (participants) [Number]
25-29 years old	1 7.7%	1 7.7%	2 15.4%	4 10.3%
30-39 years old	11 84.6%	6 46.2%	7 53.8%	24 61.5%
40-45 years old	1 7.7%	6 46.2%	4 30.8%	11 28.2%
Sex: Female, Male (Count of Participants)
Female	13 100%	13 100%	13 100%	39 100%
Male	0 0%	0 0%	0 0%	0 0%
Race/Ethnicity, Customized (participants) [Number]
White	8 61.5%	10 76.9%	10 76.9%	28 71.8%
Black	1 7.7%	0 0%	0 0%	1 2.6%
Hispanic	1 7.7%	0 0%	1 7.7%	2 5.1%
Other/Mixed	2 15.4%	1 7.7%	1 7.7%	4 10.3%
Not collected	1 7.7%	2 15.4%	1 7.7%	4 10.3%
Region of Enrollment (participants) [Number]
United States	13 100%	13 100%	13 100%	39 100%
Marital Status (participants) [Number]
Married	7 53.8%	8 61.5%	9 69.2%	24 61.5%
Single/Divorced/Widowed	5 38.5%	5 38.5%	4 30.8%	14 35.9%
Not collected	1 7.7%	0 0%	0 0%	1 2.6%
Number of pregnancies (participants) [Number]
0 pregnancies	6 46.2%	3 23.1%	5 38.5%	14 35.9%
1 pregnancy	3 23.1%	1 7.7%	0 0%	4 10.3%
2+ pregnancies	4 30.8%	9 69.2%	8 61.5%	21 53.8%
Years with PMS (participants) [Number]
<4 years	6 46.2%	2 15.4%	6 46.2%	14 35.9%
5-10 years	3 23.1%	6 46.2%	1 7.7%	10 25.6%
>10 years	3 23.1%	5 38.5%	6 46.2%	14 35.9%
Number of years not collected	1 7.7%	0 0%	0 0%	1 2.6%
Ever spoken to a doctor about PMS (participants) [Number]
Number [participants]	4 30.8%	5 38.5%	6 46.2%	15 38.5%
OB-GYN asked about PMS (participants) [Number]
Number [participants]	2 15.4%	5 38.5%	2 15.4%	9 23.1%
Thought about getting help for PMS (participants) [Number]
Number [participants]	7 53.8%	7 53.8%	6 46.2%	20 51.3%
Concurrent oral contraceptive use (participants) [Number]
Number [participants]	4 30.8%	3 23.1%	3 23.1%	10 25.6%
Baseline Symptom Scores (units on a scale) [Mean (Standard Deviation) ]
Inventory of Depressive Symptomatology (IDS-C30)	31.85 (9.14)	30.92 (7.62)	28.85 (9.97)	30.54 (5.17)
Premenstrual Tension Syndrome-Observer (PMTS-O)	24.15 (5.40)	21.58 (3.73)	20.85 (6.62)	22.19 (3.11)
Daily Record of Severity of Problems (DRSP)	2.16 (0.86)	1.12 (0.38)	1.29 (0.60)	1.52 (0.37)
Clinical Global Impression - Severity (CGI-S)	4.92 (0.95)	4.46 (1.27)	4.15 (1.28)	4.51 (0.68)

Outcome Measures

1. Secondary Outcome

Title	Proportion of Participants With DRSP LOCF Response to Treatment (50% Improvement)
Description	DRSP: Daily Record of Severity of Problems, which combines responses to 21 items each with scale: 1=no symptoms, 6=extreme. LOCF: the last observation carried forward.
Time Frame	over duration of treatment, 4 menstrual cycles averaging 4 months after baseline visit

Outcome Measure Data

Analysis Population Description

Response analysis includes all data from all subjects with the last observation carried forward to Visit 5.

Arm/Group Title	I: Fluoxetine	II: Calcium	III: Placebo
Arm/Group Description	Fluoxetine : Fluoxetine 20 mg per day for 4 menstrual cycles.	Calcium : 1200 mg of calcium to be taken for 4 menstrual cycles.	Placebo : For 4 cycles, women will receive placebo.
Measure Participants	10	12	12
Number [proportion of participants]	0.80 6.2%	0.42 3.2%	0.42 3.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	I: Fluoxetine, II: Calcium, III: Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.15
	Comments
	Method	Chi-squared
	Comments

2. Secondary Outcome

Title	Proportion of Participants With IDS LOCF Response to Treatment (50% Improvement)
Description	IDS: Inventory of Depressive Symptomatology: measures depressive symptoms during the previous premenstrual phase with high internal consistency: sum of responses to 28 of 30 possible items each scored 0 to 3 points with total scoring (0=least severe, 84=most severe). LOCF: last observation carried forward.
Time Frame	over duration of treatment, 4 menstrual cycles averaging 4 months after baseline visit

Outcome Measure Data

Analysis Population Description

Response analysis includes all data from all subjects with the last observation carried forward to Visit 5.

Arm/Group Title	I: Fluoxetine	II: Calcium	III: Placebo
Arm/Group Description	Fluoxetine : Fluoxetine 20 mg per day for 4 menstrual cycles.	Calcium : 1200 mg of calcium to be taken for 4 menstrual cycles.	Placebo : For 5 cycles, women will receive placebo.
Measure Participants	13	13	13
Number [proportion of participants]	0.77 5.9%	0.31 2.4%	0.31 2.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	I: Fluoxetine, II: Calcium, III: Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.05
	Comments
	Method	Chi-squared
	Comments

3. Secondary Outcome

Title	Proportion of Participants With PMTS LOCF Response to Treatment (50% Improvement)
Description	PMTS: Premenstrual Tension Syndrome (Observer Rating) Scale: a clinician-administered retrospective scale developed for the study of PMS, a sum of responses to 10 items each with 4 points (0=no symptoms, 40=most severe). LOCF: last observation carried forward.
Time Frame	over duration of treatment, 4 menstrual cycles averaging 4 months after baseline visit

Outcome Measure Data

Analysis Population Description

Response analysis includes all data from all subjects with the last observation carried forward to Visit 5.

Arm/Group Title	I: Fluoxetine	II: Calcium	III: Placebo
Arm/Group Description	Fluoxetine : Fluoxetine 20 mg per day for 4 menstrual cycles.	Calcium : 1200 mg of calcium to be taken for 4 menstrual cycles.	Placebo : For 4 cycles, women will receive placebo.
Measure Participants	13	12	13
Number [proportion of participants]	0.62 4.8%	0.33 2.5%	0.16 1.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	I: Fluoxetine, II: Calcium, III: Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.06
	Comments
	Method	Chi-squared
	Comments

4. Secondary Outcome

Title	Proportion of Participants With DRSP Visit-wise Response to Treatment (50% Improvement)
Description	Visit-wise response considers participants who remained in the study until Visit 5 and provided data for the visit. DRSP = Daily Record of Severity of Problems, which combines responses to 21 items each with scale: 1=no symptoms, 6=extreme.
Time Frame	over duration of treatment from baseline to visit 5, including 4 menstrual cycles averaging 4 months after baseline visit

Outcome Measure Data

Analysis Population Description

For fluoxetine, calcium and placebo groups, 8, 11 and 12 participants remained in the trial until Visit 5. However, Visit 5 DRSP calendars were missing for an additional 3 subjects in the fluoxetine group and for one subject in each of the calcium and placebo cells.

Arm/Group Title	I: Fluoxetine	II: Calcium	III: Placebo
Arm/Group Description	Fluoxetine : Fluoxetine 20 mg per day for 4 menstrual cycles.	Calcium : 1200 mg of calcium to be taken for 4 menstrual cycles.	Placebo : For 5 cycles, women will receive placebo.
Measure Participants	5	8	6
Number [proportion of participants]	1.00 7.7%	0.50 3.8%	0.33 2.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	I: Fluoxetine, II: Calcium, III: Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.09
	Comments
	Method	Chi-squared
	Comments

5. Secondary Outcome

Title	Proportion of Patients With IDS Visit-wise Response to Treatment (50% Improvement)
Description	Visit-wise response considers participants who remained in the study until Visit 5 and provided data for the visit. IDS = Inventory of Depressive Symptomatology: measures depressive symptoms during the previous premenstrual phase with high internal consistency, sum of responses to 28 of 30 possible items each scored 0 to 3 points with total scoring (0=no symptoms, 84=most severe).
Time Frame	over duration of treatment from baseline to visit 5, including 4 menstrual cycles averaging 4 months after baseline visit

Outcome Measure Data

Analysis Population Description

For fluoxetine, calcium and placebo groups, 8, 11 and 12 participants remained in the trial until Visit 5.

Arm/Group Title	I: Fluoxetine	II: Calcium	III: Placebo
Arm/Group Description	Fluoxetine : Fluoxetine 20 mg per day for 4 menstrual cycles.	Calcium : 1200 mg of calcium to be taken for 4 menstrual cycles.	Placebo : For 4 cycles, women will receive placebo.
Measure Participants	8	11	12
Number [proportion of participants]	1.00 7.7%	0.36 2.8%	0.33 2.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	I: Fluoxetine, II: Calcium, III: Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.005
	Comments
	Method	Chi-squared
	Comments

6. Secondary Outcome

Title	Proportion of Patients With PMTS Visit-wise Response to Treatment (50% Improvement)
Description	Visit-wise response considers participants who remained in the study until Visit 5 and provided data for the visit. PMTS = Premenstrual Tension Syndrome (Observer Rating) Scale: a clinician-administered retrospective scale developed for the study of PMS, a sum of responses to 10 items each with 4 points (0=no symptoms, 40=most severe).
Time Frame	over duration of treatment from baseline to visit 5, including 4 menstrual cycles averaging 4 months after baseline visit

Outcome Measure Data

Analysis Population Description

For fluoxetine, calcium and placebo groups, 8, 11 and 12 participants remained in the trial until Visit 5.

Arm/Group Title	I: Fluoxetine	II: Calcium	III: Placebo
Arm/Group Description	Fluoxetine : Fluoxetine 20 mg per day for 4 menstrual cycles.	Calcium : 1200 mg of calcium to be taken for 4 menstrual cycles.	Placebo : For 4 cycles, women will receive placebo.
Measure Participants	8	11	12
Number [proportion of participants]	0.75 5.8%	0.36 2.8%	0.17 1.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	I: Fluoxetine, II: Calcium, III: Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.04
	Comments
	Method	Chi-squared
	Comments

7. Primary Outcome

Title	Comparison of the Change in IDS Symptom Scores Among Groups
Description	IDS = Inventory of Depressive Symptomatology: measures depressive symptoms during the previous premenstrual phase with high internal consistency: sum of responses to 28 of 30 possible items each scored 0 to 3 points with total scoring (0=no symptoms, 84=most severe). This outcome is a measure of effect size between the two trial groups and the placebo group, with the placebo effect size value used as a reference.
Time Frame	over duration of treatment, 4 menstrual cycles averaging 4 months after baseline visit

Outcome Measure Data

Analysis Population Description

Intention to treat cohort.

Arm/Group Title	I: Fluoxetine	II: Calcium	III: Placebo
Arm/Group Description	Fluoxetine : Fluoxetine 20 mg per day for 4 menstrual cycles.	Calcium : 1200 mg of calcium to be taken for 4 menstrual cycles.	Placebo : For 4 cycles, women will receive placebo.
Measure Participants	13	13	13
Visit 1	31.85 (9.14)	30.92 (7.62)	28.85 (9.97)
Visit 2	14.08 (9.53)	25.77 (7.74)	20.69 (12.20)
Visit 3	11.44 (7.94)	18.55 (10.40)	20.15 (14.25)
Visit 4	11.78 (8.50)	18.50 (9.01)	16.46 (11.00)
Visit 5	10.00 (6.41)	19.55 (9.04)	18.08 (9.17)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	I: Fluoxetine, III: Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.07
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Slope
	Estimated Value	-2.63
	Confidence Interval	(2-Sided) 95%; -5.51 to 0.24
	Parameter Dispersion	Type: Value:
	Estimation Comments	Slope represents average change in fluoxetine group IDS score as compared to placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	II: Calcium, III: Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.94
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Slope
	Estimated Value	-0.10
	Confidence Interval	(2-Sided) 95%; -2.85 to 2.65
	Parameter Dispersion	Type: Value:
	Estimation Comments	Slope represents average change in calcium group IDS scores as compared to placebo

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	I: Fluoxetine, III: Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.07
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Cohen's d effect size
	Estimated Value	1.15
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments	Cohen's d effect sizes were calculated by subtracting the difference between changes in the fluoxetine group between visits 1 and 5 and changes in the placebo group between Visits 1 and 5, divided by the std dev in the placebo group at Visit 5

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	II: Calcium, III: Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.94
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Cohen's d effect size
	Estimated Value	0.10
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments	Cohen's d effect sizes were calculated by subtracting the difference between changes in the calcium group between visits 1 and 5 and changes in the placebo group between Visits 1 and 5, divided by the std dev in the placebo group at Visit 5

8. Primary Outcome

Title	Comparison of the Change in PMTS Symptom Scores Among Groups
Description	PMTS = Premenstrual Tension Syndrome (Observer Rating) Scale: a clinician-administered retrospective scale developed for the study of PMS, a sum of responses to 10 items each with 4 points (0=no symptoms, 40=most severe). This outcome is a measure of effect size between the two trial groups and the placebo group, with the placebo effect size value used as a reference.
Time Frame	over duration of treatment, 4 menstrual cycles averaging 4 months after baseline visit

Outcome Measure Data

Analysis Population Description

Intention to treat cohort.

Arm/Group Title	I: Fluoxetine	II: Calcium	III: Placebo
Arm/Group Description	Fluoxetine : Fluoxetine 20 mg per day for 4 menstrual cycles.	Calcium : 1200 mg of calcium to be taken for 4 menstrual cycles.	Placebo : For 4 cycles, women will receive placebo.
Measure Participants	13	13	13
Visit 1	24.15 (5.40)	21.58 (3.73)	20.85 (6.62)
Visit 2	11.15 (5.77)	18.54 (5.36)	16.00 (8.15)
Visit 3	10.33 (6.40)	13.36 (5.75)	16.38 (10.52)
Visit 4	12.11 (7.13)	12.83 (4.73)	12.77 (8.21)
Visit 5	10.13 (3.56)	11.91 (4.48)	14.58 (7.58)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	I: Fluoxetine, III: Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.10
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Slope
	Estimated Value	-1.63
	Confidence Interval	(2-Sided) 95%; -3.60 to 0.34
	Parameter Dispersion	Type: Value:
	Estimation Comments	Slope represents average change in fluoxetine group PMTS scores as compared to placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	II: Calcium, III: Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.40
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Slope
	Estimated Value	-0.81
	Confidence Interval	(2-Sided) 95%; -2.71 to 1.09
	Parameter Dispersion	Type: Value:
	Estimation Comments	Slope represents average change in calcium group PMTS scores as compared to placebo

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	I: Fluoxetine, III: Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.10
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Cohen's d effect size
	Estimated Value	1.06
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments	Cohen's d effect sizes were calculated by subtracting the difference between changes in the fluoxetine group between visits 1 and 5 and changes in the placebo group between Visits 1 and 5, divided by the std dev in the placebo group at Visit 5

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	II: Calcium, III: Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.40
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Cohen's d effect size
	Estimated Value	0.37
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments	Cohen's d effect sizes were calculated by subtracting the difference between changes in the calcium group between visits 1 and 5 and changes in the placebo group between Visits 1 and 5, divided by the std dev in the placebo group at Visit 5

9. Primary Outcome

Title	Comparison of the Change in CGI-S Symptom Scores Among Groups
Description	CGI-S = Clinical Global Impression-Severity: a severity scale widely used in psychopharmacology research (1=normal not at all ill, 7=among most extremely ill). This outcome is a measure of effect size between the two trial groups and the placebo group, with the placebo effect size value used as a reference.
Time Frame	over duration of treatment, 4 menstrual cycles averaging 4 months after baseline visit

Outcome Measure Data

Analysis Population Description

Intention to treat cohort.

Arm/Group Title	I: Fluoxetine	II: Calcium	III: Placebo
Arm/Group Description	Fluoxetine : Fluoxetine 20 mg per day for 4 menstrual cycles.	Calcium : 1200 mg of calcium to be taken for 4 menstrual cycles.	Placebo : For 4 cycles, women will receive placebo.
Measure Participants	13	13	13
Visit 1	4.92 (0.95)	4.46 (1.27)	4.15 (1.28)
Visit 2	2.54 (1.13)	4.23 (1.01)	3.38 (1.66)
Visit 3	2.33 (1.00)	3.00 (1.10)	3.38 (1.98)
Visit 4	2.56 (1.13)	2.73 (0.90)	2.92 (1.50)
Visit 5	2.50 (0.76)	2.91 (1.04)	3.17 (1.47)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	I: Fluoxetine, III: Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.07
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Slope
	Estimated Value	-0.35
	Confidence Interval	(2-Sided) 95%; -0.73 to 0.03
	Parameter Dispersion	Type: Value:
	Estimation Comments	Slope represents average change in fluoxetine group CGI-S scores as compared to placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	II: Calcium, III: Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.36
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Slope
	Estimated Value	-0.17
	Confidence Interval	(2-Sided) 95%; -0.54 to 0.20
	Parameter Dispersion	Type: Value:
	Estimation Comments	Slope represents average change in calcium group CGI-S scores as compared to placebo

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	I: Fluoxetine, III: Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.07
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Cohen's d effect size
	Estimated Value	0.92
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments	Cohen's d effect sizes were calculated by subtracting the difference between changes in the fluoxetine group between visits 1 and 5 and changes in the placebo group between Visits 1 and 5, divided by the std dev in the placebo group at Visit 5

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	II: Calcium, III: Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.36
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Cohen's d effect size
	Estimated Value	0.44
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments	Cohen's d effect sizes were calculated by subtracting the difference between changes in the calcium group between visits 1 and 5 and changes in the placebo group between Visits 1 and 5, divided by the std dev in the placebo group at Visit 5

10. Primary Outcome

Title	Comparison of the Change in DRSP Symptom Scores Among Groups
Description	DRSP = Daily Record of Severity of Problems, which combines responses to 21 items each with scale: 1=no symptoms, 6=extreme. This outcome is a measure of effect size between the two trial groups and the placebo group, with the placebo effect size value used as a reference.
Time Frame	over duration of treatment, 4 menstrual cycles averaging 4 months after baseline visit

Outcome Measure Data

Analysis Population Description

Intention to treat cohort.

Arm/Group Title	I: Fluoxetine	II: Calcium	III: Placebo
Arm/Group Description	Fluoxetine : Fluoxetine 20 mg per day for 4 menstrual cycles.	Calcium : 1200 mg of calcium to be taken for 4 menstrual cycles.	Placebo : For 4 cycles, women will receive placebo.
Measure Participants	13	13	13
Visit 1	2.16 (0.86)	1.12 (0.38)	1.29 (0.60)
Visit 2	0.97 (0.72)	0.76 (0.78)	0.93 (0.54)
Visit 3	0.27 (0.78)	0.61 (0.78)	1.19 (1.06)
Visit 4	0.72 (0.78)	0.51 (0.33)	0.59 (0.63)
Visit 5	0.44 (0.34)	0.75 (0.42)	0.74 (0.54)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	I: Fluoxetine, III: Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.02
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Slope
	Estimated Value	-0.28
	Confidence Interval	(2-Sided) 95%; -0.53 to -0.04
	Parameter Dispersion	Type: Value:
	Estimation Comments	Slope represents average change in fluoxetine group DRSP scores as compared to placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	II: Calcium, III: Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.58
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Slope
	Estimated Value	0.06
	Confidence Interval	(2-Sided) 95%; -0.16 to 0.28
	Parameter Dispersion	Type: Value:
	Estimation Comments	Slope represents average change in calcium group DRSP scores as compared to placebo

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	I: Fluoxetine, III: Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.02
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Cohen's d effect size
	Estimated Value	2.08
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments	Cohen's d effect sizes were calculated by subtracting the difference between changes in the fluoxetine group between visits 1 and 5 and changes in the placebo group between Visits 1 and 5, divided by the std dev in the placebo group at Visit 5

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	II: Calcium, III: Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.58
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Cohen's d effect size
	Estimated Value	0.18
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments	Cohen's d effect sizes were calculated by subtracting the difference between changes in the calcium group between visits 1 and 5 and changes in the placebo group between Visits 1 and 5, divided by the std dev in the placebo group at Visit 5

11. Primary Outcome

Title	Comparison of the Change in CGI Improvement Scores Among Groups
Description	CGI-I = Clinical Global Impression Improvement: the improvement subscale of CGI measuring change at each visit as compared to visit 1 (1=very much improved, 7=very much worse). This outcome is a measure of effect size between the two trial groups and the placebo group, with the placebo effect size value used as a reference.
Time Frame	over duration of treatment, 4 menstrual cycles averaging 4 months after baseline visit

Outcome Measure Data

Analysis Population Description

Intention to treat cohort.

Arm/Group Title	I: Fluoxetine	II: Calcium	III: Placebo
Arm/Group Description	Fluoxetine : Fluoxetine 20 mg per day for 4 menstrual cycles.	Calcium : 1200 mg of calcium to be taken for 4 menstrual cycles.	Placebo : For 4 cycles, women will receive placebo.
Measure Participants	13	13	13
Visit 1	NA (NA)	NA (NA)	NA (NA)
Visit 2	2.23 (0.83)	3.46 (0.78)	3.00 (1.35)
Visit 3	1.67 (0.87)	2.30 (0.82)	3.08 (1.50)
Visit 4	1.75 (1.16)	2.36 (1.03)	2.77 (1.17)
Visit 5	1.88 (0.64)	2.45 (0.82)	2.83 (1.19)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	I: Fluoxetine, III: Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.04
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Slope
	Estimated Value	-1.03
	Confidence Interval	(2-Sided) 95%; -1.70 to -0.35
	Parameter Dispersion	Type: Value:
	Estimation Comments	Slope represents average change in fluoxetine group CGI Improvement scores as compared to placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	II: Calcium, III: Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.54
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Slope
	Estimated Value	-0.20
	Confidence Interval	(2-Sided) 95%; -0.86 to 0.46
	Parameter Dispersion	Type: Value:
	Estimation Comments	Slope represents average change in calcium group CGI Improvement scores as compared to placebo

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	I: Fluoxetine, III: Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.04
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Cohen's d effect size
	Estimated Value	0.80
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments	Cohen's d effect sizes were calculated by subtracting the difference between changes in the fluoxetine group between visits 2 and 5 and changes in the placebo group between Visits 2 and 5, divided by the std dev in the placebo group at Visit 5

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	II: Calcium, III: Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.54
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Cohen's d effect size
	Estimated Value	0.32
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments	Cohen's d effect sizes were calculated by subtracting the difference between changes in the calcium group between visits 2 and 5 and changes in the placebo group between Visits 2 and 5, divided by the std dev in the placebo group at Visit 5

Adverse Events

Time Frame	From patient randomization to completion of study
Adverse Event Reporting Description	Final adverse event data were only available for the 32 patients randomized at the Yale site. There were no severe adverse events by self-report. Events were uncommon and occurred in all 3 groups with a numerically higher number in the calcium group.
Arm/Group Title	I: Fluoxetine		II: Calcium		III: Placebo
Arm/Group Description	Fluoxetine : Fluoxetine 20 mg per day for 4 menstrual cycles.		Calcium : 1200 mg of calcium to be taken for 4 menstrual cycles.		Placebo : For 4 cycles, women will receive placebo.
All Cause Mortality
	I: Fluoxetine		II: Calcium		III: Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	I: Fluoxetine		II: Calcium		III: Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/10 (0%)		0/11 (0%)		0/11 (0%)
Other (Not Including Serious) Adverse Events
	I: Fluoxetine		II: Calcium		III: Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/10 (40%)		8/11 (72.7%)		2/11 (18.2%)
Gastrointestinal disorders
Abdominal ache	0/10 (0%)	0	1/11 (9.1%)	1	0/11 (0%)	0
Burping	0/10 (0%)	0	1/11 (9.1%)	1	0/11 (0%)	0
Constipation	1/10 (10%)	1	0/11 (0%)	0	0/11 (0%)	0
Decreased appetite	0/10 (0%)	0	0/11 (0%)	0	1/11 (9.1%)	1
Diarrhea	1/10 (10%)	1	0/11 (0%)	0	0/11 (0%)	0
Nausea	1/10 (10%)	1	4/11 (36.4%)	4	2/11 (18.2%)	2
General disorders
Feeling spacy	0/10 (0%)	0	2/11 (18.2%)	2	0/11 (0%)	0
Difficulty Concentrating	0/10 (0%)	0	1/11 (9.1%)	1	0/11 (0%)	0
Dizziness	1/10 (10%)	1	2/11 (18.2%)	2	0/11 (0%)	0
Dry mouth	2/10 (20%)	2	0/11 (0%)	0	0/11 (0%)	0
Fatigue	0/10 (0%)	0	1/11 (9.1%)	1	1/11 (9.1%)	1
Headache	1/10 (10%)	1	3/11 (27.3%)	3	2/11 (18.2%)	2
Irritability	0/10 (0%)	0	0/11 (0%)	0	1/11 (9.1%)	1
Sweating	0/10 (0%)	0	1/11 (9.1%)	1	0/11 (0%)	0
Vertigo	0/10 (0%)	0	1/11 (9.1%)	1	0/11 (0%)	0
Reproductive system and breast disorders
Cramps	1/10 (10%)	1	0/11 (0%)	0	0/11 (0%)	0
Decreased sex drive	0/10 (0%)	0	1/11 (9.1%)	1	0/11 (0%)	0

Limitations/Caveats

small sample size

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.