How to do a study? Prof. P. Devroey

Why to do a study? To know more To improve practice To improve the results To treat better To reduce the cost

It depends on what you are seeking for.. What kind of study should we perform? It depends on what you are seeking for..

Type of studies and level of evidence RCT Cohort studies Case series case reports LEVEL I evidence LEVEL II evidence LEVEL III evidence

THE STUDY PROTOCOL …..possibly the most important part of the trial

The proper study protocol for RCT Inclusion-exclusion criteria Appropriate statistical analysis Randomization procedure Clearly defined interventions One primary endpoint Data management

Ethical considerations Internal review board approval Ethics committee Local or national Informed consent Trial registration (number) i.e. http://clinicaltrials.gov

Institutional Review Board (IRB) approval All institutions should have an IRB to evaluate whether it is ethical to conduct the study Submit the protocol and wait for acceptance prior to conducting a trial Explain in detail the rationale, the population, the interventions and the goals of the study

Register your trial After approval of IRB and by the ethics committee register the trial (e.g. clinicaltrials.gov) Journals require trial registration prior to conduction of the study

The research question One question and one answer In accordance with the available evidence Why is such a study valuable? Can it change clinical practice?

The population to include.. Clearly defined Easy to recruit Easy to follow

Unclear population…not replicable results 47 randomized trials using 41 definitions for poor ovarian responders No more than 3 trials used the same definition Even trials from the same research group used different definition Who are the poor ovarian responders? Polyzos and Devroey. Fertil Steril 2011

Sample size calculation Power-sample calculation 80% power, level of significance 0.05 Estimate your sample based on previous evidence Do not make your sample size based on unrealistic assumptions During the protocol formulation describe the statistics you will use

The feasibility of conducting the study Resources available Available number of patients Easy to follow your patients

Select your people for conducting the trial Investigators Study nurse Co-ordinator Statistician Follow rigorously the ethical guidelines Do not attempt to publish at any cost! Define the mechanism of publishing: primary author and co-authors

OCP + GnRH antagonist ( n) (%) Oral contraceptive pills in GnRH antagonist protocol versus long protocol OCP + GnRH antagonist ( n) (%) Long Protocol (n) (%) Ongoing PR 55/115 (48) 61/113 (54) Multiples 15/55 (27) 18/61 (30) Implantation Rate 75/207 (36) 80/204 (39) Live birth rate 51/115 (44) 53/113 (47) Garcia-Velasquo FS 2011

Results after 1 embryo SET GnRH antagonist Standard FSH Low dose hCG Live birth rate Cycle (%) 10 / 35 (29) 13 / 35 (37) OPU (%) 10 / 32 (31) 13 / 29 (45) ET (%) 10 / 29 (35) 13 / 27 (48) Blockeel C et al HR 2009

GnRH agonist GnRH antagonist Standard Low dose P FSH (U) 2800 1900 < 0.001 1617 1273 0.001 Duration (d) 11.6 11.9 8.2 8.7 rFSH (U) 8.6 6.4 E2 (ng/ml) 2358 3235 < 0.05 2044 2200 NS Prog (ng/ml) 1.1 1.2 Filicori FS 2005 Blockeel HR 2009

Cost evaluation GnRH agonist long protocol n = 1000 cycles GnRH agonist long protocol GnRH antagonist + low dose hCG Cost (Euro) 1 073 000 487 000 Price difference (euro) SAVINGS 586 000 Personal communication

Randomization Patients received 10.000 IU of hCG as soon as ≥ 3 follicles of ≥ 17 mm were present in ultrasound early hCG group, 208 patients or 2 days later after this criterion was met late hCG group, 205 patients Kolibianakis Albano Camus Tournaye Van Steirteghem Devroey FS 2004

Prolongation of the follicular phase in IVF results in a lower probability of pregnancy Early-hCG group Late-hCG group P Ongoing pregnancy rate per OPU (n) 35.6% (69/194) 25% (49/196) 0.027 Ongoing pregnancy rate per ET (n) 39.2% (69/176) 27.7% (49/177) 0.024 Ongoing implantation rate (n) 22.6% (87/385) 15.1% (58/383) 0.009 Kolibianakis FS 2004

Elevated progesterone levels at initiation of stimulation are associated with a significantly lower chance of pregnancy Normal P group High P group P Difference (95% CI) Ongoing pregnancy rate Per started cycle % (n) 31.8 (124/390) 5.0 (1/20) 0.011 26.8 (7.7-33.1) Per oocyte retrieval % (n) 33.8 (124/367) 6.3 (1/16) 0.026 27.5 (5.0-34.7) Further research Initiation of antagonist on day 1? Kolibianakis HR 2004

Impact on cycle outcome Bosch et al HR 2010

Endometrial biopsy on the day of ovulation , natural cycle No secretory features

Endometrial biopsy on the day of oocyte retrieval , GnRH agonist and gonadotrophin stimulation cycle Clear secretory features

Is there any relation between endometrial advancement and ongoing pregnancy rates ? YES or NO Answer : Yes ≤ 3 days > 3 days P hMG / agonist 10 / 32 0 / 7 recFSH / antagonist 8 / 49 0 / 6 TOTAL 18 / 81 0 / 13 < 0.05 Endometrial advancement Kolibianakis FS 2002

Recombinant LH after antagonist initiation Pill pre-treatment/ 3 day interval, variable starting dose of rec FSH Single dose antagonist administration by a follicle of 14-16mm Cedrin-Durnerin HR 2004

Well-written papers are Read Remembered Cited 31 March 2011 Well-written papers are Read Remembered Cited Poorly written papers are not… Agonist triggering and freeze-all: How and when to freeze - D. Stoop

Which journal? Select the journal relevant to the work done 31 March 2011 Which journal? Select the journal relevant to the work done Read the ‘guidelines for authors’ on the website of the journal Depends on the ‘quality’ of the research performed Innovative Design of the study Size of the study Human or animal Effect on clinical practice Agonist triggering and freeze-all: How and when to freeze - D. Stoop

Hirsch factor Number of citations by other papers P. Devroey 12 04 2017 Citations: 48 011 h-index: 109

Conclusion The research needs to be innovative A randomized controlled trial is preferential Sample size and power calculation have to be respected Any prospective trial needs registration Only one primary endpoint A positive or a negative finding of the research question is of equal value Acknowledgements to Helena Deryckere