Introduction
Methods
Review question
PICO model
Data sources, search strategy, and eligible criteria
Data collection process
Risk of bias and quality of evidence assessment
Data synthesis
Results
Study | Sponsor | Study design | Setting | Study period | Nr. of included subjects | Age of study participants | Main inclusion and exclusion criteria | Interventions | Primary endpoint | Synthesis of results (primary endpoint) |
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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. |
Qualitative analysis
Phase 1 RCTs
Phase 2 RCTs
Phase 3 RCTs
Quantitative analysis
Ovarian response endpoints
Duration of stimulation
Outcomes | Anticipated absolute effects (95%CI) | Relative effect (95% CI) | Number of participants | Quality of the evidence (GRADE) | Comments | |
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Risk with follitropin alfa/beta | Risk with follitropin delta | |||||
Duration of stimulation | The mean duration of stimulation in the control group ranged from 8.6 to 8.8 days | The duration of stimulation was longer in the group of women treated with follitropin delta compared to women treated with follitropin alfa/beta (MD 0.34, 95%CI: 0.14, 0.53; studies: 3) | // | 2682 | ⊕⊕⊕⊕ High | // |
Total dose of gonadotropin | The mean total dose of gonadotropin administered in the control group ranged from 103.7 to 149.9 µg | The total dose of gonadotropin administered was lower in the group of women treated with follitropin delta compared to women treated with follitropin alfa/beta (MD -37.07; 95%CI: -59.01, -15.13; studies: 3) | // | 2682 | ⊕⊕⊕⊝ Moderate1 | // |
Number of oocytes retrieved | The mean number of oocytes retrieved in the control group ranged from 10.4 to 12.4 oocytes | The mean number of oocytes retrieved was comparable between study groups (MD -1.32; 95%CI:-2.64, -0.00; studies: 3) | // | 2682 | ⊕⊕⊝⊝ Low1,2 | // |
Fertilization rate | The fertilization rate in the control group ranged from 56 to 64% | The fertilization rate did not differ between study groups (studies: 2) | // | // | ⊕⊝⊝⊝ Very low1,2,3 | Data of included studies could not be pooled because the denominator was not extractable |
Number of day 3 embryos | The mean number of day 3 embryos obtained in the control group ranged from 5.7 to 8.7 | The mean number of day 3 embryos obtained did not differ between study groups (studies: 2) | // | // | ⊕⊝⊝⊝ Very low1,2,3 | Data of included studies could not be pooled because the denominator was not extractable |
Number of blastocysts | The mean number of blastocysts obtained in the control group ranged from 3.5 to 4.2 | The mean number of blastocysts obtained did not differ between study groups (studies: 2) | // | // | ⊕⊝⊝⊝ Very low1,2,3 | Data of included studies could not be pooled because the denominator was not extractable |
CPR | 442 per 1348 (studies: 3) | 455 per 1334 (studies: 3) | OR 1.06; 95%CI: 0.90, 1.24 | 2682 | ⊕⊕⊕⊝ Moderate4 | // |
OPR | 373 per 1348 (studies: 3) | 400 per 1334 (studies: 3) | OR 1.15; 95%CI: 0.90, 1.46 | 2682 | ⊕⊕⊕⊝ Moderate4 | // |
LBR | 362 per 1348 (studies: 3) | 394 per 1334 (studies: 3) | OR 1.18; 95%CI: 0.89, 1.55 | 2682 | ⊕⊕⊝⊝ Low5 | // |
LBR at 4 weeks after birth | 327 per 1171 (studies: 2) | 354 per 1164 (studies: 2) | OR 1.15; 95%CI: 0.81, 1.63 | 2335 | ⊕⊕⊝⊝ Low5 | // |
Adoption of preventive strategies for OHSS | 87 per 1348 (studies: 3) | 41 per 1334 (studies: 3) | OR 0.45; 95%CI: 0.30, 0.66 | 2682 | ⊕⊕⊝⊝ Low5 | // |
Early OHSS | 86 per 1348 (studies: 3) | 54 per 1334 (studies: 3) | OR 0.46; 95%CI: 0.31, 0.67 | 2682 | ⊕⊕⊝⊝ Low5 | // |
All forms of OHSS | 100 per 1348 (studies: 3) | 62 per 1334 (studies: 3) | 0.61; 95%CI: 0.44, 0.84 | 2682 | ⊕⊕⊝⊝ Low5 | // |
Total dose of gonadotropin administered
Number of oocytes retrieved
Fertilization rate
Number of embryos obtained
Reproductive outcomes
CPR
OPR
LBR
Cumulative endpoints
Safety outcomes
OHSS
Risk of bias in included studies
Random sequence generation
Allocation concealment
Blinding
Incomplete outcome data
Selective reporting
Quality of evidence
Discussion
Why it is important to do this review
Summary of the main results
Agreements and disagreements with other studies
Quality of the evidence
How the intervention works
Overall completeness and applicability of evidence
Registry | Trial ID | Country (the first setting is reported) | Sample size (estimated for ongoing trial) | Study aim | Sponsor/funds | Status | Study start | Study competition (estimated) |
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ClinicalTrials.gov EU-CTR | NCT01426386 EudraCT number: 2011-000633-36 | Belgium (multicenter) | 265 Caucasian infertile eumenorrheic patients aged between 18 and 37 years, with BMI between 18.5 and 32.0 kg/m2, and without anovulatory PCOS stratified for AMH levels. | To investigate the effects of different doses of follitropin delta in women undergoing controlled stimulation for IVF/ICSI treatment on oocyte retrieved. | Ferring Pharmaceuticals | Completed, with results (published by Arce et al., 2014 [22]) | 2011-09-08 | 2013-03 |
ClinicalTrials.gov EU-CTR | NCT01956110 EudraCT number: 2013-001669-17 | Belgium (multicenter) | 1329 Caucasian infertile eumenorrheic patients aged between 18 and 40 years, basal FSH levels less than 15 UI/l, and BMI between 17.5 and 32.0 kg/m2. | To compare the efficacy and safety of follitropin delta with follitropin alfa having as primary endpoints the ongoing pregnancy and implantation rate in women undergoing ovarian stimulation for IVF/ICSI. | Ferring Pharmaceuticals | Completed, with results (ESTHER-1 TRIAL published by Nyboe Andersen et al., 2017 [15]) | 2013-10 | 2017-01-03 |
ClinicalTrials.gov EU-CTR | NCT01956123 EudraCT number: 2013-001616-30 | Belgium (multicenter) | 513 infertile patients included in a previous trial (NCT01956110) and failed to achieve an ongoing pregnancy but who undergone oocyte retrieval or had cycle cancellation prior to oocyte retrieval due to poor ovarian response or excessive ovarian response, in the previous cycle(s). | To investigate in repeated cycles the immunogenicity of follitropin delta having follitropin alfa as comparator arm. | Ferring Pharmaceuticals | Completed, with results (ESTHER-2 TRIAL published by Bosh et al., 2019 [23]) | 2014-03-26 | 2017-01-03 |
ClinicalTrials.gov | NCT02309671 | Japan | 159 infertile eumenorrheic patients aged between 20 and 39 years without PCOS. | To investigate the effects of different doses of follitropin delta having as comparator arm follitropin alfa in infertile women undergoing IVF/ICSI treatment. | Ferring Pharmaceuticals | Completed, with results (published by Ishihara et al. 2021 – phase 2 trial [25]) | 2014-12 | 2016-09 |
ClinicalTrials.gov | NCT03228680 | Japan (multicenter) | 373 Japanese infertile eumenorrheic patients aged between 20 and 40 years, basal FSH levels less than 15 UI/l, and BMI between17.5 and 32.0 kg/m2. | Non-inferiority study comparing follitropin delta and follitropin beta in terms of number of oocytes retrieved in women undergoing ovarian stimulation for IVF/ICSI. | Ferring Pharmaceuticals | Completed, with results (STORK trial published by Ishihara et al., 2021 [26]) | 2017-07-29 | 2019-07-08 |
ClinicalTrials.gov | NCT03296527 | China (multicenter) | 1011 Asian infertile eumenorrheic patients aged between 20 and 40 years, basal FSH levels less than 15 UI/l, and BMI between 17.5 and 32.0 kg/m2. | To demonstrate non-inferiority of follitropin delta in comparison with follitropin alfa in terms of ongoing pregnancy rate in women undergoing controlled ovarian stimulation for IVF treatment. | Ferring Pharmaceuticals | Completed, with results (GRAPE TRIAL published by Qiao et al., 2021 [24]) | 2017-12-01 | 2020-07-26 |
ClinicalTrials.gov ANZCTR | NCT03393780 Specific number not available | Australia (multicenter) | 1018 infertile patients aged more than 18 years never treated with IVF/ICSI treatments | Observational study aimed to monitor the use in routine clinical practice of follitropin delta in patients who never underwent previous IVF/ICSI treatments. | Ferring Pharmaceuticals | Completed, with results (Blockeel et al., 2022 [39]) | 2018-03-16 | 2020-07-17 |
ClinicalTrials.gov EU-CTR | NCT03564509 EudraCT number: 2017-003810-13 | Belgium (multicenter) | 620 infertile patients aged between 30 and 42 years with AMH levels between 5.0 and 35.0 pmol/L, and without anovulatory PCOS. | To investigate the efficacy of FE 999,302 as add-on treatment to follitropin delta in women undergoing ovarian stimulation for IVF/ICSI in a long GnRH-a protocol, and to assess the safety profile, the potential immunogenicity, and the impact of body weight. | Ferring Pharmaceuticals | Completed, with results (Rainbow trial published by Fernández Sánchez et al., 2022 [21]) | 2018-05-14 | 2020-01-08 |
ClinicalTrials.gov | NCT03738618 | United States (multicenter) | 521 infertile eumenorrheic patients aged between 35 and 42 years, basal FSH levels less than 15 UI/l, and BMI between 17.5 and 38.0 kg/m2. | To investigate the safety and efficacy of follitropin delta in comparison to placebo arm. | Ferring Pharmaceuticals | Completed | 2018-10-29 | 2020-12-21 |
ClinicalTrials.gov | NCT03740737 | United States | 579 infertile eumenorrheic patients aged between 18 and 34 years, basal FSH levels less than 15 UI/l, and BMI between17.5 and 38.0 kg/m2. | To investigate the safety and efficacy of follitropin delta in comparison to placebo arm. | Ferring Pharmaceuticals | Completed | 2018-10-26 | 2020-11-20 |
ClinicalTrials.gov EU-CTR | NCT03809429 EudraCT number: 2017-002783-40 | Austria (multicenter) | 437 patients aged between 18 and 40 years with BMI between17.5 and 38.0 kg/m2 and without elevated markers of ovarian reserve. | To compare the efficacy and safety of follitropin delta for ovarian stimulation in IVF/ICSI cycles down-regulated with long GnRH agonist protocol vs. a short GnRH antagonist protocol. | Ferring Pharmaceuticals | Completed, with results1 | 2019-04-29 | 2022-02-16 |
ClinicalTrials.gov | NCT04150861 | China (multicenter) | 24 Chinese infertile patients eumenorrheic patients aged between 21 and 40 years, with BMI between 18.5 and 25.0 kg/m2, and without PCOS. | Open-label study to investigate the pharmacokinetic, safety and tolerability of follitropin delta in single subcutaneous dose in GnRH-agonist down-regulated IVF cycles. | Ferring Pharmaceuticals | Completed, with results (published by Shao et al., 2023 [27]) | 2019-06-23 | 2019-12-16 |
ClinicalTrials.gov | NCT04654039 | Korea | 600 Korean infertile patients who were prescribed follitropin delta for the first time. | Post-marketing surveillance study for re-examine the safety of follitropin delta to identify potential new adverse events, and to confirm its safety and effectiveness. | Ferring Pharmaceuticals | Recruiting | 2020-10-26 | 2023-10-31 |
ClinicalTrials.gov | NCT04773353 | India (multicenter) | 220 Indian infertile eumenorrheic patients aged between 21 and 40 years, basal FSH levels less than 15 UI/l, and BMI between 17.5 and 32.0 kg/m2. | Non-inferiority study comparing follitropin delta and follitropin alfa in terms of ongoing pregnancy rate in women undergoing ovarian stimulation for IVF/ICSI. | Ferring Pharmaceuticals | Active, not recruiting | 2021-12-03 | 2024-02 |
ClinicalTrials.gov EU-CTR | NCT05263388 EudraCT number: 2021-001785-38 | Austria (multicenter) | 300 infertile eumenorrheic patients aged between 18 and 40 years. | To compare the efficacy of follitropin delta (starting dose of 15 µg daily) in comparison with follitropin alfa (starting dose of 225 IU daily) for ovarian stimulation in IVF/ICSI cycles in terms of oocytes retrieved. | Ferring Pharmaceuticals | Recruiting | 2022-07-10 | 2024-04-15 |
EU-CTR | EudraCT number: 2017-003810-13 | 773 subjects were screened of 619 subjects were exposed to investigational medicinal product (IMP): 515 to FE 999,302 and 104 to placebo. | To investigate the efficacy and safety of FE 999,302 as add-on treatment to follitropin delta in women undergoing ovarian stimulation in a long GnRH-a protocol | Ferring Pharmaceuticals | Completed with results unpublished. | 2019-10-21 | 2020-01-30 | |
ReBec | U1111-1247-3260 | Brasil | 44 (intervention group) vs. 280 (historical control group) infertile eumenorrheic patients aged between 18 and 40 years, basal FSH levels less than 15 UI/l, and BMI between 17.5 and 32.0 kg/m2. | Prospective interventional study with historical control aimed to evaluate the effect of hp-FSH addition at standard staring doses (150 UI daily) in patients who receive follitropin delta. | Ferring Pharmaceuticals | Not yet recruiting | 2020-01-03 | 2020-12-31 |