Table 1 RCTs selected and included in the systematic review (qualitative analysis)

Arce et al., 2014 [22]

Ferring Pharmaceuticals

Randomized, controlled, assessor-blinded, AMH-stratified (low: 5.0–14.9 pmol/L; high: 15.0–44.9 pmol/L) trial (Phase 2 trial)

Seven IVF centers in four countries (Belgium, Czech Republic, Denmark, and Spain)

From September 2011 to May 2013

A total of 265 eligible patients were randomized, with a distribution of 56% (n = 148) and 44% (n = 117) in the high and low AMH stratum, respectively

18–37 years

Inclusion criteria: women scheduled for IVF/ICSI for tubal infertility, unexplained infertility, infertility related to endometriosis stage I/II, or for male factor infertility; BMI between 18.5 and 32.0 kg/m²; infertility for at least 1 year; regular menstrual cycles; uterus consistent with expected normal function; presence and adequate visualization of both ovaries, without evidence of significant abnormality; early follicular phase FSH serum concentration of 1–12 IU/L and total antral follicle count ≥ 6 and ≤ 25 for both ovaries combined; serum AMH concentration of 5.0–44.9 pmol/L

On day 2–3 of the menstrual cycle, patients were randomly assigned, in a 1:1:1:1:1:1 ratio, to receive fixed daily SC injections of either 5.2 mg, 6.9 mg, 8.6 mg, 10.3 mg, or 12.1 mg of follitropin delta (FE 999,049; Ferring Pharmaceuticals), or 11 mg (150 IU) of follitropin alfa (Gonal-F® filled by mass; Merck Serono)

Number of oocytes retrieved

The number of oocytes retrieved increased in a dose–dependent manner, from 5.2 ± 3.3 oocytes with 5.2 mg/d to 12.2 ± 5.9 with 12.1 mg/d. The slopes of the dose–response curves differed significantly between the two AMH strata

Nyboe Andersen et al., 2017 [15]

Ferring Pharmaceuticals

Randomized, assessor-blinded, noninferiority trial (Phase 3 trial)

Thirty-seven IVF centers in 11 countries (Belgium, Brazil, Canada, Czech Republic, Denmark, France, Italy, Poland, Russia, Spain, and United Kingdom)

From October 8, 2013 to May 11, 2015, with live birth follow-up completed on January 11, 2016

A total of 1329 eligible women were randomized.

1326 were exposed to study drug: 665 to individualized follitropin delta and 661 to conventional follitropin alfa

18–40 years

Inclusion criteria: women scheduled for IVF/ICSI for tubal infertility, unexplained infertility, infertility related to endometriosis stage I/II, or for male factor infertility; BMI between 17.5 and 32.0 kg/m²; regular menstrual cycles of 24–35 days; presence of both ovaries; early follicular phase FSH serum concentration 1–15 IU/L. Exclusion criteria: endometriosis stage III–IV; history of recurrent miscarriage; use of hormonal preparations (except for thyroid medication) during the last menstrual cycle before randomization

Follitropin delta (AMH < 15 pmol/L: 12 mg/d; AMH ≥ 15 pmol/L: 0.10–0.19 mg/kg/d; maximum 12 mg/d), or follitropin alfa (150 IU/d for 5 days with potential subsequent dose adjustments up to 450 IU/d)

Ongoing pregnancy and ongoing implantation rates

Individualized follitropin delta was noninferior to conventional follitropin alfa for the primary efficacy endpoints

Bosch et al., 2019 [23]

Ferring Pharmaceuticals

Randomized, controlled, assessor-blinded trial (Phase 3 trial)

Thirty-two IVF centers in 10 countries: Belgium, Brazil, Canada, Czech Republic, Denmark, Italy, Poland, Russia, Spain, and the UK

From The trial was conducted between 26 March 2014 and 26 June 2015, with live birth follow-up completed on 26 January 2016.

In cycle 2, 513 women were enrolled and exposed; 252 to follitropin delta and 261 to follitropin alfa. In cycle 3, 189 women were enrolled, of whom 188 were exposed; 95 to follitropin delta and 93 to follitropin alfa.

18–40 years

Inclusion criteria: infertile patients who had participated in cycle 1 (Nyboe Anderson et al., 2017) and failed to achieve an ongoing pregnancy were eligible for cycle 2 and women who failed to achieve an ongoing pregnancy in cycle 2 were eligible for cycle 3. Exclusion criteria: patients with severe OHSS in a previous cycle, or patients with any clinically relevant change to any of the eligibility criteria or any clinically relevant medical history since the previous cycle.

The participating patients had in cycle 1 been randomized 1:1 to treatment with either follitropin delta (FE 999,049, Ferring Pharmaceuticals) or follitropin alfa (Gonal-F®, Merck Serono) and remained on the same gonadotrophin in cycles 2 and 3.

Proportion of women with treatment-induced anti-FSH antibodies after one and two repeated cycles of ovarian stimulation with follitropin delta

The incidence of treatment-induced anti-FSH antibodies with follitropin delta was 0.8% and 1.1% in cycles 2 and 3, respectively, which was similar to the incidence in cycle 1 (1.1%). No antibodies were of neutralizing capacity

Qiao et al., 2021 [24]

Ferring Pharmaceuticals

Randomized, controlled, assessor-blind, parallel groups, multi-center, non-inferiority trial (Phase 3 trial)

Twenty-six IVF centers in four countries/regions: mainland China, South Korea, Taiwan and Vietnam

From 1 December 2017 to 3 January 2020, with pregnancy follow-up completed on 1 September 2020

A total of 1009 women were randomized and exposed, of whom 499 were treated with follitropin delta in its individualized fixed-dose regimen and 510 with follitropin alfa in a conventional and adjustable dosing regimen.

20–40 years

Inclusion criteria: Asian reproductive-aged women scheduled for their first ovarian stimulation cycle for IVF/ ICSI for tubal infertility, unexplained infertility, endometriosis stage I/II or for male factor infertility; regular menstrual cycles of 24–35 days; presence of both ovaries; follicular phase FSH serum levels of 1–15 IU/L; BMI between 17.5 and 32.0 kg/m². Exclusion criteria: women with endometriosis stage III/IV; history of recurrent miscarriage; women with one or more follicles ≥ 10 mm observed prior to randomization.

The follitropin delta treatment consisted of a fixed daily dose individualized according to each patient’s initial AMH level and body weight (AMH < 15 pmol/L: 12 µg; AMH ≥ 15 pmol/L: 0.19 to 0.10 µg/kg; min-max 6–12 µg). The follitropin alfa dose was 150 IU/day for the first 5 days with subsequent potential dose adjustments according to individual response.

Ongoing pregnancy rate

Individualized follitropin delta was noninferior to conventional follitropin alfa for the ongoing pregnancy rate (31.3% vs. 25.7%, respectively)

Ishihara et al., 2021 [25]

Ferring Pharmaceuticals

Randomized, controlled, assessor-blinded, AMH-stratified (low 5.0–14.9 pmol/L; high 15.0–44.9 pmol/L) dose-response trial (Phase 2 trial)

Ten IVF centers in Japan

From December 15, 2014 to December 29, 2015, with pregnancy follow-up data completed on October 12, 2016.

A total of 159 women were randomized, of whom 158 were exposed: 117 in the follitropin delta groups (37 in 6 µg/d, 40 in 9 µg/d, and 40 in 12 µg/d) and 41 in the 150 IU/d follitropin beta group

20–39 years

Inclusion criteria: Japanese women eligible for IVF/ICSI with tubal infertility, unexplained infertility, or infertility related to endometriosis stage I/II or with partners diagnosed with male factor infertility; BMI between 17.5 and 32.0 kg/m²; regular menstrual cycles of 24–35 days; presence of both ovaries; AMH: 5.0–44.9 pmol/L; early follicular phase FSH of 1–12 IU/L. Exclusion criteria: endometriosis stage III/IV; 3 or more controlled ovarian stimulation cycles for IVF/ICSI; history of recurrent miscarriage; use of hormonal preparations (except for thyroid medication) during the last menstrual cycle before randomization

Ovarian stimulation with 6, 9, or 12 mg/d of follitropin delta or 150 IU/d follitropin beta as a reference arm in a gonadotropin-releasing hormone antagonist cycle

Number of oocytes retrieved

A significant dose-relation was established between follitropin delta doses and oocytes retrieved (mean number ± SD; 7.0 ± 4.1, 9.1 ± 5.6, and 11.6 ± 5.6 for 6 µg/d, 9 µg/d, and 12 µg/d follitropin delta groups respectively) That finding remained significant within each AMH strata

Ishihara and Arce, 2021 [26]

Ferring Pharmaceuticals

Randomized, controlled, assessor-blind, multicenter, non-inferiority trial (Phase 3 trial)

17 investigational sites in Japan

Trial conducted between 7 July 2017 and 11 September 2018

A total of 347 Japanese women were randomized and exposed to ovarian stimulation, of which 170 were treated with individualized follitropin delta treatment and 177 with conventional follitropin beta treatment

20–40 years

Inclusion criteria: Japanese women scheduled to first IVF/ICSI cycle for tubal infertility, unexplained infertility or infertility related to endometriosis stage I/II, or for a partner diagnosed with male factor infertility; BMI between 17.5 and 32.0 kg/m2; regular menstrual cycles of 24–35 days; presence of both ovaries; early follicular phase FSH: 1–15 IU/l. Exclusion criteria: endometriosis stage III/IV; history of recurrent miscarriage; use of hormonal preparations (except for thyroid medication) during the last menstrual cycle before randomization

Women were randomized to individualized follitropin delta (AMH < 15 pmol/L; AMH ≥ 15 pmol/L) or conventional follitropin beta (150 IU/day for the first 5 days, with potential subsequent dose adjustments)

Number of oocytes retrieved with a pre-specified non-inferiority margin (-3.0 oocytes)

The number of oocytes retrieved after individualized follitropin delta treatment and conventional follitropin beta treatment are similar (9.3 versus 10.5; lower boundary of 95% CI: −2.3)

Shao et al., 2023 [27]

Ferring Pharmaceuticals

Randomized, open-label study (Phase 1 trial)

Jiangsu Province Hospital,

China

From June through December 2019

A total of 24 healthy women were randomized. Eight women were assigned to each follitropin delta dose group (12, 18, and 24 µg). All 24 women completed the trial

21–40 years

Inclusion criteria: infertile women scheduled for IVF/ICSI cycles. Exclusion criteria: history/presence of any disease, including cardiovascular, musculoskeletal, immunological, endocrine, or metabolic disease; presence or history of severe allergy or anaphylactic reactions to any non-registered investigational drug were also ruled out; use of gonadotropin preparations within the 6 months prior to screening were excluded. Women were also not enrolled if they had participated in other clinical trials or donated blood in the past 4 weeks.

On the morning of the gonadotropin administration day, women were randomly assigned to receive a single dose of follitropin delta in a 1:1:1 ratio (12, 18, or 24 µg)

Not clearly reported.

The study aims were to assess the pharmacokinetic characteristics, dose proportionality, and safety of follitropin delta in healthy Chinese women

The administration of single doses of follitropin delta to healthy Chinese women demonstrated dose-proportional pharmacokinetics over the dose range of 12–24 µg, and these doses were well tolerated.