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Efficacy and Safety of FE 999049 in Controlled Ovarian Stimulation in Japanese Women

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ClinicalTrials.gov Identifier: NCT03228680
Recruitment Status : Completed
First Posted : July 25, 2017
Results First Posted : March 24, 2021
Last Update Posted : January 14, 2022
Sponsor:
Information provided by (Responsible Party):
Ferring Pharmaceuticals

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Double (Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Infertility
Interventions Drug: Follitropin delta
Drug: Follitropin beta
Enrollment 373
Recruitment Details A total of 17 investigational sites in Japan randomized participants to the trial between 29 July 2017 to 08 July 2019.
Pre-assignment Details A total of 373 participants were screened. Of these, 25 were screening failures and 348 participants were randomized: 170 participants were exposed to FE 999049 & 177 participants were exposed to FOLLISTIM. One participant was randomized to FOLLISTIM but not exposed to investigational medicinal product (IMP) was considered a randomization failure.
Arm/Group Title FE 999049 (Follitropin Delta) FOLLISTIM (Follitropin Beta)
Hide Arm/Group Description FE 999049 was administered as single daily subcutaneous injections in the abdomen. Participants randomized to FE 999049 had their individual dose determined on the basis of their anti-Müllerian hormone (AMH) level at screening and their body weight at randomization. The daily FE 999049 dose was fixed throughout the stimulation period. The minimum allowed daily FE 999049 dose was 6 μg and maximum allowed daily dose was 12 μg. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days. FOLLISTIM was administered as single daily subcutaneous injections in the abdomen. The starting dose of FOLLISTIM was 150 IU and fixed for the first five stimulation days, after which it could be adjusted by 75 IU based on the individual response. The maximum allowed daily dose was 375 IU. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
Period Title: Overall Study
Started 170 178
Completed 147 143
Not Completed 23 35
Reason Not Completed
Adverse Event             13             18
Randomization failure             0             1
Withdrawal by Subject             1             0
Other             9             16
Arm/Group Title FE 999049 (Follitropin Delta) FOLLISTIM (Follitropin Beta) Total
Hide Arm/Group Description FE 999049 was administered as single daily subcutaneous injections in the abdomen. Participants randomized to FE 999049 had their individual dose determined on the basis of their AMH level at screening and their body weight at randomization. The daily FE 999049 dose was fixed throughout the stimulation period. The minimum allowed daily FE 999049 dose was 6 μg and maximum allowed daily dose was 12 μg. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days. FOLLISTIM was administered as single daily subcutaneous injections in the abdomen. The starting dose of FOLLISTIM was 150 IU and fixed for the first five stimulation days, after which it could be adjusted by 75 IU based on the individual response. The maximum allowed daily dose was 375 IU. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days. Total of all reporting groups
Overall Number of Baseline Participants 170 177 347
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous   [1] 
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 170 participants 177 participants 347 participants
34.2  (3.5) 34.0  (3.4) 34.1  (3.5)
[1]
Measure Description: Number analyzed differs from the overall population as one subject in the FOLLISTIM (Follitropin beta) group was randomized but not exposed to treatment.
Sex: Female, Male   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 170 participants 177 participants 347 participants
Female
170
 100.0%
177
 100.0%
347
 100.0%
Male
0
   0.0%
0
   0.0%
0
   0.0%
[1]
Measure Description: Number analyzed differs from the overall population as one subject in the FOLLISTIM (Follitropin beta) group was randomized but not exposed to treatment.
Ethnicity (NIH/OMB)   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 170 participants 177 participants 347 participants
Hispanic or Latino
0
   0.0%
0
   0.0%
0
   0.0%
Not Hispanic or Latino
170
 100.0%
177
 100.0%
347
 100.0%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
[1]
Measure Description: Number analyzed differs from the overall population as one subject in the FOLLISTIM (Follitropin beta) group was randomized but not exposed to treatment.
Race (NIH/OMB)   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 170 participants 177 participants 347 participants
American Indian or Alaska Native
0
   0.0%
0
   0.0%
0
   0.0%
Asian
170
 100.0%
177
 100.0%
347
 100.0%
Native Hawaiian or Other Pacific Islander
0
   0.0%
0
   0.0%
0
   0.0%
Black or African American
0
   0.0%
0
   0.0%
0
   0.0%
White
0
   0.0%
0
   0.0%
0
   0.0%
More than one race
0
   0.0%
0
   0.0%
0
   0.0%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
[1]
Measure Description: Number analyzed differs from the overall population as one subject in the FOLLISTIM (Follitropin beta) group was randomized but not exposed to treatment.
Region of Enrollment   [1] 
Measure Type: Number
Unit of measure:  Participants
Japan Number Analyzed 170 participants 177 participants 347 participants
170 177 347
[1]
Measure Description: Number analyzed differs from the overall population as one subject in the FOLLISTIM (Follitropin beta) group was randomized but not exposed to treatment.
1.Primary Outcome
Title Number of Oocytes Retrieved
Hide Description The number of oocytes retrieved was recorded at the oocyte retrieval visit.
Time Frame 36h (± 2h) after triggering of final follicular maturation (On day of oocyte retrieval)
Hide Outcome Measure Data
Hide Analysis Population Description
The full analysis set (FAS) comprised all randomized and exposed participants.
Arm/Group Title FE 999049 (Follitropin Delta) FOLLISTIM (Follitropin Beta)
Hide Arm/Group Description:
FE 999049 was administered as single daily subcutaneous injections in the abdomen. Participants randomized to FE 999049 had their individual dose determined on the basis of their AMH level at screening and their body weight at randomization. The daily FE 999049 dose was fixed throughout the stimulation period. The minimum allowed daily FE 999049 dose was 6 μg and maximum allowed daily dose was 12 μg. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
FOLLISTIM was administered as single daily subcutaneous injections in the abdomen. The starting dose of FOLLISTIM was 150 IU and fixed for the first five stimulation days, after which it could be adjusted by 75 IU based on the individual response. The maximum allowed daily dose was 375 IU. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
Overall Number of Participants Analyzed 170 177
Mean (Standard Deviation)
Unit of Measure: Oocytes retrieved
9.3  (5.4) 10.5  (6.1)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection FE 999049 (Follitropin Delta), FOLLISTIM (Follitropin Beta)
Comments Mean number of oocytes retrieved.
Type of Statistical Test Non-Inferiority
Comments The pre-specified non-inferiority (NI) margin was -3.0 oocytes. The NI was evaluated based on the two-sided 95% CI from the ANOVA on 'number of oocytes retrieved' with treatment and AMH stratum as fixed factors.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -1.2
Confidence Interval (2-Sided) 95%
-2.3 to -0.1
Estimation Comments If the lower bound of 95% CI was well above pre-specified NI limit of -3.0 oocytes, then NI of FE 999049 to FOLLISTIM with respect to number of oocytes retrieved in women undergoing controlled ovarian stimulation would be demonstrated
2.Secondary Outcome
Title Clinical Pregnancy Rate
Hide Description Clinical pregnancy was defined as at least one gestational sac 5-6 weeks after transfer.
Time Frame 5-6 weeks after transfer (up to approximately 3 months after start of stimulation)
Hide Outcome Measure Data
Hide Analysis Population Description
The FAS comprised of all randomized and exposed participants.
Arm/Group Title FE 999049 (Follitropin Delta) FOLLISTIM (Follitropin Beta)
Hide Arm/Group Description:
FE 999049 was administered as single daily subcutaneous injections in the abdomen. Participants randomized to FE 999049 had their individual dose determined on the basis of their AMH level at screening and their body weight at randomization. The daily FE 999049 dose was fixed throughout the stimulation period. The minimum allowed daily FE 999049 dose was 6 μg and maximum allowed daily dose was 12 μg. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
FOLLISTIM was administered as single daily subcutaneous injections in the abdomen. The starting dose of FOLLISTIM was 150 IU and fixed for the first five stimulation days, after which it could be adjusted by 75 IU based on the individual response. The maximum allowed daily dose was 375 IU. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
Overall Number of Participants Analyzed 170 177
Measure Type: Number
Unit of Measure: percentage of participants
25.3 23.7
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection FE 999049 (Follitropin Delta), FOLLISTIM (Follitropin Beta)
Comments Percentage of participants with at least one gestational sac 5-6 weeks after transfer.
Type of Statistical Test Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Difference (RD)
Estimated Value 1.6
Confidence Interval (2-Sided) 95%
-7.5 to 10.6
Estimation Comments The difference (FE 999049-FOLLISTIM) in rates was estimated and a two-sided 95% Cl was constructed using the Mantel-Haenszel method to combine results across AMH strata.
3.Secondary Outcome
Title Positive Beta Unit of Human Chorionic Gonadotropin (Beta-hCG) Rate
Hide Description Defined as positive serum beta-hCG test 13-15 days after transfer.
Time Frame 13-15 days after transfer (up to approximately 1.5 months after start of stimulation)
Hide Outcome Measure Data
Hide Analysis Population Description
The FAS comprised of all randomized and exposed participants.
Arm/Group Title FE 999049 (Follitropin Delta) FOLLISTIM (Follitropin Beta)
Hide Arm/Group Description:
FE 999049 was administered as single daily subcutaneous injections in the abdomen. Participants randomized to FE 999049 had their individual dose determined on the basis of their AMH level at screening and their body weight at randomization. The daily FE 999049 dose was fixed throughout the stimulation period. The minimum allowed daily FE 999049 dose was 6 μg and maximum allowed daily dose was 12 μg. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
FOLLISTIM was administered as single daily subcutaneous injections in the abdomen. The starting dose of FOLLISTIM was 150 IU and fixed for the first five stimulation days, after which it could be adjusted by 75 IU based on the individual response. The maximum allowed daily dose was 375 IU. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
Overall Number of Participants Analyzed 170 177
Measure Type: Number
Unit of Measure: percentage of participants
29.4 29.4
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection FE 999049 (Follitropin Delta), FOLLISTIM (Follitropin Beta)
Comments Percentage of participants with positive beta-hCG.
Type of Statistical Test Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Difference (RD)
Estimated Value 0.0
Confidence Interval (2-Sided) 95%
-9.5 to 9.6
Estimation Comments The difference (FE 999049-FOLLISTIM) in rates was estimated and a two-sided 95% Cl was constructed using the Mantel-Haenszel method to combine results across AMH strata.
4.Secondary Outcome
Title Vital Pregnancy Rate
Hide Description Vital pregnancy was defined as at least one intrauterine gestational sac with fetal heart beat 5-6 weeks after transfer.
Time Frame 5-6 weeks after transfer (up to approximately 3 months after start of stimulation)
Hide Outcome Measure Data
Hide Analysis Population Description
The FAS comprised of all randomized and exposed participants.
Arm/Group Title FE 999049 (Follitropin Delta) FOLLISTIM (Follitropin Beta)
Hide Arm/Group Description:
FE 999049 was administered as single daily subcutaneous injections in the abdomen. Participants randomized to FE 999049 had their individual dose determined on the basis of their AMH level at screening and their body weight at randomization. The daily FE 999049 dose was fixed throughout the stimulation period. The minimum allowed daily FE 999049 dose was 6 μg and maximum allowed daily dose was 12 μg. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
FOLLISTIM was administered as single daily subcutaneous injections in the abdomen. The starting dose of FOLLISTIM was 150 IU and fixed for the first five stimulation days, after which it could be adjusted by 75 IU based on the individual response. The maximum allowed daily dose was 375 IU. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
Overall Number of Participants Analyzed 170 177
Measure Type: Number
Unit of Measure: percentage of participants
23.5 21.5
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection FE 999049 (Follitropin Delta), FOLLISTIM (Follitropin Beta)
Comments Percentage of participants with vital pregnancy.
Type of Statistical Test Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Difference (RD)
Estimated Value 2.0
Confidence Interval (2-Sided) 95%
-6.7 to 10.8
Estimation Comments The difference (FE 999049-FOLLISTIM) in rates was estimated and a two-sided 95% Cl was constructed using the Mantel-Haenszel method to combine results across AMH strata.
5.Secondary Outcome
Title Implantation Rate
Hide Description Implantation rate was defined as the number of gestational sacs 5-6 weeks after transfer divided by the number of blastocysts transferred.
Time Frame 5-6 weeks after transfer (up to approximately 3 months after start of stimulation)
Hide Outcome Measure Data
Hide Analysis Population Description
The FAS comprised of all randomized and exposed participants with blastocyst transfer.
Arm/Group Title FE 999049 (Follitropin Delta) FOLLISTIM (Follitropin Beta)
Hide Arm/Group Description:
FE 999049 was administered as single daily subcutaneous injections in the abdomen. Participants randomized to FE 999049 had their individual dose determined on the basis of their AMH level at screening and their body weight at randomization. The daily FE 999049 dose was fixed throughout the stimulation period. The minimum allowed daily FE 999049 dose was 6 μg and maximum allowed daily dose was 12 μg. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
FOLLISTIM was administered as single daily subcutaneous injections in the abdomen. The starting dose of FOLLISTIM was 150 IU and fixed for the first five stimulation days, after which it could be adjusted by 75 IU based on the individual response. The maximum allowed daily dose was 375 IU. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
Overall Number of Participants Analyzed 170 177
Overall Number of Units Analyzed
Type of Units Analyzed: Embryos transferred
135 141
Measure Type: Number
Unit of Measure: % of sacs/blastocysts transferred
31.9 29.8
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection FE 999049 (Follitropin Delta), FOLLISTIM (Follitropin Beta)
Comments Percentage of implanted embryos 5-6 weeks after transfer.
Type of Statistical Test Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Difference (RD)
Estimated Value 1.9
Confidence Interval (2-Sided) 95%
-8.9 to 12.8
Estimation Comments The difference (FE 999049-FOLLISTIM) in rates was estimated and a two-sided 95% Cl was constructed using the Mantel-Haenszel method to combine results across AMH strata.
6.Secondary Outcome
Title Proportion of Participants With Cycle Cancellation Due to Poor or Excessive Ovarian Response
Hide Description [Not Specified]
Time Frame End-of-stimulation (up to 20 stimulation days)
Hide Outcome Measure Data
Hide Analysis Population Description
The FAS comprised of all randomized and exposed participants.
Arm/Group Title FE 999049 (Follitropin Delta) FOLLISTIM (Follitropin Beta)
Hide Arm/Group Description:
FE 999049 was administered as single daily subcutaneous injections in the abdomen. Participants randomized to FE 999049 had their individual dose determined on the basis of their AMH level at screening and their body weight at randomization. The daily FE 999049 dose was fixed throughout the stimulation period. The minimum allowed daily FE 999049 dose was 6 μg and maximum allowed daily dose was 12 μg. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
FOLLISTIM was administered as single daily subcutaneous injections in the abdomen. The starting dose of FOLLISTIM was 150 IU and fixed for the first five stimulation days, after which it could be adjusted by 75 IU based on the individual response. The maximum allowed daily dose was 375 IU. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
Overall Number of Participants Analyzed 170 177
Measure Type: Number
Unit of Measure: percentage of participants
Cycle cancelled due to poor ovarian response 1.2 0.6
Cycle cancelled due to excessive ovarian response 0 1.1
7.Secondary Outcome
Title Proportion of Participants With Blastocyst Transfer Cancellation Due to Excessive Ovarian Response / OHSS Risk
Hide Description [Not Specified]
Time Frame End-of-stimulation (up to 20 stimulation days)
Hide Outcome Measure Data
Hide Analysis Population Description
The FAS comprised of all randomized and exposed participants.
Arm/Group Title FE 999049 (Follitropin Delta) FOLLISTIM (Follitropin Beta)
Hide Arm/Group Description:
FE 999049 was administered as single daily subcutaneous injections in the abdomen. Participants randomized to FE 999049 had their individual dose determined on the basis of their AMH level at screening and their body weight at randomization. The daily FE 999049 dose was fixed throughout the stimulation period. The minimum allowed daily FE 999049 dose was 6 μg and maximum allowed daily dose was 12 μg. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
FOLLISTIM was administered as single daily subcutaneous injections in the abdomen. The starting dose of FOLLISTIM was 150 IU and fixed for the first five stimulation days, after which it could be adjusted by 75 IU based on the individual response. The maximum allowed daily dose was 375 IU. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
Overall Number of Participants Analyzed 170 177
Measure Type: Number
Unit of Measure: percentage of participants
7.6 11.3
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection FE 999049 (Follitropin Delta), FOLLISTIM (Follitropin Beta)
Comments Proportion of participants with blastocyst transfer cancellation.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.244
Comments P-value was based on likelihood ratio chi-square test.
Method Regression, Logistic
Comments The model included treatment and AMH stratum (<15 pmol/L and ≥15 pmol/L) as fixed factors.
8.Secondary Outcome
Title Proportion of Participants With <4, 4-7, 8-14, 15-19 and ≥20 Oocytes Retrieved
Hide Description Defined as proportion of participants grouped according to the number of oocytes retrieved. The proportion of participants with <4 oocytes (low response), 4-7 oocytes (moderate response), 8-14 oocytes (targeted response), 15-19 oocytes (hyperresponse) and ≥20 oocytes (severe hyperresponse) are presented.
Time Frame On the day of oocyte retrieval (up to 22 days after start of stimulation)
Hide Outcome Measure Data
Hide Analysis Population Description
The FAS comprised of all randomized and exposed participants.
Arm/Group Title FE 999049 (Follitropin Delta) FOLLISTIM (Follitropin Beta)
Hide Arm/Group Description:
FE 999049 was administered as single daily subcutaneous injections in the abdomen. Participants randomized to FE 999049 had their individual dose determined on the basis of their AMH level at screening and their body weight at randomization. The daily FE 999049 dose was fixed throughout the stimulation period. The minimum allowed daily FE 999049 dose was 6 μg and maximum allowed daily dose was 12 μg. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
FOLLISTIM was administered as single daily subcutaneous injections in the abdomen. The starting dose of FOLLISTIM was 150 IU and fixed for the first five stimulation days, after which it could be adjusted by 75 IU based on the individual response. The maximum allowed daily dose was 375 IU. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
Overall Number of Participants Analyzed 169 173
Measure Type: Number
Unit of Measure: percentage of participants
Low response (<4 oocytes) 8.3 5.2
Moderate response (4-7 oocytes) 36.1 26.6
Targeted response (8-14 oocytes) 40.8 42.8
Hyperresponse (15-19 oocytes) 10.1 14.5
Severe hyperresponse (≥ 20 oocytes) 4.7 11.0
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection FE 999049 (Follitropin Delta), FOLLISTIM (Follitropin Beta)
Comments Proportion of participants with <4 oocytes retrieved (low response).
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.254
Comments P-value was based on likelihood ratio chi-square test.
Method Regression, Logistic
Comments The model included treatment and AMH stratum (<15 pmol/L and ≥15 pmol/L) as fixed factors.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection FE 999049 (Follitropin Delta), FOLLISTIM (Follitropin Beta)
Comments Proportion of participants with 4-7 oocytes retrieved (moderate response).
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.041
Comments P-value was based on likelihood ratio test.
Method Regression, Logistic
Comments The model included treatment and AMH stratum (<15 pmol/L and ≥15 pmol/L) as fixed factors.
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection FE 999049 (Follitropin Delta), FOLLISTIM (Follitropin Beta)
Comments Proportion of participants with 8-14 oocytes retrieved (targeted response).
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.705
Comments P-value was based on likelihood ratio test.
Method Regression, Logistic
Comments The model included treatment and AMH stratum (<15 pmol/L and ≥15 pmol/L) as fixed factors.
Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection FE 999049 (Follitropin Delta), FOLLISTIM (Follitropin Beta)
Comments Proportion of participants with 15-19 oocytes retrieved (hyperresponse).
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.183
Comments P-value was based on likelihood ratio test.
Method Regression, Logistic
Comments The model included treatment and AMH stratum (<15 pmol/L and ≥15 pmol/L) as fixed factors.
Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection FE 999049 (Follitropin Delta), FOLLISTIM (Follitropin Beta)
Comments Proportion of participants with >= (more than equal to) 20 oocytes retrieved (severe hyperresponse).
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.030
Comments P-value was based on likelihood ratio chi-square test.
Method Regression, Logistic
Comments The model included treatment and AMH stratum (<15 pmol/L and ≥15 pmol/L) as fixed factors.
9.Secondary Outcome
Title Proportion of Participants With Extreme Ovarian Responses (Defined as <4, ≥15 or ≥20 Oocytes Retrieved) in Risk Population
Hide Description [Not Specified]
Time Frame On the day of oocyte retrieval (up to 22 days after start of stimulation)
Hide Outcome Measure Data
Hide Analysis Population Description
The FAS comprised of all randomized and exposed participants.
Arm/Group Title FE 999049 (Follitropin Delta) FOLLISTIM (Follitropin Beta)
Hide Arm/Group Description:
FE 999049 was administered as single daily subcutaneous injections in the abdomen. Participants randomized to FE 999049 had their individual dose determined on the basis of their AMH level at screening and their body weight at randomization. The daily FE 999049 dose was fixed throughout the stimulation period. The minimum allowed daily FE 999049 dose was 6 μg and maximum allowed daily dose was 12 μg. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
FOLLISTIM was administered as single daily subcutaneous injections in the abdomen. The starting dose of FOLLISTIM was 150 IU and fixed for the first five stimulation days, after which it could be adjusted by 75 IU based on the individual response. The maximum allowed daily dose was 375 IU. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
Overall Number of Participants Analyzed 169 173
Measure Type: Number
Unit of Measure: percentage of participants
AMH < 15 pmol/L (<4 oocytes retrieved) Number Analyzed 69 participants 73 participants
11.6 12.3
AMH >= 15 pmol/L (>=15 oocytes retrieved) Number Analyzed 100 participants 100 participants
22.0 42.0
AMH >= 15 pmol/L (>=20 oocytes retrieved) Number Analyzed 100 participants 100 participants
8.0 19.0
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection FE 999049 (Follitropin Delta), FOLLISTIM (Follitropin Beta)
Comments Proportion of participants with extreme ovarian responses: AMH < 15 pmol/L (<4 oocytes retrieved)
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.893
Comments P-value was based on likelihood ratio chi-square test.
Method Chi-squared
Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection FE 999049 (Follitropin Delta), FOLLISTIM (Follitropin Beta)
Comments Proportion of participants with extreme ovarian responses: AMH >= 15 pmol/L (>=15 oocytes retrieved)
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.002
Comments P-value was based on likelihood ratio chi-square test.
Method Chi-squared
Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection FE 999049 (Follitropin Delta), FOLLISTIM (Follitropin Beta)
Comments Proportion of participants with extreme ovarian responses: AMH >= 15 pmol/L (>=20 oocytes retrieved)
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.021
Comments P-value based on likelihood ratio chi-square test.
Method Chi-squared
Comments [Not Specified]
10.Secondary Outcome
Title Proportion of Participants With Preventive Interventions for Early Ovarian Hyperstimulation Syndrome (OHSS)
Hide Description [Not Specified]
Time Frame ≤9 days after triggering of final follicular maturation
Hide Outcome Measure Data
Hide Analysis Population Description
The FAS comprised of all participants randomized or exposed.
Arm/Group Title FE 999049 (Follitropin Delta) FOLLISTIM (Follitropin Beta)
Hide Arm/Group Description:
FE 999049 was administered as single daily subcutaneous injections in the abdomen. Participants randomized to FE 999049 had their individual dose determined on the basis of their AMH level at screening and their body weight at randomization. The daily FE 999049 dose was fixed throughout the stimulation period. The minimum allowed daily FE 999049 dose was 6 μg and maximum allowed daily dose was 12 μg. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
FOLLISTIM was administered as single daily subcutaneous injections in the abdomen. The starting dose of FOLLISTIM was 150 IU and fixed for the first five stimulation days, after which it could be adjusted by 75 IU based on the individual response. The maximum allowed daily dose was 375 IU. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
Overall Number of Participants Analyzed 170 177
Measure Type: Number
Unit of Measure: percentage of participants
Cycle cancellation 0 1.1
Triggering with GnRH agonist 1.2 1.1
Administration of dopamine agonist 0.6 1.7
11.Secondary Outcome
Title Proportions of Participants With Early OHSS (Including OHSS of Moderate/Severe Grade) and/or Preventive Interventions for Early OHSS
Hide Description Defined as proportion of participants with early OHSS, early OHSS of moderate or severe grade, preventive interventions for early OHSS, early OHSS and/or preventive interventions for early OHSS, and early OHSS of moderate or severe grade and/or preventive interventions for early OHSS are presented.
Time Frame Up to 9 days after triggering of final follicular maturation
Hide Outcome Measure Data
Hide Analysis Population Description
The FAS comprised of all participants randomized and exposed.
Arm/Group Title FE 999049 (Follitropin Delta) FOLLISTIM (Follitropin Beta)
Hide Arm/Group Description:
FE 999049 was administered as single daily subcutaneous injections in the abdomen. Participants randomized to FE 999049 had their individual dose determined on the basis of their AMH level at screening and their body weight at randomization. The daily FE 999049 dose was fixed throughout the stimulation period. The minimum allowed daily FE 999049 dose was 6 μg and maximum allowed daily dose was 12 μg. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
FOLLISTIM was administered as single daily subcutaneous injections in the abdomen. The starting dose of FOLLISTIM was 150 IU and fixed for the first five stimulation days, after which it could be adjusted by 75 IU based on the individual response. The maximum allowed daily dose was 375 IU. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
Overall Number of Participants Analyzed 170 177
Measure Type: Number
Unit of Measure: percentage of participants
Early OHSS (any grade) 10.0 18.6
Early OHSS (moderate/severe) 6.5 13.0
Early OHSS (any grade) and/or preventive 10.6 20.9
Early OHSS (moderate/severe) and/or preventive 7.6 16.4
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection FE 999049 (Follitropin Delta), FOLLISTIM (Follitropin Beta)
Comments Proportions of participants with early OHSS (any grade).
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.017
Comments P-value was based on likelihood ratio chi-square test.
Method Regression, Logistic
Comments The model included treatment and AMH stratum (<15 pmol/L and ≥15 pmol/L) as fixed factors.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection FE 999049 (Follitropin Delta), FOLLISTIM (Follitropin Beta)
Comments Proportion of participants with early OHSS (moderate/severe).
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.035
Comments P-value was based on likelihood ratio chi-square test.
Method Regression, Logistic
Comments The model included treatment and AMH stratum (<15 pmol/L and ≥15 pmol/L) as fixed factors.
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection FE 999049 (Follitropin Delta), FOLLISTIM (Follitropin Beta)
Comments Proportion of participants with early OHSS (any grade) and/or preventive interventions.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.006
Comments P-value was based on likelihood ratio chi-square test.
Method Regression, Logistic
Comments The model included treatment and AMH stratum (<15 pmol/L and ≥15 pmol/L) as fixed factors.
Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection FE 999049 (Follitropin Delta), FOLLISTIM (Follitropin Beta)
Comments Proportion of participants with early OHSS (moderate/severe) and/or preventive interventions.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.009
Comments P-value was based on likelihood ratio chi-square test.
Method Regression, Logistic
Comments The model included treatment and AMH stratum (<15 pmol/L and ≥15 pmol/L) as fixed factors.
12.Secondary Outcome
Title Proportions of Participants With Late OHSS (Including OHSS of Moderate/Severe Grade)
Hide Description

Defined as proportions of participants with late OHSS (including OHSS of moderate/severe grade).

Late OHSS was defined as OHSS with onset >9 days after triggering of final follicular maturation. The proportion of participants with late OHSS, and late OHSS of moderate or severe grade are presented. All OHSS cases were graded as mild, moderate, or severe.

Time Frame >9 days after triggering of final follicular maturation
Hide Outcome Measure Data
Hide Analysis Population Description
The FAS comprised of all participants randomized or exposed.
Arm/Group Title FE 999049 (Follitropin Delta) FOLLISTIM (Follitropin Beta)
Hide Arm/Group Description:
FE 999049 was administered as single daily subcutaneous injections in the abdomen. Participants randomized to FE 999049 had their individual dose determined on the basis of their AMH level at screening and their body weight at randomization. The daily FE 999049 dose was fixed throughout the stimulation period. The minimum allowed daily FE 999049 dose was 6 μg and maximum allowed daily dose was 12 μg. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
FOLLISTIM was administered as single daily subcutaneous injections in the abdomen. The starting dose of FOLLISTIM was 150 IU and fixed for the first five stimulation days, after which it could be adjusted by 75 IU based on the individual response. The maximum allowed daily dose was 375 IU. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
Overall Number of Participants Analyzed 170 177
Measure Type: Number
Unit of Measure: percentage of participants
Late OHSS (any grade) 1.2 1.1
Late OHSS (moderate/severe) 0.6 1.1
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection FE 999049 (Follitropin Delta), FOLLISTIM (Follitropin Beta)
Comments Proportions of participants with late OHSS (any grade).
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.968
Comments P-value was based on likelihood ratio chi-square test.
Method Regression, Logistic
Comments The model included treatment and AMH stratum (<15 pmol/L and ≥15 pmol/L) as fixed factors.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection FE 999049 (Follitropin Delta), FOLLISTIM (Follitropin Beta)
Comments Proportions of participants with late OHSS (moderate/severe).
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.582
Comments P-value was based on likelihood ratio chi-square test.
Method Regression, Logistic
Comments The model included treatment and AMH stratum (<15 pmol/L and ≥15 pmol/L) as fixed factors.
13.Secondary Outcome
Title Number of Follicles on Stimulation Day 6
Hide Description Defined as the number of follicles observed in both ovaries at the last transvaginal ultrasound (TVUS) in the stimulation phase (on stimulation Day 6).
Time Frame At Day 6 of stimulation
Hide Outcome Measure Data
Hide Analysis Population Description
The FAS comprised of all randomized or exposed participants.
Arm/Group Title FE 999049 (Follitropin Delta) FOLLISTIM (Follitropin Beta)
Hide Arm/Group Description:
FE 999049 was administered as single daily subcutaneous injections in the abdomen. Participants randomized to FE 999049 had their individual dose determined on the basis of their AMH level at screening and their body weight at randomization. The daily FE 999049 dose was fixed throughout the stimulation period. The minimum allowed daily FE 999049 dose was 6 μg and maximum allowed daily dose was 12 μg. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
FOLLISTIM was administered as single daily subcutaneous injections in the abdomen. The starting dose of FOLLISTIM was 150 IU and fixed for the first five stimulation days, after which it could be adjusted by 75 IU based on the individual response. The maximum allowed daily dose was 375 IU. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
Overall Number of Participants Analyzed 170 177
Mean (Standard Deviation)
Unit of Measure: Follicles
12.8  (7.2) 13.3  (7.1)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection FE 999049 (Follitropin Delta), FOLLISTIM (Follitropin Beta)
Comments The number of follicles on stimulation Day 6 was analyzed.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.198
Comments 2-sided
Method van Elteren test
Comments P-value was based on van Elteren test adjusted for AMH strata.
14.Secondary Outcome
Title Number of Follicles at End-of-stimulation
Hide Description Defined as the number of follicles observed in both ovaries at the last TVUS in the stimulation phase (end-of-stimulation).
Time Frame End-of-stimulation (up to 20 stimulation days)
Hide Outcome Measure Data
Hide Analysis Population Description
The FAS comprised of all randomized or exposed participants.
Arm/Group Title FE 999049 (Follitropin Delta) FOLLISTIM (Follitropin Beta)
Hide Arm/Group Description:
FE 999049 was administered as single daily subcutaneous injections in the abdomen. Participants randomized to FE 999049 had their individual dose determined on the basis of their AMH level at screening and their body weight at randomization. The daily FE 999049 dose was fixed throughout the stimulation period. The minimum allowed daily FE 999049 dose was 6 μg and maximum allowed daily dose was 12 μg. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
FOLLISTIM was administered as single daily subcutaneous injections in the abdomen. The starting dose of FOLLISTIM was 150 IU and fixed for the first five stimulation days, after which it could be adjusted by 75 IU based on the individual response. The maximum allowed daily dose was 375 IU. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
Overall Number of Participants Analyzed 170 177
Mean (Standard Deviation)
Unit of Measure: Follicles
14.9  (8.0) 16.3  (8.8)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection FE 999049 (Follitropin Delta), FOLLISTIM (Follitropin Beta)
Comments The number of follicles at end-of-stimulation was analyzed.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.036
Comments 2-sided
Method van Elteren test
Comments P-value was based on van Elteren test adjusted for AMH strata.
15.Secondary Outcome
Title Size of Follicles on Stimulation Day 6
Hide Description

Defined as size characteristics of follicles on stimulation Day 6.

Average size of 3 largest follicles has been presented in this endpoint.

Time Frame At Day 6 of stimulation
Hide Outcome Measure Data
Hide Analysis Population Description
The FAS comprised of all randomized and exposed participants
Arm/Group Title FE 999049 (Follitropin Delta) FOLLISTIM (Follitropin Beta)
Hide Arm/Group Description:
FE 999049 was administered as single daily subcutaneous injections in the abdomen. Participants randomized to FE 999049 had their individual dose determined on the basis of their AMH level at screening and their body weight at randomization. The daily FE 999049 dose was fixed throughout the stimulation period. The minimum allowed daily FE 999049 dose was 6 μg and maximum allowed daily dose was 12 μg. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
FOLLISTIM was administered as single daily subcutaneous injections in the abdomen. The starting dose of FOLLISTIM was 150 IU and fixed for the first five stimulation days, after which it could be adjusted by 75 IU based on the individual response. The maximum allowed daily dose was 375 IU. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
Overall Number of Participants Analyzed 170 177
Mean (Standard Deviation)
Unit of Measure: mm
12.7  (2.1) 12.8  (2.0)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection FE 999049 (Follitropin Delta), FOLLISTIM (Follitropin Beta)
Comments The average size of 3 largest follicles was analyzed.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.592
Comments 2-sided
Method van Elteren test
Comments P-value was based on van Elteren test adjusted for AMH strata.
16.Secondary Outcome
Title Size of Follicles at End-of-Stimulation
Hide Description

Defined as size characteristics of follicles at end-of-stimulation.

Average size of 3 largest follicles has been presented in this endpoint.

Time Frame End-of-stimulation (up to 20 stimulation days)
Hide Outcome Measure Data
Hide Analysis Population Description
The FAS comprised of all randomized and exposed participants
Arm/Group Title FE 999049 (Follitropin Delta) FOLLISTIM (Follitropin Beta)
Hide Arm/Group Description:
FE 999049 was administered as single daily subcutaneous injections in the abdomen. Participants randomized to FE 999049 had their individual dose determined on the basis of their AMH level at screening and their body weight at randomization. The daily FE 999049 dose was fixed throughout the stimulation period. The minimum allowed daily FE 999049 dose was 6 μg and maximum allowed daily dose was 12 μg. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
FOLLISTIM was administered as single daily subcutaneous injections in the abdomen. The starting dose of FOLLISTIM was 150 IU and fixed for the first five stimulation days, after which it could be adjusted by 75 IU based on the individual response. The maximum allowed daily dose was 375 IU. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
Overall Number of Participants Analyzed 170 177
Mean (Standard Deviation)
Unit of Measure: mm
19.2  (1.5) 19.4  (1.6)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection FE 999049 (Follitropin Delta), FOLLISTIM (Follitropin Beta)
Comments The average size of 3 largest follicles was analyzed.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.286
Comments 2-sided
Method van Elteren test
Comments P-value was based on van Elteren test adjusted for AMH strata.
17.Secondary Outcome
Title Fertilization Rate
Hide Description The fertilization rate was defined as the number of oocytes with 2 pronuclei divided by the number of oocytes retrieved.
Time Frame Day 1 after oocyte retrieval (up to approximately 22 days after start of stimulation)
Hide Outcome Measure Data
Hide Analysis Population Description
The FAS comprised all randomized and exposed participants
Arm/Group Title FE 999049 (Follitropin Delta) FOLLISTIM (Follitropin Beta)
Hide Arm/Group Description:
FE 999049 was administered as single daily subcutaneous injections in the abdomen. Participants randomized to FE 999049 had their individual dose determined on the basis of their AMH level at screening and their body weight at randomization. The daily FE 999049 dose was fixed throughout the stimulation period. The minimum allowed daily FE 999049 dose was 6 μg and maximum allowed daily dose was 12 μg. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
FOLLISTIM was administered as single daily subcutaneous injections in the abdomen. The starting dose of FOLLISTIM was 150 IU and fixed for the first five stimulation days, after which it could be adjusted by 75 IU based on the individual response. The maximum allowed daily dose was 375 IU. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
Overall Number of Participants Analyzed 170 177
Mean (Standard Deviation)
Unit of Measure: percentage of fertilized oocytes
54.5  (26.1) 57.1  (23.4)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection FE 999049 (Follitropin Delta), FOLLISTIM (Follitropin Beta)
Comments The fertilization rate (number of oocytes with 2 pronuclei divided by the number of oocytes retrieved) was analyzed.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.395
Comments 2-sided
Method van Elteren test
Comments P-value was based on van Elteren test adjusted for AMH strata.
18.Secondary Outcome
Title Number and Quality of Embryos
Hide Description Number of embryos (total and good-quality) on Day 3 are presented. A good-quality embryo was defined as an embryo with ≥6 blastomeres and fragmentation ≤20% on Day 3.
Time Frame Day 3 after oocyte retrieval (up to approximately 24 days after start of stimulation)
Hide Outcome Measure Data
Hide Analysis Population Description
The FAS comprised of all randomized and exposed participants.
Arm/Group Title FE 999049 (Follitropin Delta) FOLLISTIM (Follitropin Beta)
Hide Arm/Group Description:
FE 999049 was administered as single daily subcutaneous injections in the abdomen. Participants randomized to FE 999049 had their individual dose determined on the basis of their AMH level at screening and their body weight at randomization. The daily FE 999049 dose was fixed throughout the stimulation period. The minimum allowed daily FE 999049 dose was 6 μg and maximum allowed daily dose was 12 μg. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
FOLLISTIM was administered as single daily subcutaneous injections in the abdomen. The starting dose of FOLLISTIM was 150 IU and fixed for the first five stimulation days, after which it could be adjusted by 75 IU based on the individual response. The maximum allowed daily dose was 375 IU. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
Overall Number of Participants Analyzed 170 177
Mean (Standard Deviation)
Unit of Measure: Embryo
Number of embryo 5.8  (4.2) 7.0  (4.3)
Number of good-quality embryo 3.9  (3.3) 4.6  (3.3)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection FE 999049 (Follitropin Delta), FOLLISTIM (Follitropin Beta)
Comments The number of embryos on Day 3 was analyzed.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.001
Comments 2-sided
Method van Elteren test
Comments P-value was based on van Elteren test adjusted for AMH strata.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection FE 999049 (Follitropin Delta), FOLLISTIM (Follitropin Beta)
Comments The number of good-quality embryos on Day 3 was analyzed.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.004
Comments 2-sided
Method van Elteren test
Comments P-value was based on van Elteren test adjusted for AMH strata.
19.Secondary Outcome
Title Number and Quality of Blastocysts
Hide Description Number of embryos (total and good-quality) on Day 5 are presented. The quality evaluation of blastocysts consisted of assessment of three parameters, as per the Gardner & Schoolcraft system: blastocyst expansion and hatching status (graded: 1-6), inner cell mass (graded: A-D) and trophectoderm (graded: A-D). A good-quality blastocyst was defined as a blastocyst of grade 3BB or higher.
Time Frame Day 5 after oocyte retrieval (up to approximately 26 days after start of stimulation)
Hide Outcome Measure Data
Hide Analysis Population Description
The FAS comprised of all randomized and exposed participants.
Arm/Group Title FE 999049 (Follitropin Delta) FOLLISTIM (Follitropin Beta)
Hide Arm/Group Description:
FE 999049 was administered as single daily subcutaneous injections in the abdomen. Participants randomized to FE 999049 had their individual dose determined on the basis of their AMH level at screening and their body weight at randomization. The daily FE 999049 dose was fixed throughout the stimulation period. The minimum allowed daily FE 999049 dose was 6 μg and maximum allowed daily dose was 12 μg. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
FOLLISTIM was administered as single daily subcutaneous injections in the abdomen. The starting dose of FOLLISTIM was 150 IU and fixed for the first five stimulation days, after which it could be adjusted by 75 IU based on the individual response. The maximum allowed daily dose was 375 IU. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
Overall Number of Participants Analyzed 170 177
Mean (Standard Deviation)
Unit of Measure: Blastocysts
Number of blastocysts 3.1  (2.7) 4.2  (3.4)
Number of good-quality blastocysts 2.3  (2.3) 3.0  (2.6)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection FE 999049 (Follitropin Delta), FOLLISTIM (Follitropin Beta)
Comments The number of blastocysts on Day 5 was analyzed.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <.001
Comments 2-sided
Method van Elteren test
Comments P-value was based on van Elteren test adjusted for AMH strata.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection FE 999049 (Follitropin Delta), FOLLISTIM (Follitropin Beta)
Comments The number of good-quality blastocysts on Day 5 was analyzed.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments 2-sided
Method van Elteren test
Comments P-value was based on van Elteren test adjusted for AMH strata.
20.Secondary Outcome
Title Circulating Levels of Endocrine Parameters (Follicle-stimulating Hormone [FSH], Luteinising Hormone [LH]) on Stimulation Day 6
Hide Description The median and inter-quartile range (IQR) of FSH and LH levels on stimulation Day 6 are presented.
Time Frame At Day 6 of stimulation
Hide Outcome Measure Data
Hide Analysis Population Description
The FAS comprised of all randomized and exposed participants.
Arm/Group Title FE 999049 (Follitropin Delta) FOLLISTIM (Follitropin Beta)
Hide Arm/Group Description:
FE 999049 was administered as single daily subcutaneous injections in the abdomen. Participants randomized to FE 999049 had their individual dose determined on the basis of their AMH level at screening and their body weight at randomization. The daily FE 999049 dose was fixed throughout the stimulation period. The minimum allowed daily FE 999049 dose was 6 μg and maximum allowed daily dose was 12 μg. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
FOLLISTIM was administered as single daily subcutaneous injections in the abdomen. The starting dose of FOLLISTIM was 150 IU and fixed for the first five stimulation days, after which it could be adjusted by 75 IU based on the individual response. The maximum allowed daily dose was 375 IU. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
Overall Number of Participants Analyzed 166 175
Median (Inter-Quartile Range)
Unit of Measure: IU/L
FSH
15.4
(12.0 to 19.6)
14.7
(12.8 to 17.3)
LH
2.6
(1.5 to 6.2)
2.8
(1.6 to 5.9)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection FE 999049 (Follitropin Delta), FOLLISTIM (Follitropin Beta)
Comments Circulating levels of FSH on stimulation Day 6.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.228
Comments The P-value corresponds to the two-sided F-test of treatment effect.
Method ANCOVA
Comments The ANCOVA model included treatment and AMH stratum (<15 pmol/L and ≥15 pmol/L) as fixed factors and log-baseline as covariate.
Method of Estimation Estimation Parameter Mean ratio
Estimated Value 1.03
Confidence Interval (2-Sided) 95%
0.98 to 1.09
Estimation Comments Mean ratio is equal to FE 999049/FOLLISTIM.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection FE 999049 (Follitropin Delta), FOLLISTIM (Follitropin Beta)
Comments Circulating levels of LH on stimulation Day 6.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.777
Comments The P-value corresponds to the two-sided F-test of treatment effect.
Method ANCOVA
Comments The ANCOVA model included treatment and AMH stratum (<15 pmol/L and ≥15 pmol/L) as fixed factors and log-baseline as covariate.
Method of Estimation Estimation Parameter Mean ratio
Estimated Value 0.97
Confidence Interval (2-Sided) 95%
0.81 to 1.17
Estimation Comments Mean ratio is equal to FE 999049/FOLLISTIM.
21.Secondary Outcome
Title Circulating Levels of Endocrine Parameters (Follicle-stimulating Hormone [FSH], Luteinising Hormone [LH]) at End-of-stimulation
Hide Description The median and IQR of FSH and LH levels at end-of-stimulation are presented.
Time Frame End-of-stimulation (up to 20 stimulation days)
Hide Outcome Measure Data
Hide Analysis Population Description
The FAS comprised of all randomized and exposed participants.
Arm/Group Title FE 999049 (Follitropin Delta) FOLLISTIM (Follitropin Beta)
Hide Arm/Group Description:
FE 999049 was administered as single daily subcutaneous injections in the abdomen. Participants randomized to FE 999049 had their individual dose determined on the basis of their AMH level at screening and their body weight at randomization. The daily FE 999049 dose was fixed throughout the stimulation period. The minimum allowed daily FE 999049 dose was 6 μg and maximum allowed daily dose was 12 μg. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
FOLLISTIM was administered as single daily subcutaneous injections in the abdomen. The starting dose of FOLLISTIM was 150 IU and fixed for the first five stimulation days, after which it could be adjusted by 75 IU based on the individual response. The maximum allowed daily dose was 375 IU. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
Overall Number of Participants Analyzed 169 172
Median (Inter-Quartile Range)
Unit of Measure: IU/L
FSH
14.3
(11.6 to 19.7)
16.4
(13.5 to 20.4)
LH
1.6
(1.0 to 2.5)
1.4
(0.9 to 2.3)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection FE 999049 (Follitropin Delta), FOLLISTIM (Follitropin Beta)
Comments Circulating levels of FSH at end-of-stimulation.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments The P-value corresponds to the two-sided F-test of treatment effect.
Method ANCOVA
Comments The ANCOVA model included treatment and AMH stratum (<15 pmol/L and ≥15 pmol/L) as fixed factors and log-baseline as covariate.
Method of Estimation Estimation Parameter Mean ratio
Estimated Value 0.89
Confidence Interval (2-Sided) 95%
0.84 to 0.94
Estimation Comments Mean ratio is equal to FE 999049/FOLLISTIM.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection FE 999049 (Follitropin Delta), FOLLISTIM (Follitropin Beta)
Comments Circulating levels of LH at end-of-stimulation.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.057
Comments The P-value corresponds to the two-sided F-test of treatment effect.
Method ANCOVA
Comments The ANCOVA model included treatment and AMH stratum (<15 pmol/L and ≥15 pmol/L) as fixed factors and log-baseline as covariate.
Method of Estimation Estimation Parameter Mean ratio
Estimated Value 1.17
Confidence Interval (2-Sided) 95%
1.00 to 1.39
Estimation Comments Mean ratio is equal to FE 999049/FOLLISTIM.
22.Secondary Outcome
Title Circulating Levels of Endocrine Parameter (Estradiol) on Stimulation Day 6
Hide Description The median and IQR of estradiol levels on stimulation Day 6 are presented.
Time Frame At Day 6 of stimulation
Hide Outcome Measure Data
Hide Analysis Population Description
The FAS comprised of all randomized and exposed participants.
Arm/Group Title FE 999049 (Follitropin Delta) FOLLISTIM (Follitropin Beta)
Hide Arm/Group Description:
FE 999049 was administered as single daily subcutaneous injections in the abdomen. Participants randomized to FE 999049 had their individual dose determined on the basis of their AMH level at screening and their body weight at randomization. The daily FE 999049 dose was fixed throughout the stimulation period. The minimum allowed daily FE 999049 dose was 6 μg and maximum allowed daily dose was 12 μg. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
FOLLISTIM was administered as single daily subcutaneous injections in the abdomen. The starting dose of FOLLISTIM was 150 IU and fixed for the first five stimulation days, after which it could be adjusted by 75 IU based on the individual response. The maximum allowed daily dose was 375 IU. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
Overall Number of Participants Analyzed 166 175
Median (Inter-Quartile Range)
Unit of Measure: pmol/L
2277.1
(1479.4 to 3580.1)
2680.0
(1608.8 to 4685.9)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection FE 999049 (Follitropin Delta), FOLLISTIM (Follitropin Beta)
Comments Circulating levels of estradiol on stimulation Day 6.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.002
Comments The P-value corresponds to the two-sided F-test of treatment effect.
Method ANCOVA
Comments The ANCOVA model included treatment and AMH stratum (<15 pmol/L and ≥15 pmol/L) as fixed factors and log-baseline as covariate.
Method of Estimation Estimation Parameter Mean ratio
Estimated Value 0.81
Confidence Interval (2-Sided) 95%
0.71 to 0.93
Estimation Comments Mean ratio is equal to FE 999049/FOLLISTIM.
23.Secondary Outcome
Title Circulating Levels of Endocrine Parameter (Estradiol) at End-of-stimulation
Hide Description The median and IQR of estradiol levels at end-of-stimulation are presented.
Time Frame End-of-stimulation (up to 20 stimulation days)
Hide Outcome Measure Data
Hide Analysis Population Description
The FAS comprised of all randomized and exposed participants.
Arm/Group Title FE 999049 (Follitropin Delta) FOLLISTIM (Follitropin Beta)
Hide Arm/Group Description:
FE 999049 was administered as single daily subcutaneous injections in the abdomen. Participants randomized to FE 999049 had their individual dose determined on the basis of their AMH level at screening and their body weight at randomization. The daily FE 999049 dose was fixed throughout the stimulation period. The minimum allowed daily FE 999049 dose was 6 μg and maximum allowed daily dose was 12 μg. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
FOLLISTIM was administered as single daily subcutaneous injections in the abdomen. The starting dose of FOLLISTIM was 150 IU and fixed for the first five stimulation days, after which it could be adjusted by 75 IU based on the individual response. The maximum allowed daily dose was 375 IU. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
Overall Number of Participants Analyzed 169 172
Median (Inter-Quartile Range)
Unit of Measure: pmol/L
6517.0
(4465.3 to 9033.4)
7438.8
(5363.6 to 10283.1)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection FE 999049 (Follitropin Delta), FOLLISTIM (Follitropin Beta)
Comments Circulating levels of estradiol at end-of-stimulation.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.003
Comments The P-value corresponds to the two-sided F-test of treatment effect.
Method ANCOVA
Comments The ANCOVA model included treatment and AMH stratum (<15 pmol/L and ≥15 pmol/L) as fixed factors and log-baseline as covariate.
Method of Estimation Estimation Parameter Mean ratio
Estimated Value 0.85
Confidence Interval (2-Sided) 95%
0.76 to 0.95
Estimation Comments Mean ratio is equal to FE 999049/FOLLISTIM.
24.Secondary Outcome
Title Circulating Levels of Endocrine Parameter (Progesterone) on Stimulation Day 6
Hide Description The median and IQR of progesterone levels on stimulation Day 6 are presented.
Time Frame At Day 6 of stimulation
Hide Outcome Measure Data
Hide Analysis Population Description
The FAS comprised of all randomized and exposed participants.
Arm/Group Title FE 999049 (Follitropin Delta) FOLLISTIM (Follitropin Beta)
Hide Arm/Group Description:
FE 999049 was administered as single daily subcutaneous injections in the abdomen. Participants randomized to FE 999049 had their individual dose determined on the basis of their AMH level at screening and their body weight at randomization. The daily FE 999049 dose was fixed throughout the stimulation period. The minimum allowed daily FE 999049 dose was 6 μg and maximum allowed daily dose was 12 μg. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
FOLLISTIM was administered as single daily subcutaneous injections in the abdomen. The starting dose of FOLLISTIM was 150 IU and fixed for the first five stimulation days, after which it could be adjusted by 75 IU based on the individual response. The maximum allowed daily dose was 375 IU. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
Overall Number of Participants Analyzed 166 175
Median (Inter-Quartile Range)
Unit of Measure: nmol/L
1.7
(0.8 to 2.4)
1.7
(0.8 to 2.65)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection FE 999049 (Follitropin Delta), FOLLISTIM (Follitropin Beta)
Comments Circulating levels of progesterone on stimulation Day 6.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.814
Comments The P-value corresponds to the two-sided F-test of treatment effect.
Method ANCOVA
Comments The ANCOVA model included treatment and AMH stratum (<15 pmol/L and ≥15 pmol/L) as fixed factors and log-baseline as covariate.
Method of Estimation Estimation Parameter Mean ratio
Estimated Value 1.02
Confidence Interval (2-Sided) 95%
0.89 to 1.16
Estimation Comments Mean ratio is equal to FE 999049/FOLLISTIM.
25.Secondary Outcome
Title Circulating Levels of Endocrine Parameter (Progesterone) at End-of-stimulation
Hide Description The median and IQR of progesterone levels at end-of-stimulation are presented.
Time Frame End-of-stimulation (up to 20 stimulation days)
Hide Outcome Measure Data
Hide Analysis Population Description
The FAS comprised of all randomized and exposed participants.
Arm/Group Title FE 999049 (Follitropin Delta) FOLLISTIM (Follitropin Beta)
Hide Arm/Group Description:
FE 999049 was administered as single daily subcutaneous injections in the abdomen. Participants randomized to FE 999049 had their individual dose determined on the basis of their AMH level at screening and their body weight at randomization. The daily FE 999049 dose was fixed throughout the stimulation period. The minimum allowed daily FE 999049 dose was 6 μg and maximum allowed daily dose was 12 μg. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
FOLLISTIM was administered as single daily subcutaneous injections in the abdomen. The starting dose of FOLLISTIM was 150 IU and fixed for the first five stimulation days, after which it could be adjusted by 75 IU based on the individual response. The maximum allowed daily dose was 375 IU. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
Overall Number of Participants Analyzed 168 172
Median (Inter-Quartile Range)
Unit of Measure: nmol/L
2.5
(1.9 to 3.5)
3.1
(2.3 to 4.3)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection FE 999049 (Follitropin Delta), FOLLISTIM (Follitropin Beta)
Comments Circulating levels of progesterone levels at end-of-stimulation.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments The P-value corresponds to the two-sided F-test of treatment effect.
Method ANCOVA
Comments The ANCOVA model included treatment and AMH stratum (<15 pmol/L and ≥15 pmol/L) as fixed factors and log-baseline as covariate.
Method of Estimation Estimation Parameter Mean ratio
Estimated Value 0.78
Confidence Interval (2-Sided) 95%
0.68 to 0.88
Estimation Comments Mean ratio is equal to FE 999049/FOLLISTIM.
26.Secondary Outcome
Title Circulating Levels of Endocrine Parameters (Inhibin A) on Stimulation Day 6
Hide Description The median and IQR of Inhibin A levels on stimulation Day 6 are presented.
Time Frame At Day 6 of stimulation
Hide Outcome Measure Data
Hide Analysis Population Description
The FAS comprised of all randomized and exposed participants.
Arm/Group Title FE 999049 (Follitropin Delta) FOLLISTIM (Follitropin Beta)
Hide Arm/Group Description:
FE 999049 was administered as single daily subcutaneous injections in the abdomen. Participants randomized to FE 999049 had their individual dose determined on the basis of their AMH level at screening and their body weight at randomization. The daily FE 999049 dose was fixed throughout the stimulation period. The minimum allowed daily FE 999049 dose was 6 μg and maximum allowed daily dose was 12 μg. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
FOLLISTIM was administered as single daily subcutaneous injections in the abdomen. The starting dose of FOLLISTIM was 150 IU and fixed for the first five stimulation days, after which it could be adjusted by 75 IU based on the individual response. The maximum allowed daily dose was 375 IU. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
Overall Number of Participants Analyzed 166 175
Median (Inter-Quartile Range)
Unit of Measure: ng/L
113.1
(75.1 to 171.9)
129.8
(81.6 to 210.6)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection FE 999049 (Follitropin Delta), FOLLISTIM (Follitropin Beta)
Comments Circulating levels of Inhibin A on stimulation Day 6.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments The P-value corresponds to the two-sided F-test of treatment effect.
Method ANCOVA
Comments The ANCOVA model included treatment and AMH stratum (<15 pmol/L and ≥15 pmol/L) as fixed factors and log-baseline as covariate.
Method of Estimation Estimation Parameter Mean ratio
Estimated Value 0.82
Confidence Interval (2-Sided) 95%
0.73 to 0.92
Estimation Comments Mean ratio is equal to FE 999049/FOLLISTIM.
27.Secondary Outcome
Title Circulating Levels of Endocrine Parameters (Inhibin A) at End-of-stimulation
Hide Description The median and IQR of Inhibin A levels at end-of-stimulation are presented.
Time Frame End-of-stimulation (up to 20 stimulation days)
Hide Outcome Measure Data
Hide Analysis Population Description
The FAS comprised of all randomized and exposed participants.
Arm/Group Title FE 999049 (Follitropin Delta) FOLLISTIM (Follitropin Beta)
Hide Arm/Group Description:
FE 999049 was administered as single daily subcutaneous injections in the abdomen. Participants randomized to FE 999049 had their individual dose determined on the basis of their AMH level at screening and their body weight at randomization. The daily FE 999049 dose was fixed throughout the stimulation period. The minimum allowed daily FE 999049 dose was 6 μg and maximum allowed daily dose was 12 μg. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
FOLLISTIM was administered as single daily subcutaneous injections in the abdomen. The starting dose of FOLLISTIM was 150 IU and fixed for the first five stimulation days, after which it could be adjusted by 75 IU based on the individual response. The maximum allowed daily dose was 375 IU. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
Overall Number of Participants Analyzed 169 172
Median (Inter-Quartile Range)
Unit of Measure: ng/L
323.8
(222.1 to 458.8)
390.3
(301.0 to 551.1)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection FE 999049 (Follitropin Delta), FOLLISTIM (Follitropin Beta)
Comments Circulating levels of Inhibin A at end-of-stimulation.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments The P-value corresponds to the two-sided F-test of treatment effect.
Method ANCOVA
Comments The ANCOVA model included treatment and AMH stratum (<15 pmol/L and ≥15 pmol/L) as fixed factors and log-baseline as covariate.
Method of Estimation Estimation Parameter Mean ratio
Estimated Value 0.80
Confidence Interval (2-Sided) 95%
0.72 to 0.88
Estimation Comments Mean ratio is equal to FE 999049/FOLLISTIM.
28.Secondary Outcome
Title Circulating Levels of Endocrine Parameters (Inhibin B) on Stimulation Day 6
Hide Description The median and IQR of inhibin B levels on stimulation Day 6 are presented.
Time Frame At Day 6 of stimulation
Hide Outcome Measure Data
Hide Analysis Population Description
The FAS comprised of all randomized and exposed participants.
Arm/Group Title FE 999049 (Follitropin Delta) FOLLISTIM (Follitropin Beta)
Hide Arm/Group Description:
FE 999049 was administered as single daily subcutaneous injections in the abdomen. Participants randomized to FE 999049 had their individual dose determined on the basis of their AMH level at screening and their body weight at randomization. The daily FE 999049 dose was fixed throughout the stimulation period. The minimum allowed daily FE 999049 dose was 6 μg and maximum allowed daily dose was 12 μg. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
FOLLISTIM was administered as single daily subcutaneous injections in the abdomen. The starting dose of FOLLISTIM was 150 IU and fixed for the first five stimulation days, after which it could be adjusted by 75 IU based on the individual response. The maximum allowed daily dose was 375 IU. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
Overall Number of Participants Analyzed 166 175
Median (Inter-Quartile Range)
Unit of Measure: ng/L
570.5
(396.0 to 853.0)
686.0
(431.0 to 1004.0)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection FE 999049 (Follitropin Delta), FOLLISTIM (Follitropin Beta)
Comments Circulating levels of Inhibin B on stimulation Day 6.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments The P-value corresponds to the two-sided F-test of treatment effect.
Method ANCOVA
Comments The ANCOVA model included treatment and AMH stratum (<15 pmol/L and ≥15 pmol/L) as fixed factors and log-baseline as covariate.
Method of Estimation Estimation Parameter Mean ratio
Estimated Value 0.83
Confidence Interval (2-Sided) 95%
0.75 to 0.93
Estimation Comments Mean ratio is equal to FE 999049/FOLLISTIM.
29.Secondary Outcome
Title Circulating Levels of Endocrine Parameters (Inhibin B) at End-of-stimulation
Hide Description The median and IQR of inhibin B levels at end-of-stimulation are presented.
Time Frame End-of-stimulation (up to 20 stimulation days)
Hide Outcome Measure Data
Hide Analysis Population Description
The FAS comprised of all randomized and exposed participants.
Arm/Group Title FE 999049 (Follitropin Delta) FOLLISTIM (Follitropin Beta)
Hide Arm/Group Description:
FE 999049 was administered as single daily subcutaneous injections in the abdomen. Participants randomized to FE 999049 had their individual dose determined on the basis of their AMH level at screening and their body weight at randomization. The daily FE 999049 dose was fixed throughout the stimulation period. The minimum allowed daily FE 999049 dose was 6 μg and maximum allowed daily dose was 12 μg. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
FOLLISTIM was administered as single daily subcutaneous injections in the abdomen. The starting dose of FOLLISTIM was 150 IU and fixed for the first five stimulation days, after which it could be adjusted by 75 IU based on the individual response. The maximum allowed daily dose was 375 IU. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
Overall Number of Participants Analyzed 169 172
Median (Inter-Quartile Range)
Unit of Measure: ng/L
686.0
(461.0 to 1057.0)
734.5
(492.5 to 1120.5)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection FE 999049 (Follitropin Delta), FOLLISTIM (Follitropin Beta)
Comments Circulating levels of Inhibin B at end-of-stimulation.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.027
Comments The P-value corresponds to the two-sided F-test of treatment effect.
Method ANCOVA
Comments The ANCOVA model included treatment and AMH stratum (<15 pmol/L and ≥15 pmol/L) as fixed factors and log-baseline as covariate.
Method of Estimation Estimation Parameter Mean ratio
Estimated Value 0.88
Confidence Interval (2-Sided) 95%
0.79 to 0.99
Estimation Comments Mean ratio is equal to FE 999049/FOLLISTIM.
30.Secondary Outcome
Title Number of Stimulation Days
Hide Description [Not Specified]
Time Frame End-of-stimulation (up to 20 stimulation days)
Hide Outcome Measure Data
Hide Analysis Population Description
The safety analysis set comprised of all randomized and exposed participants.
Arm/Group Title FE 999049 (Follitropin Delta) FOLLISTIM (Follitropin Beta)
Hide Arm/Group Description:
FE 999049 was administered as single daily subcutaneous injections in the abdomen. Participants randomized to FE 999049 had their individual dose determined on the basis of their AMH level at screening and their body weight at randomization. The daily FE 999049 dose was fixed throughout the stimulation period. The minimum allowed daily FE 999049 dose was 6 μg and maximum allowed daily dose was 12 μg. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
FOLLISTIM was administered as single daily subcutaneous injections in the abdomen. The starting dose of FOLLISTIM was 150 IU and fixed for the first five stimulation days, after which it could be adjusted by 75 IU based on the individual response. The maximum allowed daily dose was 375 IU. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
Overall Number of Participants Analyzed 170 177
Mean (Standard Deviation)
Unit of Measure: Days
8.9  (1.9) 8.8  (1.7)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection FE 999049 (Follitropin Delta), FOLLISTIM (Follitropin Beta)
Comments The number of stimulation days at end-of-stimulation.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.694
Comments 2-sided
Method van Elteren test
Comments P-value was based on van Elteren test adjusted for AMH strata.
31.Secondary Outcome
Title Total Gonadotropin Dose of FE 999049
Hide Description [Not Specified]
Time Frame End-of-stimulation (up to 20 stimulation days)
Hide Outcome Measure Data
Hide Analysis Population Description
The safety analysis set comprised of all randomized and exposed participants.
Arm/Group Title FE 999049 (Follitropin Delta)
Hide Arm/Group Description:
FE 999049 was administered as single daily subcutaneous injections in the abdomen. Participants randomized to FE 999049 had their individual dose determined on the basis of their AMH level at screening and their body weight at randomization. The daily FE 999049 dose was fixed throughout the stimulation period. The minimum allowed daily FE 999049 dose was 6 μg and maximum allowed daily dose was 12 μg. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
Overall Number of Participants Analyzed 170
Mean (Standard Deviation)
Unit of Measure: μg
83.5  (28.9)
32.Secondary Outcome
Title Total Gonadotropin Dose of FOLLISTIM
Hide Description [Not Specified]
Time Frame End-of-stimulation (up to 20 stimulation days)
Hide Outcome Measure Data
Hide Analysis Population Description
The safety analysis set comprised of all randomized and exposed participants.
Arm/Group Title FOLLISTIM (Follitropin Beta)
Hide Arm/Group Description:
FOLLISTIM was administered as single daily subcutaneous injections in the abdomen. The starting dose of FOLLISTIM was 150 IU and fixed for the first five stimulation days, after which it could be adjusted by 75 IU based on the individual response. The maximum allowed daily dose was 375 IU. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
Overall Number of Participants Analyzed 177
Mean (Standard Deviation)
Unit of Measure: IU
1499  (514)
33.Secondary Outcome
Title Number of Participants With Adverse Events (AEs) Stratified by Intensity
Hide Description The frequency of participants with total AEs and AEs by categories of intensity (mild, moderate, severe) are presented. An AE was any untoward medical occurrence in a participants participating in clinical trial. The intensity of AE was classified using the following 3-point scale: mild = awareness of signs or symptoms, but no disruption of usual activity); moderate = event sufficient to affect usual activity (disturbing); or severe = inability to work or perform usual activities (unacceptable).
Time Frame From signed informed consent up to 5-6 weeks after transfer
Hide Outcome Measure Data
Hide Analysis Population Description
The safety analysis set comprised of all randomized and exposed participants.
Arm/Group Title FE 999049 (Follitropin Delta) FOLLISTIM (Follitropin Beta)
Hide Arm/Group Description:
FE 999049 was administered as single daily subcutaneous injections in the abdomen. Participants randomized to FE 999049 had their individual dose determined on the basis of their AMH level at screening and their body weight at randomization. The daily FE 999049 dose was fixed throughout the stimulation period. The minimum allowed daily FE 999049 dose was 6 μg and maximum allowed daily dose was 12 μg. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
FOLLISTIM was administered as single daily subcutaneous injections in the abdomen. The starting dose of FOLLISTIM was 150 IU and fixed for the first five stimulation days, after which it could be adjusted by 75 IU based on the individual response. The maximum allowed daily dose was 375 IU. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
Overall Number of Participants Analyzed 170 177
Measure Type: Number
Unit of Measure: Participants
Any AE 73 92
Mild AE 69 86
Moderate AE 8 12
Severe AE 0 1
34.Secondary Outcome
Title Proportion of Participants Who Had Markedly Abnormal Value Changes From Baseline in Clinical Chemistry Parameters at End-of-stimulation
Hide Description Defined as number of participants with at least one markedly abnormal finding in clinical chemistry parameters (as assessed by investigator) were reported. The clinical chemistry parameters included: alanine transaminase (ALT), albumin, alkaline phosphatase (ALP), aspartate aminotransferase (AST), bicarbonate, bilirubin direct, bilirubin total, blood urea nitrogen, calcium, chloride, cholesterol total, creatinine, gamma-glutamyl transpeptidase, glucose, lactate dehydrogenase, phosphorus, potassium, sodium, total protein, uric acid.
Time Frame End-of-stimulation (up to 20 stimulation days)
Hide Outcome Measure Data
Hide Analysis Population Description
The safety analysis set comprised of all randomized and exposed participants.
Arm/Group Title FE 999049 (Follitropin Delta) FOLLISTIM (Follitropin Beta)
Hide Arm/Group Description:
FE 999049 was administered as single daily subcutaneous injections in the abdomen. Participants randomized to FE 999049 had their individual dose determined on the basis of their AMH level at screening and their body weight at randomization. The daily FE 999049 dose was fixed throughout the stimulation period. The minimum allowed daily FE 999049 dose was 6 μg and maximum allowed daily dose was 12 μg. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
FOLLISTIM was administered as single daily subcutaneous injections in the abdomen. The starting dose of FOLLISTIM was 150 IU and fixed for the first five stimulation days, after which it could be adjusted by 75 IU based on the individual response. The maximum allowed daily dose was 375 IU. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
Overall Number of Participants Analyzed 170 177
Measure Type: Number
Unit of Measure: participants
ALT (IU/L): Normal to markedly high (>3xULN) 0 1
AST (IU/L): Normal to markedly high (>3xULN) 0 1
35.Secondary Outcome
Title Proportion of Participants Who Had Markedly Abnormal Value Changes From Baseline in Hematology Parameters at End-of-stimulation
Hide Description Defined as number of participants with at least one markedly abnormal changes in hematology parameters (as assessed by investigator) were reported. Hematology parameters included: red blood cells, white blood cells, red blood cells morphology, white blood cells morphology, haemoglobin, haematocrit, mean corpuscular volume, mean corpuscular haemoglobin, mean corpuscular haemoglobin concentration, platelets.
Time Frame End-of-stimulation (up to 20 stimulation days)
Hide Outcome Measure Data
Hide Analysis Population Description
The safety analysis set comprised of all randomized and exposed participants.
Arm/Group Title FE 999049 (Follitropin Delta) FOLLISTIM (Follitropin Beta)
Hide Arm/Group Description:
FE 999049 was administered as single daily subcutaneous injections in the abdomen. Participants randomized to FE 999049 had their individual dose determined on the basis of their AMH level at screening and their body weight at randomization. The daily FE 999049 dose was fixed throughout the stimulation period. The minimum allowed daily FE 999049 dose was 6 μg and maximum allowed daily dose was 12 μg. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
FOLLISTIM was administered as single daily subcutaneous injections in the abdomen. The starting dose of FOLLISTIM was 150 IU and fixed for the first five stimulation days, after which it could be adjusted by 75 IU based on the individual response. The maximum allowed daily dose was 375 IU. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
Overall Number of Participants Analyzed 170 177
Measure Type: Number
Unit of Measure: participants
0 0
36.Secondary Outcome
Title Proportion of Participants Who Had Markedly Abnormal Value Changes From Baseline in Clinical Chemistry Parameters at End-of-trial
Hide Description Defined as number of participants with at least one markedly abnormal finding in clinical chemistry parameters (as assessed by investigator) were reported. The clinical chemistry parameters included: alanine transaminase (ALT), albumin, alkaline phosphatase (ALP), aspartate aminotransferase (AST), bicarbonate, bilirubin direct, bilirubin total, blood urea nitrogen, calcium, chloride, cholesterol total, creatinine, gamma-glutamyl transpeptidase, glucose, lactate dehydrogenase, phosphorus, potassium, sodium, total protein, uric acid.
Time Frame Up to 5-6 weeks after transfer
Hide Outcome Measure Data
Hide Analysis Population Description
The safety analysis set comprised of all randomized and exposed participants.
Arm/Group Title FE 999049 (Follitropin Delta) FOLLISTIM (Follitropin Beta)
Hide Arm/Group Description:
FE 999049 was administered as single daily subcutaneous injections in the abdomen. Participants randomized to FE 999049 had their individual dose determined on the basis of their AMH level at screening and their body weight at randomization. The daily FE 999049 dose was fixed throughout the stimulation period. The minimum allowed daily FE 999049 dose was 6 μg and maximum allowed daily dose was 12 μg. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
FOLLISTIM was administered as single daily subcutaneous injections in the abdomen. The starting dose of FOLLISTIM was 150 IU and fixed for the first five stimulation days, after which it could be adjusted by 75 IU based on the individual response. The maximum allowed daily dose was 375 IU. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
Overall Number of Participants Analyzed 170 177
Measure Type: Number
Unit of Measure: participants
0 0
37.Secondary Outcome
Title Proportion of Participants Who Had Markedly Abnormal Value Changes From Baseline in Hematology Parameters at End-of-trial
Hide Description Defined as number of participants with at least one markedly abnormal changes in hematology parameters (as assessed by investigator) were reported. Hematology parameters included: red blood cells, white blood cells, red blood cells morphology, white blood cells morphology, haemoglobin, haematocrit, mean corpuscular volume, mean corpuscular haemoglobin, mean corpuscular haemoglobin concentration, platelets.
Time Frame Up to 5-6 weeks after transfer
Hide Outcome Measure Data
Hide Analysis Population Description
The safety analysis set comprised of all randomized and exposed participants.
Arm/Group Title FE 999049 (Follitropin Delta) FOLLISTIM (Follitropin Beta)
Hide Arm/Group Description:
FE 999049 was administered as single daily subcutaneous injections in the abdomen. Participants randomized to FE 999049 had their individual dose determined on the basis of their AMH level at screening and their body weight at randomization. The daily FE 999049 dose was fixed throughout the stimulation period. The minimum allowed daily FE 999049 dose was 6 μg and maximum allowed daily dose was 12 μg. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
FOLLISTIM was administered as single daily subcutaneous injections in the abdomen. The starting dose of FOLLISTIM was 150 IU and fixed for the first five stimulation days, after which it could be adjusted by 75 IU based on the individual response. The maximum allowed daily dose was 375 IU. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
Overall Number of Participants Analyzed 170 177
Measure Type: Number
Unit of Measure: participants
Leukocytes (10^9/L) Normal to markedly high (>=16) 0 1
Hemoglobin (g/L) Normal to markedly low 0 1
Hematocrit (ratio) Normal to markedly low (>=0.56) 0 1
38.Secondary Outcome
Title Frequency and Intensity of Injection Site Reactions
Hide Description The presence of of injection site reactions (redness, itching, pain, swelling and bruising) immediately, 30 minutes and 24 hours after the injection are presented. The injection site reactions were assessed as none, mild, moderate and severe. The number of injection site reactions (mild, moderate or severe) based on all assessments performed is presented.
Time Frame End-of-stimulation (up to 20 stimulation days)
Hide Outcome Measure Data
Hide Analysis Population Description
The safety analysis set comprised of all randomized and exposed participants.
Arm/Group Title FE 999049 (Follitropin Delta) FOLLISTIM (Follitropin Beta)
Hide Arm/Group Description:
FE 999049 was administered as single daily subcutaneous injections in the abdomen. Participants randomized to FE 999049 had their individual dose determined on the basis of their AMH level at screening and their body weight at randomization. The daily FE 999049 dose was fixed throughout the stimulation period. The minimum allowed daily FE 999049 dose was 6 μg and maximum allowed daily dose was 12 μg. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
FOLLISTIM was administered as single daily subcutaneous injections in the abdomen. The starting dose of FOLLISTIM was 150 IU and fixed for the first five stimulation days, after which it could be adjusted by 75 IU based on the individual response. The maximum allowed daily dose was 375 IU. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
Overall Number of Participants Analyzed 170 177
Measure Type: Number
Unit of Measure: events
Any mild injection site reaction 271 719
Any moderate injection site reaction 7 19
Any severe injection site reaction 1 0
Mild redness 140 174
Moderate redness 2 0
Severe redness 0 0
Mild itching 4 5
Moderate itching 1 0
Severe itching 0 0
Mild pain 19 411
Moderate pain 1 16
Severe pain 0 0
Mild swelling 6 10
Moderate swelling 0 0
Severe swelling 0 0
Mild bruising 102 119
Moderate bruising 3 3
Severe bruising 1 0
39.Secondary Outcome
Title Technical Malfunctions of the Administration Pens
Hide Description [Not Specified]
Time Frame End-of-stimulation (up to 20 stimulation days)
Hide Outcome Measure Data
Hide Analysis Population Description
The safety analysis set comprised of all randomized and exposed participants.
Arm/Group Title FE 999049 (Follitropin Delta) FOLLISTIM (Follitropin Beta)
Hide Arm/Group Description:
FE 999049 was administered as single daily subcutaneous injections in the abdomen. Participants randomized to FE 999049 had their individual dose determined on the basis of their AMH level at screening and their body weight at randomization. The daily FE 999049 dose was fixed throughout the stimulation period. The minimum allowed daily FE 999049 dose was 6 μg and maximum allowed daily dose was 12 μg. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
FOLLISTIM was administered as single daily subcutaneous injections in the abdomen. The starting dose of FOLLISTIM was 150 IU and fixed for the first five stimulation days, after which it could be adjusted by 75 IU based on the individual response. The maximum allowed daily dose was 375 IU. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
Overall Number of Participants Analyzed 170 177
Measure Type: Number
Unit of Measure: percentage of participants
0 0
Time Frame Adverse events were monitored from the time of obtaining informed consent until the last visit (end-of-trial) (up to approximately 2 years) .
Adverse Event Reporting Description Adverse events with onset after start of first administration of IMP were considered treatment -emergent and are presented for the safety analysis set.
 
Arm/Group Title FE 999049 (Follitropin Delta) FOLLISTIM (Follitropin Beta)
Hide Arm/Group Description FE 999049 was administered as single daily subcutaneous injections in the abdomen. Participants randomized to FE 999049 had their individual dose determined on the basis of their AMH level at screening and their body weight at randomization. The daily FE 999049 dose was fixed throughout the stimulation period. The minimum allowed daily FE 999049 dose was 6 μg and maximum allowed daily dose was 12 μg. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days. FOLLISTIM was administered as single daily subcutaneous injections in the abdomen. The starting dose of FOLLISTIM was 150 IU and fixed for the first five stimulation days, after which it could be adjusted by 75 IU based on the individual response. The maximum allowed daily dose was 375 IU. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
All-Cause Mortality
FE 999049 (Follitropin Delta) FOLLISTIM (Follitropin Beta)
Affected / at Risk (%) Affected / at Risk (%)
Total   0/170 (0.00%)      0/177 (0.00%)    
Hide Serious Adverse Events
FE 999049 (Follitropin Delta) FOLLISTIM (Follitropin Beta)
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   0/170 (0.00%)      2/177 (1.13%)    
Reproductive system and breast disorders     
Ovarian hyperstimulation syndrome  1  0/170 (0.00%)  0 2/177 (1.13%)  2
1
Term from vocabulary, MedDRA (20.0)
Indicates events were collected by systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 2%
FE 999049 (Follitropin Delta) FOLLISTIM (Follitropin Beta)
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   73/170 (42.94%)      92/177 (51.98%)    
Gastrointestinal disorders     
Constipation  1  4/170 (2.35%)  4 5/177 (2.82%)  6
General disorders     
Injection site erythema  1  13/170 (7.65%)  14 15/177 (8.47%)  15
Injection site pruritus  1  0/170 (0.00%)  0 5/177 (2.82%)  5
Infections and infestations     
Viral upper respiratory tract infection  1  6/170 (3.53%)  6 6/177 (3.39%)  6
Nervous system disorders     
Headache  1  4/170 (2.35%)  4 4/177 (2.26%)  4
Pregnancy, puerperium and perinatal conditions     
Biochemical pregnancy  1  6/170 (3.53%)  6 10/177 (5.65%)  10
Abortion spontenous  1  3/170 (1.76%)  3 4/177 (2.26%)  4
Haemorrhage in pregnancy  1  4/170 (2.35%)  4 0/177 (0.00%)  0
Reproductive system and breast disorders     
Ovarian hyperstimulation syndrome  1  19/170 (11.18%)  19 35/177 (19.77%)  35
Ovarian cyst  1  5/170 (2.94%)  5 7/177 (3.95%)  7
Ovarian enlargement  1  5/170 (2.94%)  5 5/177 (2.82%)  5
Pelvic fluid collection  1  4/170 (2.35%)  4 4/177 (2.26%)  4
1
Term from vocabulary, MedDRA (20.0)
Indicates events were collected by systematic assessment
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
The only disclosure restriction on the PI is that the sponsor can review the draft manuscript prior to publication and can request delay of publication where any contents are deemed patentable by the sponsor or confidential to the sponsor. Comments will be given within four weeks from receipt of the draft manuscript. Additional time may be required to allow Ferring to seek patent protection of the invention.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Clinical Development Support
Organization: Ferring Pharmaceuticals
EMail: DK0-Disclosure@ferring.com
Layout table for additonal information
Responsible Party: Ferring Pharmaceuticals
ClinicalTrials.gov Identifier: NCT03228680    
Other Study ID Numbers: 000273
First Submitted: July 13, 2017
First Posted: July 25, 2017
Results First Submitted: January 20, 2021
Results First Posted: March 24, 2021
Last Update Posted: January 14, 2022