The Safety and Pharmacokinetics of Primapur and Gonal-f

Study Overview
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Brief Summary
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The purpose of the current phase I study was to establish bioequivalence, safety, and tolerance of single 300 IU subcutaneous dose of follitropin alfa biosimilar (Primapur) in comparison to that of reference follitropin alfa preparation (Gonal-F) in healthy young female volunteers.

Detailed Description
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A Phase I, prospective, randomized, open-label, crossover, 2-period, two treatment, clinical study in healthy female volunteers. Objectives of the study: To evaluate the frequency and severity of adverse events (AE) following a single 300 IU subcutaneous injection of Primapur (IVFarma, LLC, Russia) and Gonal-F (Merck Serono S.p.A., Italy) to healthy volunteers. To determine the AUC0-t value of Primapur following a single 300 IU subcutaneous injection to healthy volunteers. To determine the T½ value of Primapur following a single 300 IU subcutaneous injection to healthy volunteers. To determine the Сmax value of Primapur following a single 300 IU subcutaneous injection to healthy volunteers. To determine the Tmax value of Primapur following a single 300 IU subcutaneous injection to healthy volunteers. To compare the obtained pharmacokinetic characteristics of Primapur and Gonal-F.

Official Title
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Study of Safety, Tolerance and Pharmacokinetics of Primapur and Gonal-f Upon Single-dose Subcutaneous Administration in Healthy Volunteers

Conditions
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Area Under Curve, Pharmacokinetics, Absorption

Intervention / Treatment
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* Drug: Follitropin alfa (Primapur)
* Drug: Follitropin alfa (Gonal-F)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy female volunteers aged 18 to 40 years. Body mass index (BMI) of 18.5 to 30.0 kg/m2. Subjects who have used oral contraceptives for at least 2 menstrual cycles before study entry. Regular menstruation cycle (24 to 35 days) before initiation of oral contraception. Presence of both ovaries. Subjects who are negative for drugs of abuse and alcohol tests at screening. Subjects who are healthy as validated by pre study medical history, physical examination. Subjects with acceptable clinical laboratory test results. A signed informed consent form that confirms in writing the volunteer's consent to participate in this clinical study and the volunteer's willingness to comply with all physician recommendations and protocol limitations for the time of participation in the clinical study. Ability to comply with the requirements of the protocol. Participants in the study, as well as their sexual partners, are knowledgeable and willing to voluntarily, starting from the week before being included in the study and up to 4 weeks after the last dose of the study drug, and in addition to the contraceptive used, use at least 1 barrier contraceptive method or spermicide. Exclusion Criteria: Hypersensitivity to follitropin alpha, combined oral contraceptive (ethinylestradiol and drospirenone) or excipients. Allergy, angioedema (hereditary or idiopathic) in history. Previous history of ovarian hyperstimulation syndrome (OHSS). Inability to establish a venous catheter for blood sampling. Presence of polycystic ovaries (PCO) and ovarian cysts. Neoplasia and a history of malignant disease. Deep vein thrombosis, pulmonary embolism. Subjects with impaired thyroid function. Regular usage or administration of any drugs, including non-prescription drugs, vitamins, homeopathic remedies and dietary supplements, less than 2 weeks before the study (with the exception of contraceptive pills). Admission less than 2 months before the start of the study of drugs that have a pronounced effect on hemodynamics, liver function, and medication contained follicle stimulating hormone (FSH), luteinizing hormone (LH), chorionic gonadotropin (hCG), clomiphene, gonadotropin-releasing hormone (GnRH) analogues. Cardiovascular, bronchopulmonary, nervous, endocrine systems, gastrointestinal tract, liver, kidney, hematopoietic, immune systems, mental diseases. Acute infectious diseases less than 4 weeks before the start of the study. Systolic pressure less than 100 mm or above 130 mm Hg; diastolic pressure less than 70 mm or above 90 mm Hg; heart rate less than 60 or more than 80 beats/min. Blood donation less than 3 months before the start of the study. Participation in clinical studies of drugs less than 3 months before the start of the present study. More than 5 alcohol units per week (1 unit is equal to 50 ml of a strong alcoholic drink, 200 ml of dry wine or 500 ml of beer) or anamnestic information about alcoholism, drug addiction, drug abuse. Smoking more than 5 cigarettes/day. Narcomania, alcoholism. Presence of pregnancy. Lactating. Any reason that, in the opinion of the investigator, could interfere with safety of the subject or interfere with the objectives of the study. Subjects with a lactose intolerance, lactase deficiency or glucose-galactose malabsorption.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 40 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sequence A: Primapur - Gonal-F<br>Subjects were randomly assigned to receive treatment sequence A: single subcutaneous injection of 300 IU Primapur on study day 1, after 10 days of wash out period a single subcutaneous injection of 300 IU Gonal-F. | Drug: Follitropin alfa (Primapur)<br>* During the crossover pharmacokinetic phase, after 42 days of combined oral contraceptive (ethinylestradiol and drospirenone) administration subjects with endogenous level of follicle stimulating hormone (FSH) less than 5 IU/l were randomly assigned to receive one of the following treatment sequences: Sequence A: Single subcutaneous injection of 300 IU Primapur on study day 1, after 10 days of wash out a single subcutaneous injection of 300 IU Gonal-F. Sequence B: Single subcutaneous injection of 300 IU US Gonal-F on study day 1, after 10 days of wash out a single subcutaneous injection of 300 IU Primapur.<br>* Other names: Follitropin;Drug: Follitropin alfa (Gonal-F)<br>* During the crossover pharmacokinetic phase, after 42 days of combined oral contraceptive (ethinylestradiol and drospirenone) administration subjects with endogenous level of follicle stimulating hormone (FSH) less than 5 IU/l were randomly assigned to receive one of the following treatment sequences: Sequence A: Single subcutaneous injection of 300 IU Primapur on study day 1, after 10 days of wash out a single subcutaneous injection of 300 IU Gonal-F. Sequence B: Single subcutaneous injection of 300 IU US Gonal-F on study day 1, after 10 days of wash out a single subcutaneous injection of 300 IU Primapur.<br>* Other names: Follitropin;|
| Active Comparator: Sequence B: Gonal-F - Primapur<br>Subjects were randomly assigned to receive treatment sequence B: single subcutaneous injection of 300 IU Gonal-F on study day 1, after 10 days of wash out period a single subcutaneous injection of 300 IU Primapur. | Drug: Follitropin alfa (Primapur)<br>* During the crossover pharmacokinetic phase, after 42 days of combined oral contraceptive (ethinylestradiol and drospirenone) administration subjects with endogenous level of follicle stimulating hormone (FSH) less than 5 IU/l were randomly assigned to receive one of the following treatment sequences: Sequence A: Single subcutaneous injection of 300 IU Primapur on study day 1, after 10 days of wash out a single subcutaneous injection of 300 IU Gonal-F. Sequence B: Single subcutaneous injection of 300 IU US Gonal-F on study day 1, after 10 days of wash out a single subcutaneous injection of 300 IU Primapur.<br>* Other names: Follitropin;Drug: Follitropin alfa (Gonal-F)<br>* During the crossover pharmacokinetic phase, after 42 days of combined oral contraceptive (ethinylestradiol and drospirenone) administration subjects with endogenous level of follicle stimulating hormone (FSH) less than 5 IU/l were randomly assigned to receive one of the following treatment sequences: Sequence A: Single subcutaneous injection of 300 IU Primapur on study day 1, after 10 days of wash out a single subcutaneous injection of 300 IU Gonal-F. Sequence B: Single subcutaneous injection of 300 IU US Gonal-F on study day 1, after 10 days of wash out a single subcutaneous injection of 300 IU Primapur.<br>* Other names: Follitropin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Serum Concentration of Follicle Stimulating Hormone (FSH) - Time Curve (AUC(0-192)) | Area under curve (AUC), Time frame: From 0 (predose), 1, 2, 4, 6, 8, 10, 12, 16, 24, 36, 48, 72, 120, 168 and 192 hours postdose. Blood samples to study the pharmacokinetics are to be collected via a venous catheter, which is placed by means of vein puncture before any injection of r-hFSH. Blood sampling were carried out at certain time points according to the specified scheme: - 20 minutes (20 minutes before the drug injection), 0 hours (immediately prior to injection), and 1, 2, 4, 6, 8, 10, 12, 16, 24, 36, 48, 72, 120, 168, and 192 hours after each injection of the drug product. | 0-192 hours | 
| Maximum Serum Concentration of Follicle Stimulating Hormone (FSH) (Cmax) | Maximum serum concentration (Cmax), Time frame: From 0 (predose), 1, 2, 4, 6, 8, 10, 12, 16, 24, 36, 48, 72, 120, 168 and 192 hours postdose. | 0-192 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Reach a Maximum Follicle Stimulating Hormone (FSH) Serum Concentration (Tmax) | Time to reach a maximum serum concentration (Tmax), Time frame: From 0 (predose), 1, 2, 4, 6, 8, 10, 12, 16, 24, 36, 48, 72, 120, 168 and 192 hours postdose. | 0-192 hours | 
| Follicle Stimulating Hormone (FSH) Apparent Terminal Half-life (T1/2) | Terminal half-life (T1/2), Time frame: From 0 (predose), 1, 2, 4, 6, 8, 10, 12, 16, 24, 36, 48, 72, 120, 168 and 192 hours postdose. | 0-192 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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biosimilar, follitropin alfa, follicle stimulating hormone, hormones, hormone substitutes, and hormone antagonists, physiological effects of drugs, bioequivalence