Abstract：
OBJECTIVE: How does a gonadotrophin-releasing hormone (GnRH) agonist versus a GnRH antagonist protocol affect ovarian response when using an individualized fixed daily dose of follitropin delta for ovarian stimulation?
CONCLUSIONS: The BEYOND trial data demonstrate thatindividualized fixed-dose follitropin delta is effective when used in a GnRH agonist protocol, compared with a GnRH antagonist protocol, in women with anti-Müllerian hormone (AMH) ≤35 pmol/l and no increased risk of ovarian hyperstimulation syndrome (OHSS).
BACKGROUND: The efficacy and safety of an individualized fixed daily dose of follitropin delta (based on body weight and AMH) have been established in randomized controlled trials (RCTs) using a GnRH antagonist protocol. Preliminary study data indicate that individualized follitropin delta is also efficacious in a GnRH agonist protocol (RAINBOW trial, NCT03564509). There are no prospective comparative data using individualized follitropin delta for ovarian stimulation in a GnRH agonist versus a GnRH antagonist protocol.
METHODS: This is the first randomized, controlled, open-label, multi-centre trial exploring efficacy and safety of individualized follitropin delta dosing in a GnRH agonist versus a GnRH antagonist protocol in participants undergoing their first ovarian stimulation cycle for IVF/ICSI. A total of 437 participants were randomized centrally and stratified by centre and age. The primary endpoint was the number of oocytes retrieved. Secondary endpoints included ongoing pregnancy rates, adverse drug reactions (including OHSS), live births, and neonatal outcomes.
METHODS: Participants (18-40 years; AMH ≤35 pmol/l) were enrolled at specialist reproductive health clinics in Austria, Denmark, Israel, Italy, the Netherlands, Norway, and Switzerland. The mean number of oocytes retrieved was compared between the GnRH agonist and antagonist protocols using a negative binomial regression model with age and AMH at screening as factors. Analyses were based on all randomized subjects, using a multiple imputation method for randomized subjects withdrawing before the start of stimulation.
RESULTS: Of the 437 randomized subjects, 221 were randomized to the GnRH agonist, and 216 were randomized to the GnRH antagonist protocol. The participants had a mean age of 32.3 ± 4.3 years and a mean serum AMH of 16.6 ± 7.8 pmol/l. A total of 202 and 204 participants started ovarian stimulation with follitropin delta in the GnRH agonist and antagonist groups, respectively. The mean number of oocytes retrieved was statistically significantly higher in the agonist group (11.1 ± 5.9) versus the antagonist group (9.6 ± 5.5), with an estimated mean difference of 1.31 oocytes (95% CI: 0.22; 2.40, P = 0.0185). The difference in number of oocytes retrieved was influenced by the patients\' age and ovarian reserve, with a greater difference observed in patients aged <35 years and in patients with high ovarian reserve (AMH >15 pmol/l). Both the GnRH agonist and antagonist groups had a similar proportion of cycle cancellations (2.0% [4/202] versus 3.4% [7/204]) and fresh blastocyst transfer cancellations (13.4% [27/202] versus 14.7% [30/204]). The estimated ongoing pregnancy rate per started cycle was numerically higher in the GnRH agonist group (36.9% versus 29.1%; difference: 7.74% [95% CI: -1.49; 16.97, P = 0.1002]). The most commonly reported adverse events (≥1% in either group; headache, OHSS, nausea, pelvic pain, or discomfort and abdominal pain) were similar in both groups. The incidence of early moderate/severe OHSS was low (1.5% for the agonist group versus 2.5% for antagonist groups). Estimated live birth rates per started cycle were 35.8% and 28.7% in the GnRH agonist and antagonist groups, respectively (treatment difference 7.15%; 95% CI: -2.02; 16.31; P = 0.1265). The two treatment groups were comparable with respect to neonatal health data for singletons and twins and for incidence of congenital malformations (2.7% and 3.3% for the GnRH agonist versus antagonist groups, respectively).
CONCLUSIONS: All participants had AMH ≤35 pmol/l and were ≤40 years old. Clinicians should remain cautious when using a GnRH agonist protocol in patients with AMH >35 pmol/l (i.e. those with an increased OHSS risk). The incidence of OHSS in the GnRH antagonist group may have been lower if a GnRH agonist trigger had been allowed. Outcomes of transfers with cryopreserved blastocysts were not followed up, therefore the cumulative live birth rates and neonatal outcomes after cryotransfer are unknown.
CONCLUSIONS: In women with AMH ≤35 pmol/l, an individualized fixed daily dose of follitropin delta resulted in a significantly higher number of oocytes retrieved when used in a GnRH agonist protocol compared with a GnRH antagonist protocol, with no additional safety signals observed and no additional risk of OHSS. Live birth rates following ovarian stimulation with individualized follitropin delta were not statistically different between the GnRH protocols; however, the trial was not powered to assess this endpoint. There were no safety concerns with respect to neonatal health after ovarian stimulation with follitropin delta in either protocol.
BACKGROUND: The trial was funded by Ferring Pharmaceuticals. EE, EP, and MS have no competing interests. AP has received research support from Ferring, and Gedeon Richter, and honoraria or consultation fees from Preglem, Novo Nordisk, Ferring, Gedeon Richter, Cryos, Merck A/S. BC has received consulting fees from Ferring and Merck, and his department received fees from Ferring to cover the costs of patient enrolment. MBS has received support to attend meetings and/or travel from Ferring, and was a board member for FertiPROTEKT e.V. until 2023. JS has received honoraria or consultation fees from Ferring and Merck, and support for attending meetings and/or travel from Ferring, Merck, and GoodLife. TS has received support/travel expenses from Ferring for attending a congress meeting, and participated in an advisory board for Merck. YS has received grants/research support from Ferring and support to attend a professional society congress meeting from Merck. RL and PP are employees of Ferring Pharmaceuticals. PP is a BOD member of PharmaBiome and owns stocks of Takeda Pharmaceuticals.
BACKGROUND: ClinicalTrials.gov identifier NCT03809429; EudraCT Number 2017-002783-40.
UNASSIGNED: 7 April 2019.
UNASSIGNED: 2 May 2019.
CONCLUSIONS: The BEYOND trial data demonstrate thatindividualized fixed-dose follitropin delta is effective when used in a GnRH agonist protocol, compared with a GnRH antagonist protocol, in women with anti-Müllerian hormone (AMH) ≤35 pmol/l and no increased risk of ovarian hyperstimulation syndrome (OHSS).
BACKGROUND: The efficacy and safety of an individualized fixed daily dose of follitropin delta (based on body weight and AMH) have been established in randomized controlled trials (RCTs) using a GnRH antagonist protocol. Preliminary study data indicate that individualized follitropin delta is also efficacious in a GnRH agonist protocol (RAINBOW trial, NCT03564509). There are no prospective comparative data using individualized follitropin delta for ovarian stimulation in a GnRH agonist versus a GnRH antagonist protocol.
METHODS: This is the first randomized, controlled, open-label, multi-centre trial exploring efficacy and safety of individualized follitropin delta dosing in a GnRH agonist versus a GnRH antagonist protocol in participants undergoing their first ovarian stimulation cycle for IVF/ICSI. A total of 437 participants were randomized centrally and stratified by centre and age. The primary endpoint was the number of oocytes retrieved. Secondary endpoints included ongoing pregnancy rates, adverse drug reactions (including OHSS), live births, and neonatal outcomes.
METHODS: Participants (18-40 years; AMH ≤35 pmol/l) were enrolled at specialist reproductive health clinics in Austria, Denmark, Israel, Italy, the Netherlands, Norway, and Switzerland. The mean number of oocytes retrieved was compared between the GnRH agonist and antagonist protocols using a negative binomial regression model with age and AMH at screening as factors. Analyses were based on all randomized subjects, using a multiple imputation method for randomized subjects withdrawing before the start of stimulation.
RESULTS: Of the 437 randomized subjects, 221 were randomized to the GnRH agonist, and 216 were randomized to the GnRH antagonist protocol. The participants had a mean age of 32.3 ± 4.3 years and a mean serum AMH of 16.6 ± 7.8 pmol/l. A total of 202 and 204 participants started ovarian stimulation with follitropin delta in the GnRH agonist and antagonist groups, respectively. The mean number of oocytes retrieved was statistically significantly higher in the agonist group (11.1 ± 5.9) versus the antagonist group (9.6 ± 5.5), with an estimated mean difference of 1.31 oocytes (95% CI: 0.22; 2.40, P = 0.0185). The difference in number of oocytes retrieved was influenced by the patients\' age and ovarian reserve, with a greater difference observed in patients aged <35 years and in patients with high ovarian reserve (AMH >15 pmol/l). Both the GnRH agonist and antagonist groups had a similar proportion of cycle cancellations (2.0% [4/202] versus 3.4% [7/204]) and fresh blastocyst transfer cancellations (13.4% [27/202] versus 14.7% [30/204]). The estimated ongoing pregnancy rate per started cycle was numerically higher in the GnRH agonist group (36.9% versus 29.1%; difference: 7.74% [95% CI: -1.49; 16.97, P = 0.1002]). The most commonly reported adverse events (≥1% in either group; headache, OHSS, nausea, pelvic pain, or discomfort and abdominal pain) were similar in both groups. The incidence of early moderate/severe OHSS was low (1.5% for the agonist group versus 2.5% for antagonist groups). Estimated live birth rates per started cycle were 35.8% and 28.7% in the GnRH agonist and antagonist groups, respectively (treatment difference 7.15%; 95% CI: -2.02; 16.31; P = 0.1265). The two treatment groups were comparable with respect to neonatal health data for singletons and twins and for incidence of congenital malformations (2.7% and 3.3% for the GnRH agonist versus antagonist groups, respectively).
CONCLUSIONS: All participants had AMH ≤35 pmol/l and were ≤40 years old. Clinicians should remain cautious when using a GnRH agonist protocol in patients with AMH >35 pmol/l (i.e. those with an increased OHSS risk). The incidence of OHSS in the GnRH antagonist group may have been lower if a GnRH agonist trigger had been allowed. Outcomes of transfers with cryopreserved blastocysts were not followed up, therefore the cumulative live birth rates and neonatal outcomes after cryotransfer are unknown.
CONCLUSIONS: In women with AMH ≤35 pmol/l, an individualized fixed daily dose of follitropin delta resulted in a significantly higher number of oocytes retrieved when used in a GnRH agonist protocol compared with a GnRH antagonist protocol, with no additional safety signals observed and no additional risk of OHSS. Live birth rates following ovarian stimulation with individualized follitropin delta were not statistically different between the GnRH protocols; however, the trial was not powered to assess this endpoint. There were no safety concerns with respect to neonatal health after ovarian stimulation with follitropin delta in either protocol.
BACKGROUND: The trial was funded by Ferring Pharmaceuticals. EE, EP, and MS have no competing interests. AP has received research support from Ferring, and Gedeon Richter, and honoraria or consultation fees from Preglem, Novo Nordisk, Ferring, Gedeon Richter, Cryos, Merck A/S. BC has received consulting fees from Ferring and Merck, and his department received fees from Ferring to cover the costs of patient enrolment. MBS has received support to attend meetings and/or travel from Ferring, and was a board member for FertiPROTEKT e.V. until 2023. JS has received honoraria or consultation fees from Ferring and Merck, and support for attending meetings and/or travel from Ferring, Merck, and GoodLife. TS has received support/travel expenses from Ferring for attending a congress meeting, and participated in an advisory board for Merck. YS has received grants/research support from Ferring and support to attend a professional society congress meeting from Merck. RL and PP are employees of Ferring Pharmaceuticals. PP is a BOD member of PharmaBiome and owns stocks of Takeda Pharmaceuticals.
BACKGROUND: ClinicalTrials.gov identifier NCT03809429; EudraCT Number 2017-002783-40.
UNASSIGNED: 7 April 2019.
UNASSIGNED: 2 May 2019.
摘要：
目的：促性腺激素释放激素（GnRH）激动剂与GnRH拮抗剂方案在使用个体化固定日剂量的叶酸δ刺激卵巢时，如何影响卵巢反应？
结论：BEYOND试验数据表明，在GnRH方案中使用个体化固定剂量的叶酸δ激动剂是有效的，与GnRH拮抗剂方案相比，在抗苗勒管激素（AMH）≤35pmol/l且卵巢过度刺激综合征（OHSS）风险未增加的女性中。
背景：在使用GnRH拮抗剂方案的随机对照试验（RCTs）中已经确定了个体化固定日剂量的follitropindelta（基于体重和AMH）的有效性和安全性。初步研究数据表明，在GnRH激动剂方案中，个体化follitropindelta也是有效的（RAINBOW试验，NCT03564509)。在GnRH激动剂与GnRH拮抗剂方案中，没有使用个体化促卵泡素δ进行卵巢刺激的前瞻性比较数据。
方法：这是第一个随机分组，控制,开放标签，多中心试验探索在接受IVF/ICSI的第一个卵巢刺激周期的参与者中,GnRH激动剂与GnRH拮抗剂方案中个体化follitropindelta给药的有效性和安全性.共有437名参与者被集中随机分配，并按中心和年龄分层。主要终点是检索到的卵母细胞数。次要终点包括持续怀孕率，药物不良反应（包括OHSS），活产,和新生儿结局。
方法：参与者（18-40岁；AMH≤35pmol/l）在奥地利的专业生殖健康诊所注册，丹麦,以色列,意大利,荷兰,挪威,和瑞士。使用阴性二项回归模型，以筛选时的年龄和AMH为因子，比较GnRH激动剂和拮抗剂方案之间检索的卵母细胞平均数。分析基于所有随机受试者，使用多重插补方法对随机受试者在刺激开始前退出。
结果：在437名随机受试者中，221人被随机分配给GnRH激动剂，216人被随机分配到GnRH拮抗剂方案。参与者的平均年龄为32.3±4.3岁，平均血清AMH为16.6±7.8pmol/l。在GnRH激动剂和拮抗剂组中，共有202和204名参与者开始使用follitropindelta进行卵巢刺激，分别。激动剂组（11.1±5.9）与拮抗剂组（9.6±5.5）相比，卵母细胞的平均数量在统计学上显着增加，估计平均差异为1.31个卵母细胞（95％CI：0.22;2.40，P=0.0185）。取卵数量的差异受患者年龄和卵巢储备的影响，在年龄<35岁的患者和高卵巢储备患者（AMH>15pmol/l）中观察到更大的差异。GnRH激动剂组和拮抗剂组有相似的周期取消比例(2.0%[4/202]对3.4%[7/204])和新鲜胚泡转移取消比例(13.4%[27/202]对14.7%[30/204])。GnRH激动剂组每个开始周期的估计持续妊娠率在数值上较高(36.9%对29.1%;差异:7.74%[95%CI:-1.49;16.97,P=0.1002])。最常报告的不良事件（两组均≥1％；头痛，OHSS,恶心,盆腔疼痛,或不适和腹痛）两组相似。早期中度/重度OHSS的发生率较低（激动剂组为1.5%，拮抗剂组为2.5%）。GnRH激动剂和拮抗剂组每个周期的估计活产率分别为35.8%和28.7%。治疗差异分别为7.15%；95%CI：-2.02；16.31；P=0.1265。这两个治疗组的新生儿健康数据与单胎和双胎以及先天性畸形发生率具有可比性（GnRH激动剂组和拮抗剂组分别为2.7%和3.3%，分别)。
结论：所有参与者的AMH≤35pmol/l，年龄≤40岁。在AMH>35pmol/l（即OHSS风险增加的患者）中使用GnRH激动剂方案时，临床医生应保持谨慎。如果允许使用GnRH激动剂触发剂，则GnRH拮抗剂组中OHSS的发生率可能较低。冷冻保存的胚泡移植的结果没有随访，因此,冷冻转移后的累计活产率和新生儿结局尚不清楚.
结论：在AMH≤35pmol/l的女性中，与GnRH拮抗剂方案相比，在GnRH激动剂方案中使用时，个体化固定日剂量的follitropindelta导致获得的卵母细胞数量显着增加，没有观察到额外的安全信号，也没有额外的OHSS风险。用个体化follitropindelta刺激卵巢后的活产率在GnRH方案之间没有统计学差异；然而，本试验的功效不足以评估该终点.在两种方案中都没有使用follitropindelta进行卵巢刺激后对新生儿健康的安全性问题。
背景：该试验由FerringPharmaceuticals资助。EE,EP,和MS没有竞争的利益。美联社获得了费林的研究支持，还有GedeonRichter,以及来自Preglem的酬金或咨询费，诺和诺德,套圈,GedeonRichter,Cryos,默克公司A/S.BC已收到Ferring和Merck的咨询费，他的部门从Ferring那里收到了费用，以支付患者登记的费用。MBS已获得Ferring参加会议和/或旅行的支持，并在2023年之前担任FertiPROTEKTe.V.的董事会成员。JS已从Ferring和Merck获得酬金或咨询费，并支持参加会议和/或从Ferring旅行，默克,和GoodLife。TS已收到Ferring参加大会的支持/差旅费，并参加了默克公司的顾问委员会。YS已获得Ferring的资助/研究支持，并支持参加默克公司的专业协会大会。RL和PP是FerringPharmaceuticals的员工。PP是PharmaBiome的董事会成员，拥有武田制药的股票。
背景：ClinicalTrials.gov标识符NCT03809429；EudraCT编号2017-002783-40。
■2019年4月7日。
■2019年5月2日。
结论：BEYOND试验数据表明，在GnRH方案中使用个体化固定剂量的叶酸δ激动剂是有效的，与GnRH拮抗剂方案相比，在抗苗勒管激素（AMH）≤35pmol/l且卵巢过度刺激综合征（OHSS）风险未增加的女性中。
背景：在使用GnRH拮抗剂方案的随机对照试验（RCTs）中已经确定了个体化固定日剂量的follitropindelta（基于体重和AMH）的有效性和安全性。初步研究数据表明，在GnRH激动剂方案中，个体化follitropindelta也是有效的（RAINBOW试验，NCT03564509)。在GnRH激动剂与GnRH拮抗剂方案中，没有使用个体化促卵泡素δ进行卵巢刺激的前瞻性比较数据。
方法：这是第一个随机分组，控制,开放标签，多中心试验探索在接受IVF/ICSI的第一个卵巢刺激周期的参与者中,GnRH激动剂与GnRH拮抗剂方案中个体化follitropindelta给药的有效性和安全性.共有437名参与者被集中随机分配，并按中心和年龄分层。主要终点是检索到的卵母细胞数。次要终点包括持续怀孕率，药物不良反应（包括OHSS），活产,和新生儿结局。
方法：参与者（18-40岁；AMH≤35pmol/l）在奥地利的专业生殖健康诊所注册，丹麦,以色列,意大利,荷兰,挪威,和瑞士。使用阴性二项回归模型，以筛选时的年龄和AMH为因子，比较GnRH激动剂和拮抗剂方案之间检索的卵母细胞平均数。分析基于所有随机受试者，使用多重插补方法对随机受试者在刺激开始前退出。
结果：在437名随机受试者中，221人被随机分配给GnRH激动剂，216人被随机分配到GnRH拮抗剂方案。参与者的平均年龄为32.3±4.3岁，平均血清AMH为16.6±7.8pmol/l。在GnRH激动剂和拮抗剂组中，共有202和204名参与者开始使用follitropindelta进行卵巢刺激，分别。激动剂组（11.1±5.9）与拮抗剂组（9.6±5.5）相比，卵母细胞的平均数量在统计学上显着增加，估计平均差异为1.31个卵母细胞（95％CI：0.22;2.40，P=0.0185）。取卵数量的差异受患者年龄和卵巢储备的影响，在年龄<35岁的患者和高卵巢储备患者（AMH>15pmol/l）中观察到更大的差异。GnRH激动剂组和拮抗剂组有相似的周期取消比例(2.0%[4/202]对3.4%[7/204])和新鲜胚泡转移取消比例(13.4%[27/202]对14.7%[30/204])。GnRH激动剂组每个开始周期的估计持续妊娠率在数值上较高(36.9%对29.1%;差异:7.74%[95%CI:-1.49;16.97,P=0.1002])。最常报告的不良事件（两组均≥1％；头痛，OHSS,恶心,盆腔疼痛,或不适和腹痛）两组相似。早期中度/重度OHSS的发生率较低（激动剂组为1.5%，拮抗剂组为2.5%）。GnRH激动剂和拮抗剂组每个周期的估计活产率分别为35.8%和28.7%。治疗差异分别为7.15%；95%CI：-2.02；16.31；P=0.1265。这两个治疗组的新生儿健康数据与单胎和双胎以及先天性畸形发生率具有可比性（GnRH激动剂组和拮抗剂组分别为2.7%和3.3%，分别)。
结论：所有参与者的AMH≤35pmol/l，年龄≤40岁。在AMH>35pmol/l（即OHSS风险增加的患者）中使用GnRH激动剂方案时，临床医生应保持谨慎。如果允许使用GnRH激动剂触发剂，则GnRH拮抗剂组中OHSS的发生率可能较低。冷冻保存的胚泡移植的结果没有随访，因此,冷冻转移后的累计活产率和新生儿结局尚不清楚.
结论：在AMH≤35pmol/l的女性中，与GnRH拮抗剂方案相比，在GnRH激动剂方案中使用时，个体化固定日剂量的follitropindelta导致获得的卵母细胞数量显着增加，没有观察到额外的安全信号，也没有额外的OHSS风险。用个体化follitropindelta刺激卵巢后的活产率在GnRH方案之间没有统计学差异；然而，本试验的功效不足以评估该终点.在两种方案中都没有使用follitropindelta进行卵巢刺激后对新生儿健康的安全性问题。
背景：该试验由FerringPharmaceuticals资助。EE,EP,和MS没有竞争的利益。美联社获得了费林的研究支持，还有GedeonRichter,以及来自Preglem的酬金或咨询费，诺和诺德,套圈,GedeonRichter,Cryos,默克公司A/S.BC已收到Ferring和Merck的咨询费，他的部门从Ferring那里收到了费用，以支付患者登记的费用。MBS已获得Ferring参加会议和/或旅行的支持，并在2023年之前担任FertiPROTEKTe.V.的董事会成员。JS已从Ferring和Merck获得酬金或咨询费，并支持参加会议和/或从Ferring旅行，默克,和GoodLife。TS已收到Ferring参加大会的支持/差旅费，并参加了默克公司的顾问委员会。YS已获得Ferring的资助/研究支持，并支持参加默克公司的专业协会大会。RL和PP是FerringPharmaceuticals的员工。PP是PharmaBiome的董事会成员，拥有武田制药的股票。
背景：ClinicalTrials.gov标识符NCT03809429；EudraCT编号2017-002783-40。
■2019年4月7日。
■2019年5月2日。
