Induction of Ovulation With Raloxifene or Clomiphene Citrate in Polycystic Ovarian Syndrome

• Sponsor: Hospital de Clinicas de Porto Alegre (Other)
• Overall Status: Completed
• CT.gov ID: NCT00427700
• Collaborator: (none)
• Enrollment: 82
• Location: 1
• Arms: 2
• Duration (Months): 12
• Patients Per Site Per Month: 6.8

Study Details

Study Description

Brief Summary

The Polycystic Ovarian Syndrome (PCOS) is a common disorder related to ovulation problems. Clomiphene citrate (CC) is the drug of first choice for this condition. Nevertheless, CC has a detrimental effect over uterine receptivity.

Raloxifene is a Selective Estrogen Receptor Modulator, that does not have a detrimental effect over the endometrium, and also increase the serum levels of FSH, thus, inducting ovulation.

The objective of this study is to compare the ovulation rate in PCOS patients between clomiphene citrate and raloxifene in a double blind randomized trial.

Condition or Disease	Intervention/Treatment	Phase
Polycystic Ovary Syndrome	Drug: clomiphene citrate; Drug: raloxifene	Phase 3

Detailed Description

-Introduction The Polycystic Ovarian Syndrome (PCOS) is a frequent endocrine among women in reproductive ages, with a prevalence of 10%. In 2003, a consensus among the European and American Society of Human Reproduction (ESRHE and ASRM) defined that PCOS is a ovarian disfunction which present at least 2 out of 3 criteria: oligomenorrhea or anovulation; clinical or laboratorial signs of hyperandrogenism and polycystic ovaries on ultrasound; other causes, such as congenital adrenal hyperplasia, androgen secretory tumors, Cushing syndrome and hyperprolactinemia must be rule out.

Patients with PCOS who desire to became pregnant need, in their majority, induction of ovulation. Traditionally, clomiphene citrate, an estrogen receptor agonist, is the most used drug for this type of anovulation. The mechanism of action of clomiphene is related to a negative feedback to the endogenous estrogen, resulting in a higher amplitude of gonadotrophin surges, i.e., luteinizing hormone(LH) and follicle stimulating hormone(FSH). Nevertheless, recent studies have been shown that clomiphene citrate has a deleterious effect in the endometrium. The markers of uterine receptivity, among them, the integrin beta3 subunit, has its expression diminished, which implicate in a reduced fecundation rate.

The raloxifene is a selective estrogen receptor modulator. It has an agonist and antagonist activity over different organs. The daily therapy with raloxifene increase bone density, reduce cholesterol serum concentrations (LDL) and do not stimulate the endometrium in post-menopausal women (Delmas PD et al., 1997). Recent studies have shown that this drug is safe in healthy pre-menopausal women (Baker VL et al., 1998). A daily dosi of 100mg per 28 days, beginning on the 3rd day of the cycle, has shown that FSH and LH levels were not affected when compared to controls during the menstrual cycle. However, women who had received 100mg of raloxifene had a 31% increase in their FSH serum levels during the follicular phase, when compared to controls. An increase to 200mg did not increase FSH levels (Baker VL et al, 1998). Furthermore, it has been shown that raloxifene significantly increase the in vitro expression of αvβ3 integrin, suggesting a beneficial effect over the endometrium in relation to clomiphene (Lessey BA, personal communication, 2006).

-Objective To compare the ovulation rate between raloxifene and clomiphene among women with polycystic ovarian syndrome.

To identify the endometrial alterations compatible with ovulations, i.e., secretory endometrium, through endometrial biopsy between the women who used raloxifene or clomiphene.

-Patients and Methods

Patients with the diagnosis of polycystic ovarian syndrome (because of infertility or hirsutism) who had a consultation at outpatient clinic of Hospital de Clínicas de Porto Alegre will be invited to participate in the study, after signing the informed consent. A standard interview will be performed. In the first consultation, the laboratorial exams will reviewed: total testosterone, 17 OH-progesterone, fasting glucose, TSH, prolactin. After the interview, the patient will be randomized for one of the treatments:

100mg of clomiphene or 100mg of raloxifene from day 3 of the menstrual cycle, for 5 days. Menstruation will be induced with 10mg of oral medroxyprogesterone per 10 days. On day 10, urinary LH will be collected daily along with endovaginal ultrasound for assessing follicular development. On post-ovulatory day 8_{10, progesterone levels will be measured from blood. An endometrial biopsy on day 8}10 post-ovulation will be performed in those patients who do not wish to became pregnant. The endometrial biopsy will divided into 2 parts and kept in liquid nitrogen and formol for immunohistochemistry and histological analysis respectively.

Sample size and statistical analysis

Ethical aspects

Study Design

• Study Type: Interventional
• Actual Enrollment: 82 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Induction of Ovulation With Raloxifene or Clomiphene Citrate in Polycystic Ovarian Syndrome
• Study Start Date: Aug 1, 2008
• Actual Primary Completion Date: Aug 1, 2009
• Actual Study Completion Date: Aug 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Clomiphene Uso of 100mg of clomiphene citrate during days 5-9 of the menstrual cycle	Drug: clomiphene citrate; 100mg PO on days 5-9 of the menstrual cycle; Other Names: Clomid
Experimental: Raloxifene Use of 100mg of raloxifene during days 5-9 of the menstrual cycle	Drug: raloxifene; 100mg PO on days 5-9 of the menstrual cycle; Other Names: Evista

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants With Ovulation Detected by Ultrasound [cycle day 14-20]

   Ovulation detected by ultrasound was defined as the percentage of a participants with ovulation detected by ultrasound, defined as the dominant follicle and its subsequent collapse. If a dominant follicle was not observed by day 21 after menses, the ovulation induction was considered to be a failure.

Secondary Outcome Measures

1. Serum Levels of Progesterone [8-10 days after ovulation]

   The level of serum progesterone that indicated ovulation was considered to be 3 ng/mL or greater, on days 8 to 10 after ovulation.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 38 Years
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• All patients with polycystic ovarian syndrome will be invited to participate in the study. The PCOS criteria are according to modified Rotterdam criteria (7); i.e., oligoovulation defined as < 6 menstrual periods per year, signs of clinical hyperandrogenism (Ferriman and Gallwey >8) or laboratorial (total Testosterone >=0.81 ng/dL) or polycystic ovary > 10cm3.

Furthermore, all patients with infertility diagnosis based solely on ovulation factor will included in the protocol

• Age >18 years old and <= 38 years old.

• No endometriosis on laparoscopy

Exclusion Criteria:

• Not willing to participate in the study

• use of IUD or contraceptive pill within 2 months before the study.

• Hyperprolactinemia (>20ng/mL)

• Abnormal serum levels of TSH(normal range:0.4-40 mUI/mL).

• High 17-OH progesterone (>=4.9ng/mL)

• Endometriosis

• Known allergy to clomiphene or raloxifene

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Hospital de Clínicas de Porto Alegre	Porto Alegre	Rio Grande do Sul	Brazil	90035-003

Sponsors and Collaborators

• Hospital de Clinicas de Porto Alegre

Investigators

• Principal Investigator: Ricardo F Savaris, MD, PhD, Hospital de Clínicas de Porto Alegre
• Study Chair: Helena Corleta, MD, PhD, Hospital de Clínicas de Porto Alegre
• Study Director: Bruce A Lessey, MD, PhD, Greenville Hospital System

Study Documents (Full-Text)

None provided.

More Information

Publications

• Azziz R. Controversy in clinical endocrinology: diagnosis of polycystic ovarian syndrome: the Rotterdam criteria are premature. J Clin Endocrinol Metab. 2006 Mar;91(3):781-5. Epub 2006 Jan 17.
• Baker VL, Draper M, Paul S, Allerheiligen S, Glant M, Shifren J, Jaffe RB. Reproductive endocrine and endometrial effects of raloxifene hydrochloride, a selective estrogen receptor modulator, in women with regular menstrual cycles. J Clin Endocrinol Metab. 1998 Jan;83(1):6-13.
• Bayar U, Tanriverdi HA, Barut A, Ayoğlu F, Ozcan O, Kaya E. Letrozole vs. clomiphene citrate in patients with ovulatory infertility. Fertil Steril. 2006 Apr;85(4):1045-8. Epub 2006 Mar 9.
• Dehbashi S, Vafaei H, Parsanezhad MD, Alborzi S. Time of initiation of clomiphene citrate and pregnancy rate in polycystic ovarian syndrome. Int J Gynaecol Obstet. 2006 Apr;93(1):44-8. Epub 2006 Mar 10.
• Delmas PD, Bjarnason NH, Mitlak BH, Ravoux AC, Shah AS, Huster WJ, Draper M, Christiansen C. Effects of raloxifene on bone mineral density, serum cholesterol concentrations, and uterine endometrium in postmenopausal women. N Engl J Med. 1997 Dec 4;337(23):1641-7.
• Grimes DA. The "CONSORT" guidelines for randomized controlled trials in Obstetrics & Gynecology. Obstet Gynecol. 2002 Oct;100(4):631-2.
• Hollis S, Campbell F. What is meant by intention to treat analysis? Survey of published randomised controlled trials. BMJ. 1999 Sep 11;319(7211):670-4. Review.
• Lessey BA, Castelbaum AJ, Buck CA, Lei Y, Yowell CW, Sun J. Further characterization of endometrial integrins during the menstrual cycle and in pregnancy. Fertil Steril. 1994 Sep;62(3):497-506.
• Lessey BA, Castelbaum AJ, Sawin SW, Sun J. Integrins as markers of uterine receptivity in women with primary unexplained infertility. Fertil Steril. 1995 Mar;63(3):535-42.
• Lessey BA, Ilesanmi AO, Lessey MA, Riben M, Harris JE, Chwalisz K. Luminal and glandular endometrial epithelium express integrins differentially throughout the menstrual cycle: implications for implantation, contraception, and infertility. Am J Reprod Immunol. 1996 Mar;35(3):195-204.
• Moher D, Schulz KF, Altman D; CONSORT Group (Consolidated Standards of Reporting Trials). The CONSORT statement: revised recommendations for improving the quality of reports of parallel-group randomized trials. JAMA. 2001 Apr 18;285(15):1987-91. Review.
• Savaris RF, Pedrini JL, Flores R, Fabris G, Zettler CG. Expression of alpha 1 and beta 3 integrins subunits in the endometrium of patients with tubal phimosis or hydrosalpinx. Fertil Steril. 2006 Jan;85(1):188-92.

• Responsible Party: Hospital de Clinicas de Porto Alegre
• ClinicalTrials.gov Identifier: NCT00427700
• Other Study ID Numbers: RACLO
• First Posted: Jan 29, 2007
• Last Update Posted: Oct 6, 2016
• Last Verified: Aug 1, 2016

• Individual Participant Data (IPD) Sharing Statement: Undecided
• Plan to Share IPD: Undecided
• Keywords provided by Hospital de Clinicas de Porto Alegre: Polycystic Ovary Syndrome; clomiphene citrate; Raloxifene
• Additional relevant MeSH terms: Polycystic Ovary Syndrome; Syndrome; Raloxifene Hydrochloride; Clomiphene; Enclomiphene; Zuclomiphene

Study Results

Participant Flow

Recruitment Details	Recruitment occurred between September 2008 and October 2009 at Hospital de Clínicas de Porto Alegre, a tertiary teaching hospital.
Pre-assignment Detail	Women were excluded if they had elevated levels of thyroid-stimulating hormone, prolactin, or 17α-hydroxyprogesterone, if they had used oral contraceptives in the previous 2 months, or if they had a history of endometriosis.

Arm/Group Title	Clomiphene	Raloxiphene
Arm/Group Description	Uso of 100mg of clomiphene citrate during days 5-9 of the menstrual cycle	Use of 100mg of raloxifene during days 5-9 of the menstrual cycle
Period Title: Overall Study
STARTED	40	42
COMPLETED	37	31
NOT COMPLETED	3	11

Baseline Characteristics

Arm/Group Title	Raloxifene	Clomiphene	Total
Arm/Group Description	Use of 100mg of raloxifene during days 5-9 of the menstrual cycle raloxifene: 100mg PO on days 5-9 of the menstrual cycle	Uso of 100mg of clomiphene citrate during days 5-9 of the menstrual cycle clomiphene citrate: 100mg PO on days 5-9 of the menstrual cycle	Total of all reporting groups
Overall Participants	42	40	82
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	42 100%	40 100%	82 100%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	28.21 (5.3)	28.7 (4.8)	28.4 (5.3)
Sex: Female, Male (Count of Participants)
Female	42 100%	40 100%	82 100%
Male	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
Brazil	42 100%	40 100%	82 100%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With Ovulation Detected by Ultrasound
Description	Ovulation detected by ultrasound was defined as the percentage of a participants with ovulation detected by ultrasound, defined as the dominant follicle and its subsequent collapse. If a dominant follicle was not observed by day 21 after menses, the ovulation induction was considered to be a failure.
Time Frame	cycle day 14-20

Outcome Measure Data

Analysis Population Description

intention to treat.

Arm/Group Title	Clomiphene	Raloxifene
Arm/Group Description	Uso of 100mg of clomiphene citrate during days 5-9 of the menstrual cycle	Use of 100mg of raloxifene during days 5-9 of the menstrual cycle
Measure Participants	40	42
Number (95% Confidence Interval) [percentage of participants]	52.5 125%	40.4 101%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Clomiphene, Raloxifene
	Comments	The null hypothesis is that there is no significant difference between two drugs for ovulation induction.A sample size of 40 women per arm was calculated for this superiority trial, considering an alpha and beta error of 0.05 and 0.2, respectively, to find an absolute difference of 30% in the ovulation rate between groups, based on a previous study published by Mitwally and Casper (18) where the ovulation rate with CC was approximately 45%.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3
	Comments
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	12
	Confidence Interval	(2-Sided) 95%; -9 to 33
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Serum Levels of Progesterone
Description	The level of serum progesterone that indicated ovulation was considered to be 3 ng/mL or greater, on days 8 to 10 after ovulation.
Time Frame	8-10 days after ovulation

Outcome Measure Data

Analysis Population Description

Intention to treat.Cases that were lost to follow-up observation, dropped out of the study, failed to collect progesterone on days 22 to 24, and lacked menses after medroxyprogesterone acetate treatment were considered as failures according to the intention-to-treat analysis.

Arm/Group Title	Clomiphene	Raloxiphene
Arm/Group Description	Uso of 100mg of clomiphene citrate during days 5-9 of the menstrual cycle	Use of 100mg of raloxifene during days 5-9 of the menstrual cycle
Measure Participants	40	42
Mean (95% Confidence Interval) [ng/mL]	26.1	40

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Clomiphene, Raloxifene
	Comments	Null hypothesis: There is no difference between the mean values of progesterone between both groups.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	13
	Confidence Interval	(2-Sided) 95%; - 6 to 34
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	1 year
Arm/Group Title	Clomiphene Citrate		Raloxifene
Arm/Group Description	Use of 100mg of clomiphene citrate during days 5-9 of the menstrual cycle clomiphene citrate: 100mg PO on days 5-9 of the menstrual cycle One woman in the CC group had nausea, headache, and abdominal bloating.		Use of 100mg of raloxifene during days 5-9 of the menstrual cycle raloxifene: 100mg PO on days 5-9 of the menstrual cycle Two cases: one woman had nausea, and the other woman had nausea, headache, and pelvic pain. All mild
All Cause Mortality
	Clomiphene Citrate		Raloxifene
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Clomiphene Citrate		Raloxifene
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/40 (0%)		0/42 (0%)
Other (Not Including Serious) Adverse Events
	Clomiphene Citrate		Raloxifene
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/40 (2.5%)		2/42 (4.8%)
Gastrointestinal disorders
nausea	1/40 (2.5%)	1	2/42 (4.8%)	2
abdominal bloating	1/40 (2.5%)	1	0/42 (0%)	0
Nervous system disorders
headache	1/40 (2.5%)	1	1/42 (2.4%)	1
Reproductive system and breast disorders
pelvic pain	0/40 (0%)	0	1/42 (2.4%)	1

Limitations/Caveats

[Not Specified]

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.