Conditions: Area Under Curve Pharmacokinetics Absorption
Keywords: follitropin alfa follicle stimulating hormone hormones, hormone substitutes, and hormone antagonists physiological effects of drugs biosimilar bioequivalence
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 28
Healthy volunteers: yes

Brief summary:
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:
A Phase I, prospective, randomized, open-label, crossover, 2-period, two treatment, clinical study in healthy female volunteers.

Objectives of the study:

1. 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.
2. To determine the AUC0-t value of Primapur following a single 300 IU subcutaneous injection to healthy volunteers.
3. To determine the T½ value of Primapur following a single 300 IU subcutaneous injection to healthy volunteers.
4. To determine the Сmax value of Primapur following a single 300 IU subcutaneous injection to healthy volunteers.
5. To determine the Tmax value of Primapur following a single 300 IU subcutaneous injection to healthy volunteers.
6. To compare the obtained pharmacokinetic characteristics of Primapur and Gonal-F.

Arms:
arm 1: 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. arm 2: 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.

Interventions: intervention 1: Follitropin alfa (Primapur) intervention 2: Follitropin alfa (Gonal-F)
Intervention descriptions: intervention 1: 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. intervention 2: 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.

Protocol document:
Prot_SAP_000.pdf: 


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STUDY EXECUTIVE SUMMARY 
Study Sponsor: 
iVFarma, LLC, Russia 
Study name: 
Comparative 
randomized 
crossover 
study 
of 
tolerance 
and 
pharmacokinetics of Primapur, solution for subcutaneous injection 300 IU 
(iVFarma, LLC, Russia), and Gonal-f®, solution for subcutaneous injection 
300 IU (Merck Serono S.p.A., Italy), given subcutaneously as a single dose 
to healthy volunteers 
Study type 
Phase I 
Protocol No.: 
No. FSG-01-01 
Version: 
1.0 of June 26, 2015 
Aims and objectives of 
the study: 
Aim: to study the safety and tolerability, as well as to compare the 
pharmacokinetic characteristics of Primapur (iVFarma, LLC, Russia) and 
Gonal-f® (Merck Serono S.p.A., Italy) given subcutaneously as a single 
300 IU dose to healthy volunteers 
Objectives of the study:  
1. 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. 
2. To determine the AUC0-t value of Primapur (iVFarma, LLC, Russia) 
following a single 300 IU subcutaneous injection to healthy volunteers. 
3. To determine the T½ value of Primapur (iVFarma, LLC, Russia) 
following a single 300 IU subcutaneous injection to healthy volunteers. 
4. To determine the Сmax value of Primapur (iVFarma, LLC, Russia) 
following a single 300 IU subcutaneous injection to healthy volunteers. 
5. To determine the Tmax value of Primapur (iVFarma, LLC, Russia) 
following a single 300 IU subcutaneous injection to healthy volunteers. 
6. To compare the obtained pharmacokinetic characteristics of Primapur 
(iVFarma, LLC, Russia) and Gonal-f® (Merck Serono S.p.A., Italy) 
Study drug: 
Drug product name: 
Primapur 
Active substance: 
Follitropin alfa 


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Presentation: 
Solution for subcutaneous injection 
33 µg/0.75 mL. 
Manufacturer: 
Medgamal Branch of the N. F. 
Gamaleya Federal Research Center 
for Epidemiology & Microbiology of 
the Ministry of Healthcare of the 
Russian Federation 
Dose 
22 µg (300 IU) of the solution for 
subcutaneous injection, follitropin 
alfa (0.5 mL) 
Administration: 
Injected subcutaneously once 
Comparator drug: 
Drug product name: 
Gonal-f® 
Active substance: 
Follitropin alfa 
Presentation: 
Solution for subcutaneous injection 
22 µg/0.5 mL. 
Manufacturer: 
Merck Serono S.p.A., Italy 
Dose 
1 pre-filled syringe with follitropin 
alfa 22 µL (300 IU) 
Administration: 
Injected subcutaneously once 
Study design: 
A prospective randomized cross-over two-stage clinical study with the use 
of the active comparator drug in healthy volunteers. 
Study population 
It is planned to include 24 healthy female volunteers aged 18 to 40 years 
inclusively, who have been enrolled according to the inclusion and non-
inclusion criteria.  
4 back-ups are planned to be enrolled in the study to replace the volunteers 
excluded before the study completion.  
Wash-out period 
between the treatments 
10 days 
Blood samples collection 
for testing 
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 will be 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 


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the drug product. 
It corresponds to 34 blood samples per one volunteer during the whole 
study (2 periods) and to a maximal total number of 816 samples within the 
study (provided 24 volunteers are randomized). 
Examination of the 
volunteers at screening 
Obtaining of the informed consent, primary physical check-up, collection 
of anthropometric data (body weight, growth, BMI calculation), and 
medical history (including medicinal products); recording of 12-lead ECG; 
assessment of vital signs (BP, pulse, body temperature); examination by a 
gynecologist, USI of pelvic organs, X-ray, urine analysis; complete blood 
count; blood biochemistry (creatinine, glucose, bilirubin, AST, ALT, AP, 
free T3, free T4); coagulogram; blood analysis for HIV, HbsAg, HCV, 
RW; urine analysis for drugs and narcotic substances abuse; pregnancy test 
(for women of child-bearing potential), respiratory alcohol level test. 
After the screening period, the volunteers will have to discontinue the 
combined oral contraceptives (COC) for 1 week, and after that they will 
receive Yarina® (Bayer Pharma AG, Germany) 1 tablet daily (in the 
evening after meal) to suppress endogenous production of gonadotropins. 
Yarina® is prescribed for 6 weeks (42 days in total). 1 day before injection 
of one of the study drugs (day 20 of Yarina® administration – day 27 of the 
study – visit No. 1), blood samples are taken in the volunteers to determine 
the endogenous FSH. If, according to the analysis results, the FSH level is 
5 IU/L or less (sufficient suppression of the endogenous gonadotropin 
production), the volunteers can be invited to the study centre to have a 
subcutaneous injection of the study drug or the comparator drug made. If 
the FSH level appears to be higher than 5 IU/L, the volunteers will have to 
be excluded from the study and replaced by the back-ups. 
After the 28-day preparation period (including 7 days without COC and 21 
days of Yarina® administration), the volunteers with the FSH level of 5 
IU/L and less are to continue with Yarina®. 
Examination of the 
volunteers at the study 
stage I and II 
Before each drug product administration, major vital signs (BP, pulse, and 
body temperature) will be evaluated, physical check-up will be carried out, 
pregnancy test (for women of child bearing potential), respiratory alcohol 
level test, urine analysis for drugs and narcotic substances abuse, USI of 
pelvic organs; blood sampling for endogenous FSH (control point to assess 


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the suppression of endogenous gonadotropins production), luteinizing 
hormone, and estradiol will be performed. During the whole study, major 
vital signs are periodically evaluated (BP, pulse, and body temperature); 
concomitant therapy is assessed, and the undesirable events are collected 
and recorded. 
Control examination 
The control check-up (7 days after the last injection of follitropin alfa) 
includes: physical check-up; 12-lead ECG recording; major vital signs 
evaluation (BP, pulse, and body temperature); urine analysis; complete 
blood count, blood biochemistry; coagulogram. During the subsequent 
period until day 28 of the follow-up period, the Study Doctor should ring 
up the volunteers to clarify the information about their well-being after 14, 
21, and 28 days (i.e. every week) following the last injection of follitropin 
alfa.  
Inclusion criteria: 
1. Women aged 18 to 40 years, inclusively; 
available Informed Consent form signed by the volunteer to be enrolled in 
the study. 
2. body mass index (BMI) of 18.5 to 30 kg/m2 according to the Quetelet 
index, in case of a body weight of more than 45 kg; 
3. According to the Investigator, the ability of the volunteer to follow the 
requirements set forth in the Protocol; 
4. Verified "healthy" diagnosis according to the data from the medical 
history, as well as standard clinical, laboratory, and instrumental 
examination data: 
- absence of abnormalities of the cardiovascular, respiratory, nervous, 
hematological, endocrine, and gastrointestinal systems, hepatic and renal 
disorders in past medical history and at the time of screening examination; 
- results of complete blood count and blood biochemistry, coagulogram, 
and urine analysis during the screening examination should be within the 
reference values accepted at the study centre. Screening laboratory 
examinations should be performed not more than 7 days before the study 
enrollment; 
5. Administration of combined oral contraceptives for at least 2 consecutive 
menstrual periods before the study enrollment; 
6. Regular menstrual periods (with a duration of 24-35 days) that existed 


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prior to the initiation of oral contraceptives. 
7. Presence of both ovaries 
8. Negative urine test for narcotic substances and super-potent drugs; 
9. negative respiratory alcohol level test. 
10. The study female participants and their sexual partners are informed 
and are voluntarily ready to use at least one barrier contraceptive method or 
a spermicide in addition to the administered contraceptive, starting from the 
week before the study enrollment and up to 4 weeks after the last dose of 
the study drug; 
Non-inclusion criteria: 
1. Known hypersensitivity to the active substance or to any of the 
excipients of the study drugs or their intolerance, as well as to the active 
substance or to any of the excipients of Yarina®;  
2. A positive history of allergies, angioedema (congenital or idiopathic) in 
past medical history – the risk of rapid growth of angioedema; 
3. Ovarian hyperstimulation syndrome events in past medical history (at 
any time before the study enrollment); 
4. Impossibility to insert a venous catheter for blood sampling (for 
example, as a result of dermal diseases in vein puncture sites); 
5. Polycystic ovarian syndrome, cystic lesions or idiopathic ovarian 
enlargement, menstrual disorders of any origin, female genital organ 
neoplasms (in particular, in past medical history), and dysplastic/neoplastic 
processes in the neck of the uterus (including those found during the 
screening examination); 
6. Deep vein thrombosis, thromboembolism of the pulmonary artery 
(including those in past medical history). 
7. Malignant neoplasms in past medical history at any time before the 
study entry; 
8. Thyroid dysfunction; 
9. Regular oral or parenteral administration of any drug products, 
including over-the-counter agents, vitamins, homeopathic medicines, and 
biologically active supplements, less than two weeks before the study 
enrollment (with the exception of COCs); 
10. Intake or parenteral administration of any drug products, including 
over-the-counter agents, vitamins, homeopathic medicines, and biologically 
active supplements, producing expressed effects on hemodynamics, hepatic 


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function, as well as of the following medicinal products: 
- FSH preparations 
- LH preparations 
- HCG preparations 
- clomifene 
- gonadotrophin-releasing hormone analogues; 
11. Cardiovascular, bronchopulmonary, nervous, and endocrine diseases, as 
well as gastrointestinal, hepatic, renal, hematological, immune, and mental 
diseases; 
12. Acute infectious diseases less than 4 weeks before the initiation of the 
study; 
13. Systolic pressure lower than 100 mm Hg or higher than 130 mm Hg; 
diastolic pressure lower than 70 mm Hg or higher than 90 mm Hg; heart 
rate lower than 60 bpm or higher than 80 bpm; 
14. Blood donation (450 mL of blood or plasma and more) less than 3 
months before the initiation of the study; 
15. Participation in clinical studies of drug products less than 3 months 
before the initiation of this study; 
16. Intake of more than 5 units of alcohol per week (where each unit is 
equal to 50 mL of distilled spirits, 200 mL of dry wine, or 500 mL of beer) 
or history of alcohol addiction, drug addition, abuse of medicinal products; 
17.  Smoking of more than 5 cigarettes per day; 
18.  Positive urine analysis for drugs and narcotic substances abuse, 
including cocaine, cannabis, amphetamines, barbiturates, and opioids; 
19.  Positive respiratory alcohol level test; 
20.  Positive pregnancy test in women; 
21.  Lactation period; 
22.  Any reason, which according to the Investigator, may prevent 
participation of the volunteer in the study; 
23. Congenital lactose intolerance, lactase deficiency, or glucose-galactose 
malabsorption (due to lactose monohydrate contained in Yarina).  
Study duration: 
Expected duration of participation in the study for each subject is about 73 
days, including the screening period (up to 7 days), preparation period (up 
to 28 days), the 1st period (9 days), the 2nd period (9 days), and the follow-
up period (28 days starting from the first day of the 2nd period). The wash-


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out period is 10 days. 
Analytical method 
Blood plasma concentrations of follitropin alfa will be determined by 
enzyme-linked immunosorbent assay (ELISA). 
Pharmacokinetic 
parameters 
Areas under the pharmacokinetic "concentration-time" curves 
(AUC0-t), peak concentration (Cmax), 
time to peak concentration (Tmax), elimination half-life (Т1/2), relative 
absorption rate Сmax/AUC0-t  
Statistical analysis: 
Statistical comparison of the obtained results will comprise the calculation 
of parametric bilateral 90 % confidence intervals for the ratios of the 
corresponding mean values of the pharmacokinetic parameters of the study 
drug and comparator drug. The equivalence of the pharmacokinetics of the 
drug products will be proven if the limits of the evaluated confidence 
intervals for the ratios of the mean values of AUC0-t, Сmax и Сmax/ AUC0-t of 
follitropin alpha following the administration of the study drug and 
comparator drug are in the range of 80-125 %.