A Phase IV, Prospective, Observational, Open Label, Single Centre Cohort Trial to be Conducted in Norway During One Year to Assess the Cumulative Pregnancy Rate in a New Series of In-vitro Fertilization (IVF) Treatment Cycles Following Three or More Previous IVF Treatment Cycles Without Live Birth
Condition: Infertility
MeSH terms: Infertility
Study type: Observational

Summary: 
      The primary objective of this observational study is to assess the cumulative rate of ongoing
      pregnancy at 10 ±2 weeks after hCG administration in a new series of IVF-treatment cycles in
      a total of 176 subjects, who have undergone three or more previous IVF-treatment cycles
      without live birth. Secondary objectives include subgroup analysis on the effect of age on
      the likelihood of pregnancy at 10 ±2 weeks after hCG administration in a new series of
      IVF-treatment cycles in patients < 35 years and ≥ 35 years, who have undergone three or more
      previous IVF-treatment cycles without live birth.

      The information obtained from this trial will be helpful for subjects who are considering
      further IVF treatments and for IVF centres, as well as for the formulation of governmental
      policies regarding healthcare reimbursement in Norway.
    

Detailed description: 
      Since IVF processes were established in 1978, there has been a dramatic increase in the
      numbers of IVF treatment cycles performed worldwide. In 2003, the total numbers of reported
      IVF cycles were 132,932 from 725 clinics in 28 European countries, 7,535 IVF/intra
      cytoplasmic sperm injection (ICSI) cycles from 24 centres in Canada, and over 100,000 IVF
      cycles from 399 centres in the U.S.

      Of all the assisted reproductive technology (ART) procedures available, IVF leads to the
      highest pregnancy rate per cycle. The degree to which governments reimburse subjects for IVF
      treatment varies widely among countries in Europe and North America. In Norway, infertile
      subjects are offered a maximum of three IVF-cycles reimbursed by the government. If three
      cycles are unsuccessful, subjects must pay for further treatments. This policy might lead
      subjects to believe that the probability of achieving pregnancy after four or more cycles is
      very low and, therefore, not worth the cost or effort.

      However, a number of published studies show evidence of successful outcomes for additional
      IVF-cycles after three (or more) cycles with negative results. Many studies show only a
      modest decline of success with repeated IVF cycles. In addition, a preliminary retrospective
      analysis of the clinical pregnancy rate in subjects treated at the trial centre during 2007
      showed that subjects, who underwent additional one to three IVF-treatment cycles, had a
      cumulative success rate of 52% (based on clinical experience from 62 subjects at the Hausken
      clinic in 2007). Thus, these studies indicate that there is a reasonable chance of achieving
      a healthy pregnancy and live birth after three previous IVF-treatment failures.

      In fact, age is likely to be a more important factor than the number of previous IVF
      treatment failures in determining a successful outcome. Several studies have demonstrated
      that older women have lower rates of conception and live births, and higher rates of
      pregnancy failure.

      Treatment of subfertility and infertility by ART such as IVF and embryo transfer (ET)
      requires multiple follicular development to increase the number of female gametes, and the
      chances of a successful treatment outcome. Ovarian stimulation in IVF/ICSI currently includes
      suppression of endogenous luteinising hormone (LH) secretion by administration of a
      gonadotropin releasing hormone (GnRH) analogue, followed by stimulation of multiple
      follicular development by exogenous follicular stimulating hormone (FSH) administration. When
      adequate follicular development is achieved, a single dose of human chorionic gonadotropin
      (hCG) or LH is administered to mimic the endogenous LH surge and induce oocyte maturation.

      A total of 176 subjects who had previously undergone three or more IVF-treatment cycles that
      did not result in live birth will undergo a new series of IVF-treatment cycles using Gonal-f
      or Pergoveris or Gonal-f and Luveris. Subjects both < 35 years and ≥ 35 years will be
      included. Subgroup analysis will take into account the effect of age on the likelihood of
      success after repeated cycles of IVF. The investigators will systematically follow-up these
      subjects to observe their cumulative ongoing pregnancy rate.

      The study will consist of a screening period (≤-4months) during which the following trial
      assessments will be made: demographics, medical history, concomitant medications, clinical
      examination, vital signs, number of antral follicles and a subject diary will be handed out
      to the subjects. Between screening and the beginning of treatment, there will an optional
      telephone consultation during which any screening information or changes in concomitant
      medications will be updated. Down-regulation treatment will start within 3 months following
      the screening visit during the pre treatment period with GnRH daily agonist or antagonist
      commercially available in Norway, for pituitary gonadotrope cell desensitisation. FSH
      treatment will begin by administering either Gonal-f or Pergoveris or Gonal-f and Luveris
      after at least 2 weeks of GnRH agonist down-regulation. If a GnRH antagonist protocol is
      used, FSH injections will start on Day 2 of the menstrual cycle.

      Follicular development will be monitored according to the centre's standard practice by
      ultrasound and/or estradiol (E2) levels, until the protocol hCG requirement is met (i.e. at
      least 1 follicle ≥18 mm and 2 follicles ≥16 mm) at which time the subject will receive hCG
      (Day 0), according to the routine practice of the centre, in order to induce final oocyte
      maturation. Ovum Pick Up (Day 2), IVF, ET (Day 4-7) and luteal phase support will be
      performed as per the centre's standard practice. During the treatment period several
      assessments will be made and any adverse events (AEs) observed during the trial will be
      recorded. A urine pregnancy test will be performed 16 days post hCG administration. In case
      of negative urine pregnancy test, the subject will be assessed for the post-treatment safety
      follow-up and the cycle will be considered as 'completed'. The post-treatment safety
      follow-up can take place simultaneously with the next cycle's screenings visit. If subject
      drops out, the early termination visit will replace the post-treatment safety follow-up. If
      the urine pregnancy test is positive, clinical and later ongoing pregnancy will be
      subsequently confirmed by ultrasound scan according to the centre's routine practice. At this
      last visit, all subjects will be assessed for the post-treatment safety follow-up and will be
      considered 'completed'. Pregnancy outcome in pregnant subjects will be optionally followed up
      until delivery.

      Adverse events and serious adverse events (SAEs) will be assessed if spontaneously reported
      by the subjects at all study visits: during an optional telephone consultation between
      screening and the beginning of treatment, ultrasound scan (Day -7-0), OPU (Day 2), telephone
      consultation (Day 3), embryo transfer (Day 4-7), telephone consultation (Day 16), scan week
      12 (assessed 10 weeks after hCG administration), post-treatment safety follow-up, 1-Year
      follow-up, and at early termination (if applicable).
    

Observational model: Cohort
Time perspective: Prospective
Sampling method: Probability Sample
Study population: 
        A total of 176 subjects justifying IVF therapy at a single IVF centre in Norway will be
        recruited into this trial. Subjects must have been treated with three or more previous
        IVF-cycles without live birth.
      
Keywords: Infertility; Gonal-f; Pergoveris; Luveris