"Stair Step Study"
Condition: Ovulation Disorder
Study type: Interventional
Phase: Phase 4

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.
    

Intervention name(s): Medroxyprogesterone Acetate 10 MG; Stair step protocol without Medroxyprogesterone Acetate
Intervention type(s): Drug; Other
Intervention description(s): 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.; 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 intervention name(s): Provera; Stair step
Intervention MeSH terms: Medroxyprogesterone Acetate; Medroxyprogesterone
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