Reducing the Treatment Burden of IVF
Reducing the Treatment Burden of IVF
Devroey P, Boostanfar R, Koper NP, Mannaerts BM, Ijzerman-Boon PC, Fauser BC; ENGAGE Investigators
Hum Reprod. 2009;24:3063-3072
Infertility is a stressful "test" for couples. It is often difficult to accept that a basic function like reproduction is not working. Tests may be needed to assess this very intimate process, and frequently, invasive interventions are required to improve the chances for reproduction. Patients who eventually require in vitro fertilization (IVF) must first come to terms with the fact of infertility, and then must accept daily injections, retrieval under sedation, and laboratory manipulation of gametes. The worst period for most patients is the waiting after embryo transfer, and the need to emotionally prepare for a new trial in case of failure. Therefore, any improvement in this process should increase patient compliance and the likelihood that they will not give up but will return for a new treatment if needed.
Corifollitropin alfa is a hybrid molecule that is made up of recombinant follicle-stimulating hormone (rFSH) and the carboxy terminal of the human chorionic gonadotropin (hCG) molecule. Owing to a 2.5-fold increase in half-life, a single dose of corifollitropin alfa is effective for 7 days and can reduce both the number of injections and the number of clinic visits that must be made during monitoring. This double-blind, double-dummy, randomized controlled trial evaluated the efficacy and safety of corifollitropin alfa compared with daily administered rFSH.
Women between the ages of 18-36, with regular menstrual cycles and body mass index between 18-32 kg/m, were recruited. Treatment was started on day 2 or 3 of the cycle. One treatment group began with a single dose of 150-µg corifollitropin alfa, followed by daily placebo injections. The other group received a placebo injection on day 1 and daily fixed-dose injections of 200 IU rFSH. The dose of rFSH could have been reduced from day 6 of stimulation onward but on day 6 and 7 of stimulation this only led to a true reduction of rFSH in the daily rFSH group. A gonadotropin-releasing hormone antagonist to prevent premature luteinizing hormone surges was started on day 5 of stimulation.
A minimum sample size of 1380 participants was needed for this noninferiority study; 1506 women were randomly assigned. Baseline characteristics were comparable in the 2 groups. No difference in the primary outcome measure was observed: Ongoing pregnancy rates per started cycles were 38.9% for the corifollitropin alfa group and 38.1% for the rFSH group. The duration of stimulation was similar. The number of follicles > 11 mm on the day of hCG administration and the mean number of oocytes were higher in the corifollitropin alfa group (13.7 vs 12.5). In the corifollitropin alfa group, the dose (placebo) was more often reduced on day 6 or 7 of stimulation (11.3% vs 8.4%). The proportion of patients who developed ovarian hyperstimulation syndrome was similar in the 2 groups. Fertilization rates and embryo quality parameters did not differ. As mentioned, clinical and ongoing pregnancy rates were comparable. Slightly more multiple embryos occurred in the corifollitropin alfa group (28.2% vs 23.1%).
IVF has undergone significant changes during the past few decades. The technology has changed (eg, IVF became an outpatient procedure, transvaginal retrieval replaced laparoscopy), laboratory procedures have improved, and medications have undergone significant changes. Instead of urinary gonadotropins, most stimulation protocols now include recombinant preparations. The long protocol necessitating month-long daily injections is now increasingly replaced by the antagonist protocol that requires only about 10 days of injections. All these improvements have made IVF easier, safer, and more effective . An important aim of these changes is to reduce the stress that accompanies infertility treatment.
The development of the long-acting FSH preparation is just another step in this direction by further reducing the required number of injections and perhaps even the number of office visits. Before these preparations could become routine, we had to establish their efficacy and safety, which was done in this large randomized study. In the study sample, the long-acting FSH was just as effective as the daily administered rFSH. Slightly more follicles were recruited, and slightly more oocytes were collected. In addition, a dose reduction was needed more often after 5 days of treatment in this group. The effect of corifollitropin alfa lasts for 7 days; as a result one cannot actually lower the dose after the first 5 days when the initial evaluation is traditionally conducted, which theoretically increases the risk for hyperstimulation and hyperresponse. To avoid this, patients who use the preparation must be carefully screened for ovarian hyperstimulation syndrome (OHSS) with irregular cycles, high baseline luteinizing hormone, polycystic ovaries, high antral follicle count, or previous OHSS, as they will not be good candidates. Poor responders should probably also not use corifollitropin alfa because they may need dose adjustments during the first 7 days.
Still, plenty of patients could benefit from the long-acting FSH. Its effect as part of other stimulation protocols will have to be evaluated. The best management when an antagonist is used (eg, flexible or fixed regimen) also remains to be determined. Because of its design, this study was unable to assess the effect of what is presumably the most important benefit of the drug -- fewer injections. Future studies should also assess patient satisfaction and cost effectiveness. Based on current information it appears that this new preparation could make IVF stimulation more patient-friendly without compromising treatment outcomes in a select group of patients.
Abstract
A Double-Blind, Non-Inferiority RCT Comparing Corifollitropin Alfa and Recombinant FSH During the First Seven Days of Ovarian Stimulation Using a GnRH Antagonist Protocol
Devroey P, Boostanfar R, Koper NP, Mannaerts BM, Ijzerman-Boon PC, Fauser BC; ENGAGE Investigators
Hum Reprod. 2009;24:3063-3072
Background
Infertility is a stressful "test" for couples. It is often difficult to accept that a basic function like reproduction is not working. Tests may be needed to assess this very intimate process, and frequently, invasive interventions are required to improve the chances for reproduction. Patients who eventually require in vitro fertilization (IVF) must first come to terms with the fact of infertility, and then must accept daily injections, retrieval under sedation, and laboratory manipulation of gametes. The worst period for most patients is the waiting after embryo transfer, and the need to emotionally prepare for a new trial in case of failure. Therefore, any improvement in this process should increase patient compliance and the likelihood that they will not give up but will return for a new treatment if needed.
Corifollitropin alfa is a hybrid molecule that is made up of recombinant follicle-stimulating hormone (rFSH) and the carboxy terminal of the human chorionic gonadotropin (hCG) molecule. Owing to a 2.5-fold increase in half-life, a single dose of corifollitropin alfa is effective for 7 days and can reduce both the number of injections and the number of clinic visits that must be made during monitoring. This double-blind, double-dummy, randomized controlled trial evaluated the efficacy and safety of corifollitropin alfa compared with daily administered rFSH.
Study Summary
Women between the ages of 18-36, with regular menstrual cycles and body mass index between 18-32 kg/m, were recruited. Treatment was started on day 2 or 3 of the cycle. One treatment group began with a single dose of 150-µg corifollitropin alfa, followed by daily placebo injections. The other group received a placebo injection on day 1 and daily fixed-dose injections of 200 IU rFSH. The dose of rFSH could have been reduced from day 6 of stimulation onward but on day 6 and 7 of stimulation this only led to a true reduction of rFSH in the daily rFSH group. A gonadotropin-releasing hormone antagonist to prevent premature luteinizing hormone surges was started on day 5 of stimulation.
A minimum sample size of 1380 participants was needed for this noninferiority study; 1506 women were randomly assigned. Baseline characteristics were comparable in the 2 groups. No difference in the primary outcome measure was observed: Ongoing pregnancy rates per started cycles were 38.9% for the corifollitropin alfa group and 38.1% for the rFSH group. The duration of stimulation was similar. The number of follicles > 11 mm on the day of hCG administration and the mean number of oocytes were higher in the corifollitropin alfa group (13.7 vs 12.5). In the corifollitropin alfa group, the dose (placebo) was more often reduced on day 6 or 7 of stimulation (11.3% vs 8.4%). The proportion of patients who developed ovarian hyperstimulation syndrome was similar in the 2 groups. Fertilization rates and embryo quality parameters did not differ. As mentioned, clinical and ongoing pregnancy rates were comparable. Slightly more multiple embryos occurred in the corifollitropin alfa group (28.2% vs 23.1%).
Viewpoint
IVF has undergone significant changes during the past few decades. The technology has changed (eg, IVF became an outpatient procedure, transvaginal retrieval replaced laparoscopy), laboratory procedures have improved, and medications have undergone significant changes. Instead of urinary gonadotropins, most stimulation protocols now include recombinant preparations. The long protocol necessitating month-long daily injections is now increasingly replaced by the antagonist protocol that requires only about 10 days of injections. All these improvements have made IVF easier, safer, and more effective . An important aim of these changes is to reduce the stress that accompanies infertility treatment.
The development of the long-acting FSH preparation is just another step in this direction by further reducing the required number of injections and perhaps even the number of office visits. Before these preparations could become routine, we had to establish their efficacy and safety, which was done in this large randomized study. In the study sample, the long-acting FSH was just as effective as the daily administered rFSH. Slightly more follicles were recruited, and slightly more oocytes were collected. In addition, a dose reduction was needed more often after 5 days of treatment in this group. The effect of corifollitropin alfa lasts for 7 days; as a result one cannot actually lower the dose after the first 5 days when the initial evaluation is traditionally conducted, which theoretically increases the risk for hyperstimulation and hyperresponse. To avoid this, patients who use the preparation must be carefully screened for ovarian hyperstimulation syndrome (OHSS) with irregular cycles, high baseline luteinizing hormone, polycystic ovaries, high antral follicle count, or previous OHSS, as they will not be good candidates. Poor responders should probably also not use corifollitropin alfa because they may need dose adjustments during the first 7 days.
Still, plenty of patients could benefit from the long-acting FSH. Its effect as part of other stimulation protocols will have to be evaluated. The best management when an antagonist is used (eg, flexible or fixed regimen) also remains to be determined. Because of its design, this study was unable to assess the effect of what is presumably the most important benefit of the drug -- fewer injections. Future studies should also assess patient satisfaction and cost effectiveness. Based on current information it appears that this new preparation could make IVF stimulation more patient-friendly without compromising treatment outcomes in a select group of patients.
Abstract
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