Optimizing Ovulation Induction in the Poor Responder
|First Received Date ICMJE||August 23, 2010|
|Last Updated Date||November 19, 2012|
|Start Date ICMJE||October 2010|
|Estimated Primary Completion Date||October 2011 (Final data collection date for primary outcome measure)|
|Current Primary Outcome Measures ICMJE
||Follicular response and synchrony [ Time Frame: 2 years ]
We will measure follicular response and synchrony following adminstration of extradiol patches or oral contraceptive pills.
|Original Primary Outcome Measures ICMJE||Same as current|
|Change History||Complete list of historical versions of study NCT01200537 on ClinicalTrials.gov Archive Site|
|Current Secondary Outcome Measures ICMJE
||IVF outcomes [ Time Frame: 2 years ]
We will compare IVF outcomes in the estradiol patch and OCP groups.
|Original Secondary Outcome Measures ICMJE||Same as current|
|Current Other Outcome Measures ICMJE||Not Provided|
|Original Other Outcome Measures ICMJE||Not Provided|
|Brief Title ICMJE||Optimizing Ovulation Induction in the Poor Responder|
|Official Title ICMJE||Optimizing Ovulation Induction in the Poor Responder: a Randomized Clinical Trial of Luteal Phase Estradiol Versus Combined Oral Contraceptive Pill on Ovarian Morphology and Biomarkers Prior to Ovulation Induction|
|Brief Summary||The purpose of this randomized controlled trial is to compare the efficacy and effect of luteal estradiol and combined oral contraceptive pills (COPC) on follicle recruitment and synchrony in a poor responder population. The randomized groups consist of: 1. patients receiving luteal estradiol prior to ovulation induction; and 2. patients receiving COCPs for 1 month prior to ovulation induction. Follicle characteristics and serum biomarkers will be followed and compared in each group. Coefficient of variation will be used to evaluate follicle size discrepancy. Chi square analysis will be used to compare categorical variables between treatment groups. Both estradiol and COPCs are used clinically in assisted reproduction, so this study affords no additional risks to the participants.|
The study is a randomized controlled trial.
Baseline studies preceding ovulation induction:
Cycle day 3 FSH, inhibin B, estradiol, androstenedione, AMH, and AFC will be performed the cycle of OCP or luteal pretreatment and the cycle of ovulation induction.
• Ovarian morphology and dimensions will be obtained using a vaginal probe ultrasound. All study ultrasounds will be recorded and read by a single investigator (at each center) blinded to patient treatment group.
Block randomization will occur by computer algorithm to two groups:
5. Selection of Subjects:
The Emory Reproductive Center (ERC) and Duke Fertility Center (DFC) are assisted reproductive technology centers offering ovulation induction, IVF, gamete micromanipulation, and embryo cryopreservation. Between the two centers, approximately 250-300 stimulated cycles are completed each year. While the study is open, all women at risk for poor response to ovulation induction at the two centers will be offered participation by the PI, Co-PI, Co-Investigator or coordinating research nurse.
Please see section #5. There will be no patient compensation.
7. Consent Process:
An IRB-approved written informed consent will be obtained from each subject at entry into the study; elements of informed consent will include: (a) having the subject review the study consent form; (b) having the investigator(s) or study staff meet with the subject to review the consent, confirm understanding, and answer any questions; and (c) once the investigator(s) or study staff are convinced that the protocol is understood and that there is agreement to participate, having the consent signed in the presence of a witness. The potential participant will have until the beginning of her first stimulated cycle to decide whether or not she is participating in the study. The consent will be discussed and signed in person at Emory Reproductive Center or Duke Fertility Center. The consent process, as outlined above, will occur in private consultation rooms. There is no time minimum or maximum for the consent process. The consent process is determined to be complete when the participant verbalizes understanding, states that she has no further questions and signs the consent forms. The PI, Co-PI, Co-Investigators and coordinating research nurse will be readily available by telephone or in person at ERC and/or DFC to answer questions concerning the consent. In order to reduce potential coercion and perceived influence by the study personnel, the study details and consent forms will be discussed in a matter-of-fact and consistent manner. Only patients who speak and read English will be admitted into the study.
8. Subject's Capacity to Give Legally Effective Consent:
Only patients with the capacity to give legally effective consent will be included in the study.
9. Study Interventions:
Please see section #4.
10. Risk/Benefit Assessment:
The treatments used in this study have been studied individually and are used in clinical practice. Our goal is to see which one is better. Therefore the risks of this study are the same as the risk of ovulation induction to which the subjects will be exposed whether they are enrolled in the study or not.
11. Costs to the Subject:
There is no additional cost to the subject above the regular fees assessed for ART.
12. Data Analysis & Statistical Considerations:
Coefficient of variation will be used to evaluate follicular size discrepancy by the following formula: Coefficient of variation = 100 * Standard deviation / mean of the set
We predict that a difference of 1.2 mm between mean follicular size before and after COCPs will be clinically significant. This is based on observations by Fanchin in which women treated with luteal estradiol displayed a decrease in mean follicular size on day 3 of 1.2 mm that was associated with a significant decrease in coefficient of variation between follicles and an increase in mature follicles >16 mm number on day of hCG administration.
Power to detect a difference between groups Number cycles/group to demonstrate COCP equivalence Number cycles/group to demonstrate COCP superiority 80% 7 25 85% 7 29 90% 9 33 95% 11 41
To detect equivalence of COCP to luteal estradiol with a power of 90% at an alpha of .05 assuming a 10% attrition rate, we will enroll women into each study group so as to achieve final number of 10 cycles per treatment group. We assume that an additional 50% decrease in follicular size would prove COCP superiority. To detect superiority of COCP to luteal estradiol with a power of 80% at an alpha of 0.05 assuming 10% attrition rate, we will enroll women into each study group so as to achieve a final number of 28 cycles per treatment group. Only newly initiated treatment cycles will be included; only the first cycle of patients' crossing over to the other treatment group will count toward this recruitment goal. The second cross over cycle will be compared within patient.
µ1-µ 2 = 4.9 - 3.7 mm = 1.2 (µ1-µ 2)2 = 1.44 (COCP equivalence) µ1-µ 2 = 1.8 - 1.2 mm = 0.6 (µ1-µ 2)2 = 0.36 (COCP superiority) SD = б=0.75 б2 = 0.5625 2 б2 = 1.125 α = 0.05 Zα = 1.96 (2-sided test) β = 0.20 1- β = 0.80 Z β = 0.84 (1-sided) (Zα +Zβ)2= 7.84 β =0.15 1- β = 0.85 Z β = 1.03 (1-sided) (Zα +Zβ) 2= 8.94 β = 0.10 1- β = 0.90 Z β = 1.28 (1-sided) (Zα +Zβ) 2= 10.498 β = 0.05 1- β = 0.95 Z β = 1.645 (1-sided) (Zα +Zβ) 2 =12.996
Calculation: n= (Zα +Zβ)2* 2(б2) / (µ1-µ 2)2
Methods of Analysis
Chi square analysis will be used to compare categorical variables between treatment groups. Student's t test will be used to compare the mean follicle measurements between treatment groups.
13. Data & Safety Monitoring:
Adherence and Monitoirng Statement: The Data Safety Monitoring Plan (DSMP) outlined below will adhere to the protocol approved by the IRB at both Emory University School of Medicine and Duke University School of Medicine. The Principal investigator (PI) will review all data collection forms at least annually for completeness and accuracy of the data as well as protocol compliance. The PI will review this protocol on a continuing basis for subject safety and include the results of the review in annual progress reports submitted to the IRB. Adverse events and serious adverse events will also be reviewed by the PI weekly.
Patient Monitoring: Performed by the P.I., the Co-P.I. and/or Co Investigators.
Patient safety data examination, monitoring procedures/oversight: All adverse events (AEs) will be graded as to their attribution (unrelated to protocol, or possibly, probably, or definitely related to protocol). Any AE that is reported to either the PI or her designated research associates by a study subject or by medical staff caring for the subject and which meets the criteria will be documented as such.
Serious adverse events (SAEs) are predefined as any experience that suggests a significant hazard, such as events which: a) are fatal, b) are life threatening, c) result in permanent disability, d) require inpatient hospitalization, or e) involve cancer, a congenital anomaly, or drug overdose.
Any AEs will be reported to the IRB at Emory and Duke within 24-48 hours of the event. The standard Emory and Duke IRB reporting guidelines for AE and SAE reporting will be followed. The investigators and staff will evaluate the SAEs in close coordination with the Emory and Duke IRB.
Expected adverse events are detailed in the Consent Form and include the following: side effects of estradiol and combined oral contraceptive pills (breakthrough bleeding, nausea, headaches, depression, breast tenderness, changes in blood pressure, and increase in risk of blood clotting); risks of ovulation induction (multiple birth, ovarian hyperstimulation syndrome, ovarian cyst development, failure to achieve pregnancy); risks of multiple birth and ovarian hyperstimulation syndrome are less in poor responders regardless of treatment used; risk of failure to achieve pregnancy is greater in poor responders regardless of treatment used.
Procedures for minimizing risks: Monitoring with serial ultrasound and blood work will be used to minimize risks.
Plans for transmission of temporary or permanent suspension actions: Any actions that mandate temporary or permanent suspension of study will be transmitted to the Emory and Duke IRB, and, if appropriate, to the FDA and the National Institutes of Health.
Plans for assuring data accuracy and protocol human safety compliance: The above detailed plans should assure data accuracy and protocol human safety compliance. These include computerized database management, and IRB oversight and communication. This plan, together with proposed monitoring by the IRB, should be sufficient without the addition of more faculty members to constitute a DSMB.
14. Privacy, Data Storage & Confidentiality:
All information and materials will be obtained for research purposes only and the data will be kept in strict confidence. Confidentiality will be assured by the use of subject codes rather than personal identifiers. The study database will be secured, and information will only be entered using subject identifier codes rather than personal identifiers. Electronic communication will involve only coded, unidentifiable information. All adverse event reports and annual summaries will not include subject-identifiable material.
|Study Type ICMJE||Interventional|
|Study Phase||Not Provided|
|Study Design ICMJE||Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
|Condition ICMJE||IVF Poor Responders|
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Withdrawn|
|Estimated Completion Date||October 2012|
|Estimated Primary Completion Date||October 2011 (Final data collection date for primary outcome measure)|
|Eligibility Criteria ICMJE||
|Ages||20 Years to 50 Years (Adult)|
|Accepts Healthy Volunteers||Yes|
|Contacts ICMJE||Contact information is only displayed when the study is recruiting subjects|
|Listed Location Countries ICMJE||United States|
|Removed Location Countries|
|NCT Number ICMJE||NCT01200537|
|Other Study ID Numbers ICMJE||Pro00022374|
|Has Data Monitoring Committee||No|
|U.S. FDA-regulated Product||Not Provided|
|Plan to Share Data||Not Provided|
|IPD Description||Not Provided|
|Responsible Party||Susannah Copland, MD, Duke University Medical Center|
|Study Sponsor ICMJE||Duke University|
|Collaborators ICMJE||Emory University|
|PRS Account||Duke University|
|Verification Date||November 2012|
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