UMIN-CTR Clinical Trial

Public title

A real-world retrospective study comparing two ovarian stimulation drugs (follitropin delta and follitropin alpha) in Japanese IVF practice

Acronym

FALCON Study (Follitropin ALfa vs delta CONparison)

Scientific Title

Comparative effectiveness and safety of follitropin delta versus follitropin alpha in Japanese real-world ART practice: a propensity score-matched retrospective observational cohort study (FALCON study)

Scientific Title:Acronym

FALCON Study

Region

Japan

Condition

Infertility (cases with indication for in-vitro fertilization and embryo transfer)

Classification by specialty

Obstetrics and Gynecology

Classification by malignancy

Others

Genomic information

NO

Narrative objectives1

Follitropin delta is a novel recombinant FSH derived from a human cell line, characterized by an individualized dosing algorithm based on serum anti-Mullerian hormone and body weight. While its non-inferiority to Follitropin alfa has been demonstrated in large-scale RCTs, real-world comparative data in Japanese clinical practice remain limited. This study aims to compare the clinical effectiveness and safety of Follitropin alfa and Follitropin delta using single-center retrospective cohort data, with patient background balanced through propensity score matching.

Basic objectives2

Safety,Efficacy

Basic objectives -Others

Trial characteristics_1

Trial characteristics_2

Developmental phase

Primary outcomes

Number of good-quality blastocysts per oocyte retrieval cycle (num_good_bl)
Statistical model: Negative binomial regression with cluster-robust standard errors (clustered by patient)
Effect measure: Rate ratio (RR) with 95% confidence interval
Non-inferiority margin: lower bound of 95% CI for RR > 0.80

Key secondary outcomes

Number of oocytes retrieved
Number of mature (M2) oocytes
Number of fertilized embryos
Number of good-quality cleavage-stage embryos
Number of blastocysts
Number of frozen embryos
Clinical pregnancy rate per cycle (gestational sac confirmed at 5 weeks)
Ongoing pregnancy rate per cycle (fetal heartbeat at 9 weeks)
Live birth rate per cycle
Incidence of moderate or severe ovarian hyperstimulation syndrome (OHSS, Golan grade 2)
Incidence of severe OHSS (Golan grade 3)
Rate of reaching embryo transfer

Study type

Observational

Basic design

Randomization

Randomization unit

Blinding

Control

Stratification

Dynamic allocation

Institution consideration

Blocking

Concealment

No. of arms

Purpose of intervention

Type of intervention

Interventions/Control_1

Interventions/Control_2

Interventions/Control_3

Interventions/Control_4

Interventions/Control_5

Interventions/Control_6

Interventions/Control_7

Interventions/Control_8

Interventions/Control_9

Interventions/Control_10

Age-lower limit

20

years-old

<=

Age-upper limit

43

years-old

>

Gender

Female

Key inclusion criteria

Cycles in which controlled ovarian stimulation with either Follitropin alfa or Follitropin delta was performed for in-vitro fertilization
Cycles in which oocyte retrieval was performed
Cycles treated at the participating institution within the study period

Key exclusion criteria

Non-IVF stimulation purposes (e.g., in-vitro maturation)
Natural cycles without exogenous stimulation
Cycles with missing critical baseline covariate (age)

Target sample size

4000

Name of lead principal investigator

1st name	Shinnosuke
Middle name
Last name	Komiya

Organization

HORAC Grand Front Osaka Clinic

Division name

Gynecology

Zip code

530-0011

Address

Grand Front Osaka Tower B 15F, 3-1, Ofuka-cho, Kita-ku, Osaka city, Osaka, Japan

TEL

0663778824

Email

komiya520@ivfjapan.com

Name of contact person

1st name	Shinnosuke
Middle name
Last name	Komiya

Organization

HORAC Grand Front Osaka Clinic

Division name

Gynecology

Zip code

530-0011

Address

Grand Front Osaka Tower B 15F, 3-1, Ofuka-cho, Kita-ku, Osaka city, Osaka, Japan

TEL

0663778824

Homepage URL

Email

komiya520@ivfjapan.com

Institute

HORAC Grand Front Osaka Clinic

Institute

Department

Personal name

Organization

Self-funding

Organization

Division

Category of Funding Organization

Self funding

Nationality of Funding Organization

Co-sponsor

Name of secondary funder(s)

Organization

HORAC Grand Front Osaka Clinic

Address

Grand Frront Osaka Tower B 15F, 3-1, Ofuka-cho, Kita-ku, Osaka city, Osaka, Japan

Tel

0663778824

Email

komiya520@ivfjapan.com

Secondary IDs

NO

Study ID_1

Org. issuing International ID_1

Study ID_2

Org. issuing International ID_2

IND to MHLW

Institutions

Date of disclosure of the study information

2025

Year

01

Month

20

Day

URL releasing protocol

Publication of results

Partially published

URL related to results and publications

Number of participants that the trial has enrolled

4056

Results

From 4,056 eligible cycles (alpha 3,598; delta 458), 1:1 propensity score matching after 20 imputations yielded a mean of 456 pairs. The primary outcome of good blastocysts per cycle had adjusted RR 1.12 (95%CI 0.84-1.49), meeting the pre-specified non-inferiority margin of 0.80. Oocyte yield was lower with delta (RR 0.91) but fertilization, blastocyst, pregnancy, and live birth rates were similar. Moderate-to-severe OHSS was numerically lower with delta (20.4% vs 23.9%; OR 0.77, 95%CI 0.51-1.16).

Results date posted

2026

Year

05

Month

25

Day

Results Delayed

Delay expected

Results Delay Reason

A manuscript reporting the full results of this study has been submitted and is currently under peer review. Detailed final results will be publicly available upon journal publication.

Date of the first journal publication of results

Baseline Characteristics

Baseline characteristics in the eligible cohort (n=4,056 cycles): follitropin alpha (n=3,598) vs follitropin delta (n=458).
Age: 37.1 +/- 4.1 vs 35.8 +/- 4.2 years (SMD -0.307)
BMI (median, IQR): 20.58 (19.22-22.50) vs 20.70 (19.22-22.21) kg/m^2 (SMD -0.025)
AMH (median, IQR): 1.65 (0.75-3.35) vs 2.60 (1.58-4.28) ng/mL (SMD +0.284)
Basal FSH (median, IQR): 8.10 (6.50-10.10) vs 7.30 (6.30-8.90) mIU/mL (SMD -0.323)
Primary infertility: 46.0% vs 48.9% (SMD +0.058)
Stimulation protocol: GnRH antagonist 43.0% vs 43.7%; PPOS 29.1% vs 52.6% (SMD +0.492); mild stimulation 24.7% vs 3.1% (SMD -0.659); GnRH agonist 3.0% vs 0.7%
CC/letrozole co-administration: 23.9% vs 5.7% (SMD -0.532)
Fertilization method: ICSI 74.7% vs 74.7%; IVF 12.5% vs 16.4%; split 3.7% vs 5.5%
Calendar year of OPU: 2022, 22.0% vs 23.8%; 2023, 38.4% vs 38.0%; 2024, 39.5% vs 38.2%
Total dose (median, IQR): alpha 1,350 (900-1,725) IU; delta 72 (54-96) mcg
After 1:1 propensity score matching (representative imputation: 914 cycles), all 16 covariates achieved absolute SMD < 0.10. Post-matching mean age was 35.6-35.8 years in both groups, median AMH 2.50-2.59 ng/mL, PPOS use 52.5-53.6%, and CC/letrozole co-administration 4.4-5.7%.

Participant flow

Source database: 4,885 cycles / 2,487 patients (January 2022 - December 2024).
Excluded (n=18): IVM cycles 9, natural cycles (dose=0) 9. After IVM and natural cycle exclusion: 4,867 cycles.
Excluded (n=811): age <20 years 2, age >=43 years 809.
Eligible cohort (UMIN-CTR criteria): 4,056 cycles / 2,271 patients (alpha 3,598; delta 458). After multiple imputation by chained equations (m=20, predictive mean matching), the propensity score was estimated by L2-penalized logistic regression (age, BMI, AMH, FSH, parity, method, year, CC, fertilization). 1:1 nearest-neighbor matching with caliper 0.2 x SD(logit PS) without replacement was performed independently in each of the 20 imputed datasets. Matched pairs per imputation: 455-458 (mean 456). Unmatched delta cycles per imputation: 0-3 (mean 2; no alpha control within caliper). Representative matched cohort: 914 cycles / 775 patients. Doubly-robust outcome analysis (negative binomial regression for count outcomes; logistic regression for binary outcomes; patient-level cluster-robust standard errors) was conducted on each of the 20 matched cohorts, and effect estimates were pooled across imputations using Rubin's rules.

Adverse events

The pre-specified safety outcomes were ovarian hyperstimulation syndrome (OHSS) events graded by the Golan classification. Results in the matched cohort (n=914; 457 cycles per group):
Moderate-to-severe OHSS (Golan grade >= 2): follitropin alpha 109/457 (23.9%); follitropin delta 93/457 (20.4%). Absolute risk difference -3.5 percentage points (number needed to treat approximately 29 to prevent one moderate-to-severe OHSS event). Adjusted OR 0.77 (95% CI 0.51-1.16; p=0.206).
Severe OHSS (Golan grade >= 3): alpha 10/457 (2.2%); delta 11/457 (2.4%). Adjusted OR 0.90 (95% CI 0.27-2.94; p=0.859).
No other drug-related serious adverse events were recorded in this dataset. As a retrospective observational study using routine clinical data, adverse event ascertainment relied on documentation during standard clinical care. No additional drug-related deaths or discontinuation events were reported during the study period.

Outcome measures

Primary outcome (pre-specified): number of good-quality blastocysts per oocyte retrieval cycle (Gardner >=3BB at days 5-6). In the matched cohort, alpha 1.01 +/- 1.97 (median 0, IQR 0-1) vs delta 1.09 +/- 1.97 (median 0, IQR 0-1). Doubly-robust adjusted RR 1.12 (95% CI 0.84-1.49; p=0.427). Pre-specified non-inferiority margin (lower 95% CI bound > 0.80) was met.
Secondary outcomes (matched cohort, n=457 per group):
Oocytes retrieved: 10.77 vs 9.49 (RR 0.91, 95% CI 0.83-0.99, p=0.033)
M2 oocytes: 8.50 vs 7.46 (RR 0.89, 95% CI 0.81-0.98, p=0.017)
Fertilized embryos: 6.01 vs 5.79 (RR 0.98, 95% CI 0.87-1.10, p=0.698)
Good cleavage embryos: 4.77 vs 4.54 (RR 0.96, 95% CI 0.85-1.09, p=0.551)
Blastocysts: 2.34 vs 2.29 (RR 1.04, 95% CI 0.83-1.31, p=0.724)
Frozen embryos: 2.86 vs 2.73 (RR 0.99, 95% CI 0.85-1.14, p=0.860)
Reached embryo transfer: 289/457 (63.2%) vs 319/457 (69.8%) (OR 1.23, 95% CI 0.84-1.78, p=0.283)
Clinical pregnancy per cycle (5-week GS): 138/457 (30.2%) vs 141/457 (30.9%) (OR 1.00, 95% CI 0.69-1.45, p=0.999)
Ongoing pregnancy per cycle (9-week HB): 112/457 (24.5%) vs 117/457 (25.6%) (OR 1.06, 95% CI 0.72-1.57, p=0.767)
Live birth per cycle (strict; ongoing as failure): 78/457 (17.1%) vs 76/457 (16.6%) (OR 0.98, 95% CI 0.62-1.53, p=0.914)
Live birth per cycle (optimistic; ongoing as success): 109/457 (23.9%) vs 113/457 (24.7%) (OR 1.05, 95% CI 0.70-1.57, p=0.813)
All effect estimates were doubly-robust adjusted (propensity score covariates also entered in the outcome model), with patient-level cluster-robust standard errors, pooled across 20 imputed datasets using Rubin's rules. The pre-specified non-inferiority margin applied to the primary outcome only (achieved).

Plan to share IPD

Sharing plan: Available on reasonable request (conditional sharing)

IPD sharing Plan description

The individual participant data analyzed in this study will not be deposited in a public repository because they contain detailed individual-level clinical information (including treatment dates, demographics, and reproductive outcomes) for which patient privacy considerations preclude open sharing. De-identified data may be made available from the corresponding author on reasonable request, subject to a data-sharing agreement and approval by the institutional review board of Medical Corporation Sankeikai. Sharing will be limited to requests with the same scientific purpose (comparative effectiveness and safety of follitropin delta vs alpha) or for meta-analysis. Analytical code is available from the corresponding author on reasonable request. Requests will be accepted for 3 years after publication.

Recruitment status

No longer recruiting

Date of protocol fixation

2025

Year

01

Month

20

Day

Date of IRB

2025

Year

01

Month

20

Day

Anticipated trial start date

2025

Year

01

Month

20

Day

Last follow-up date

2026

Year

12

Month

31

Day

Date of closure to data entry

Date trial data considered complete

Date analysis concluded

Other related information

none

Registered date

2025

Year

01

Month

20

Day

Last modified on

2026

Year

05

Month

25

Day

Link to view the page

Value
https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000064874