Clinical Trial Results:
A randomised, controlled, assessor-blind, parallel groups, multicentre, multinational trial comparing the ovarian response of a starting dose of 15 µg follitropin delta (REKOVELLE) to a starting dose of 225 IU follitropin alfa (GONAL-F) in conventional regimens in controlled ovarian stimulation in women undergoing an assisted reproductive technology programme.
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Summary
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EudraCT number |
2021-001785-38 |
Trial protocol |
ES IT FR AT |
Global end of trial date |
16 Apr 2024
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Results information
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Results version number |
v1(current) |
This version publication date |
28 Mar 2025
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First version publication date |
28 Mar 2025
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Other versions |
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Summary report(s) |
Trial results |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
000401
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT05263388 | ||
WHO universal trial number (UTN) |
U1111-1267-1119 | ||
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Sponsors
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Sponsor organisation name |
Ferring Pharmaceuticals A/S
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Sponsor organisation address |
Amager Strandvej 405, Kastrup, Denmark, 2770
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Public contact |
Global Clinical Compliance, Ferring Pharmaceuticals A/S, +1 8622865200, disclosure@ferring.com
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Scientific contact |
Global Clinical Compliance, Ferring Pharmaceuticals A/S, +1 8622865200, disclosure@ferring.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
23 Aug 2024
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
16 Apr 2024
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
The main objective of the trial was to compare a starting dose of 15 µg Rekovelle to a starting dose of 225 IU Gonal-f in conventional regimens with respect to ovarian response in women undergoing controlled ovarian stimulation. The trial consisted of a stimulation period of max 20 days, during which a GnRH antagonist was initiated on stimulation day 5 or day 6 and continued throughout the stimulation period. After stimulation, triggering of final follicular maturation was done with either human chorionic gonadotropin (hCG) or a GnRH agonist. After triggering, oocyte retrieval occurred within 36h (±2h). After fertilization, either fresh or thawed blastocysts were transferred. The end-of-trial visit took place within max 14 days after triggering.
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Protection of trial subjects |
The trial was conducted in accordance with the Declaration of Helsinki (2013) and International Council for Harmonisation (ICH) Good Clinical Practice (2016).
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
01 Aug 2022
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
United Kingdom: 42
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Country: Number of subjects enrolled |
Spain: 132
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Country: Number of subjects enrolled |
Austria: 68
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Country: Number of subjects enrolled |
France: 8
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Country: Number of subjects enrolled |
Italy: 50
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Worldwide total number of subjects |
300
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EEA total number of subjects |
258
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
300
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
A total of 17 investigational sites in 5 countries randomised participants in the trial: 2 sites in Austria, 2 in France, 4 in Italy, 7 in Spain, 2 in United Kingdom. | |||||||||||||||||||||||||||||||||
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Pre-assignment
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Screening details |
Participants were screened within 90 days prior to randomisation, for compliance with the inclusion and exclusion criteria. On day 2-3 of the menstrual cycle, subjects were randomised in a 2:1 ratio to treatment with either REKOVELLE or GONAL-F, and stimulation was initiated. | |||||||||||||||||||||||||||||||||
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Period 1
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Period 1 title |
Trial main part (overall period)
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Is this the baseline period? |
Yes | |||||||||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Single blind [1] | |||||||||||||||||||||||||||||||||
Roles blinded |
Data analyst, Assessor [2] | |||||||||||||||||||||||||||||||||
Blinding implementation details |
The trial was open-label but assessor-blind. The assessor-blinding ensured blinding and thereby unbiased evaluation by the investigators and other assessors such as embryologists. Similarly, sponsor staff also remained blinded to individual participant treatment allocation during the conduct of the trial.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Rekovelle (follitropin delta) | |||||||||||||||||||||||||||||||||
Arm description |
Rekovelle administered as single daily subcutaneous injections in the abdomen. | |||||||||||||||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Rekovelle
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Investigational medicinal product code |
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Other name |
follitropin delta, FE 999049
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
Rekovelle administered as single daily subcutaneous injections in the abdomen. Daily starting dose of 15 µg, fixed for at least the first four stimulation days. Dose adjustments could be implemented on the day of starting the gonadotropin-releasing hormone antagonist (stimulation day 5 or day 6) or later, and could occur no more frequently than once every second day. At each dose adjustment, the daily Rekovelle dose could be increased or decreased by 5 µg based on the participant’s response. The minimum Rekovelle dose was 5 µg and the maximum Rekovelle dose was 20 µg. Participants could be treated for a maximum of 20 days.
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Arm title
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Gonal-f (follitropin alfa) | |||||||||||||||||||||||||||||||||
Arm description |
Gonal-f administered as single daily subcutaneous injections in the abdomen. | |||||||||||||||||||||||||||||||||
Arm type |
Active comparator | |||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Gonal-f
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Investigational medicinal product code |
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Other name |
follitropin alfa
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
Gonal-f administered as single daily subcutaneous injections in the abdomen. Daily starting dose of 225 IU, fixed for at least the first four stimulation days. Dose adjustments could be implemented on the day of starting the gonadotropin-releasing hormone antagonist (stimulation day 5 or day 6) or later, and could occur no more frequently than once every second day. At each dose adjustment, the daily Gonal-f dose could be adjusted by 75 IU based on the participant’s response. The minimum Gonal-f dose was 75 IU and the maximum Gonal-f dose was 300 IU. Participants could be treated for a maximum of 20 days.
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| Notes [1] - The number of roles blinded appears inconsistent with a single blinded trial. It is expected that there will be one role blinded in a single blind trial. Justification: The trial was single-blinded, as it was open-label but assessor-blind. The assessor-blinding ensured blinding and thereby unbiased evaluation by the investigators and other assessors such as embryologists. Similarly, sponsor staff (including 'Data Analyst') also remained blinded to individual participant treatment allocation during the conduct of the trial. [2] - The roles blinded appear inconsistent with a simple blinded trial. Justification: The trial was single-blinded, as it was open-label but assessor-blind. The assessor-blinding ensured blinding and thereby unbiased evaluation by the investigators and other assessors such as embryologists. Similarly, sponsor staff (including 'Data Analyst') also remained blinded to individual participant treatment allocation during the conduct of the trial. |
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Baseline characteristics reporting groups
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Reporting group title |
Rekovelle (follitropin delta)
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Reporting group description |
Rekovelle administered as single daily subcutaneous injections in the abdomen. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Gonal-f (follitropin alfa)
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Reporting group description |
Gonal-f administered as single daily subcutaneous injections in the abdomen. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Rekovelle (follitropin delta)
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Reporting group description |
Rekovelle administered as single daily subcutaneous injections in the abdomen. | ||
Reporting group title |
Gonal-f (follitropin alfa)
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Reporting group description |
Gonal-f administered as single daily subcutaneous injections in the abdomen. | ||
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End point title |
Number of oocytes retrieved | ||||||||||||
End point description |
The number of oocytes retrieved was recorded at the oocyte retrieval visit.
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End point type |
Primary
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End point timeframe |
On day of oocyte retrieval (up to 22 days after start of stimulation).
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Statistical analysis title |
Primary analysis of primary endpoint | ||||||||||||
Comparison groups |
Rekovelle (follitropin delta) v Gonal-f (follitropin alfa)
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Number of subjects included in analysis |
300
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Analysis specification |
Pre-specified
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Analysis type |
other | ||||||||||||
Method |
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Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
0
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Confidence interval |
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95% | ||||||||||||
sides |
2-sided
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lower limit |
-1.3 | ||||||||||||
upper limit |
1.2 | ||||||||||||
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End point title |
Number of follicles (total) at end-of-stimulation | ||||||||||||
End point description |
Counted by ultrasound for the right and left ovary for each participant.
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End point type |
Secondary
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End point timeframe |
At end-of-stimulation (up to 20 stimulation days).
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Size of the follicles at end-of-stimulation | ||||||||||||
End point description |
Measured by ultrasound for the right and left ovary for each subject.
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End point type |
Secondary
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End point timeframe |
At end-of-stimulation (up to 20 stimulation days).
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Serum concentrations of estradiol at end-of-stimulation | ||||||||||||
End point description |
Blood samples for analysis of circulating concentrations of estradiol were drawn.
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End point type |
Secondary
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End point timeframe |
At end-of-stimulation (up to 20 stimulation days).
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Serum concentrations of progesterone at end-of-stimulation | ||||||||||||
End point description |
Blood samples for analysis of circulating concentrations of progesterone were drawn.
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End point type |
Secondary
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End point timeframe |
At end-of-stimulation (up to 20 stimulation days).
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Number of fertilized oocytes | ||||||||||||
End point description |
The number of pronuclei were counted after insemination. Fertilized oocytes with 2 pronuclei (2PN) were regarded as correctly fertilized.
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End point type |
Secondary
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End point timeframe |
On day 1 after oocyte retrieval (up to 23 days after start of stimulation).
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Fertilization rate | ||||||||||||
End point description |
The fertilization rate was defined as the number of oocytes with 2 pronuclei (2PN) divided by the number of oocytes retrieved.
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End point type |
Secondary
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End point timeframe |
On day 1 after oocyte retrieval (up to 23 days after start of stimulation).
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Number of Blastocysts and Number of Good Quality Blastocysts | ||||||||||||||||||
End point description |
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.
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End point type |
Secondary
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End point timeframe |
On Day 5 or Day 6 (as applicable) after oocyte retrieval (up to 27 or 28 days after start of stimulation).
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
Total gonadotropin dose | ||||||||||||
End point description |
Calculated by start dates, end dates and daily dose of investigational medicinal product (IMP).
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End point type |
Secondary
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End point timeframe |
Up to 20 stimulation days.
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Number of stimulation days | ||||||||||||
End point description |
Calculated by start dates and end dates.
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End point type |
Secondary
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End point timeframe |
Up to 20 stimulation days.
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Proportion of subjects with early ovarian hyperstimulation syndrome (OHSS) (overall and by grade) and/or preventive interventions for early OHSS | ||||||||||||||||||||||||
End point description |
Early ovarian hyperstimulation syndrome (OHSS) was defined as OHSS with onset ≤9 days after triggering of final follicular maturation. Classification of grade was according to Golan's classification system, and all OHSS cases were graded as mild, moderate or severe. Unit: %.
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End point type |
Secondary
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End point timeframe |
Time Frame: Up to 9 days after triggering of final follicular maturation.
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| No statistical analyses for this end point | |||||||||||||||||||||||||
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Adverse events information
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Timeframe for reporting adverse events |
Adverse events with onset after start of IMP administration and up to and including the end-of-trial visit.
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Assessment type |
Non-systematic | |||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | |||||||||||||||||||||||||||||||||||||||
Dictionary version |
25.0
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Reporting groups
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Reporting group title |
Rekovelle (follitropin delta)
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Reporting group description |
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Reporting group title |
Gonal-f (follitropin alfa)
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Reporting group description |
- | |||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | ||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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21 Jan 2022 |
The main protocol updates introduced with amendment were the addition of exclusion criteria, addition of specific trial stopping criteria, collection of late OHSS data, and changes related to switching EDC system (including a switch to performing randomisation through the IRT system). In addition, the amendment introduced the possibility to use different formulations of a non-investigational medicinal product (OVITRELLE). Finally, it introduced a change to the duration of culturing blastocysts (removal of day 3 as option for last day of culture; all blastocysts cultured to day 5 or 6), and the possibility of triggering with GnRH agonist in case the participant was at risk of developing OHSS, to align with other clinical trial protocols in development for follitropin delta (REKOVELLE) at the same time. |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
