Synchronization of Follicle Wave Emergence and Ovarian Stimulation
Condition: Infertility
MeSH terms: Infertility
Study type: Interventional
Phase: Phase 4

Summary: 
      The objective of the study is to elucidate the effect of synchronizing initiation of ovarian
      stimulation treatment with follicular wave emergence in poor responder patients undergoing
      IVF/ICSI and ET. We hypothesize that initiating treatment on day 1 versus day 4 of the cycle
      will increase the number of follicles recruited and oocytes retrieved.
    

Detailed description: 
      Sample Population Eligible patients undergoing IVF or ICSI for the treatment of infertility
      in the Assisted Reproductive Technologies Center at the University of Saskatchewan (ARTUS;
      Department of Obstetrics, Gynecology and Reproductive Sciences) in Saskatoon, Saskatchewan
      and the Genesis Fertility Centre in Vancouver, British Columbia will be identified by study
      physicians and nurses. Patients with a history of poor response to ovarian stimulation
      therapy in a previous IVF or ICSI cycle, who have already decided to undergo a subsequent
      treatment cycle, will be contacted by a study physician and offered enrolment into the study.
      Patients exhibiting all inclusion criteria and no exclusion criteria will be eligible to
      participate.

      Inclusion Criteria:

        -  Informed consent obtained

        -  Age of 43 years or younger

        -  18<BMI<35

        -  History of poor response to ovarian stimulation as determined by:

        -  previously cancelled oocyte retrieval procedure due to < 4 follicles greater than 12 mm
           on ultrasound OR

        -  < 3 mature oocytes

        -  Physical exam performed within the past 12 months

        -  Normal or corrected levels of TSH and Prolactin within the past 12 months

        -  Has not taken ovarian suppression therapy within 1 month of initiating study drug

      Exclusion Criteria:

        -  Chronic medical conditions such as renal failure

        -  Documented ovarian failure

        -  Presence of only one ovary

        -  Serum Day 3 FSH > 12 IU/L within the past 6 months

        -  Ovaries inaccessible transvaginally

        -  Concomitant glucocorticoid use

        -  Ongoing pregnancy

        -  Any contraindications to ovarian stimulation treatment

        -  Participation in an investigational drug trial in the 30 days prior to the pre-study
           visit

      Cycle Cancellation Criteria:

        -  The development of < 3 follicles > 12 mm.

      Sample Size A sample size of 80 women (40 women per treatment group) has been chosen. This
      calculation was based on a standard deviation of 3.0 in each treatment group, a significance
      level of 0.05 (2-tailed test), a mean difference of 2.0 follicles and a power of 80%. The
      standard deviation used in the power calculation was based on similar studies performed in
      domestic animal species. Approximately 120 IVF/ICSI cycles are performed each year in the
      Department of Obstetrics, Gynecology and Reproductive Sciences at the University of
      Saskatchewan and approximately 600 cycles are performed at the Genesis Fertility Centre.
      Approximately 5-10% of patients are proven poor responders. Thus, with an anticipated 75%
      recruitment rate, we expect to recruit 80 patients in the study over a 24 month period. It is
      expected that 25% of research subjects will be enrolled at the ARTUS Centre and 75% of
      subjects will be enrolled at the Genesis Fertility Centre.

      Study Procedures Women who are believed to be eligible for the study will be asked to visit
      the Assisted Reproductive Technologies Center at the University of Saskatchewan (ARTUS) or
      the Genesis Fertility Centre in Vancouver, British Columbia for a pre-study appointment. At
      this visit, inclusion and exclusion criteria will be reviewed. If patients meet all study
      criteria, consent will be obtained and each woman will be randomized to either the control
      group (i.e. treatment starting on day 4) or experimental group (i.e., treatment starting on
      day 1). A medical history and vital signs will be performed. Study drug administration, diary
      card use and potential adverse reactions will be reviewed at the pre-study visit. Diary cards
      will be used to monitor study drug administration, adverse reactions, and concomitant
      medications used during the study. Diary cards will be reviewed with the patient by study
      personnel throughout the duration of the study. Serious adverse events will be reported by
      the investigators to the drug safety group of the study drug manufacturers and the Biomedical
      Research Ethics Board, in accordance with Tri-Council Policy guidelines.

      All patients will be instructed to call the clinic on day 1 of menses. If menses begins
      before 6 pm, that day will be considered day 1. If menses begins after 6 pm, the next day
      will be considered day 1. Women randomized to the day 1 treatment group will be instructed to
      begin ovarian stimulation therapy (Gonal-f, Serono Canada) on day 1 and visit the clinic to
      undergo their first transvaginal ultrasound examination on day 2. Women randomized to the day
      4 treatment group will be instructed to begin ovarian stimulation on day 4 and visit the
      clinic on day 4 for their first transvaginal ultrasound examination. Ultrasound examinations
      will be performed to determine the number of follicles developing in the ovaries. Ultrasound
      examinations will continue every 2-4 days for each woman, as per the normal standard of care.
      Blood will be drawn intermittently during stimulation to determine serum concentrations of
      estradiol-17B. Each participant will be asked to perform a home urine pregnancy test before
      taking their first dose of study medication. If a woman is found to be pregnant, she will be
      withdrawn from the study.

      When a follicle > 13 mm is detected OR if 6 or more follicles > 10 mm develop and E2 is >
      1000 pmol/L, women will be instructed to begin taking a Gonadotropin Releasing Hormone
      Antagonist (Cetrotide, Serono Canada) and recombinant Luteinizing Hormone (Luveris, Serono
      Canada). Gonal F, Cetrotide and Luveris administration will continue daily until human
      Chorionic Gonadotropin (hCG, Pharmaceutical Partners of Canada Inc.) is administered when > 3
      follicles reach > 17 mm in diameter. It is anticipated that the duration of ovarian
      stimulation therapy will be 8-16 days. Shorter or longer stimulation intervals may result in
      cycle cancellation. Oocytes will be isolated, evaluated and fertilized following hCG
      administration, according to the normal standard of care.

      The type and dose of stimulation therapy will be standardized among women as noted in
      Appendix B. Women will be asked to visit the clinic for a follow-up appointment with the
      physician and study nurse approximately 4 weeks after the oocyte retrieval. Adverse events,
      concomitant medications and diaries will be reviewed at this time. After the follow-up
      appointment, women will have completed all study-related procedures. Adverse events
      persisting at the time of study completion will be followed as deemed medically appropriate.

      All procedures performed in this study adhere to Good Clinical Practice guidelines. The only
      procedures that differ from those carried out for routine patient care are the initiation of
      ovarian stimulation therapy on day 1, the urine pregnancy test prior to initiating therapy
      and the completion of diary cards by the patients to monitor study drug administration,
      adverse events and concomitant medications.

      Study Endpoints

      Primary study endpoints include:

        -  number of follicles > 15 mm on day of hCG

        -  peak serum estradiol concentrations

      Secondary study endpoints include:

        -  number of antral follicles (day 1 or day 4)

        -  number of follicles aspirated

        -  number of oocytes obtained

        -  oocyte morphology

        -  fertilization rates

        -  number of viable embryos (day 3 and day 5)

        -  blastocyst rate

        -  number of embryos transferred

        -  clinical pregnancy rate (serum ß-hCG)

      All study endpoints will be compared between women in the control versus experimental group.
      An interim analysis will be performed by the study investigators once 40 patients have
      completed study procedures. The overall incidence of Ovarian Hyperstimulation Syndrome (OHSS)
      requiring hospitalization in women undergoing IVF/ICSI is approximately 3%. Therefore, in 40
      normal responder patients we would expect an incidence of OHSS-related hospitalization to be
      approximately 1.2%. If more than 1 patient in each treatment group has been admitted to the
      hospital for OHSS after 40 women have completed study procedures, the study will be reviewed
      for possible termination.

      Foreseeable Risks and Discomfort

      Potential risks during study participation include:

        -  discomfort during transvaginal ultrasound examination

        -  discomfort and bruising at the site of venipuncture

        -  redness, swelling and discomfort at the drug injection site

        -  ovarian hyperstimulation

      In 1-10% of normally-responding patients, ovarian hyperstimulation syndrome (OHSS) occurs in
      which too many follicles develop, placing the woman at risk for hospitalization. Because a
      suboptimal number of follicles develop in women who respond poorly to ovarian stimulation
      therapy, we believe that the risk of ovarian hyperstimulation is extremely low to zero.
      However, because we cannot predict the outcome of initiating therapy on day 1 of the
      menstrual cycle, we cannot guarantee that hyperstimulation will not occur.

      All of the above-mentioned risks are related to current standard of care for IVF. The risks
      of OHSS will be minimized by adherence to the usual standard of care for ovarian stimulation
      monitoring. Patients felt to be at risk for developing OHSS will have their dose of exogenous
      FSH and hCG therapy dropped, as per the usual standard of care.

      In the event that patients become ill or injured as a result of participating in this study,
      necessary medical treatment will be made available at no additional cost to the patient. By
      signing the consent form, patients do not waive any of their legal rights.

      Benefits There are no guaranteed benefits for women participating in this study. However, if
      our hypothesis is proven, women may benefit from an increased number of recruited follicles.
      We anticipate that the results of this study will increase our understanding of poor response
      to ovarian stimulation, and lead to the development of better treatments for couples
      undergoing IVF/ICSI and ET in the future.

      Costs Partial drug coverage will be provided by Serono Canada Inc. to participants in this
      study.

      Confidentiality All participants will be identified in the study by their initials and
      assigned patient study number. Only study personnel will have access to study-related records
      during the conduct of the study. The contents of study related records will not be available
      to any party other than the University of Saskatchewan Ethics Board, the study sponsor, and
      government regulatory agencies unless required by law. A report of the results of this study
      may be made to Health Canada (HC) and the Food and Drug Administration (FDA, USA) while
      maintaining confidentiality of patient identification. The results of this study may also be
      used for medical and scientific publications but patient identity will not be disclosed.
      Study files will be archived by the scientific investigator for 25 years at Royal University
      Hospital.

      Voluntary Participation/Withdrawal from Study Participation in this study is voluntary.
      Patients may decide not to participate or may withdraw at any time. Refusal to participate
      in, or withdrawal from, the study will not affect the future medical care of the patient.

      Participation in this study may be ended at any time, without patient consent. Reasons may
      include, but are not limited to, patient's failure to follow study instructions, the
      appearance of side effects, or study cancellation due to administrative reasons. If < 3
      follicles develop to a diameter of 12 mm or larger, the patient will be withdrawn from the
      study and the IVF/ICSI cycle may be cancelled.
    

Intervention name(s): Gonal F; Luveris; Cetrotide; hCG
Intervention type(s): Drug; Drug; Drug; Drug
Intervention description(s): 450 IU Gonal-f (Serono Canada) subcutaneously daily (225 IU BID; injections to be given after bloodwork).
Dosing to begin on day 1 or day 4 (day 1=first day of menses), continuing until administration of human Chorionic Gonadotropin (hCG; see below).
Gonal-f dose may be further reduced, at the discretion of the study physician, to minimize the risk of OHSS.; 0.250 mg Cetrotide (Serono Canada) and 75 IU Luveris (Serono Canada) subcutaneously daily when one or more of the following conditions are met:
leading follicle is > 13 mm in diameter
if 6 or more follicles develop to > 10 mm and E2 > 1000 pmol/L
Dosing to continue until administration of hCG (see below).; 0.250 mg Cetrotide (Serono Canada) and 75 IU Luveris (Serono Canada) subcutaneously daily when one or more of the following conditions are met:
leading follicle is > 13 mm in diameter
if 6 or more follicles develop to > 10 mm and E2 > 1000 pmol/L
Dosing to continue until administration of hCG (see below).; - 10,000 IU hCG (Pharmaceutical Partners of Canada Inc.) subcutaneously when:
o > 3 follicles are > 17 mm in diameter
Intervention MeSH terms: Cetrorelix
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: follicle; ovary; poor responder; stimulation; follicle wave emergence