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"Stair Step Study"

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ClinicalTrials.gov Identifier: NCT03309176
Recruitment Status : Completed
First Posted : October 13, 2017
Last Update Posted : June 6, 2018
Sponsor:
Information provided by (Responsible Party):
Radboud University

Tracking Information
First Submitted Date  ICMJE August 9, 2017
First Posted Date  ICMJE October 13, 2017
Last Update Posted Date June 6, 2018
Actual Study Start Date  ICMJE June 21, 2016
Actual Primary Completion Date November 30, 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 12, 2017)
  • 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
  • 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
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: October 12, 2017)
  • 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
  • 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.
  • 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.
  • 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
  • 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.
  • The number of eligible patients [ Time Frame: Inclusion 16 months, follow-up 3 months. ]
    The total number of patients that fits the inclusion criteria.
  • The number of protocol violations [ Time Frame: duration: maximum of 3 cycles (each 28-35 days) ]
    The total number of protocol violations.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE "Stair Step Study"
Official Title  ICMJE Is Endometrial Withdrawal Bleeding Necessary Prior to Ovulation Induction With Clomiphene Citrate? A Randomized Controlled Trial and Feasibility Study
Brief Summary

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.

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  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

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.

Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Ovulation Disorder
Intervention  ICMJE
  • 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 Name: Provera
  • 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 Name: Stair step
Study Arms  ICMJE
  • 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.
    Intervention: Drug: Medroxyprogesterone Acetate 10 MG
  • 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.
    Intervention: Other: Stair step protocol without Medroxyprogesterone Acetate
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: October 12, 2017)
42
Original Estimated Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE May 31, 2018
Actual Primary Completion Date November 30, 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: Female
Gender Based Eligibility: Yes
Ages  ICMJE 18 Years to 41 Years   (Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Netherlands
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03309176
Other Study ID Numbers  ICMJE NL56254.091.15
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Radboud University
Study Sponsor  ICMJE Radboud University
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account Radboud University
Verification Date August 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP