Trial Outcomes & Findings for Study to Compare the Pharmacokinetics, Pharmacodynamics, Safety, Tolerability, and Immunogenicity of Biosimilar Denosumab With Prolia® in Healthy Adult Male Volunteers (NCT NCT05245669)

Last Updated: 2025-12-23

Results Overview

A total of twenty four blood PK samples of 2.5 mL each were collected from each subject in the study. Pre-dose sample were collected within 30 minutes prior to IP administration. Post-dose samples up to Day 2 were collected within ± 10 minutes, within ± 2 hours from Day 3 to Day 21, within ± 1 day on Day 28, within ± 3 days from Day 42 to Day 180 and within ±5 days from Day 224 to Day 270. Serum concentrations of denosumab were measured at central laboratory by a validated analytical method.

Recruitment status

COMPLETED

Study phase

PHASE1

Target enrollment

207 participants

Primary outcome timeframe

270 days

Results posted on

2025-12-23

Participant Flow

Participant milestones

Participant milestones
Measure	ENZ215 ENZ215 Injection:- 60 mg Denosumab (ENZ215) will be administered subcutaneously on day 1.	EU Sourced Prolia EU sourced Prolia Injection:- 60 mg Denosumab (EU sourced Prolia) will be administered subcutaneously on day 1.	US Sourced Prolia US sourced Prolia Injection:- 60 mg Denosumab (US sourced Prolia) will be administered subcutaneously on day 1.
Overall Study STARTED	68	69	70
Overall Study COMPLETED	66	67	67
Overall Study NOT COMPLETED	2	2	3

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Study to Compare the Pharmacokinetics, Pharmacodynamics, Safety, Tolerability, and Immunogenicity of Biosimilar Denosumab With Prolia® in Healthy Adult Male Volunteers

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	ENZ215 n=68 Participants ENZ215 is the proposed biosimilar for Prolia® (denosumab). Subjects in this arm received a single 60 mg dose of ENZ215 as a subcutaneous injection. ENZ215 (denosumab biosimilar) : Single dose of 60mg SC administered	EU Sourced Prolia n=69 Participants EU-Prolia® (denosumab) is the proposed active comparator for ENZ215. Subjects in this arm received a single 60 mg dose of EU-Prolia® as a subcutaneous injection. EU-Prolia® : Single dose of 60mg SC administered	US Licensed Prolia n=70 Participants US-Prolia® (denosumab) is the proposed active comparator for ENZ215. Subjects in this arm received a single 60 mg dose of US-Prolia® as a subcutaneous injection. US-Prolia® : Single dose of 60mg SC administered	Total n=207 Participants Total of all reporting groups
Age, Continuous	37.9 Years STANDARD_DEVIATION 8.1 • n=68 Participants	38.9 Years STANDARD_DEVIATION 7.7 • n=4 Participants	40.1 Years STANDARD_DEVIATION 7.8 • n=219 Participants	39.0 Years STANDARD_DEVIATION 7.9 • n=219 Participants
Sex: Female, Male Female	0 Participants n=68 Participants	0 Participants n=4 Participants	0 Participants n=219 Participants	0 Participants n=219 Participants
Sex: Female, Male Male	68 Participants n=68 Participants	69 Participants n=4 Participants	70 Participants n=219 Participants	207 Participants n=219 Participants
Race/Ethnicity, Customized Asian	1 Participants n=68 Participants	0 Participants n=4 Participants	0 Participants n=219 Participants	1 Participants n=219 Participants
Race/Ethnicity, Customized White	67 Participants n=68 Participants	69 Participants n=4 Participants	70 Participants n=219 Participants	206 Participants n=219 Participants
Height	178.39 cm STANDARD_DEVIATION 6.22 • n=68 Participants	178.96 cm STANDARD_DEVIATION 6.44 • n=4 Participants	178.41 cm STANDARD_DEVIATION 7.69 • n=219 Participants	178.59 cm STANDARD_DEVIATION 6.79 • n=219 Participants
BMI	26.219 kg/m^2 STANDARD_DEVIATION 2.601 • n=68 Participants	26.260 kg/m^2 STANDARD_DEVIATION 2.760 • n=4 Participants	25.562 kg/m^2 STANDARD_DEVIATION 2.835 • n=219 Participants	26.010 kg/m^2 STANDARD_DEVIATION 2.740 • n=219 Participants
Weight	83.62 kg STANDARD_DEVIATION 10.75 • n=68 Participants	84.16 kg STANDARD_DEVIATION 10.34 • n=4 Participants	81.56 kg STANDARD_DEVIATION 11.67 • n=219 Participants	83.10 kg STANDARD_DEVIATION 10.94 • n=219 Participants

PRIMARY outcome

Timeframe: 270 days

Population: Pharmacokinetic population includes subjects who complied sufficiently with the protocol, who received a single-dose of the study drug and had 1 pre-dose and at least 1 post-dose measurement of any of the PK assessment not impacted by any protocol deviations.

Outcome measures

Outcome measures
Measure	US Sourced Prolia n=69 Participants US sourced Prolia Injection:- 60 mg Denosumab (US sourced Prolia) will be administered subcutaneously on day 1.	ENZ215 n=68 Participants ENZ215 Injection:- 60 mg Denosumab (ENZ215) will be administered subcutaneously on day 1.	EU Sourced Prolia n=69 Participants EU sourced Prolia Injection:- 60 mg Denosumab (EU sourced Prolia) will be administered subcutaneously on day 1.
Maximum Observed Drug Concentration (Cmax) of ENZ215 and EU- and US-sourced Prolia®	8033.14 ng/ml Geometric Coefficient of Variation 24.9	7662.99 ng/ml Geometric Coefficient of Variation 32.6	7742.64 ng/ml Geometric Coefficient of Variation 23.2

PRIMARY outcome

Timeframe: 270 days

Outcome measures

Outcome measures
Measure	US Sourced Prolia n=69 Participants US sourced Prolia Injection:- 60 mg Denosumab (US sourced Prolia) will be administered subcutaneously on day 1.	ENZ215 n=68 Participants ENZ215 Injection:- 60 mg Denosumab (ENZ215) will be administered subcutaneously on day 1.	EU Sourced Prolia n=69 Participants EU sourced Prolia Injection:- 60 mg Denosumab (EU sourced Prolia) will be administered subcutaneously on day 1.
Area Under the Drug Concentration-time Curve From Day 0 to Day 270 (AUC0-t) of ENZ215, EU- and US-sourced Prolia®. and EU- and US-sourced Prolia®	7842297.13 h*ng/mL Geometric Coefficient of Variation 28.8	7508134.18 h*ng/mL Geometric Coefficient of Variation 36.8	7674912.81 h*ng/mL Geometric Coefficient of Variation 24.9

PRIMARY outcome

Timeframe: 270 days

Outcome measures

Outcome measures
Measure	US Sourced Prolia n=69 Participants US sourced Prolia Injection:- 60 mg Denosumab (US sourced Prolia) will be administered subcutaneously on day 1.	ENZ215 n=68 Participants ENZ215 Injection:- 60 mg Denosumab (ENZ215) will be administered subcutaneously on day 1.	EU Sourced Prolia n=69 Participants EU sourced Prolia Injection:- 60 mg Denosumab (EU sourced Prolia) will be administered subcutaneously on day 1.
Area Under the Drug Concentration-time Curve From Time 0 to Infinity (AUC0-inf) of ENZ215, EU- and US-sourced Prolia®. and EU- and US-sourced Prolia®	7934699.65 h*ng/mL Geometric Coefficient of Variation 28.9	7622698.42 h*ng/mL Geometric Coefficient of Variation 36.4	7779487.60 h*ng/mL Geometric Coefficient of Variation 24.7

SECONDARY outcome

Timeframe: 28 days

AUC0-28 days were compared between ENZ215 and Prolia® using tests after log-transformation wherever appropriate.

Outcome measures

Outcome measures
Measure	US Sourced Prolia n=67 Participants US sourced Prolia Injection:- 60 mg Denosumab (US sourced Prolia) will be administered subcutaneously on day 1.	ENZ215 n=66 Participants ENZ215 Injection:- 60 mg Denosumab (ENZ215) will be administered subcutaneously on day 1.	EU Sourced Prolia n=67 Participants EU sourced Prolia Injection:- 60 mg Denosumab (EU sourced Prolia) will be administered subcutaneously on day 1.
Partial Area Under the Drug Concentration-time Curve From Time 0 (Pre-dose) to Day 28	3796048.41 h*ng/mL Geometric Coefficient of Variation 22.5	3608894.44 h*ng/mL Geometric Coefficient of Variation 28.9	3721138.61 h*ng/mL Geometric Coefficient of Variation 20.6

SECONDARY outcome

Timeframe: 270 days

The non-parametric analysis was used for the comparison of tmax between ENZ215 and Prolia®.

Outcome measures

Outcome measures
Measure	US Sourced Prolia n=69 Participants US sourced Prolia Injection:- 60 mg Denosumab (US sourced Prolia) will be administered subcutaneously on day 1.	ENZ215 n=68 Participants ENZ215 Injection:- 60 mg Denosumab (ENZ215) will be administered subcutaneously on day 1.	EU Sourced Prolia n=69 Participants EU sourced Prolia Injection:- 60 mg Denosumab (EU sourced Prolia) will be administered subcutaneously on day 1.
Time to Reach Cmax (Tmax)	120.28 hours Interval 46.98 to 479.92	120.62 hours Interval 47.22 to 360.63	120.08 hours Interval 46.93 to 359.75

SECONDARY outcome

Timeframe: 270 days

t1/2 was compared between ENZ215 and Prolia® using tests after log-transformation wherever appropriate.

Outcome measures

Outcome measures
Measure	US Sourced Prolia n=67 Participants US sourced Prolia Injection:- 60 mg Denosumab (US sourced Prolia) will be administered subcutaneously on day 1.	ENZ215 n=66 Participants ENZ215 Injection:- 60 mg Denosumab (ENZ215) will be administered subcutaneously on day 1.	EU Sourced Prolia n=67 Participants EU sourced Prolia Injection:- 60 mg Denosumab (EU sourced Prolia) will be administered subcutaneously on day 1.
Terminal Elimination Half-life (t1/2)	441.262 hours Geometric Coefficient of Variation 27.1	450.745 hours Geometric Coefficient of Variation 28.3	450.207 hours Geometric Coefficient of Variation 23.2

SECONDARY outcome

Timeframe: 270 days

CL/F was compared between ENZ215 and Prolia® using tests after log-transformation wherever appropriate.

Outcome measures

Outcome measures
Measure	US Sourced Prolia n=67 Participants US sourced Prolia Injection:- 60 mg Denosumab (US sourced Prolia) will be administered subcutaneously on day 1.	ENZ215 n=66 Participants ENZ215 Injection:- 60 mg Denosumab (ENZ215) will be administered subcutaneously on day 1.	EU Sourced Prolia n=67 Participants EU sourced Prolia Injection:- 60 mg Denosumab (EU sourced Prolia) will be administered subcutaneously on day 1.
Apparent Systemic Clearance (CL/F)	0.008 mL/h Geometric Coefficient of Variation 28.9	0.008 mL/h Geometric Coefficient of Variation 36.4	0.008 mL/h Geometric Coefficient of Variation 24.7

SECONDARY outcome

Timeframe: 270 days

Population: Pharmacodynamic population includes subjects who complied sufficiently with the protocol, who received a single-dose of the study drug and had 1 pre-dose and at least 1 post-dose measurement of any of the PD assessment.

The AUEC was calculated as the area under the effect curve from baseline until CTX-1 values return to baseline for the first time. A total of sixteen (16) blood samples for serum CTX-1 estimation of 3.5 mL each was collected from each subject in the study. For CTX-1, blood samples were collected at the same time and after a minimum of 10 hours of fasting.

Outcome measures

Outcome measures
Measure	US Sourced Prolia n=69 Participants US sourced Prolia Injection:- 60 mg Denosumab (US sourced Prolia) will be administered subcutaneously on day 1.	ENZ215 n=68 Participants ENZ215 Injection:- 60 mg Denosumab (ENZ215) will be administered subcutaneously on day 1.	EU Sourced Prolia n=69 Participants EU sourced Prolia Injection:- 60 mg Denosumab (EU sourced Prolia) will be administered subcutaneously on day 1.
Area Under the Effect Curve (AUEC) From Time 0 to Day 270 for Serum CTX-1 Percent Inhibition Percent Inhibition	436622.000 h*% Geometric Coefficient of Variation 18.6	432174.780 h*% Geometric Coefficient of Variation 20.1	442806.204 h*% Geometric Coefficient of Variation 13.6

OTHER_PRE_SPECIFIED outcome

Timeframe: 270 days

Population: Total 207 subjects randomized i.e. in 68 subjects in ENZ215, 70 subjects in US-Prolia® \& 69 subjects in EU-Prolia® randomized. However, in US-Prolia® 69 subjects dosed as 1 subject withdrawn his consent before dosing, in ENZ215 \& EU-Prolia® all randomized subjects dosed. Hence in US-Prolia® 69 subjects, EU-Prolia® 69 subjects \& ENZ215 68 subjects evaluated in the study. Number subjects showed nAb.

A total of 10 blood Immunogenicity assessment samples of 5.0 mL for NAb and ADA were collected from each subject in the study. The frequency and percentage of positive ADA or NAb result was provided. The proportion of positive ADA or NAb in each treatment group was compared using chi-square or Fisher's exact tests. The p-value, relative risk, and corresponding 95% CI was presented.

Outcome measures

Outcome measures
Measure	US Sourced Prolia n=69 Participants US sourced Prolia Injection:- 60 mg Denosumab (US sourced Prolia) will be administered subcutaneously on day 1.	ENZ215 n=68 Participants ENZ215 Injection:- 60 mg Denosumab (ENZ215) will be administered subcutaneously on day 1.	EU Sourced Prolia n=69 Participants EU sourced Prolia Injection:- 60 mg Denosumab (EU sourced Prolia) will be administered subcutaneously on day 1.
Number of Subjects Who Developed Denosumab Neutralizing Antibodies and Antidrug Antibodies. Antibodies nAb positive subjects	2 participants	3 participants	3 participants
Number of Subjects Who Developed Denosumab Neutralizing Antibodies and Antidrug Antibodies. Antibodies ADA positive subjects	69 participants	68 participants	69 participants

OTHER_PRE_SPECIFIED outcome

Timeframe: 270 days

Adverse events and SAEs as and when occurred, were properly recorded, evaluated, managed, and reported from signing informed consent till end of Study Assessment visit. All AEs were summarized using appropriate medical coding dictionary.

Outcome measures

Outcome measures
Measure	US Sourced Prolia n=69 Participants US sourced Prolia Injection:- 60 mg Denosumab (US sourced Prolia) will be administered subcutaneously on day 1.	ENZ215 n=68 Participants ENZ215 Injection:- 60 mg Denosumab (ENZ215) will be administered subcutaneously on day 1.	EU Sourced Prolia n=69 Participants EU sourced Prolia Injection:- 60 mg Denosumab (EU sourced Prolia) will be administered subcutaneously on day 1.
Incidence of Adverse Events	32 Participants	28 Participants	39 Participants

Adverse Events

ENZ215

Serious events: 0 serious events

Other events: 28 other events

Deaths: 0 deaths

EU Sourced Prolia®

Serious events: 1 serious events

Other events: 39 other events

Deaths: 0 deaths

US Licensed Prolia®

Serious events: 0 serious events

Other events: 32 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	ENZ215 n=68 participants at risk ENZ215 is the proposed biosimilar for Prolia® (denosumab). Subjects in this arm received a single 60 mg dose of ENZ215 as a subcutaneous injection. ENZ215 (denosumab biosimilar) : Single dose of 60mg SC administered	EU Sourced Prolia® n=69 participants at risk EU-Prolia® (denosumab) is the proposed active comparator for ENZ215. Subjects in this arm received a single 60 mg dose of EU-Prolia® as a subcutaneous injection. EU-Prolia® : Single dose of 60mg SC administered	US Licensed Prolia® n=69 participants at risk US-Prolia® (denosumab) is the proposed active comparator for ENZ215. Subjects in this arm received a single 60 mg dose of US-Prolia® as a subcutaneous injection. US-Prolia® : Single dose of 60mg SC administered.
Injury, poisoning and procedural complications Ligament rupture	0.00% 0/68 • from signing of informed consent to 270 days that is end of study All AEs were classified according to the Medical Dictionary for Regulatory Activities (MedDRA), Version 25.0 for subjects of site 01 and from MedDRA dictionary, Version 26.1 for subjects of site 02 and 03.	1.4% 1/69 • Number of events 1 • from signing of informed consent to 270 days that is end of study All AEs were classified according to the Medical Dictionary for Regulatory Activities (MedDRA), Version 25.0 for subjects of site 01 and from MedDRA dictionary, Version 26.1 for subjects of site 02 and 03.	0.00% 0/69 • from signing of informed consent to 270 days that is end of study All AEs were classified according to the Medical Dictionary for Regulatory Activities (MedDRA), Version 25.0 for subjects of site 01 and from MedDRA dictionary, Version 26.1 for subjects of site 02 and 03.

Other adverse events

Additional Information

Dr. Akhilesh Sharma

Alkem Laboratories Limited

Phone: +91- 9701346369

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	ENZ215 n=68 participants at risk ENZ215 is the proposed biosimilar for Prolia® (denosumab). Subjects in this arm received a single 60 mg dose of ENZ215 as a subcutaneous injection. ENZ215 (denosumab biosimilar) : Single dose of 60mg SC administered	EU Sourced Prolia® n=69 participants at risk EU-Prolia® (denosumab) is the proposed active comparator for ENZ215. Subjects in this arm received a single 60 mg dose of EU-Prolia® as a subcutaneous injection. EU-Prolia® : Single dose of 60mg SC administered	US Licensed Prolia® n=69 participants at risk US-Prolia® (denosumab) is the proposed active comparator for ENZ215. Subjects in this arm received a single 60 mg dose of US-Prolia® as a subcutaneous injection. US-Prolia® : Single dose of 60mg SC administered.
Gastrointestinal disorders Toothache	0.00% 0/68 • from signing of informed consent to 270 days that is end of study All AEs were classified according to the Medical Dictionary for Regulatory Activities (MedDRA), Version 25.0 for subjects of site 01 and from MedDRA dictionary, Version 26.1 for subjects of site 02 and 03.	4.3% 3/69 • Number of events 3 • from signing of informed consent to 270 days that is end of study All AEs were classified according to the Medical Dictionary for Regulatory Activities (MedDRA), Version 25.0 for subjects of site 01 and from MedDRA dictionary, Version 26.1 for subjects of site 02 and 03.	1.4% 1/69 • Number of events 1 • from signing of informed consent to 270 days that is end of study All AEs were classified according to the Medical Dictionary for Regulatory Activities (MedDRA), Version 25.0 for subjects of site 01 and from MedDRA dictionary, Version 26.1 for subjects of site 02 and 03.
Nervous system disorders Migraine	2.9% 2/68 • Number of events 3 • from signing of informed consent to 270 days that is end of study All AEs were classified according to the Medical Dictionary for Regulatory Activities (MedDRA), Version 25.0 for subjects of site 01 and from MedDRA dictionary, Version 26.1 for subjects of site 02 and 03.	0.00% 0/69 • from signing of informed consent to 270 days that is end of study All AEs were classified according to the Medical Dictionary for Regulatory Activities (MedDRA), Version 25.0 for subjects of site 01 and from MedDRA dictionary, Version 26.1 for subjects of site 02 and 03.	0.00% 0/69 • from signing of informed consent to 270 days that is end of study All AEs were classified according to the Medical Dictionary for Regulatory Activities (MedDRA), Version 25.0 for subjects of site 01 and from MedDRA dictionary, Version 26.1 for subjects of site 02 and 03.
Infections and infestations Upper Respiratory Tract Infection	4.4% 3/68 • Number of events 3 • from signing of informed consent to 270 days that is end of study All AEs were classified according to the Medical Dictionary for Regulatory Activities (MedDRA), Version 25.0 for subjects of site 01 and from MedDRA dictionary, Version 26.1 for subjects of site 02 and 03.	10.1% 7/69 • Number of events 7 • from signing of informed consent to 270 days that is end of study All AEs were classified according to the Medical Dictionary for Regulatory Activities (MedDRA), Version 25.0 for subjects of site 01 and from MedDRA dictionary, Version 26.1 for subjects of site 02 and 03.	1.4% 1/69 • Number of events 1 • from signing of informed consent to 270 days that is end of study All AEs were classified according to the Medical Dictionary for Regulatory Activities (MedDRA), Version 25.0 for subjects of site 01 and from MedDRA dictionary, Version 26.1 for subjects of site 02 and 03.
Investigations SARS-CoV-2 test positive	2.9% 2/68 • Number of events 2 • from signing of informed consent to 270 days that is end of study All AEs were classified according to the Medical Dictionary for Regulatory Activities (MedDRA), Version 25.0 for subjects of site 01 and from MedDRA dictionary, Version 26.1 for subjects of site 02 and 03.	8.7% 6/69 • Number of events 6 • from signing of informed consent to 270 days that is end of study All AEs were classified according to the Medical Dictionary for Regulatory Activities (MedDRA), Version 25.0 for subjects of site 01 and from MedDRA dictionary, Version 26.1 for subjects of site 02 and 03.	1.4% 1/69 • Number of events 1 • from signing of informed consent to 270 days that is end of study All AEs were classified according to the Medical Dictionary for Regulatory Activities (MedDRA), Version 25.0 for subjects of site 01 and from MedDRA dictionary, Version 26.1 for subjects of site 02 and 03.
Nervous system disorders Headache	13.2% 9/68 • Number of events 18 • from signing of informed consent to 270 days that is end of study All AEs were classified according to the Medical Dictionary for Regulatory Activities (MedDRA), Version 25.0 for subjects of site 01 and from MedDRA dictionary, Version 26.1 for subjects of site 02 and 03.	13.0% 9/69 • Number of events 11 • from signing of informed consent to 270 days that is end of study All AEs were classified according to the Medical Dictionary for Regulatory Activities (MedDRA), Version 25.0 for subjects of site 01 and from MedDRA dictionary, Version 26.1 for subjects of site 02 and 03.	20.3% 14/69 • Number of events 20 • from signing of informed consent to 270 days that is end of study All AEs were classified according to the Medical Dictionary for Regulatory Activities (MedDRA), Version 25.0 for subjects of site 01 and from MedDRA dictionary, Version 26.1 for subjects of site 02 and 03.
Infections and infestations Gastrointestinal infection	0.00% 0/68 • from signing of informed consent to 270 days that is end of study All AEs were classified according to the Medical Dictionary for Regulatory Activities (MedDRA), Version 25.0 for subjects of site 01 and from MedDRA dictionary, Version 26.1 for subjects of site 02 and 03.	1.4% 1/69 • Number of events 1 • from signing of informed consent to 270 days that is end of study All AEs were classified according to the Medical Dictionary for Regulatory Activities (MedDRA), Version 25.0 for subjects of site 01 and from MedDRA dictionary, Version 26.1 for subjects of site 02 and 03.	2.9% 2/69 • Number of events 2 • from signing of informed consent to 270 days that is end of study All AEs were classified according to the Medical Dictionary for Regulatory Activities (MedDRA), Version 25.0 for subjects of site 01 and from MedDRA dictionary, Version 26.1 for subjects of site 02 and 03.
Infections and infestations Gastrointestinal viral infection	0.00% 0/68 • from signing of informed consent to 270 days that is end of study All AEs were classified according to the Medical Dictionary for Regulatory Activities (MedDRA), Version 25.0 for subjects of site 01 and from MedDRA dictionary, Version 26.1 for subjects of site 02 and 03.	0.00% 0/69 • from signing of informed consent to 270 days that is end of study All AEs were classified according to the Medical Dictionary for Regulatory Activities (MedDRA), Version 25.0 for subjects of site 01 and from MedDRA dictionary, Version 26.1 for subjects of site 02 and 03.	2.9% 2/69 • Number of events 2 • from signing of informed consent to 270 days that is end of study All AEs were classified according to the Medical Dictionary for Regulatory Activities (MedDRA), Version 25.0 for subjects of site 01 and from MedDRA dictionary, Version 26.1 for subjects of site 02 and 03.
Infections and infestations Influenza	2.9% 2/68 • Number of events 2 • from signing of informed consent to 270 days that is end of study All AEs were classified according to the Medical Dictionary for Regulatory Activities (MedDRA), Version 25.0 for subjects of site 01 and from MedDRA dictionary, Version 26.1 for subjects of site 02 and 03.	0.00% 0/69 • from signing of informed consent to 270 days that is end of study All AEs were classified according to the Medical Dictionary for Regulatory Activities (MedDRA), Version 25.0 for subjects of site 01 and from MedDRA dictionary, Version 26.1 for subjects of site 02 and 03.	0.00% 0/69 • from signing of informed consent to 270 days that is end of study All AEs were classified according to the Medical Dictionary for Regulatory Activities (MedDRA), Version 25.0 for subjects of site 01 and from MedDRA dictionary, Version 26.1 for subjects of site 02 and 03.
Infections and infestations Nasopharyngitis	8.8% 6/68 • Number of events 6 • from signing of informed consent to 270 days that is end of study All AEs were classified according to the Medical Dictionary for Regulatory Activities (MedDRA), Version 25.0 for subjects of site 01 and from MedDRA dictionary, Version 26.1 for subjects of site 02 and 03.	15.9% 11/69 • Number of events 13 • from signing of informed consent to 270 days that is end of study All AEs were classified according to the Medical Dictionary for Regulatory Activities (MedDRA), Version 25.0 for subjects of site 01 and from MedDRA dictionary, Version 26.1 for subjects of site 02 and 03.	18.8% 13/69 • Number of events 14 • from signing of informed consent to 270 days that is end of study All AEs were classified according to the Medical Dictionary for Regulatory Activities (MedDRA), Version 25.0 for subjects of site 01 and from MedDRA dictionary, Version 26.1 for subjects of site 02 and 03.
Infections and infestations Rhinitis	0.00% 0/68 • from signing of informed consent to 270 days that is end of study All AEs were classified according to the Medical Dictionary for Regulatory Activities (MedDRA), Version 25.0 for subjects of site 01 and from MedDRA dictionary, Version 26.1 for subjects of site 02 and 03.	2.9% 2/69 • Number of events 2 • from signing of informed consent to 270 days that is end of study All AEs were classified according to the Medical Dictionary for Regulatory Activities (MedDRA), Version 25.0 for subjects of site 01 and from MedDRA dictionary, Version 26.1 for subjects of site 02 and 03.	1.4% 1/69 • Number of events 1 • from signing of informed consent to 270 days that is end of study All AEs were classified according to the Medical Dictionary for Regulatory Activities (MedDRA), Version 25.0 for subjects of site 01 and from MedDRA dictionary, Version 26.1 for subjects of site 02 and 03.
Gastrointestinal disorders Aphthous ulcer	2.9% 2/68 • Number of events 2 • from signing of informed consent to 270 days that is end of study All AEs were classified according to the Medical Dictionary for Regulatory Activities (MedDRA), Version 25.0 for subjects of site 01 and from MedDRA dictionary, Version 26.1 for subjects of site 02 and 03.	1.4% 1/69 • Number of events 1 • from signing of informed consent to 270 days that is end of study All AEs were classified according to the Medical Dictionary for Regulatory Activities (MedDRA), Version 25.0 for subjects of site 01 and from MedDRA dictionary, Version 26.1 for subjects of site 02 and 03.	2.9% 2/69 • Number of events 2 • from signing of informed consent to 270 days that is end of study All AEs were classified according to the Medical Dictionary for Regulatory Activities (MedDRA), Version 25.0 for subjects of site 01 and from MedDRA dictionary, Version 26.1 for subjects of site 02 and 03.
Injury, poisoning and procedural complications Skin abrasion	0.00% 0/68 • from signing of informed consent to 270 days that is end of study All AEs were classified according to the Medical Dictionary for Regulatory Activities (MedDRA), Version 25.0 for subjects of site 01 and from MedDRA dictionary, Version 26.1 for subjects of site 02 and 03.	4.3% 3/69 • Number of events 3 • from signing of informed consent to 270 days that is end of study All AEs were classified according to the Medical Dictionary for Regulatory Activities (MedDRA), Version 25.0 for subjects of site 01 and from MedDRA dictionary, Version 26.1 for subjects of site 02 and 03.	0.00% 0/69 • from signing of informed consent to 270 days that is end of study All AEs were classified according to the Medical Dictionary for Regulatory Activities (MedDRA), Version 25.0 for subjects of site 01 and from MedDRA dictionary, Version 26.1 for subjects of site 02 and 03.
Metabolism and nutrition disorders Hypocalcaemia	4.4% 3/68 • Number of events 3 • from signing of informed consent to 270 days that is end of study All AEs were classified according to the Medical Dictionary for Regulatory Activities (MedDRA), Version 25.0 for subjects of site 01 and from MedDRA dictionary, Version 26.1 for subjects of site 02 and 03.	4.3% 3/69 • Number of events 3 • from signing of informed consent to 270 days that is end of study All AEs were classified according to the Medical Dictionary for Regulatory Activities (MedDRA), Version 25.0 for subjects of site 01 and from MedDRA dictionary, Version 26.1 for subjects of site 02 and 03.	2.9% 2/69 • Number of events 2 • from signing of informed consent to 270 days that is end of study All AEs were classified according to the Medical Dictionary for Regulatory Activities (MedDRA), Version 25.0 for subjects of site 01 and from MedDRA dictionary, Version 26.1 for subjects of site 02 and 03.
Musculoskeletal and connective tissue disorders Arthralgia	1.5% 1/68 • Number of events 1 • from signing of informed consent to 270 days that is end of study All AEs were classified according to the Medical Dictionary for Regulatory Activities (MedDRA), Version 25.0 for subjects of site 01 and from MedDRA dictionary, Version 26.1 for subjects of site 02 and 03.	5.8% 4/69 • Number of events 4 • from signing of informed consent to 270 days that is end of study All AEs were classified according to the Medical Dictionary for Regulatory Activities (MedDRA), Version 25.0 for subjects of site 01 and from MedDRA dictionary, Version 26.1 for subjects of site 02 and 03.	0.00% 0/69 • from signing of informed consent to 270 days that is end of study All AEs were classified according to the Medical Dictionary for Regulatory Activities (MedDRA), Version 25.0 for subjects of site 01 and from MedDRA dictionary, Version 26.1 for subjects of site 02 and 03.
Musculoskeletal and connective tissue disorders Back pain	2.9% 2/68 • Number of events 2 • from signing of informed consent to 270 days that is end of study All AEs were classified according to the Medical Dictionary for Regulatory Activities (MedDRA), Version 25.0 for subjects of site 01 and from MedDRA dictionary, Version 26.1 for subjects of site 02 and 03.	0.00% 0/69 • from signing of informed consent to 270 days that is end of study All AEs were classified according to the Medical Dictionary for Regulatory Activities (MedDRA), Version 25.0 for subjects of site 01 and from MedDRA dictionary, Version 26.1 for subjects of site 02 and 03.	1.4% 1/69 • Number of events 1 • from signing of informed consent to 270 days that is end of study All AEs were classified according to the Medical Dictionary for Regulatory Activities (MedDRA), Version 25.0 for subjects of site 01 and from MedDRA dictionary, Version 26.1 for subjects of site 02 and 03.
Nervous system disorders Dizziness	0.00% 0/68 • from signing of informed consent to 270 days that is end of study All AEs were classified according to the Medical Dictionary for Regulatory Activities (MedDRA), Version 25.0 for subjects of site 01 and from MedDRA dictionary, Version 26.1 for subjects of site 02 and 03.	2.9% 2/69 • Number of events 2 • from signing of informed consent to 270 days that is end of study All AEs were classified according to the Medical Dictionary for Regulatory Activities (MedDRA), Version 25.0 for subjects of site 01 and from MedDRA dictionary, Version 26.1 for subjects of site 02 and 03.	1.4% 1/69 • Number of events 1 • from signing of informed consent to 270 days that is end of study All AEs were classified according to the Medical Dictionary for Regulatory Activities (MedDRA), Version 25.0 for subjects of site 01 and from MedDRA dictionary, Version 26.1 for subjects of site 02 and 03.
Respiratory, thoracic and mediastinal disorders Oropharyngeal pain	2.9% 2/68 • Number of events 2 • from signing of informed consent to 270 days that is end of study All AEs were classified according to the Medical Dictionary for Regulatory Activities (MedDRA), Version 25.0 for subjects of site 01 and from MedDRA dictionary, Version 26.1 for subjects of site 02 and 03.	1.4% 1/69 • Number of events 1 • from signing of informed consent to 270 days that is end of study All AEs were classified according to the Medical Dictionary for Regulatory Activities (MedDRA), Version 25.0 for subjects of site 01 and from MedDRA dictionary, Version 26.1 for subjects of site 02 and 03.	0.00% 0/69 • from signing of informed consent to 270 days that is end of study All AEs were classified according to the Medical Dictionary for Regulatory Activities (MedDRA), Version 25.0 for subjects of site 01 and from MedDRA dictionary, Version 26.1 for subjects of site 02 and 03.
Respiratory, thoracic and mediastinal disorders Rhinorrhoea	2.9% 2/68 • Number of events 2 • from signing of informed consent to 270 days that is end of study All AEs were classified according to the Medical Dictionary for Regulatory Activities (MedDRA), Version 25.0 for subjects of site 01 and from MedDRA dictionary, Version 26.1 for subjects of site 02 and 03.	0.00% 0/69 • from signing of informed consent to 270 days that is end of study All AEs were classified according to the Medical Dictionary for Regulatory Activities (MedDRA), Version 25.0 for subjects of site 01 and from MedDRA dictionary, Version 26.1 for subjects of site 02 and 03.	2.9% 2/69 • Number of events 2 • from signing of informed consent to 270 days that is end of study All AEs were classified according to the Medical Dictionary for Regulatory Activities (MedDRA), Version 25.0 for subjects of site 01 and from MedDRA dictionary, Version 26.1 for subjects of site 02 and 03.
Skin and subcutaneous tissue disorders Rash	4.4% 3/68 • Number of events 3 • from signing of informed consent to 270 days that is end of study All AEs were classified according to the Medical Dictionary for Regulatory Activities (MedDRA), Version 25.0 for subjects of site 01 and from MedDRA dictionary, Version 26.1 for subjects of site 02 and 03.	0.00% 0/69 • from signing of informed consent to 270 days that is end of study All AEs were classified according to the Medical Dictionary for Regulatory Activities (MedDRA), Version 25.0 for subjects of site 01 and from MedDRA dictionary, Version 26.1 for subjects of site 02 and 03.	0.00% 0/69 • from signing of informed consent to 270 days that is end of study All AEs were classified according to the Medical Dictionary for Regulatory Activities (MedDRA), Version 25.0 for subjects of site 01 and from MedDRA dictionary, Version 26.1 for subjects of site 02 and 03.