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OPTIMIST trial

Optimisation of cost effectiveness through individualised FSH Stimulation dosages for IVF treatment  /  the OPTIMIST trial

Go to the OPTIMIST website


Objective
The present study will assess the cost-effectiveness of routine use of ovarian reserve tests (ORTs) and subsequent use of individualised FSH dosages in predicted poor and hyper responders as compared to a policy without ORT using standard dosages of FSH.

The following questions will be answered:

  • What is the prevalence of abnormal ORTs in subfertile women who qualify for IVF?
  • Can cancellation of cycles be prevented by dose optimalisation in the first cycle? 
  • Is there additional benefit in terms of more pregnancies leading to live birth in women in whom the dose of gonadotrophins is increased after predicted poor response? 
  • Is there additional benefit in terms of more pregnancies leading to live birth in women in whom the dose of gonadotrophins is increased after predicted hyper response? 
  • Is there additional benefit in terms of prevented hyperresponse and OHSS in women in whom the dose of gonadotrophins is decreased after predicted hyper response? 
  • What are the additional costs and potential savings of a strategy of individualized dose adjustment for FSH as compared to a standard dosage?

Study design
The study will be designed as a large nationwide multicenter cohort study, with two RCTs embedded in this cohort. The cohort will consist of 1,500 women screened for ovarian capacity by an antral follicle count (AFC) prior to starting IVF treatment.

Study population
Patients will be recruited from the list of IVF/ICSI indicated couples in 15 hospitals with a special interest in infertility care.
Inclusion criteria:

  • Regular indication for IVF or ICSI
  • Female age < 44 years 
  • Regular cycle (average length 25-35 days) 
  • No major uterine or ovarian abnormalities detected by transvaginal sonography
  • No previous IVF cycles
  • Written informed consent

Exclusion criteria:

  • Oocyte donation
  • Medical contra indication for pregnancy or IVF treatment
  • Polycystic Ovary Syndrome (PCOS)
  • Endocrine or metabolic abnormalities (pituitary, adrenal, pancreas, liver or renal)


Intervention
Patients with predicted poor response (AFC below 10) will be randomly allocated to a treatment strategy based on an increased FSH dose versus standard FSH dose. If they are randomised to dose adjustment they will start with 450 IU of FSH/day if the AFC is below 8, and with 225 IU if the AFC is 8-10. Women in the control group will start with 150 IU/ day. All study and control participants will undergo a maximum of three cycles during a treatment period of maximally 18 months. 
Patients will also be subjected to the assigned dosage in the subsequent cycles. However, based on the response in preceding cycles, dose adjustments are allowed in a subsequent cycle, if the assigned dosage was the standard dosage (150 IU/day), as follows: if there has been a poor or hyper response (poor response defined as the retrieval of less than 5 oocytes or the cancellation of a stimulation cycle where less than two follicles sized more than 12 mm are observed at ultrasound; hyperresponse defined as the retrieval of more than 15 oocytes or the cancellation of a stimulation cycle where more than 20 follicles sized more than 12 mm are growing and estradiol levels exceed 11.700 pmol/L (= 3187,08 ng/L) or if more than 30 follicles over 12 mm are growing) a dose adjustment in the second or third cycle is allowed, but cannot exceed a step of 50 IU/day.
Dose adjustments in subsequent cycles in the experimental dose group are not allowed.

Patients with predicted hyper response (AFC more than 15) will be randomly allocated to a treatment strategy based on decreased FSH dose versus standard FSH dose. If they are randomised to dose adjustment they will start with 100 IU of FSH/day. Women in the control group will start with 150 IU/day. All study and control participants will undergo a maximum of three cycles during a treatment period of maximally 18 months.
Patients will also be subjected to the assigned dosage in subsequent cycles.
However, based on the response in preceding cycles dose adjustments are permitted in a subsequent cycle, if the assigned dosage was the standard dosage (150 IU/day), as follows:
if there is a poor or hyper response (poor response defined as the retrieval of less than 5 oocytes or the cancellation of a stimulation cycle where less than two follicles over 12 mm in diameter are observed on ultrasound; hyper response defined as the retrieval of more than 15 oocytes or the cancellation of a stimulation cycle where more than 20 follicles over 12 mm in diameter are growing and estradiol levels exceed 11.700 pmol/L (= 3187,08 ng/L) or if more than 30 follicles over 12 mm are growing) a dose adjustment in the second or third cycle is allowed, but cannot exceed a step of 50 IU/day.
Dose adjustments in subsequent cycles in the experimental dose group are not allowed. The reason for this is the fact that a scientific rationale for dose adjustments, as they are applied in the daily routine of IVF practice, is completely absent. The ovarian response is largely determined by the number of available follicles that can grow in response to FSH administration and for a small part by the dosing level of the administered FSH. The number of follicles varies between patients, cycles and with age. A standardised effect of dose adjustment can therefore not be expected. By choosing for a rationalised dosage level determined by the AFC, we will be able to demonstrate whether the use of unaltered dose levels, as in the experimental study arms, will allow for an improved cost-efficiency with the basic assumption that efficacy will not be reduced.

Outcome measures
Main study outcomes:

  • Ongoing pregnancy resulting in live birth within 18 months after randomisation. These pregnancies can be obtained in treatment cycles with fresh embryos, as well as in subsequent cryo/thaw cycles after completion of any fresh stimulation cycle. Spontaneous pregnancies between treatment cycles will also be taken into account.
  • Costs of treatment: direct medical costs, direct non-medical costs and indirect costs

Secondary study outcomes:

  • Number of oocytes
  • Poor response (less than 4 oocytes at retrieval or cancellation due to
    insufficient follicle growth, i.e. 2 or less dominant follicles sized more than 12 mm growing)
  • Hyper response (more than 16 oocytes at retrieval or cancellation due to excessive response as defined above)
  • OHSS grade 2 and 3
  • Cycle cancellation for hyper and poor response, multiple pregnancy, total IU of FSH applied per stimulation cycle

Power/data analysis
Based on the expected gain in pregnancy rate resulting in live birth reported in the study from Popovic-Todorovic7, we will expect an increase in pregnancy rate over 3 cycles with 15% from 25% to 40%. To demonstrate that such a difference will occur, we need to include 300 couples in the poor response RCT (alpha-error of 0.05 and a power of 80%, two-sided test).
In our Individual Patient Data meta-analysis on 2,300 patients in 13 studies, we found that 25% had and AFC below 6, 18% had an AFC between 6 and 9, 33% had an AFC between 10 and 15 and 24% had an AFC above 15. If we assume conservatively that 20% of the couples will be eligible for the poor response trial, we need to include a cohort of 1,500 women for ovarian reserve screening using the AFC, in order to achieve the numbers of cases needed for the two trials. This will then allow a sample size of just over 300 women for the poor response trial (RCT1).
Alternatively, if we expect a positive effect of dose adjustment in both the poor response and the hyper response group, the total sample size of 600 women in the two RCTs allows the detection of an increase of pregnancy rates from 30% after conventional treatment to 41% in the dose adjustment group (alpha-error of 0.05 and a power of 80%, two-sided test). If the net effect of dose adjustment on pregnancy rate is less than 11%, it is unlikely that ORT and dose adjustment is cost-effective. (NB The assumed 30% success rate in the conventional group in the latter calculation (RCT1+RCT2) is higher than the assumed 25% success rate in the conventional group in RCT1, as RCT 1 only contains women with expected poor response, whereas RCT2 adds women with predicted hyperresponse).
For RCT2 an increase in pregnancy rate from 35% to 42% over three cycles can be expected. With 300 participants the power to detect this difference is 24%.
A sample size calculation for the cost economy analysis is not provided. It is generally accepted that this type of sample size is not provided because the insecurity of the cost economy ratio is largely determined by the variation in the efficacy (the denominator of the ratio) and can therefore not be performed at a realistic level.

Subsidy
ZonMW

Contact
Drs. C. van Tilborg / Prof. dr. F.J.M. Broekmans / dr. H.L. Torrance
UMC Utrecht,
Divisie Vrouw en Baby
Afdeling Voortplanting
Huispostnummer F05.126
Postbus 85500
3508 GA Utrecht
Tel. 088 -7551443
ctilborg@umcutrecht.nl / f.broekmans@umcutrecht.nl / H.Torrance@umcutrecht.nl