The OPTIMIST study: optimisation of cost effectiveness through individualised FSH stimulation dosages for IVF treatment. A randomised controlled trial

Contains fulltext : 109739.pdf (publisher's version ) (Open Access)ABSTRACT: BACKGROUND: Costs of in vitro fertilisation (IVF) are high, which is partly due to the use of follicle stimulating hormone (FSH). FSH is usually administered in a standard dose. However, due to differences in ovarian reserve between women, ovarian response also differs with potential negative consequences on pregnancy rates. A Markov decision-analytic model showed that FSH dose individualisation according to ovarian reserve is likely to be cost-effective in women who are eligible for IVF. However, this has never been confirmed in a large randomised controlled trial (RCT). The aim of the present study is to assess whether an individualised FSH dose regime based on an ovarian reserve test (ORT) is more cost-effective than a standard dose regime. METHODS/DESIGN: Multicentre RCT in subfertile women indicated for a first IVF or intracytoplasmic sperm injection cycle, who are aged < 44 years, have a regular menstrual cycle and no major abnormalities at transvaginal sonography. Women with polycystic ovary syndrome, endocrine or metabolic abnormalities and women undergoing IVF with oocyte donation, will not be included. Ovarian reserve will be assessed by measuring the antral follicle count. Women with a predicted poor response or hyperresponse will be randomised for a standard versus an individualised FSH regime (150 IU/day, 225-450 IU/day and 100 IU/day, respectively). Participants will undergo a maximum of three stimulation cycles during maximally 18 months. The primary study outcome is the cumulative ongoing pregnancy rate resulting in live birth achieved within 18 months after randomisation. Secondary outcomes are parameters for ovarian response, multiple pregnancies, number of cycles needed per live birth, total IU of FSH per stimulation cycle, and costs. All data will be analysed according to the intention-to-treat principle. Cost-effectiveness analysis will be performed to assess whether the health and associated economic benefits of individualised treatment of subfertile women outweigh the additional costs of an ORT. DISCUSSION: The results of this study will be integrated into a decision model that compares cost-effectiveness of the three dose-adjustment strategies to a standard dose strategy. The study outcomes will provide scientific foundation for national and international guidelines. TRIAL REGISTRATION: NTR2657

Gonadotrophins versus clomifene citrate with or without intrauterine insemination in women with normogonadotropic anovulation and clomifene failure (M-OVIN): a randomised, two-by-two factorial trial

In many countries, clomifene citrate is the treatment of first choice in women with normogonadotropic anovulation (ie, absent or irregular ovulation). If these women ovulate but do not conceive after several cycles with clomifene citrate, medication is usually switched to gonadotrophins, with or without intrauterine insemination. We aimed to assess whether switching to gonadotrophins is more effective than continuing clomifene citrate, and whether intrauterine insemination is more effective than intercourse. In this two-by-two factorial multicentre randomised clinical trial, we recruited women aged 18 years and older with normogonadotropic anovulation not pregnant after six ovulatory cycles of clomifene citrate (maximum of 150 mg daily for 5 days) from 48 Dutch hospitals. Women were randomly assigned using a central password-protected internet-based randomisation programme to receive six cycles with gonadotrophins plus intrauterine insemination, six cycles with gonadotrophins plus intercourse, six cycles with clomifene citrate plus intrauterine insemination, or six cycles with clomifene citrate plus intercourse. Clomifene citrate dosages varied from 50 to 150 mg daily orally and gonadotrophin starting dose was 50 or 75 IU daily subcutaneously. The primary outcome was conception leading to livebirth within 8 months after randomisation defined as any baby born alive after a gestational age beyond 24 weeks. Primary analysis was by intention to treat. We made two comparisons, one in which gonadotrophins were compared with clomifene citrate and one in which intrauterine insemination was compared with intercourse. This completed study is registered with the Netherlands Trial Register, number NTR1449. Between Dec 8, 2008, and Dec 16, 2015, we randomly assigned 666 women to gonadotrophins and intrauterine insemination (n=166), gonadotrophins and intercourse (n=165), clomifene citrate and intrauterine insemination (n=163), or clomifene citrate and intercourse (n=172). Women allocated to gonadotrophins had more livebirths than those allocated to clomifene citrate (167 [52%] of 327 women vs 138 [41%] of 334 women, relative risk [RR] 1·24 [95% CI 1·05-1·46]; p=0·0124). Addition of intrauterine insemination did not increase livebirths compared with intercourse (161 [49%] vs 144 [43%], RR 1·14 [95% CI 0·97-1·35]; p=0·1152). Multiple pregnancy rates for the two comparisons were low and not different. There were three adverse events: one child with congenital abnormalities and one stillbirth in two women treated with clomifene citrate, and one immature delivery due to cervical insufficiency in a woman treated with gonadotrophins. In women with normogonadotropic anovulation and clomifene citrate failure, a switch of treatment to gonadotrophins increased the chance of livebirth over treatment with clomifene citrate; there was no evidence that addition of intrauterine insemination does so. The Netherlands Organization for Health Research and Developmen

Individualized versus standard FSH dosing in women starting IVF/ICSI:an RCT, Part 1: The predicted poor responder

\u3cp\u3eSTUDY QUESTION: Does an increased FSH dose result in higher cumulative live birth rates in women with a predicted poor ovarian response, apparent from a low antral follicle count (AFC), scheduled for IVF or ICSI? SUMMARY ANSWER: In women with a predicted poor ovarian response (AFC &lt; 11) undergoing IVF/ICSI, an increased FSH dose (225/ 450 IU/day) does not improve cumulative live birth rates as compared to a standard dose (150 IU/day). WHAT IS KNOWN ALREADY: In women scheduled for IVF/ICSI, an ovarian reserve test (ORT) can predict ovarian response to stimulation. The FSH starting dose is often adjusted based on the ORT from the belief that it will improve live birth rates. However, the existing RCTs on this topic, most of which show no benefit, are underpowered. STUDY DESIGN, SIZE, DURATION: Between May 2011 and May 2014, we performed an open-label multicentre RCT in women with an AFC &lt; 11 (Dutch Trial Register NTR2657). The primary outcome was ongoing pregnancy achieved within 18 months after randomization and resulting in a live birth. We needed 300 women to assess whether an increased dose strategy would increase the cumulative live birth rate from 25 to 40% (two-sided alpha-error 0.05, power 80%). PARTICIPANTS/MATERIALS, SETTING, METHODS: Women with an AFC ≤ 7 were randomized to an FSH dose of 450 IU/day or 150 IU/day, and women with an AFC 8–10 were randomized to 225 IU or 150 IU/day. In the standard group, dose adjustment was allowed in subsequent cycles based on pre-specified criteria. Both effectiveness and cost-effectiveness of the strategies were evaluated from an intention-to-treat perspective. MAIN RESULTS AND THE ROLE OF CHANCE: In total, 511 women were randomized, 234 with an AFC ≤ 7 and 277 with an AFC 8–10. The cumulative live birth rate for increased versus standard dosing was 42.4% (106/250) versus 44.8% (117/261), respectively [relative risk (RR): 0.95 (95%CI, 0.78–1.15), P = 0.58]. As an increased dose strategy was more expensive [delta costs/woman: €1099 (95%CI, 562–1591)], standard FSH dosing was the dominant strategy in our economic analysis. LIMITATIONS, REASONS FOR CAUTION: Despite our training programme, the AFC might have suffered from inter-observer variation. As this open study permitted small dose adjustments between cycles, potential selective cancelling of cycles in women treated with 150 IU could have influenced the cumulative results. However, since first cycle live birth rates point in the same direction we consider it unlikely that the open design masked a potential benefit for the individualized strategy. WIDER IMPLICATIONS OF THE FINDINGS: Since an increased dose in women scheduled for IVF/ICSI with a predicted poor response (AFC &lt; 11) does not improve live birth rates and is more expensive, we recommend using a standard dose of 150 IU/day in these women. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by The Netherlands Organisation for Health Research and Development (ZonMW number 171102020). T.C.T., H.L.T. and S.C.O. received an unrestricted personal grant from Merck BV. H.R.V. receives monetary compensation as a member on an external advisory board for Ferring pharmaceutical BV. B.W.J.M. is supported by a NHMRC Practitioner Fellowship (GNT1082548) and reports consultancy for OvsEva, Merck and Guerbet. F.J.M.B. receives monetary compensation as a member of the external advisory board for Ferring pharmaceutics BV (the Netherlands) and Merck Serono (the Netherlands) for consultancy work for Gedeon Richter (Belgium) and Roche Diagnostics on automated AMH assay development (Switzerland) and for a research cooperation with Ansh Labs (USA). All other authors have nothing to declare.\u3c/p\u3