Assessment of Multiple Intrauterine Gestations From Ovarian Stimulation - Full Text View

Sponsor:	Yale University
Collaborators:	Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Penn State University University of Colorado, Denver University of Michigan University of Pennsylvania University of Texas University of Vermont Wayne State University
Information provided by (Responsible Party):	Yale University
ClinicalTrials.gov Identifier:	NCT01044862

Purpose

The objective of this application is to identify a pharmacologic agent which helps couples in whom the female partner ovulates regularly successfully obtain their goal of delivering a healthy child, whose use will result in low rates of multiple gestations. The central hypothesis is that, in infertile ovulatory women undergoing ovarian stimulation (OS) and intrauterine insemination (IUI), the use of aromatase inhibitors (AI) will stimulate the ovaries sufficiently to produce no reduction in the rate of pregnancy, while significantly reducing the numbers of multiple gestational pregnancies that result from stimulation with clomiphene citrate (CC) or follicle stimulating hormone (FSH). The rationale for the proposed research is that reduction of multiple pregnancy rates could significantly reduce maternal and neonatal morbidity and mortality, as well as the cost of healthcare for these individuals and society.

Condition	Intervention	Phase
Pregnancy Unexplained Infertility	Drug: Letrozole (aromatase inhibitor) Drug: Clomiphene Citrate Drug: Follicle Stimulating Hormone (gonadotropin)	Phase 3

Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Efficacy Study Intervention Model: Parallel Assignment Masking: Double Blind (Subject, Caregiver, Investigator) Primary Purpose: Treatment
Official Title:	Assessment of Multiple Intrauterine Gestations From Ovarian Stimulation

Resource links provided by NLM:

MedlinePlus related topics: Infertility

Drug Information available for: Clomiphene citrate Citric acid Clomifene Sodium Citrate Letrozole

U.S. FDA Resources

Further study details as provided by Yale University:

Primary Outcome Measures:

Multiple gestation rate following recruitment of multiple follicular development with an AI, as compared to CC and FSH. [ Time Frame: January 2010 to January 2012 ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:

Rate of pregnancy obtained [ Time Frame: January 2010 to January 2012 ] [ Designated as safety issue: No ]
Time to pregnancy [ Time Frame: January 2010 to January 2012 ] [ Designated as safety issue: No ]
Live birth rate [ Time Frame: January 2010 to January 2012 ] [ Designated as safety issue: No ]

Estimated Enrollment:	900
Study Start Date:	June 2010
Estimated Study Completion Date:	June 2012
Estimated Primary Completion Date:	June 2012 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Active Comparator: Aromatase Inhibitors (AI) A daily dose of 5 mg of the AI, letrozole, will be administered orally for five days starting on day three of the menstrual cycle. Future cycles can be started at 2.5-7.5 mg/d. FDA approval (IND) will be obtained.	Drug: Letrozole (aromatase inhibitor) A daily dose of 5 mg of the AI, letrozole, will be administered orally for five days starting on day three of the menstrual cycle. Future cycles can be started at 2.5-7.5 mg/d. FDA approval (IND) will be obtained.
Active Comparator: Clomiphene Citrate (CC) CC will be administered at a dose of 100 mg/d on cycle days 3-7. Future cycles can be started at 50-150 mg/d.	Drug: Clomiphene Citrate CC will be administered at a dose of 100 mg/d on cycle days 3-7. Future cycles can be started at 50-150 mg/d.
Active Comparator: Follicle Stimulating Hormone (FSH) A daily injection of 150 IU of FSH will be administered subcutaneously starting on day three of the menstrual cycle and continuing until the day of hCG administration. Dosage will be able to be increased or decreased 37.5-75 IU/d beginning cycle day 7. Future cycles can be started at doses ranging from 75-225 IU/d. The same type of FSH injections will be used.	Drug: Follicle Stimulating Hormone (gonadotropin) A daily injection of 150 IU of FSH will be administered subcutaneously starting on day three of the menstrual cycle and continuing until the day of hCG administration. Dosage will be able to be increased or decreased 37.5-75 IU/d beginning cycle day 7. Future cycles can be started at doses ranging from 75-225 IU/d. The same type of FSH injections will be used.

Detailed Description:

Patient Population

The population will consist of 900 women up to and including women ≥18 to ≤40 years years of age (at time of randomization) desirous of conceiving who will be recruited over approximately a two year period from the Reproductive Medicine Network (RMN) clinical sites and possibly from the Specialized Cooperative Center Programs in Reproductive Research (SCCPIR) sites, through public notification programs.

Study Design

This will be a multi-center, prospective, partially blinded clinical trial of gonadotropins vs. clomiphene citrate vs. aromatase inhibitors. The randomization scheme will be coordinated through the data coordination center (DCC) and the randomization will be stratified by each participating site and within each site for ages 18-34 and 35-40.

Treatment

Patients will be randomized to receive either FSH, CC, or an AI according to randomization tables generated by a computer randomization program. Treatment assignments will be blocked by site and age group. Subjects randomized to pill treatment will receive medication in double blinded fashion, receiving one type of pill (overcoated CC or AI). Subjects randomized to injectable medication(FSH) will receive vials of medication.

Primary efficacy parameter

Multiple gestation rate following recruitment of multiple follicular development with an AI, as compared to CC and FSH.

Secondary efficacy parameters

Rate of pregnancy obtained, live birth rate, and time to pregnancy following administration of an aromatase inhibitor, as compared to CC and FSH as well as the live birth rate of multiple gestation pregnancies.

Eligibility

Ages Eligible for Study:	18 Years to 40 Years
Genders Eligible for Study:	Female
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Women ≥18 to ≤40 years of age, with one or more years infertility history, desirous of conceiving, regularly ovulating (defined as 9 or more menses per year), at initiation of participation.
Normal uterine cavity and at least one open fallopian tube confirmed by hysterosalpingography (HSG), sonohysterography, or laparoscopy/hysteroscopy in the last three years preceding enrollment into the study. An uncomplicated intrauterine non-IVF pregnancy and uncomplicated delivery and postpartum course resulting in live birth within the last three years will also serve as sufficient evidence of a patent tube and normal uterine cavity as long as the subject did not have, during the pregnancy or subsequently, risk factors for Asherman's syndrome or tubal disease or other disorder leading to an increased suspicion for intrauterine abnormality or tubal occlusion.
Evidence of ovarian function/reserve as assessed by day 3 (+/-2 days) FSH ≤12 IU/L within one year prior to study initiation.
Normal or corrected thyroid function within one year of study initiation.
Normal prolactin level within one year of study initiation.
In general good health, not taking any medications which could interfere with the study (e.g., FSH, insulin sensitizers).
Ability to have inseminations following hCG administration.
Male partner with total motile sperm in the ejaculate of at least 5 million sperm, within one year of study initiation.

Exclusion Criteria:

Currently pregnant or successful pregnancies within 12 months of initiating participation. Clinical intrauterine miscarriages prior to initiating participation, within ASRM guidelines: subjects over 35 must wait six months, while subjects under 35 must wait 12 months. No exclusion for biochemical pregnancies.
Undiagnosed abnormal uterine bleeding.
Suspicious ovarian mass.
Patients on oral contraceptives, depo-progestins, or hormonal implants (including Implanon). A two month washout period will be required prior to screening for patients on these agents. Longer washouts may be necessary for certain depot contraceptive forms or implants, especially when the implants are still in place. A one-month washout will be required for patients on oral cyclic progestins.
Known 21-hydroxylase deficiency or other enzyme defect causing congenital adrenal hyperplasia.
Type I or Type II diabetes mellitus, or if receiving antidiabetic medications.
Known significant anemia (Hemoglobin <10 g/dL).
History of deep venous thrombosis, pulmonary embolus, or cerebrovascular event.
Known heart disease (New York Heart Association Class II or higher).
Known Liver disease (defined as AST or ALT>2 times normal, or total bilirubin >2.5 mg/dL).
Known Renal disease (defined as BUN >30 mg/dL or serum creatinine > 1.4 mg/dL).
History of, or suspected cervical carcinoma, endometrial carcinoma or breast carcinoma.
History of alcohol abuse (defined as >14 drinks/week) or binge drinking of ≥ 6 drinks at one time).
Known Cushing's disease.
Known or suspected adrenal or ovarian androgen secreting tumors.
Allergy or contraindication to the treatment medications: AI, gonadotropins, CC or hCG.
Couples with previous sterilization procedures (e.g. vasectomy, tubal ligation) which have been reversed.
Patients with untreated poorly controlled hypertension defined as a systolic blood pressure ≥ 160 mm Hg or a diastolic ≥ 100 mm Hg obtained on two measures obtained at least 60 minutes apart.
Subjects who have undergone a bariatric surgery procedure in the recent past (< 12 months) and are in a period of acute weight loss or have been advised against pregnancy by their bariatric surgeon.
Known moderate or severe endometriosis
Known polycystic ovarian syndrome as evidenced by anovulation or oligoovulation, hirsutism and/or elevated testosterone levels, and ovarian morphology on ultrasound examination.
Donated semen.
Couples in which either partner is legally married to someone else.
Medical conditions that are contraindications to pregnancy.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT01044862

Contacts

Contact: Heping Zhang, PhD	203-785-5185	rmn-Coordinators@panlists.yale.edu
Contact: Meizhuo Zhang, PhD	203-785-6759	meizhuo.zhang@yale.edu

Locations

United States, Alabama
University of Alabama Birmingham	Recruiting
Birmingham, Alabama, United States, 35249-7333
Contact: Wright Bates, MD 205-934-1030 wright.bates@obgyn.uab.edu
Principal Investigator: Wright Bates, MD
United States, California
University of California, San Francisco	Recruiting
San Francisco, California, United States, 94115
Contact: Mitchell Rosen, MD RosenM@obgyn.ucsf.edu
Contact: Thomas A Remble, MS, MPH, DHS 415-353-7394 thomas.remble@ucsfmedctr.org
Principal Investigator: Mitchell Rosen, MD
Stanford University Medical Center	Recruiting
Stanford, California, United States, 94305-5317
Contact: Valerie Baker, MD 650-498-7408 vlbaker@stanford.edu
Contact: Kathy Turner, RN, NP 650-736-1802 kathyt@stanford.edu
Principal Investigator: Valerie Baker, MD
United States, Colorado
University of Colorado	Recruiting
Aurora, Colorado, United States, 80045
Contact: Ruben Alvero, MD Ruben.Alvero@ucdenver.edu
Contact: Mallary Crow 303-724-2064 MALLARY.CROW@UCDENVER.EDU
Principal Investigator: Ruben Alvero, MD
Sub-Investigator: Randall Meacham, MD
United States, Connecticut
Yale University	Not yet recruiting
New Haven, Connecticut, United States, 06511
Contact: Heping Zhang, PhD 203-785-5185 heping.zhang@yale.edu
Contact: Meizhuo Zhang, PhD 203-785-6759 meizhuo.zhang@yale.edu
Principal Investigator: Heping Zhang, PhD
Sub-Investigator: Robert Makuch, PhD
Sub-Investigator: Pasquale Patrizio, MD, MBE
Sub-Investigator: Lawrence Scahill, PhD
Sub-Investigator: Hugh Taylor, MD
United States, Michigan
University of Michigan	Recruiting
Ann Arbor, Michigan, United States, 48108
Contact: Gregory Christman, MD 734-764-8142 growthh@umich.edu
Contact: Janny Tang 734-998-4973 huaijing@med.umich.edu
Principal Investigator: Gregory Christman, MD
Sub-Investigator: Dana Ohl, MD
Sub-Investigator: Anjel Vahratian, PhD, MPH
Wayne State University	Recruiting
Detroit, Michigan, United States, 48201
Contact: Michael Diamond, MD 313-993-4523 mdiamond@med.wayne.edu
Contact: Karen Collins, MS 313- 993-8706 kcollins@med.wayne.edu
Principal Investigator: Michael Diamond, MD
Sub-Investigator: Joel Ager, PhD
Sub-Investigator: Stephen Krawetz, PhD
Sub-Investigator: Laura Detti, MD
Sub-Investigator: Elizabeth Puscheck, MD
Sub-Investigator: Frank Yelian, MD, PhD
Sub-Investigator: Terri Woodard, MD
United States, New Jersey
University of Medicine and Dentistry of New Jersey	Recruiting
Newark, New Jersey, United States, 07601
Contact: Aimee Seungdamrong, MD 973-972-6480 seungdai@umdnj.edu
Contact: Amy Solnica amysolnica@gmail.com
Principal Investigator: Aimee Seungdamrong, MD
United States, North Carolina
Carolinas Medical Center	Recruiting
Charlotte, North Carolina, United States, 28232-2861
Contact: Rebecca Usadi, MD 704-355-3153 Rebecca.Usadi@carolinashealthcare.org
Contact: Susan M. Kullstam 704-355-2940 Susan.Kullstam@carolinashealthcare.org
Principal Investigator: Rebecca Usadi, MD
United States, Oklahoma
University of Oklahoma Health Sciences Center	Recruiting
Oklahoma City, Oklahoma, United States, 73104
Contact: Karl Hansen, MD, PhD 405-271-8722 karl-hansen@ouhsc.edu
Contact: Michelle Rodriguez, RN 405-271-1616 michelle-rodriguez@ouhsc.edu
Principal Investigator: Karl Hansen, MD, PhD
United States, Pennsylvania
Pennsylvania State University College of Medicine	Recruiting
Hershey, Pennsylvania, United States, 17033
Contact: Richard Legro, MD 717-531-8478 RSL1@PSU.EDU
Contact: Jamie Ober, RN 717- 531-6272 JOBER@hmc.psu.edu
Principal Investigator: Richard Legro, MD
University of Pennsylvania	Recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: Christos Coutifaris, MD, PhD 215-662-2977 ccoutifaris@obgyn.upenn.edu
Contact: Regina Marunich, LPN 215-662-2935 RMarunich@obgyn.upenn.edu
Principal Investigator: Christos Coutifaris, MD, PhD
Sub-Investigator: Kurt Barnhart, MD, MSCE
Sub-Investigator: Peter Snyder, MD
Sub-Investigator: Mary Sammel, PhD
Sub-Investigator: William Stauffer
United States, Texas
University of Texas Health Science Center at San Antonio	Recruiting
San Antonio, Texas, United States, 78207
Contact: Robert Brzyski, MD, PhD 210-567-6121 brzyski@uthscsa.edu
Contact: Carann Easton, RN 210-567-6245 eastonc@uthscsa.edu
Principal Investigator: Robert Brzyski, MD, PhD
Sub-Investigator: John Case, MD
Sub-Investigator: Brad Pollock, PhD, MPH
United States, Vermont
University of Vermont	Recruiting
Burlington, Vermont, United States, 05405
Contact: Peter Casson, MD 802-847-3450 peter.casson@vtmednet.org
Contact: Sara Mallette, BS 802-656-4703 sara.mallette@uvm.edu
Principal Investigator: Peter Casson, MD
Sub-Investigator: Thomas Jackson, MD
Sub-Investigator: Taka Ashikaga, PhD
Sub-Investigator: Michael Toth, PhD

Sponsors and Collaborators

Yale University

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Penn State University

University of Colorado, Denver

University of Michigan

University of Pennsylvania

University of Texas

University of Vermont

Wayne State University

Investigators

Study Director:	Esther Eisenberg, MD, MPH	Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Study Chair:	Nanette Santoro, MD	Albert Einstein College of Medicine of Yeshiva University
Principal Investigator:	Michael Diamond, MD	Wayne State University
Study Director:	Richard Legro, MD	Pennsylvania State University College of Medicine
Study Director:	William Schlaff, MD	University of Colorado Denver Health Science Center
Study Director:	Gregory Christman, MD	University of Michigan
Study Director:	Christos Coutifaris, MD	University of Pennsylvania
Study Director:	Robert Brzyski, MD, PhD	University of Texas
Study Director:	Peter Casson, MD	University of Vermont
Study Director:	Heping Zhang, PhD	Yale University

More Information

Additional Information:

Reproductive Medicine Network Homepage This link exits the ClinicalTrials.gov site

No publications provided

Responsible Party:	Yale University
ClinicalTrials.gov Identifier:	NCT01044862 History of Changes
Other Study ID Numbers:	RMN-AMIGOS, 3U10HD055925-02S1, 5U10HD055925, 3U10HD039005-08S1, 5U10HD039005
Study First Received:	January 7, 2010
Last Updated:	January 13, 2012
Health Authority:	United States: Institutional Review Board United States: Food and Drug Administration

Keywords provided by Yale University:

Pregnancy
Infertility
Ovarian stimulation
Aromatase inhibitors
Follicle Stimulating Hormone

Additional relevant MeSH terms:

Infertility
Genital Diseases, Male
Genital Diseases, Female
Clomiphene
Follicle Stimulating Hormone
Hormones
Letrozole
Aromatase Inhibitors
Estrogen Antagonists
Estrogen Receptor Modulators
Hormone Antagonists

Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Pharmacologic Actions
Fertility Agents, Female
Fertility Agents
Reproductive Control Agents
Therapeutic Uses
Selective Estrogen Receptor Modulators
Antineoplastic Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on May 23, 2012