Comparative Pharmacokinetics of AFOLIA and US Gonal-f® RFF Redi-ject After Single Subcutaneous Application

Study Overview
=================
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)

Official Title
-----------------
Comparative Pharmacokinetics of AFOLIA and US Gonal-f® RFF Redi-ject After Single Subcutaneous Application. A Randomised, Open Label, 2-way Cross-over Study

Conditions
-----------------
Healthy Volunteers

Intervention / Treatment
-----------------
* Drug: Afolia
* Drug: US Gonal-f®


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Healthy female volunteers aged 18 to 42 years (inclusive) with a Body mass index of 18.0 to 32.0 kg/m2 (inclusive) 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 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 Subjects with a regular menstruation cycle (25 to 34 days) before initiation of oral contraception Subjects with both ovaries Subjects who are negative for drugs of abuse and alcohol tests at screening and each admission Subjects who are healthy as determined by pre study medical history, physical examination and 12-Lead electrocardiogram (ECG) Subjects whose clinical laboratory test results are not clinically relevant and are acceptable to the investigator Subjects who are able and willing to give written informed consent Exclusion Criteria: Subjects who do not conform to the above inclusion criteria Subjects with polycystic ovary syndrome Subjects with developing follicles or solid ovarian cysts >2 cm or complex cysts regardless of size Subjects with a history of hypersensitivity to FSH (Ovary Hyperstimulation Syndrome) Subjects with impaired thyroid function (treated or untreated) Subjects with a history of malignant disease Subjects with aspartate aminotransferase and/or alanine aminotransferase >2 x upper limit of normal reference range Subjects with other clinically relevant findings (ECG, blood pressure, physical, laboratory examination) Subjects with a smoking history of more than 5 cigarettes per day Subjects with evidence of abuse of drugs or alcoholic beverages 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 Subjects who have participated in a clinical trial within the 3 months prior to this study Subjects who are unlikely to co-operate with the requirements of the study Subjects with symptoms of a clinically relevant illness during the 3 weeks prior to study day -1 Subjects who are pregnant, lactating or attempting to become pregnant 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 Subjects who are vegans or have medical dietary restrictions Subjects who cannot communicate reliably with the investigator

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 42 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Afolia - US Gonal-f® (Sequence A) Arm<br>During the Cross-Over Pharmacokinetic Phase, subjects will be randomly assigned to receive treatment sequence: (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. | Drug: Afolia<br>* 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<br>* Other names: Follitropin Alfa;Drug: US Gonal-f®<br>* 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<br>* Other names: Follitropin Alfa;|
| Active Comparator: US Gonal-f® - Afolia (Sequence B) Arm:<br>During the Cross-Over Pharmacokinetic Phase, patients will be randomly assigned to receive treatment sequence (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 | Drug: Afolia<br>* 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<br>* Other names: Follitropin Alfa;Drug: US Gonal-f®<br>* 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<br>* Other names: Follitropin Alfa;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 
| 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. | From 0 hours (predose) to 192 hours postdose. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | From 0 hours (predose) to 192 hours postdose. | 
| 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. | From 0 hours (predose) to 192 hours postdose. | 
| 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. | From 0 hours (predose) to 192 hours postdose. | 
| 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. | From 0 hours (predose) to 192 hours postdose. | 
| 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. | From 0 hours (predose) to 192 hours postdose. | 
| 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. | From 0 hours (predose) to 192 hours postdose. | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Afolia, Follitropin