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To demonstrate non-inferiority of FE 999049 compared to FOLLISTIM with respect to number of oocytes retrieved in Japanese IVF/ICSI patients undergoing controlled ovarian stimulation.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Follitropin delta | Experimental | 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. |
|
| Follitropin beta | Active Comparator | 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Follitropin delta | Drug | Single daily subcutaneous administration through pre-filled injection pen |
|
| Measure | Description | Time Frame |
|---|---|---|
| Number of Oocytes Retrieved | The number of oocytes retrieved was recorded at the oocyte retrieval visit. | 36h (± 2h) after triggering of final follicular maturation (On day of oocyte retrieval) |
| Measure | Description | Time Frame |
|---|---|---|
| Clinical Pregnancy Rate | Clinical pregnancy was defined as at least one gestational sac 5-6 weeks after transfer. | 5-6 weeks after transfer (up to approximately 3 months after start of stimulation) |
| Positive Beta Unit of Human Chorionic Gonadotropin (Beta-hCG) Rate |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Global Clinical Compliance | Ferring Pharmaceuticals | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Yachiyo Hospital | Anjo | Aichi-ken | Japan | |||
| Investigational Site 8121 |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 33722477 | Result | Ishihara O, Arce JC; Japanese Follitropin Delta Phase 3 Trial (STORK) Group. Individualized follitropin delta dosing reduces OHSS risk in Japanese IVF/ICSI patients: a randomized controlled trial. Reprod Biomed Online. 2021 May;42(5):909-918. doi: 10.1016/j.rbmo.2021.01.023. Epub 2021 Feb 9. | |
| 34799275 | Result |
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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.
A total of 17 investigational sites in Japan randomized participants to the trial between 29 July 2017 to 08 July 2019.
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| ID | Title | Description |
|---|---|---|
| FG000 | FE 999049 (Follitropin Delta) | 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. |
| FG001 | FOLLISTIM (Follitropin Beta) | 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. |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | FE 999049 (Follitropin Delta) | 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. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Number analyzed differs from the overall population as one participant in the FOLLISTIM (Follitropin beta) group was randomized but not exposed to treatment. |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Number of Oocytes Retrieved | The number of oocytes retrieved was recorded at the oocyte retrieval visit. | The full analysis set (FAS) comprised all randomized and exposed participants. | Posted | Mean | Standard Deviation | Oocytes retrieved | 36h (± 2h) after triggering of final follicular maturation (On day of oocyte retrieval) |
|
Adverse events were monitored from the time of obtaining informed consent until the last visit (end-of-trial) (up to approximately 2 years) .
Adverse events with onset after start of first administration of IMP were considered treatment -emergent and are presented for the safety analysis set.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | FE 999049 (Follitropin Delta) | 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. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Ovarian hyperstimulation syndrome | Reproductive system and breast disorders | MedDRA (20.0) | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Constipation | Gastrointestinal disorders | MedDRA (20.0) | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Clinical Development Support | Ferring Pharmaceuticals | - | DK0-Disclosure@ferring.com |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Mar 16, 2018 | Jan 20, 2021 | Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Aug 22, 2019 | Jan 20, 2021 | SAP_001.pdf |
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| ID | Term |
|---|---|
| D007246 | Infertility |
| ID | Term |
|---|---|
| D000091662 | Genital Diseases |
| D000091642 | Urogenital Diseases |
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| ID | Term |
|---|---|
| C000620228 | follitropin delta |
| C000608977 | FE 999049 |
| C571802 | follitropin beta |
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| Follitropin beta | Drug | Single daily subcutaneous injection in the abdomen |
|
|
Defined as positive serum beta-hCG test 13-15 days after transfer. |
| 13-15 days after transfer (up to approximately 1.5 months after start of stimulation) |
| Vital Pregnancy Rate | Vital pregnancy was defined as at least one intrauterine gestational sac with fetal heart beat 5-6 weeks after transfer. | 5-6 weeks after transfer (up to approximately 3 months after start of stimulation) |
| Implantation Rate | Implantation rate was defined as the number of gestational sacs 5-6 weeks after transfer divided by the number of blastocysts transferred. | 5-6 weeks after transfer (up to approximately 3 months after start of stimulation) |
| Proportion of Participants With Cycle Cancellation Due to Poor or Excessive Ovarian Response | End-of-stimulation (up to 20 stimulation days) |
| Proportion of Participants With Blastocyst Transfer Cancellation Due to Excessive Ovarian Response / OHSS Risk | End-of-stimulation (up to 20 stimulation days) |
| Proportion of Participants With <4, 4-7, 8-14, 15-19 and ≥20 Oocytes Retrieved | 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. | On the day of oocyte retrieval (up to 22 days after start of stimulation) |
| Proportion of Participants With Extreme Ovarian Responses (Defined as <4, ≥15 or ≥20 Oocytes Retrieved) in Risk Population | On the day of oocyte retrieval (up to 22 days after start of stimulation) |
| Proportion of Participants With Preventive Interventions for Early Ovarian Hyperstimulation Syndrome (OHSS) | ≤9 days after triggering of final follicular maturation |
| Proportions of Participants With Early OHSS (Including OHSS of Moderate/Severe Grade) and/or Preventive Interventions for Early OHSS | 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. | Up to 9 days after triggering of final follicular maturation |
| Proportions of Participants With Late OHSS (Including OHSS of Moderate/Severe Grade) | 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. | >9 days after triggering of final follicular maturation |
| Number of Follicles on Stimulation Day 6 | Defined as the number of follicles observed in both ovaries at the last transvaginal ultrasound (TVUS) in the stimulation phase (on stimulation Day 6). | At Day 6 of stimulation |
| Number of Follicles at End-of-stimulation | Defined as the number of follicles observed in both ovaries at the last TVUS in the stimulation phase (end-of-stimulation). | End-of-stimulation (up to 20 stimulation days) |
| Size of Follicles on Stimulation Day 6 | Defined as size characteristics of follicles on stimulation Day 6. Average size of 3 largest follicles has been presented in this endpoint. | At Day 6 of stimulation |
| Size of Follicles at End-of-Stimulation | Defined as size characteristics of follicles at end-of-stimulation. Average size of 3 largest follicles has been presented in this endpoint. | End-of-stimulation (up to 20 stimulation days) |
| Fertilization Rate | The fertilization rate was defined as the number of oocytes with 2 pronuclei divided by the number of oocytes retrieved. | Day 1 after oocyte retrieval (up to approximately 22 days after start of stimulation) |
| Number and Quality of Embryos | 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. | Day 3 after oocyte retrieval (up to approximately 24 days after start of stimulation) |
| Number and Quality of Blastocysts | 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. | Day 5 after oocyte retrieval (up to approximately 26 days after start of stimulation) |
| Circulating Levels of Endocrine Parameters (Follicle-stimulating Hormone [FSH], Luteinising Hormone [LH]) on Stimulation Day 6 | The median and inter-quartile range (IQR) of FSH and LH levels on stimulation Day 6 are presented. | At Day 6 of stimulation |
| Circulating Levels of Endocrine Parameters (Follicle-stimulating Hormone [FSH], Luteinising Hormone [LH]) at End-of-stimulation | The median and IQR of FSH and LH levels at end-of-stimulation are presented. | End-of-stimulation (up to 20 stimulation days) |
| Circulating Levels of Endocrine Parameter (Estradiol) on Stimulation Day 6 | The median and IQR of estradiol levels on stimulation Day 6 are presented. | At Day 6 of stimulation |
| Circulating Levels of Endocrine Parameter (Estradiol) at End-of-stimulation | The median and IQR of estradiol levels at end-of-stimulation are presented. | End-of-stimulation (up to 20 stimulation days) |
| Circulating Levels of Endocrine Parameter (Progesterone) on Stimulation Day 6 | The median and IQR of progesterone levels on stimulation Day 6 are presented. | At Day 6 of stimulation |
| Circulating Levels of Endocrine Parameter (Progesterone) at End-of-stimulation | The median and IQR of progesterone levels at end-of-stimulation are presented. | End-of-stimulation (up to 20 stimulation days) |
| Circulating Levels of Endocrine Parameters (Inhibin A) on Stimulation Day 6 | The median and IQR of Inhibin A levels on stimulation Day 6 are presented. | At Day 6 of stimulation |
| Circulating Levels of Endocrine Parameters (Inhibin A) at End-of-stimulation | The median and IQR of Inhibin A levels at end-of-stimulation are presented. | End-of-stimulation (up to 20 stimulation days) |
| Circulating Levels of Endocrine Parameters (Inhibin B) on Stimulation Day 6 | The median and IQR of inhibin B levels on stimulation Day 6 are presented. | At Day 6 of stimulation |
| Circulating Levels of Endocrine Parameters (Inhibin B) at End-of-stimulation | The median and IQR of inhibin B levels at end-of-stimulation are presented. | End-of-stimulation (up to 20 stimulation days) |
| Number of Stimulation Days | End-of-stimulation (up to 20 stimulation days) |
| Total Gonadotropin Dose of FE 999049 | End-of-stimulation (up to 20 stimulation days) |
| Total Gonadotropin Dose of FOLLISTIM | End-of-stimulation (up to 20 stimulation days) |
| Number of Participants With Adverse Events (AEs) Stratified by Intensity | 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). | From signed informed consent up to 5-6 weeks after transfer |
| Proportion of Participants Who Had Markedly Abnormal Value Changes From Baseline in Clinical Chemistry Parameters at End-of-stimulation | 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. | End-of-stimulation (up to 20 stimulation days) |
| Proportion of Participants Who Had Markedly Abnormal Value Changes From Baseline in Hematology Parameters at End-of-stimulation | 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. | End-of-stimulation (up to 20 stimulation days) |
| Proportion of Participants Who Had Markedly Abnormal Value Changes From Baseline in Clinical Chemistry Parameters at End-of-trial | 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. | Up to 5-6 weeks after transfer |
| Proportion of Participants Who Had Markedly Abnormal Value Changes From Baseline in Hematology Parameters at End-of-trial | 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. | Up to 5-6 weeks after transfer |
| Frequency and Intensity of Injection Site Reactions | 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. | End-of-stimulation (up to 20 stimulation days) |
| Technical Malfunctions of the Administration Pens | End-of-stimulation (up to 20 stimulation days) |
| Chiba |
| Chiba |
| Japan |
| Yokota Maternity Hospital | Maebashi | Gunma | Japan |
| Sophia Ladies Clinic | Sagamihara | Kanagawa | Japan |
| Investigational Site 8122 | Sendai | Miyagi | Japan |
| Investigational Site 8123 | Higashiōsaka-shi | Osaka | Japan |
| Investigational Site 8120 | Osaka | Osaka | Japan |
| Ladies Clinic Kitahama | Osaka | Osaka | Japan |
| Investigational Site 8125 | Saitama-shi | Saitama | Japan |
| Investigational Site 8124 | Shinjuku-Ku | Tokyo | Japan |
| Akita University Hospital | Akita | Japan |
| Yamashita Ladies' Clinic | Hyōgo | Japan |
| Investigational Site 8126 | Saitama | Japan |
| Omiya Ladies Clinic | Saitama | Japan |
| Saint Women's Clinic | Saitama | Japan |
| Women's Clinic Fujimino | Saitama | Japan |
| Tokushima University Hospital | Tokushima | Japan |
| Ishihara O, Nelson SM, Arce JC. Comparison of ovarian response to follitropin delta in Japanese and White IVF/ICSI patients. Reprod Biomed Online. 2022 Jan;44(1):177-184. doi: 10.1016/j.rbmo.2021.09.014. Epub 2021 Sep 23. |
| 37156263 | Result | Fernandez-Sanchez M, Fatemi H, Garcia-Velasco JA, Heiser PW, Daftary GS, Mannaerts B. Incidence and severity of ovarian hyperstimulation syndrome (OHSS) in high responders after gonadotropin-releasing hormone (GnRH) agonist trigger in "freeze-all" approach. Gynecol Endocrinol. 2023 Dec;39(1):2205952. doi: 10.1080/09513590.2023.2205952. |
| Withdrawal by Subject |
|
| Other |
|
| BG001 | FOLLISTIM (Follitropin Beta) | 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. |
| BG002 | Total | Total of all reporting groups |
| Mean |
| Standard Deviation |
| years |
|
| Sex: Female, Male | Number analyzed differs from the overall population as one participant in the FOLLISTIM (Follitropin beta) group was randomized but not exposed to treatment. | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Number analyzed differs from the overall population as one participant in the FOLLISTIM (Follitropin beta) group was randomized but not exposed to treatment. | Count of Participants | Participants |
|
| Race (NIH/OMB) | Number analyzed differs from the overall population as one participant in the FOLLISTIM (Follitropin beta) group was randomized but not exposed to treatment. | Count of Participants | Participants |
|
| Region of Enrollment | Number analyzed differs from the overall population as one participant in the FOLLISTIM (Follitropin beta) group was randomized but not exposed to treatment. | Number | participants |
|
| OG001 | FOLLISTIM (Follitropin Beta) | 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. |
|
|
|
| Secondary | Clinical Pregnancy Rate | Clinical pregnancy was defined as at least one gestational sac 5-6 weeks after transfer. | The FAS comprised of all randomized and exposed participants. | Posted | Number | percentage of participants | 5-6 weeks after transfer (up to approximately 3 months after start of stimulation) |
|
|
|
|
| Secondary | Positive Beta Unit of Human Chorionic Gonadotropin (Beta-hCG) Rate | Defined as positive serum beta-hCG test 13-15 days after transfer. | The FAS comprised of all randomized and exposed participants. | Posted | Number | percentage of participants | 13-15 days after transfer (up to approximately 1.5 months after start of stimulation) |
|
|
|
|
| Secondary | Vital Pregnancy Rate | Vital pregnancy was defined as at least one intrauterine gestational sac with fetal heart beat 5-6 weeks after transfer. | The FAS comprised of all randomized and exposed participants. | Posted | Number | percentage of participants | 5-6 weeks after transfer (up to approximately 3 months after start of stimulation) |
|
|
|
|
| Secondary | Implantation Rate | Implantation rate was defined as the number of gestational sacs 5-6 weeks after transfer divided by the number of blastocysts transferred. | The FAS comprised of all randomized and exposed participants with blastocyst transfer. | Posted | Number | % of sacs/blastocysts transferred | 5-6 weeks after transfer (up to approximately 3 months after start of stimulation) | Embryos transferred | Embryos transferred |
|
|
|
|
| Secondary | Proportion of Participants With Cycle Cancellation Due to Poor or Excessive Ovarian Response | The FAS comprised of all randomized and exposed participants. | Posted | Number | percentage of participants | End-of-stimulation (up to 20 stimulation days) |
|
|
|
| Secondary | Proportion of Participants With Blastocyst Transfer Cancellation Due to Excessive Ovarian Response / OHSS Risk | The FAS comprised of all randomized and exposed participants. | Posted | Number | percentage of participants | End-of-stimulation (up to 20 stimulation days) |
|
|
|
|
| Secondary | Proportion of Participants With <4, 4-7, 8-14, 15-19 and ≥20 Oocytes Retrieved | 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. | The FAS comprised of all randomized and exposed participants. | Posted | Number | percentage of participants | On the day of oocyte retrieval (up to 22 days after start of stimulation) |
|
|
|
|
| Secondary | Proportion of Participants With Extreme Ovarian Responses (Defined as <4, ≥15 or ≥20 Oocytes Retrieved) in Risk Population | The FAS comprised of all randomized and exposed participants. | Posted | Number | percentage of participants | On the day of oocyte retrieval (up to 22 days after start of stimulation) |
|
|
|
|
| Secondary | Proportion of Participants With Preventive Interventions for Early Ovarian Hyperstimulation Syndrome (OHSS) | The FAS comprised of all participants randomized or exposed. | Posted | Number | percentage of participants | ≤9 days after triggering of final follicular maturation |
|
|
|
| Secondary | Proportions of Participants With Early OHSS (Including OHSS of Moderate/Severe Grade) and/or Preventive Interventions for Early OHSS | 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. | The FAS comprised of all participants randomized and exposed. | Posted | Number | percentage of participants | Up to 9 days after triggering of final follicular maturation |
|
|
|
|
| Secondary | Proportions of Participants With Late OHSS (Including OHSS of Moderate/Severe Grade) | 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. | The FAS comprised of all participants randomized or exposed. | Posted | Number | percentage of participants | >9 days after triggering of final follicular maturation |
|
|
|
|
| Secondary | Number of Follicles on Stimulation Day 6 | Defined as the number of follicles observed in both ovaries at the last transvaginal ultrasound (TVUS) in the stimulation phase (on stimulation Day 6). | The FAS comprised of all randomized or exposed participants. | Posted | Mean | Standard Deviation | Follicles | At Day 6 of stimulation |
|
|
|
|
| Secondary | Number of Follicles at End-of-stimulation | Defined as the number of follicles observed in both ovaries at the last TVUS in the stimulation phase (end-of-stimulation). | The FAS comprised of all randomized or exposed participants. | Posted | Mean | Standard Deviation | Follicles | End-of-stimulation (up to 20 stimulation days) |
|
|
|
|
| Secondary | Size of Follicles on Stimulation Day 6 | Defined as size characteristics of follicles on stimulation Day 6. Average size of 3 largest follicles has been presented in this endpoint. | The FAS comprised of all randomized and exposed participants | Posted | Mean | Standard Deviation | mm | At Day 6 of stimulation |
|
|
|
|
| Secondary | Size of Follicles at End-of-Stimulation | Defined as size characteristics of follicles at end-of-stimulation. Average size of 3 largest follicles has been presented in this endpoint. | The FAS comprised of all randomized and exposed participants | Posted | Mean | Standard Deviation | mm | End-of-stimulation (up to 20 stimulation days) |
|
|
|
|
| Secondary | Fertilization Rate | The fertilization rate was defined as the number of oocytes with 2 pronuclei divided by the number of oocytes retrieved. | The FAS comprised all randomized and exposed participants | Posted | Mean | Standard Deviation | percentage of fertilized oocytes | Day 1 after oocyte retrieval (up to approximately 22 days after start of stimulation) |
|
|
|
|
| Secondary | Number and Quality of Embryos | 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. | The FAS comprised of all randomized and exposed participants. | Posted | Mean | Standard Deviation | Embryo | Day 3 after oocyte retrieval (up to approximately 24 days after start of stimulation) |
|
|
|
|
| Secondary | Number and Quality of Blastocysts | 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. | The FAS comprised of all randomized and exposed participants. | Posted | Mean | Standard Deviation | Blastocysts | Day 5 after oocyte retrieval (up to approximately 26 days after start of stimulation) |
|
|
|
|
| Secondary | Circulating Levels of Endocrine Parameters (Follicle-stimulating Hormone [FSH], Luteinising Hormone [LH]) on Stimulation Day 6 | The median and inter-quartile range (IQR) of FSH and LH levels on stimulation Day 6 are presented. | The FAS comprised of all randomized and exposed participants. | Posted | Median | Inter-Quartile Range | IU/L | At Day 6 of stimulation |
|
|
|
|
| Secondary | Circulating Levels of Endocrine Parameters (Follicle-stimulating Hormone [FSH], Luteinising Hormone [LH]) at End-of-stimulation | The median and IQR of FSH and LH levels at end-of-stimulation are presented. | The FAS comprised of all randomized and exposed participants. | Posted | Median | Inter-Quartile Range | IU/L | End-of-stimulation (up to 20 stimulation days) |
|
|
|
|
| Secondary | Circulating Levels of Endocrine Parameter (Estradiol) on Stimulation Day 6 | The median and IQR of estradiol levels on stimulation Day 6 are presented. | The FAS comprised of all randomized and exposed participants. | Posted | Median | Inter-Quartile Range | pmol/L | At Day 6 of stimulation |
|
|
|
|
| Secondary | Circulating Levels of Endocrine Parameter (Estradiol) at End-of-stimulation | The median and IQR of estradiol levels at end-of-stimulation are presented. | The FAS comprised of all randomized and exposed participants. | Posted | Median | Inter-Quartile Range | pmol/L | End-of-stimulation (up to 20 stimulation days) |
|
|
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| Secondary | Circulating Levels of Endocrine Parameter (Progesterone) on Stimulation Day 6 | The median and IQR of progesterone levels on stimulation Day 6 are presented. | The FAS comprised of all randomized and exposed participants. | Posted | Median | Inter-Quartile Range | nmol/L | At Day 6 of stimulation |
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| Secondary | Circulating Levels of Endocrine Parameter (Progesterone) at End-of-stimulation | The median and IQR of progesterone levels at end-of-stimulation are presented. | The FAS comprised of all randomized and exposed participants. | Posted | Median | Inter-Quartile Range | nmol/L | End-of-stimulation (up to 20 stimulation days) |
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| Secondary | Circulating Levels of Endocrine Parameters (Inhibin A) on Stimulation Day 6 | The median and IQR of Inhibin A levels on stimulation Day 6 are presented. | The FAS comprised of all randomized and exposed participants. | Posted | Median | Inter-Quartile Range | ng/L | At Day 6 of stimulation |
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| Secondary | Circulating Levels of Endocrine Parameters (Inhibin A) at End-of-stimulation | The median and IQR of Inhibin A levels at end-of-stimulation are presented. | The FAS comprised of all randomized and exposed participants. | Posted | Median | Inter-Quartile Range | ng/L | End-of-stimulation (up to 20 stimulation days) |
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| Secondary | Circulating Levels of Endocrine Parameters (Inhibin B) on Stimulation Day 6 | The median and IQR of inhibin B levels on stimulation Day 6 are presented. | The FAS comprised of all randomized and exposed participants. | Posted | Median | Inter-Quartile Range | ng/L | At Day 6 of stimulation |
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| Secondary | Circulating Levels of Endocrine Parameters (Inhibin B) at End-of-stimulation | The median and IQR of inhibin B levels at end-of-stimulation are presented. | The FAS comprised of all randomized and exposed participants. | Posted | Median | Inter-Quartile Range | ng/L | End-of-stimulation (up to 20 stimulation days) |
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| Secondary | Number of Stimulation Days | The safety analysis set comprised of all randomized and exposed participants. | Posted | Mean | Standard Deviation | Days | End-of-stimulation (up to 20 stimulation days) |
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| Secondary | Total Gonadotropin Dose of FE 999049 | The safety analysis set comprised of all randomized and exposed participants. | Posted | Mean | Standard Deviation | μg | End-of-stimulation (up to 20 stimulation days) |
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| Secondary | Total Gonadotropin Dose of FOLLISTIM | The safety analysis set comprised of all randomized and exposed participants. | Posted | Mean | Standard Deviation | IU | End-of-stimulation (up to 20 stimulation days) |
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| Secondary | Number of Participants With Adverse Events (AEs) Stratified by Intensity | 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). | The safety analysis set comprised of all randomized and exposed participants. | Posted | Number | Participants | From signed informed consent up to 5-6 weeks after transfer |
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| Secondary | Proportion of Participants Who Had Markedly Abnormal Value Changes From Baseline in Clinical Chemistry Parameters at End-of-stimulation | 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. | The safety analysis set comprised of all randomized and exposed participants. | Posted | Number | participants | End-of-stimulation (up to 20 stimulation days) |
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| Secondary | Proportion of Participants Who Had Markedly Abnormal Value Changes From Baseline in Hematology Parameters at End-of-stimulation | 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. | The safety analysis set comprised of all randomized and exposed participants. | Posted | Number | participants | End-of-stimulation (up to 20 stimulation days) |
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| Secondary | Proportion of Participants Who Had Markedly Abnormal Value Changes From Baseline in Clinical Chemistry Parameters at End-of-trial | 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. | The safety analysis set comprised of all randomized and exposed participants. | Posted | Number | participants | Up to 5-6 weeks after transfer |
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| Secondary | Proportion of Participants Who Had Markedly Abnormal Value Changes From Baseline in Hematology Parameters at End-of-trial | 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. | The safety analysis set comprised of all randomized and exposed participants. | Posted | Number | participants | Up to 5-6 weeks after transfer |
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| Secondary | Frequency and Intensity of Injection Site Reactions | 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. | The safety analysis set comprised of all randomized and exposed participants. | Posted | Number | events | End-of-stimulation (up to 20 stimulation days) |
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| Secondary | Technical Malfunctions of the Administration Pens | The safety analysis set comprised of all randomized and exposed participants. | Posted | Number | percentage of participants | End-of-stimulation (up to 20 stimulation days) |
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| 0 |
| 170 |
| 0 |
| 170 |
| 73 |
| 170 |
| EG001 | FOLLISTIM (Follitropin Beta) | 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. | 0 | 177 | 2 | 177 | 92 | 177 |
| Injection site erythema | General disorders | MedDRA (20.0) | Systematic Assessment |
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| Injection site pruritus | General disorders | MedDRA (20.0) | Systematic Assessment |
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| Viral upper respiratory tract infection | Infections and infestations | MedDRA (20.0) | Systematic Assessment |
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| Headache | Nervous system disorders | MedDRA (20.0) | Systematic Assessment |
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| Biochemical pregnancy | Pregnancy, puerperium and perinatal conditions | MedDRA (20.0) | Systematic Assessment |
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| Abortion spontenous | Pregnancy, puerperium and perinatal conditions | MedDRA (20.0) | Systematic Assessment |
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| Haemorrhage in pregnancy | Pregnancy, puerperium and perinatal conditions | MedDRA (20.0) | Systematic Assessment |
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| Ovarian hyperstimulation syndrome | Reproductive system and breast disorders | MedDRA (20.0) | Systematic Assessment |
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| Ovarian cyst | Reproductive system and breast disorders | MedDRA (20.0) | Systematic Assessment |
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| Ovarian enlargement | Reproductive system and breast disorders | MedDRA (20.0) | Systematic Assessment |
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| Pelvic fluid collection | Reproductive system and breast disorders | MedDRA (20.0) | Systematic Assessment |
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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.
| Targeted response (8-14 oocytes) |
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| Hyperresponse (15-19 oocytes) |
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| Severe hyperresponse (≥ 20 oocytes) |
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Proportion of participants with 4-7 oocytes retrieved (moderate response). |
| Regression, Logistic |
The model included treatment and AMH stratum (<15 pmol/L and ≥15 pmol/L) as fixed factors. |
| 0.041 |
P-value was based on likelihood ratio test. |
| Superiority |
| Proportion of participants with 8-14 oocytes retrieved (targeted response). | Regression, Logistic | The model included treatment and AMH stratum (<15 pmol/L and ≥15 pmol/L) as fixed factors. | 0.705 | P-value was based on likelihood ratio test. | Superiority |
| Proportion of participants with 15-19 oocytes retrieved (hyperresponse). | Regression, Logistic | The model included treatment and AMH stratum (<15 pmol/L and ≥15 pmol/L) as fixed factors. | 0.183 | P-value was based on likelihood ratio test. | Superiority |
| Proportion of participants with >= (more than equal to) 20 oocytes retrieved (severe hyperresponse). | Regression, Logistic | The model included treatment and AMH stratum (<15 pmol/L and ≥15 pmol/L) as fixed factors. | 0.030 | P-value was based on likelihood ratio chi-square test. | Superiority |
| AMH >= 15 pmol/L (>=15 oocytes retrieved) |
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| AMH >= 15 pmol/L (>=20 oocytes retrieved) |
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| Chi-squared |
| 0.002 |
P-value was based on likelihood ratio chi-square test. |
| Superiority |
| Proportion of participants with extreme ovarian responses: AMH >= 15 pmol/L (>=20 oocytes retrieved) | Chi-squared | 0.021 | P-value based on likelihood ratio chi-square test. | Superiority |
| Administration of dopamine agonist |
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| Early OHSS (any grade) and/or preventive |
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| Early OHSS (moderate/severe) and/or preventive |
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Proportion of participants with early OHSS (moderate/severe). |
| Regression, Logistic |
The model included treatment and AMH stratum (<15 pmol/L and ≥15 pmol/L) as fixed factors. |
| 0.035 |
P-value was based on likelihood ratio chi-square test. |
| Superiority |
| Proportion of participants with early OHSS (any grade) and/or preventive interventions. | Regression, Logistic | The model included treatment and AMH stratum (<15 pmol/L and ≥15 pmol/L) as fixed factors. | 0.006 | P-value was based on likelihood ratio chi-square test. | Superiority |
| Proportion of participants with early OHSS (moderate/severe) and/or preventive interventions. | Regression, Logistic | The model included treatment and AMH stratum (<15 pmol/L and ≥15 pmol/L) as fixed factors. | 0.009 | P-value was based on likelihood ratio chi-square test. | Superiority |
Proportions of participants with late OHSS (moderate/severe). |
| Regression, Logistic |
The model included treatment and AMH stratum (<15 pmol/L and ≥15 pmol/L) as fixed factors. |
| 0.582 |
P-value was based on likelihood ratio chi-square test. |
| Superiority |
The number of good-quality embryos on Day 3 was analyzed.
| van Elteren test |
P-value was based on van Elteren test adjusted for AMH strata. |
| 0.004 |
2-sided |
| Superiority |
The number of good-quality blastocysts on Day 5 was analyzed.
| van Elteren test |
P-value was based on van Elteren test adjusted for AMH strata. |
| <0.001 |
2-sided |
| Superiority |
| Circulating levels of LH on stimulation Day 6. | ANCOVA | The ANCOVA model included treatment and AMH stratum (<15 pmol/L and ≥15 pmol/L) as fixed factors and log-baseline as covariate. | 0.777 | The P-value corresponds to the two-sided F-test of treatment effect. | Mean ratio | 0.97 | 2-Sided | 95 | 0.81 | 1.17 | Mean ratio is equal to FE 999049/FOLLISTIM. | Superiority |
| Circulating levels of LH at end-of-stimulation. | ANCOVA | The ANCOVA model included treatment and AMH stratum (<15 pmol/L and ≥15 pmol/L) as fixed factors and log-baseline as covariate. | 0.057 | The P-value corresponds to the two-sided F-test of treatment effect. | Mean ratio | 1.17 | 2-Sided | 95 | 1.00 | 1.39 | Mean ratio is equal to FE 999049/FOLLISTIM. | Superiority |
| Moderate AE |
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| Severe AE |
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| Hematocrit (ratio) Normal to markedly low (>=0.56) |
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| Any severe injection site reaction |
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| Mild redness |
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| Moderate redness |
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| Severe redness |
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| Mild itching |
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| Moderate itching |
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| Severe itching |
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| Mild pain |
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| Moderate pain |
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| Severe pain |
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| Mild swelling |
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| Moderate swelling |
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| Severe swelling |
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| Mild bruising |
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| Moderate bruising |
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| Severe bruising |
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