Healthy Volunteers
Conditions
Keywords
Afolia, Follitropin
Brief summary
Comparative PK study after single SC application of Afolia and the reference product (US Gonal-f®). Objective: To demonstrate equivalence within 80%-125% margin of the reference product for the area under the curve (AUC) of Afolia.
Detailed description
To demonstrate equivalence within the 80% to 125% margin of the reference product for the baseline corrected area under the follicle-stimulating hormone (FSH) serum concentration-time curve from time zero to the last quantifiable concentration of AFOLIA compared to the reference product (United States \[US\] Gonal-f® RFF)
Interventions
DRUGAfolia
During the Cross-Over Pharmacokinetic Phase, subjects will be randomly assigned to receive one of the following treatment sequences: Sequence A: Single subcutaneous injection of 225IU Afolia on study day 1, followed by a single subcutaneous injection of 225IU US Gonal-f® on study day 27. Sequence B: Single subcutaneous injection of 225IU US Gonal-f® on study day 1, followed by a single subcutaneous injection of 225IU Afolia on study day 27
DRUGUS Gonal-f®
During the Cross-Over Pharmacokinetic Phase, subjects will be randomly assigned to receive one of the following treatment sequences: Sequence A: Single subcutaneous injection of 225IU Afolia on study day 1, followed by a single subcutaneous injection of 225IU US Gonal-f® on study day 27. Sequence B: Single subcutaneous injection of 225IU US Gonal-f® on study day 1, followed by a single subcutaneous injection of 225IU Afolia on study day 27
Sponsors
Fertility Biotech AG
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 42 Years
Healthy volunteers
Yes
Inclusion criteria
1. Healthy female volunteers aged 18 to 42 years (inclusive) with a Body mass index of 18.0 to 32.0 kg/m2 (inclusive) 2. Subjects who have used oral contraceptives for at least 3 months before study entry and are prepared to stop taking oral contraception from screening and to use effective non-hormonal methods of birth control until completion of 1 menstrual cycle after the last dose administration 3. Women of child bearing potential must agree to use effective non-hormonal contraception for birth control until completion of 1 menstrual cycle after the last dose administration 4. Subjects with a regular menstruation cycle (25 to 34 days) before initiation of oral contraception 5. Subjects with both ovaries 6. Subjects who are negative for drugs of abuse and alcohol tests at screening and each admission 7. Subjects who are healthy as determined by pre study medical history, physical examination and 12-Lead electrocardiogram (ECG) 8. Subjects whose clinical laboratory test results are not clinically relevant and are acceptable to the investigator 9. Subjects who are able and willing to give written informed consent
Exclusion criteria
1. Subjects who do not conform to the above inclusion criteria 2. Subjects with polycystic ovary syndrome 3. Subjects with developing follicles or solid ovarian cysts \>2 cm or complex cysts regardless of size 4. Subjects with a history of hypersensitivity to FSH (Ovary Hyperstimulation Syndrome) 5. Subjects with impaired thyroid function (treated or untreated) 6. Subjects with a history of malignant disease 7. Subjects with aspartate aminotransferase and/or alanine aminotransferase \>2 x upper limit of normal reference range 8. Subjects with other clinically relevant findings (ECG, blood pressure, physical, laboratory examination) 9. Subjects with a smoking history of more than 5 cigarettes per day 10. Subjects with evidence of abuse of drugs or alcoholic beverages 11. Subjects with a positive screen for hepatitis B surface antigen, antibodies to the hepatitis C virus or antibodies to the human immunodeficiency virus 1/2 12. Subjects who have participated in a clinical trial within the 3 months prior to this study 13. Subjects who are unlikely to co-operate with the requirements of the study 14. Subjects with symptoms of a clinically relevant illness during the 3 weeks prior to study day -1 15. Subjects who are pregnant, lactating or attempting to become pregnant 16. Subjects with any medical condition (including a known predisposition to porphyria) that, in the opinion of the investigator, could interfere with safety of the subject or interfere with the objectives of the study 17. Subjects who are vegans or have medical dietary restrictions 18. Subjects who cannot communicate reliably with the investigator
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Baseline Corrected FSH Area Under the Serum Concentration-time Curve From Zero to the Last Quantifiable Measurement [AUC(0-last)] | From 0 (predose),0.5, 1, 3, 6, 9, 12, 16, 20, 21, 22, 23, 24, 25, 26, 27, 28, 48, 72, 96, 120, 144, 168 and 192 hours postdose. | AUC(0-last) was estimated for baseline corrected FSH in serum by noncompartmental methods using actual elapsed time from dosing. Baseline corrected concentrations were determined by subtracting the baseline concentration (collected immediately prior to dosing in that period) from the postdose concentration. Geometric mean baseline corrected FSH exposure results are presented for all subjects who received active study drug and had at least 1 measured and valid concentration at a scheduled PK time point after administration of AFOLIA or Gonal-f® RFF. |
| Baseline Corrected FSH Maximum Serum Concentration (Cmax) | From 0 hours (predose) to 192 hours postdose. | Cmax was estimated for baseline corrected FSH in serum by noncompartmental methods using actual elapsed time from dosing. Baseline corrected concentrations were determined by subtracting the baseline concentration (collected immediately prior to dosing in that period) from the postdose concentration. Geometric mean baseline corrected FSH exposure results are presented for all subjects who received active study drug and had at least 1 measured and valid concentration at a scheduled PK time point after administration of AFOLIA or Gonal-f® RFF. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Baseline Corrected FSH Apparent Terminal Half-life | From 0 hours (predose) to 192 hours postdose. | Apparent terminal half-life was defined as ln2/apparent terminal rate constant (λz). λz is determined by linear regression of the terminal points of the log-linear concentration-time curve. Visual assessment was used to identify the terminal linear phase of the baseline corrected concentration-time profile. A minimum of 3 data points was used for determination. Terminal half-life was estimated for baseline corrected FSH in serum by noncompartmental methods using actual elapsed time from dosing. Baseline corrected concentrations were determined by subtracting the baseline concentration (collected immediately prior to dosing in that period) from the postdose concentration. Geometric mean baseline corrected FSH exposure results are presented for all subjects who received active study drug and had at least 1 measured and valid concentration at a scheduled PK time point after administration of AFOLIA or Gonal-f® RFF. |
| Baseline Corrected 17ß-Estrodiol (E2) Serum Exposure AUC(0-last) | From 0 hours (predose) to 192 hours postdose. | AUC(0-last) was estimated for baseline corrected E2 in serum by noncompartmental methods using actual elapsed time from dosing. Baseline corrected concentrations were determined by subtracting the baseline concentration (collected immediately prior to dosing in that period) from the postdose concentration. Geometric mean baseline corrected E2 exposure results are presented for all subjects who received active study drug and had at least 1 measured and valid concentration at a scheduled PD time point after administration of AFOLIA or Gonal-f® RFF. |
| Baseline Corrected FSH Area Under the Serum Concentration-time Curve Extrapolated to Infinity [AUC(0-∞)] | From 0 hours (predose) to 192 hours postdose. | AUC(0-∞) was estimated for baseline corrected FSH in serum by noncompartmental methods using actual elapsed time from dosing. Baseline corrected concentrations were determined by subtracting the baseline concentration (collected immediately prior to dosing in that period) from the postdose concentration. Geometric mean baseline corrected FSH exposure results are presented for all subjects who received active study drug and had at least 1 measured and valid concentration at a scheduled PK time point after administration of AFOLIA or Gonal-f® RFF. |
| Baseline Corrected E2 Tmax | From 0 hours (predose) to 192 hours postdose. | Tmax was estimated for baseline corrected E2 in serum by noncompartmental methods using actual elapsed time from dosing. Baseline corrected concentrations were determined by subtracting the baseline concentration (collected immediately prior to dosing in that period) from the postdose concentration. Geometric mean was not calculated for Tmax and the non-transformed results are presented are for all subjects who received active study drug and had Tmax estimated in both periods. |
| Baseline Corrected E2 Cmax | From 0 hours (predose) to 192 hours postdose. | Cmax was estimated for baseline corrected E2 in serum by noncompartmental methods using actual elapsed time from dosing. Baseline corrected concentrations were determined by subtracting the baseline concentration (collected immediately prior to dosing in that period) from the postdose concentration. Geometric mean baseline corrected E2 exposure results are presented for all subjects who received active study drug and had at least 1 measured and valid concentration at a scheduled PD time point after administration of AFOLIA or Gonal-f® RFF. |
| Baseline Corrected Time to Reach Maximum FSH Serum Concentration (Tmax) | From 0 hours (predose) to 192 hours postdose. | Tmax was estimated for baseline corrected FSH in serum by noncompartmental methods using actual elapsed time from dosing. Baseline corrected concentrations were determined by subtracting the baseline concentration (collected immediately prior to dosing in that period) from the postdose concentration. Geometric mean was not calculated for Tmax and the non-transformed results are presented are for all subjects who received active study drug and had Tmax estimated in both periods. |
Countries
United Kingdom
Participant flow
Recruitment details
This was a Phase 1, randomised, open label, 2-period, 2-treatment, crossover study in healthy female subjects. 42 subjects were randomised to receive either AFOLIA on study day 1 and Gonal-f® RFF on study day 27 or Gonal-f® RFF on study day 1 and AFOLIA on study day 27.
Pre-assignment details
Screening was conducted at more than 1 visit to the clinical unit during study days -28 to -1 to allow completion of all assessments. Only subjects taking oral contraception for at least 3 months could enter the study. Subjects were required to stop taking their regular oral contraceptives so they could receive LupronDepot®.
Participants by arm
| Arm | Count |
|---|---|
| AFOLIA Then Gonal-f® RFF On study day -1 (10 days after administration of LupronDepot®) subjects were assessed for eligibility of treatment by confirmation of down regulation of endogenous FSH levels. If down regulation was not confirmed the evaluation may have been repeated up to 7 days later.
Period 1: On study day 1, eligible subjects received a single s.c. dose of the first FSH preparation, 225 International Units (IU) AFOLIA, in the abdomen. On study day 16, subjects received a second LupronDepot® i.m. injection.
Period 2: On study day 26, subjects underwent a further FSH down regulation assessment. This evaluation was repeated up to 7 days later if required and if down regulation was not confirmed after the second evaluation, the subject was no longer able to continue in the study. If eligibility was confirmed, the subject received the alternative FSH preparation, 225 IU Gonal-f® RFF on study day 27.
Exit examinations were performed on study day 35. | 21 |
| Gonal-f® RFF Then AFOLIA On study day -1 (10 days after administration of LupronDepot®) subjects were assessed for eligibility of treatment by confirmation of down regulation of endogenous FSH levels. If down regulation was not confirmed the evaluation may have been repeated up to 7 days later.
Period 1: On study day 1, eligible subjects received a single s.c. dose of the first FSH preparation, 225 IU Gonal-f® RFF, in the abdomen. On study day 16, subjects received a second LupronDepot® i.m. injection.
Period 2: On study day 26, subjects underwent a further FSH down regulation assessment. This evaluation was repeated up to 7 days later if required and if down regulation was not confirmed after the second evaluation, the subject was no longer able to continue in the study. If eligibility was confirmed, the subject received the alternative FSH preparation of 225 IU AFOLIA on study day 27.
Exit examinations were performed on study day 35. | 21 |
| Total | 42 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Abnormal Transvaginal Ultrasound | 1 | 0 |
| Overall Study | Adverse Event | 0 | 1 |
| Overall Study | Elevated Creatine Kinase | 1 | 0 |
| Overall Study | Endometrial thickness of >5 mm | 1 | 0 |
| Overall Study | Exclusion Criteria | 4 | 0 |
| Overall Study | Physician Decision | 0 | 2 |
| Overall Study | Protocol Violation | 0 | 2 |
| Overall Study | Withdrawal by Subject | 1 | 1 |
Baseline characteristics
| Characteristic | AFOLIA Then Gonal-f® RFF | Gonal-f® RFF Then AFOLIA | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 21 Participants | 21 Participants | 42 Participants |
| Age, Continuous | 27.8 years | 28.1 years | 28.0 years |
| Sex: Female, Male Female | 21 Participants | 21 Participants | 42 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 36 | 0 / 34 |
| other Total, other adverse events | 21 / 36 | 22 / 34 |
| serious Total, serious adverse events | 0 / 36 | 0 / 34 |
Outcome results
Primary
Baseline Corrected FSH Area Under the Serum Concentration-time Curve From Zero to the Last Quantifiable Measurement [AUC(0-last)]
AUC(0-last) was estimated for baseline corrected FSH in serum by noncompartmental methods using actual elapsed time from dosing. Baseline corrected concentrations were determined by subtracting the baseline concentration (collected immediately prior to dosing in that period) from the postdose concentration. Geometric mean baseline corrected FSH exposure results are presented for all subjects who received active study drug and had at least 1 measured and valid concentration at a scheduled PK time point after administration of AFOLIA or Gonal-f® RFF.
Time frame: From 0 (predose),0.5, 1, 3, 6, 9, 12, 16, 20, 21, 22, 23, 24, 25, 26, 27, 28, 48, 72, 96, 120, 144, 168 and 192 hours postdose.
Population: Analysis was performed on the Pharmacokinetic Analysis Set (PKAS) which includes all subjects who received active study drug and had at least 1 measured and valid concentration at a scheduled PK time point after administration of AFOLIA or Gonal-f® RFF. Only subjects with concentration data for determination of AUC(0-last) are included.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| AFOLIA | Baseline Corrected FSH Area Under the Serum Concentration-time Curve From Zero to the Last Quantifiable Measurement [AUC(0-last)] | 18.96 nanograms*hours/mL (ng*h/mL) |
| Gonal-f® RFF | Baseline Corrected FSH Area Under the Serum Concentration-time Curve From Zero to the Last Quantifiable Measurement [AUC(0-last)] | 10.47 nanograms*hours/mL (ng*h/mL) |
Comparison: A mixed-effects analysis of variance (ANOVA) model with sequence, treatment and period as fixed effects, and subject nested within sequence as random effect was used. Least squares (LS) means and 90% confidence intervals (CIs) for treatment differences on log-scale were obtained and back transformed to provide geometric LS mean ratios of AFOLIA over Gonal-f® RFF.90% CI: [137.82, 197.45]
Primary
Baseline Corrected FSH Maximum Serum Concentration (Cmax)
Cmax was estimated for baseline corrected FSH in serum by noncompartmental methods using actual elapsed time from dosing. Baseline corrected concentrations were determined by subtracting the baseline concentration (collected immediately prior to dosing in that period) from the postdose concentration. Geometric mean baseline corrected FSH exposure results are presented for all subjects who received active study drug and had at least 1 measured and valid concentration at a scheduled PK time point after administration of AFOLIA or Gonal-f® RFF.
Time frame: From 0 hours (predose) to 192 hours postdose.
Population: This analysis was performed on the PKAS which includes all subjects who received active study drug and had at least 1 measured and valid concentration at a scheduled PK time point after administration of AFOLIA or Gonal-f® RFF. Only subjects with concentration data for determination of Cmax are included.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| AFOLIA | Baseline Corrected FSH Maximum Serum Concentration (Cmax) | 0.4795 ng/mL |
| Gonal-f® RFF | Baseline Corrected FSH Maximum Serum Concentration (Cmax) | 0.3692 ng/mL |
Comparison: An ANOVA model with sequence, treatment and period as fixed effects, and subject nested within sequence as random effect was used. LS means and 90% CIs for treatment differences on log-scale were obtained and back-transformed to provide geometric LS mean ratios of AFOLIA over Gonal-f® RFF.90% CI: [108.12, 140.28]
Secondary
Baseline Corrected 17ß-Estrodiol (E2) Serum Exposure AUC(0-last)
AUC(0-last) was estimated for baseline corrected E2 in serum by noncompartmental methods using actual elapsed time from dosing. Baseline corrected concentrations were determined by subtracting the baseline concentration (collected immediately prior to dosing in that period) from the postdose concentration. Geometric mean baseline corrected E2 exposure results are presented for all subjects who received active study drug and had at least 1 measured and valid concentration at a scheduled PD time point after administration of AFOLIA or Gonal-f® RFF.
Time frame: From 0 hours (predose) to 192 hours postdose.
Population: This analysis was performed on the PKAS which includes all subjects who received active study drug and had at least 1 measured and valid concentration at a scheduled PK time point after administration of AFOLIA or Gonal-f® RFF. Only subjects with concentration data for determination of AUC(0-last) are included.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| AFOLIA | Baseline Corrected 17ß-Estrodiol (E2) Serum Exposure AUC(0-last) | 888 pg*h/mL |
| Gonal-f® RFF | Baseline Corrected 17ß-Estrodiol (E2) Serum Exposure AUC(0-last) | 570 pg*h/mL |
Comparison: An ANOVA model with sequence, treatment and period as fixed effects, and subject nested within sequence as random effect was used. LS means and 90% CIs for treatment differences on log-scale were obtained and back-transformed to provide geometric LS mean ratios of AFOLIA over Gonal-f® RFF.90% CI: [94, 282.67]
Secondary
Baseline Corrected E2 Cmax
Cmax was estimated for baseline corrected E2 in serum by noncompartmental methods using actual elapsed time from dosing. Baseline corrected concentrations were determined by subtracting the baseline concentration (collected immediately prior to dosing in that period) from the postdose concentration. Geometric mean baseline corrected E2 exposure results are presented for all subjects who received active study drug and had at least 1 measured and valid concentration at a scheduled PD time point after administration of AFOLIA or Gonal-f® RFF.
Time frame: From 0 hours (predose) to 192 hours postdose.
Population: This analysis was performed on the PKAS which includes all subjects who received active study drug and had at least 1 measured and valid concentration at a scheduled PK time point after administration of AFOLIA or Gonal-f® RFF. Only subjects with concentration data for determination of Cmax are included.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| AFOLIA | Baseline Corrected E2 Cmax | 28.03 pg/mL |
| Gonal-f® RFF | Baseline Corrected E2 Cmax | 15.95 pg/mL |
Comparison: An ANOVA model with sequence, treatment and period as fixed effects, and subject nested within sequence as random effect was used. LS means and 90% CIs for treatment differences on log-scale were obtained and back-transformed to provide geometric LS mean ratios of AFOLIA over Gonal-f® RFF.90% CI: [125.65, 249.81]
Secondary
Baseline Corrected E2 Tmax
Tmax was estimated for baseline corrected E2 in serum by noncompartmental methods using actual elapsed time from dosing. Baseline corrected concentrations were determined by subtracting the baseline concentration (collected immediately prior to dosing in that period) from the postdose concentration. Geometric mean was not calculated for Tmax and the non-transformed results are presented are for all subjects who received active study drug and had Tmax estimated in both periods.
Time frame: From 0 hours (predose) to 192 hours postdose.
Population: This analysis was performed on the PKAS which includes all subjects who received active study drug and had at least 1 measured and valid concentration at a scheduled PK time point after administration of AFOLIA or Gonal-f® RFF. Only subjects with Tmax estimated in both periods are included.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| AFOLIA | Baseline Corrected E2 Tmax | 47.92 hours |
| Gonal-f® RFF | Baseline Corrected E2 Tmax | 27.5 hours |
Comparison: Non-transformed Tmax was tested using the non-parametric Wilcoxon signed rank test to assess the differences between Gonal-f® RFF and AFOLIA. Median difference and corresponding 90% CIs were was calculated using an Exact Hodges-Lehmann estimate with an exact confidence interval.90% CI: [-9.91, 12.29]
Secondary
Baseline Corrected FSH Apparent Terminal Half-life
Apparent terminal half-life was defined as ln2/apparent terminal rate constant (λz). λz is determined by linear regression of the terminal points of the log-linear concentration-time curve. Visual assessment was used to identify the terminal linear phase of the baseline corrected concentration-time profile. A minimum of 3 data points was used for determination. Terminal half-life was estimated for baseline corrected FSH in serum by noncompartmental methods using actual elapsed time from dosing. Baseline corrected concentrations were determined by subtracting the baseline concentration (collected immediately prior to dosing in that period) from the postdose concentration. Geometric mean baseline corrected FSH exposure results are presented for all subjects who received active study drug and had at least 1 measured and valid concentration at a scheduled PK time point after administration of AFOLIA or Gonal-f® RFF.
Time frame: From 0 hours (predose) to 192 hours postdose.
Population: This analysis was performed on the PKAS which includes all subjects who received active study drug and had at least 1 measured concentration at a scheduled PK or PD time point after administration of AFOLIA or Gonal-f® RFF. Only subjects with suitable terminal phase profiles for determination of terminal half-life are included.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| AFOLIA | Baseline Corrected FSH Apparent Terminal Half-life | 20.4 hours |
| Gonal-f® RFF | Baseline Corrected FSH Apparent Terminal Half-life | 18.02 hours |
Secondary
Baseline Corrected FSH Area Under the Serum Concentration-time Curve Extrapolated to Infinity [AUC(0-∞)]
AUC(0-∞) was estimated for baseline corrected FSH in serum by noncompartmental methods using actual elapsed time from dosing. Baseline corrected concentrations were determined by subtracting the baseline concentration (collected immediately prior to dosing in that period) from the postdose concentration. Geometric mean baseline corrected FSH exposure results are presented for all subjects who received active study drug and had at least 1 measured and valid concentration at a scheduled PK time point after administration of AFOLIA or Gonal-f® RFF.
Time frame: From 0 hours (predose) to 192 hours postdose.
Population: This analysis was performed on the PKAS which includes all subjects who received active study drug and had at least 1 measured and valid concentration at a scheduled PK time point after administration of AFOLIA or Gonal-f® RFF. Only subjects with suitable terminal phase profiles for determination of AUC(0-∞) are included.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| AFOLIA | Baseline Corrected FSH Area Under the Serum Concentration-time Curve Extrapolated to Infinity [AUC(0-∞)] | 27.88 ng*h/mL |
| Gonal-f® RFF | Baseline Corrected FSH Area Under the Serum Concentration-time Curve Extrapolated to Infinity [AUC(0-∞)] | 20.57 ng*h/mL |
Comparison: An ANOVA model with sequence, treatment and period as fixed effects, and subject nested within sequence as random effect was used. LS means and 90% CIs for treatment differences on log-scale were obtained and back-transformed to provide geometric LS mean ratios of AFOLIA over Gonal-f® RFF.90% CI: [102.42, 174.49]
Secondary
Baseline Corrected Time to Reach Maximum FSH Serum Concentration (Tmax)
Tmax was estimated for baseline corrected FSH in serum by noncompartmental methods using actual elapsed time from dosing. Baseline corrected concentrations were determined by subtracting the baseline concentration (collected immediately prior to dosing in that period) from the postdose concentration. Geometric mean was not calculated for Tmax and the non-transformed results are presented are for all subjects who received active study drug and had Tmax estimated in both periods.
Time frame: From 0 hours (predose) to 192 hours postdose.
Population: This analysis was performed on the PKAS which includes all subjects who received active study drug and had at least 1 measured and valid concentration at a scheduled PK time point after administration of AFOLIA or Gonal-f® RFF. Only subjects with Tmax estimated in both periods are included.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| AFOLIA | Baseline Corrected Time to Reach Maximum FSH Serum Concentration (Tmax) | 24.05 hours |
| Gonal-f® RFF | Baseline Corrected Time to Reach Maximum FSH Serum Concentration (Tmax) | 16 hours |
Comparison: Non-transformed Tmax was tested using the non-parametric Wilcoxon signed rank test to assess the differences between Gonal-f® RFF and AFOLIA. Median differences and corresponding 90% CIs were calculated using an exact Hodges-Lehmann estimate.90% CI: [4.5, 11.5]