"Stair Step Study"

June 4, 2018 updated by: Radboud University Medical Center

Is Endometrial Withdrawal Bleeding Necessary Prior to Ovulation Induction With Clomiphene Citrate? A Randomized Controlled Trial and Feasibility Study

Rationale:

There is some information suggesting that a progesterone-induced withdrawal bleeding before the start of ovulation induction in women suffering from oligo- or amenorrhea reduces pregnancy and live birth rate.

Objective:

To evaluate the effects of withholding progesterone-induced endometrial withdrawal bleeding before ovulation induction on the time to pregnancy and the ongoing pregnancy rate.

Study design:

Prospective multicenter randomized controlled feasibility study

Study population:

Women with oligomenorrhea or amenorrhea according to WHO classification category 2

Intervention:

Patients will be randomized to receive one of the following two treatments:

Stair step group: blind start ovulation induction (no progesterone induced withdrawal bleeding and stair step protocol in case of treatment failure.

Control: standard care; a progesterone induced withdrawal bleeding in case of no spontaneous menses before starting an ovulation induction cycle and in between anovulatory cycles.

Main study parameters/endpoints:

The primary endpoints are the time to pregnancy and ongoing pregnancy rate within a treatment horizon of 3 cycles. Secondary endpoints include time to ovulation, endometrial thickness, multiple pregnancy and the incidence of treatment failure.

Nature and extent of the burden and risks associated with participation, benefit and group relatedness:

The number of site visits or physical examinations will not differ from accepted clinical practice.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

OBJECTIVES

Primary objective:

To demonstrate whether withholding progesterone induced endometrial shedding prior to ovulation induction improves the ongoing pregnancy rate per cycle compared to not withholding progesterone treatment and to demonstrate its impact on the time to pregnancy.

Secondary objectives:

To elucidate the impact of the two study protocols on time to ovulation, endometrial thickness, multiple follicle growth, multiple pregnancy and the incidence of treatment failure. Furthermore, in accordance to the proposed areas of focus addressed by feasibility studies [Bowen et al (2009)], the number of eligible patients, the number of protocol violations and the number of drop-outs will be recorded.

STUDY DESIGN

Prospective multicenter randomized controlled study. The participating centers are:

  • Radboud UMC, Nijmegen
  • Canisius Wilhelmina Ziekenhuis (CWZ), Nijmegen
  • Gelderse Vallei, Ede

Patients will be randomly allocated to receive one of the following treatment protocols:

  • Standard group: medroxyprogesterone acetate (Provera®) 10 mg for 10 days prior to starting ovulation induction with CC and in between anovulatory cycles.
  • Stair Step group: no Provera® prior to ovulation induction with CC, nor in between anovulatory cycles.

Standard group The standard group will receive our standard care. Provera® will be administered for 10 days (after a negative pregnancy test) to induce an endometrial whitdrawal bleeding. Menses may be expected as early as 3 days after the last pill. Prior to each treatment cycle, an ultrasound will be performed on cycle day 3 to check up on the presence of cysts after which CC 50 mg is administered for 5 days. Follicle growth will be monitored by ultrasound, starting from cycle day (CD) 11. If there is no response (defined as no follicle ≥ 14 mm) on CD 20, Provera® will be administered for 10 days. The CC dosage will be increased in the next cycle. Three days after the start of the next menses, patients will receive CC 100 mg for 5 days with follicle growth monitoring starting again from CD 11. Anovulatory patients (no follicle ≥ 14 mm) on CD 20 will receive Provera® for 10 days. Three days after the start of menses the CC dose will be increased to 150 mg and will be administered for 5 days with ultrasounds starting from CD 11-20.

Stair Step group The stair-step group will receive the following treatment: after performing an ultrasound to check for the presence of cysts or any other abnormalities and a negative pregnancy test, patients will be given CC 50 mg for 5 days. Ultrasounds will be performed on days 11-14. When there is no response on CD 14 (no follicle ≥ 14 mm), the dose of CC is immediately increased to 100 mg CC for 5 days and an ultrasound is performed 1 week following the last ultrasound. If there is no response, 150 mg CC is initiated immediately for 5 days and the ultrasound is repeated 1 week after the previous ultrasound.

In both arms, ovulation is confirmed by evidence of a preovulatory follicle followed by menses with onset at the expected time (cycle length of 25-35 days) or by pregnancy.The CC dose can be adjusted in case of a high response. Treatment failure is defined as failure to ovulate following CC 150 mg. Patients who conceive will receive an ultrasound examination at 8 weeks of gestation to confirm an ongoing pregnancy. Following this last scan the study period for the given patient will be completed. All patients will undergo a maximum of 3 treatment cycles as part of this protocol.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
42

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Netherlands
    • Gelderland
      • Ede, Gelderland, Netherlands
        • Gelderse Vallei Hospital
      • Nijmegen, Gelderland, Netherlands
        • Radboud University Medical Center
      • Nijmegen, Gelderland, Netherlands
        • Canisius-Wilhelmina Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

18 years to 41 years (Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

Female

Description

Inclusion Criteria:

  • WHO classification category 2 PCOS or non-PCOS
  • Age between 18 - 41 years
  • Patent Fallopian tubes, proven by hysterosalpingography (HSG), a negative Chlamydia antibody titre (CAT) or diagnostic laparoscopy combined with tubal testing (DLS and TT), depending on the local protocol.
  • BMI < 40 kg/m2

Exclusion Criteria:

  • BMI > 40 kg/m2
  • Previous unsuccessful ovulation induction cycles with CC
  • Double-sided tubal pathology
  • Presence of ovarian cysts on ultrasound
  • Moderate - severe male infertility (TMSC < 3 million)
  • Grade III/IV endometriosis
  • Thrombosis
  • Severe liver disease

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Active Comparator: Standard group
Intervention:Medroxyprogesterone acetate (Provera) 10 mg daily for 10 days will be used prior to starting ovulation induction with clomiphene citrate (CC) and between anovulatory cycles. On cycle day (CD) 3 CC 50 mg is administered daily for 5 days. Follicle growth will be monitored by ultrasound, starting from CD11. Anovulatory patients (defined as no follicle ≥ 14 mm) on CD20, will receive Provera 10mg daily for 10 days. The CC dosage will be increased in the next cycle. On CD3 patients will receive CC 100 mg daily for 5 days with ultrasounds performed from CD11 onwards. Anovulatory patients will receive Provera 10mg daily for 10 days. In the next cycle the CC dose will be increased to 150 mg, starting from CD3, daily for 5 days with ultrasounds starting from CD11-20.
Drug: Medroxyprogesterone Acetate 10 MG
Patients in the standard arm will receive Medroxyprogesterone Acetate 10mg daily for 10 days prior to the first ovulation induction cycle and in between anovulatory cycles.
Other Names:
  • Provera
Experimental: Stair Step group
Intervention: Stair step protocol without medroxyprogesterone acetate 10 mg prior to ovulation induction with clomiphene citrate (CC), nor in between anovulatory cycles. After performing an ultrasound to check for the presence of cysts or any other abnormalities and a negative pregnancy test, patients will receive CC 50 mg daily for 5 days. Ultrasounds will be performed on CD11-14. If there is no response on CD14 (no follicle ≥ 14 mm), the dose of CC is immediately increased to 100 mg CC daily for 5 days and an ultrasound is performed 1 week following the last ultrasound. If there is no response, 150 mg CC daily is initiated immediately for 5 days and the ultrasound is repeated 1 week after the previous ultrasound.
Other: Stair step protocol without Medroxyprogesterone Acetate
No administration of Medroxyprogesterone Acetate prior to each cycle. Stair step method: rapidly increasing the dose of clomiphene citrate in case of no follicular response
Other Names:
  • Stair step

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Ongoing pregnancy rate per cycle
Time Frame: in case of pregnancy: 8 weeks after the start of each cycle, (maximum of 3 cycles, duration of 1 cycle: 28-35 days)
Ongoing pregnancy is defined as the presence of at least one intra uterine fetus with heartbeat at 8 weeks of gestation
in case of pregnancy: 8 weeks after the start of each cycle, (maximum of 3 cycles, duration of 1 cycle: 28-35 days)
Time to pregnancy
Time Frame: duration of 1 cycle: 28-35 days, a maximum of 3 cycles will be performed (pregnancy test will be performed at the end of the cycle if there is no menstruation)
the time between obtaining informed consent and the presence of a positive pregnancy test after treatment
duration of 1 cycle: 28-35 days, a maximum of 3 cycles will be performed (pregnancy test will be performed at the end of the cycle if there is no menstruation)

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Time to ovulation
Time Frame: 3 cycles of 28-35 days, calculated as 14 days before the start of menstruation or 14 days before a positive pregnancy test
calculated as 14 days prior to the first day of menstruation or positive pregnancy test
3 cycles of 28-35 days, calculated as 14 days before the start of menstruation or 14 days before a positive pregnancy test
Endometrial thickness on the last day of ultrasonography
Time Frame: maximum of 3 cycles (each 28-35 days)
measurement of the endometrial thickness on the last day of ultrasound monitoring. This day can differ among cycles, depending on the speed of follicle growth, hence it cannot be further specified.
maximum of 3 cycles (each 28-35 days)
The incidence of multiple follicle growth on the last day of ultrasonography
Time Frame: maximum of 3 cycles (each 28-35 days)
This day can differ among cycles, depending on the speed of follicle growth, hence it cannot be further specified.
maximum of 3 cycles (each 28-35 days)
The incidence of multiple pregnancy
Time Frame: in case of pregnancy: 8 weeks after the start of a treatment cycle (maximum of 3 cycles; each 28-35 days)
ultrasound performed at 8 weeks of gestation, which is 8 weeks after the start of a treatment cycle
in case of pregnancy: 8 weeks after the start of a treatment cycle (maximum of 3 cycles; each 28-35 days)
The incidence of treatment failure
Time Frame: maximum of 3 cycles (each 28-35 days)
treatment failure is defined as no follicle ≥ 14 mm on CD 20 despite using a maximum clomiphene citrate dose of 150 mg in the standard arm. Or no follicle ≥ 14 mm after increasing the clomiphene citrate dose up to 150 mg.
maximum of 3 cycles (each 28-35 days)
The number of eligible patients
Time Frame: Inclusion 16 months, follow-up 3 months.
The total number of patients that fits the inclusion criteria.
Inclusion 16 months, follow-up 3 months.
The number of protocol violations
Time Frame: duration: maximum of 3 cycles (each 28-35 days)
The total number of protocol violations.
duration: maximum of 3 cycles (each 28-35 days)

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Radboud University Medical Center

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
June 21, 2016

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
November 30, 2017

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
May 31, 2018

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
August 9, 2017

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
October 12, 2017

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
October 13, 2017

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
June 6, 2018

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
June 4, 2018

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
August 1, 2017

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • NL56254.091.15

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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