Trial Outcomes & Findings for Lot-to-lot Consistency of Sci-B-Vac™ in Adults (NCT NCT03408730)

Last Updated: 2021-03-25

Results Overview

To demonstrate the manufacturing equivalence, in terms of immunogenicity, as measured by GMC of antibodies, of 3 independent consecutive lots of the Sci-B-Vac® 4 weeks after the third vaccination. Lot-to-lot manufacturing consistency of Sci-B-Vac® is demonstrated if the 95% CIs of the adjusted anti-HBs GMC ratios between lots are within the pre-specified range of \[0.67, 1.5\].

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

2838 participants

Primary outcome timeframe

4 weeks after third vaccination (Study Day 196)

Results posted on

2021-03-25

Participant Flow

Participant milestones

Participant milestones
Measure	Comparator: ENGERIX-B Hep B Vaccination Active Comparator: ENGERIX-B Hepatitis B Vaccination Engerix-B® Hepatitis B Vaccination, 20ug, intramuscular (IM) injection at Days 0, 28, and 168.	Sci-B-Vac Lot A Hep B Vaccination Sci-B-Vac Lot A Hepatitis B Vaccination Sci-B-Vac® Hepatitis B Vaccination, 10ug, intramuscular (IM) injection at Days 0, 28, and 168.	Sci-B-Vac Lot B Hep B Vaccination Sci-B-Vac Lot B Hepatitis B Vaccination Sci-B-Vac® Hepatitis B Vaccination, 10ug, intramuscular (IM) injection at Days 0, 28, and 168.	Sci-B-Vac Lot C Hep B Vaccination Sci-B-Vac Lot C Hepatitis B Vaccination Sci-B-Vac® Hepatitis B Vaccination, 10ug, intramuscular (IM) injection at Days 0, 28, and 168.
Overall Study STARTED	712	711	709	706
Overall Study COMPLETED	643	636	637	625
Overall Study NOT COMPLETED	69	75	72	81

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

The smoking status of one subject in group "Sci-B-Vac Lot C Hep B Vaccination" was not documented.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Comparator: ENGERIX-B Hep B Vaccination n=712 Participants Active Comparator: ENGERIX-B Hepatitis B Vaccination Engerix-B® Hepatitis B Vaccination, 20ug, intramuscular (IM) injection at Days 0, 28, and 168.	Sci-B-Vac Lot A Hep B Vaccination n=711 Participants Sci-B-Vac Lot A Hepatitis B Vaccination Sci-B-Vac® Hepatitis B Vaccination, 10ug, intramuscular (IM) injection at Days 0, 28, and 168.	Sci-B-Vac Lot B Hep B Vaccination n=708 Participants Sci-B-Vac Lot B Hepatitis B Vaccination Sci-B-Vac® Hepatitis B Vaccination, 10ug, intramuscular (IM) injection at Days 0, 28, and 168.	Sci-B-Vac Lot C Hep B Vaccination n=705 Participants Sci-B-Vac Lot C Hepatitis B Vaccination Sci-B-Vac® Hepatitis B Vaccination, 10ug, intramuscular (IM) injection at Days 0, 28, and 168.	Total n=2836 Participants Total of all reporting groups
Age, Continuous	33.4 years STANDARD_DEVIATION 8.10 • n=712 Participants	33.8 years STANDARD_DEVIATION 7.96 • n=711 Participants	32.9 years STANDARD_DEVIATION 8.00 • n=708 Participants	33.9 years STANDARD_DEVIATION 7.91 • n=705 Participants	33.5 years STANDARD_DEVIATION 8.00 • n=2836 Participants
Sex: Female, Male Female	421 Participants n=712 Participants	408 Participants n=711 Participants	395 Participants n=708 Participants	414 Participants n=705 Participants	1638 Participants n=2836 Participants
Sex: Female, Male Male	291 Participants n=712 Participants	303 Participants n=711 Participants	313 Participants n=708 Participants	291 Participants n=705 Participants	1198 Participants n=2836 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	74 Participants n=712 Participants	64 Participants n=711 Participants	70 Participants n=708 Participants	61 Participants n=705 Participants	269 Participants n=2836 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	636 Participants n=712 Participants	643 Participants n=711 Participants	638 Participants n=708 Participants	643 Participants n=705 Participants	2560 Participants n=2836 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	2 Participants n=712 Participants	4 Participants n=711 Participants	0 Participants n=708 Participants	1 Participants n=705 Participants	7 Participants n=2836 Participants
Race/Ethnicity, Customized Race · White	654 Participants n=712 Participants	650 Participants n=711 Participants	641 Participants n=708 Participants	650 Participants n=705 Participants	2595 Participants n=2836 Participants
Race/Ethnicity, Customized Race · Asian	9 Participants n=712 Participants	9 Participants n=711 Participants	15 Participants n=708 Participants	13 Participants n=705 Participants	46 Participants n=2836 Participants
Race/Ethnicity, Customized Race · Black or African American	38 Participants n=712 Participants	46 Participants n=711 Participants	43 Participants n=708 Participants	34 Participants n=705 Participants	161 Participants n=2836 Participants
Race/Ethnicity, Customized Race · American Indian or Alaska Native	2 Participants n=712 Participants	2 Participants n=711 Participants	1 Participants n=708 Participants	3 Participants n=705 Participants	8 Participants n=2836 Participants
Race/Ethnicity, Customized Race · Other	9 Participants n=712 Participants	4 Participants n=711 Participants	8 Participants n=708 Participants	5 Participants n=705 Participants	26 Participants n=2836 Participants
Region of Enrollment Canada	31 participants n=712 Participants	31 participants n=711 Participants	29 participants n=708 Participants	30 participants n=705 Participants	121 participants n=2836 Participants
Region of Enrollment United States	188 participants n=712 Participants	191 participants n=711 Participants	186 participants n=708 Participants	185 participants n=705 Participants	750 participants n=2836 Participants
Region of Enrollment Europe	493 participants n=712 Participants	489 participants n=711 Participants	493 participants n=708 Participants	490 participants n=705 Participants	1965 participants n=2836 Participants
BMI category >30 kg/m^2	117 Participants n=712 Participants	135 Participants n=711 Participants	117 Participants n=708 Participants	135 Participants n=705 Participants	504 Participants n=2836 Participants
BMI category <=30 kg/ m^2	595 Participants n=712 Participants	576 Participants n=711 Participants	591 Participants n=708 Participants	570 Participants n=705 Participants	2332 Participants n=2836 Participants
Smoking status Current smoker/ tobacco user	136 Participants n=712 Participants • The smoking status of one subject in group "Sci-B-Vac Lot C Hep B Vaccination" was not documented.	139 Participants n=711 Participants • The smoking status of one subject in group "Sci-B-Vac Lot C Hep B Vaccination" was not documented.	142 Participants n=708 Participants • The smoking status of one subject in group "Sci-B-Vac Lot C Hep B Vaccination" was not documented.	125 Participants n=704 Participants • The smoking status of one subject in group "Sci-B-Vac Lot C Hep B Vaccination" was not documented.	542 Participants n=2835 Participants • The smoking status of one subject in group "Sci-B-Vac Lot C Hep B Vaccination" was not documented.
Smoking status Former smoker/ tobacco user	141 Participants n=712 Participants • The smoking status of one subject in group "Sci-B-Vac Lot C Hep B Vaccination" was not documented.	137 Participants n=711 Participants • The smoking status of one subject in group "Sci-B-Vac Lot C Hep B Vaccination" was not documented.	131 Participants n=708 Participants • The smoking status of one subject in group "Sci-B-Vac Lot C Hep B Vaccination" was not documented.	136 Participants n=704 Participants • The smoking status of one subject in group "Sci-B-Vac Lot C Hep B Vaccination" was not documented.	545 Participants n=2835 Participants • The smoking status of one subject in group "Sci-B-Vac Lot C Hep B Vaccination" was not documented.
Smoking status Nonsmoker/ non-tobacco user	435 Participants n=712 Participants • The smoking status of one subject in group "Sci-B-Vac Lot C Hep B Vaccination" was not documented.	435 Participants n=711 Participants • The smoking status of one subject in group "Sci-B-Vac Lot C Hep B Vaccination" was not documented.	435 Participants n=708 Participants • The smoking status of one subject in group "Sci-B-Vac Lot C Hep B Vaccination" was not documented.	443 Participants n=704 Participants • The smoking status of one subject in group "Sci-B-Vac Lot C Hep B Vaccination" was not documented.	1748 Participants n=2835 Participants • The smoking status of one subject in group "Sci-B-Vac Lot C Hep B Vaccination" was not documented.

PRIMARY outcome

Timeframe: 4 weeks after third vaccination (Study Day 196)

Population: Per Protocol Set 1 included all subjects in the full analysis set who received all 3 vaccinations, had an evaluable serum immunogenicity samples at baseline and at the time point of interest, were seronegative at baseline, and had no major protocol violations leading to exclusion

Outcome measures

Outcome measures
Measure	Sci-B-Vac Lot A Hep B Vaccination n=611 Participants Sci-B-Vac Lot A Hepatitis B Vaccination Sci-B-Vac® Hepatitis B Vaccination, 10ug, intramuscular (IM) injection at Days 0, 28, and 168.	Sci-B-Vac Lot B Hep B Vaccination n=610 Participants Sci-B-Vac Lot B Hepatitis B Vaccination Sci-B-Vac® Hepatitis B Vaccination, 10ug, intramuscular (IM) injection at Days 0, 28, and 168.	Sci-B-Vac Lot C Hep B Vaccination n=619 Participants Sci-B-Vac Lot C Hepatitis B Vaccination Sci-B-Vac® Hepatitis B Vaccination, 10ug, intramuscular (IM) injection at Days 0, 28, and 168.	Sci-B-Vac Lot C Hep B Vaccination Sci-B-Vac Lot C Hepatitis B Vaccination Sci-B-Vac® Hepatitis B Vaccination, 10ug, intramuscular (IM) injection at Days 0, 28, and 168.
Geometric Mean Concentration (GMC) of Anti-HBs at Day 196 for Lot-to-Lot Consistency (Per Protocol Set 1)	5883.93 mIU/ml Standard Deviation 5.423	4824.06 mIU/ml Standard Deviation 6.293	5505.98 mIU/ml Standard Deviation 5.975	—

SECONDARY outcome

Timeframe: 4 weeks after third vaccination (Study Day 196)

Population: Per Protocol Set 2 included all subjects in Per Protocol Set 1 excluding subjects who attended visits outside of windows including Visit 3/Day 168 (±28 days) and Visit 44/Day 196 (-7/+14 days)

The difference in proportions \[SPR(Sci-B-Vac®)-SPR(Engerix-B®)\] and two-sided 95% CIs were summarized. If the lower bound of the 95% CI was \> 5%, Sci-B-Vac® was to be declared non-inferior to Engerix-B®

Outcome measures

Outcome measures
Measure	Sci-B-Vac Lot A Hep B Vaccination n=592 Participants Sci-B-Vac Lot A Hepatitis B Vaccination Sci-B-Vac® Hepatitis B Vaccination, 10ug, intramuscular (IM) injection at Days 0, 28, and 168.	Sci-B-Vac Lot B Hep B Vaccination n=1753 Participants Sci-B-Vac Lot B Hepatitis B Vaccination Sci-B-Vac® Hepatitis B Vaccination, 10ug, intramuscular (IM) injection at Days 0, 28, and 168.	Sci-B-Vac Lot C Hep B Vaccination Sci-B-Vac Lot C Hepatitis B Vaccination Sci-B-Vac® Hepatitis B Vaccination, 10ug, intramuscular (IM) injection at Days 0, 28, and 168.	Sci-B-Vac Lot C Hep B Vaccination Sci-B-Vac Lot C Hepatitis B Vaccination Sci-B-Vac® Hepatitis B Vaccination, 10ug, intramuscular (IM) injection at Days 0, 28, and 168.
Seroprotection Rate (SPR) of Anti-HBs at Day 196 for Sci-B-Vac® Compared to Day 196 for Engerix-B® (Per Protocol Set 2)	561 Participants	1740 Participants	—	—

SECONDARY outcome

Timeframe: Day of vaccine administration and six subsequent days

Population: Safety Set included all subjects in the All Enrolled Set who received at least 1 vaccination

Analysis of local and systemic solicited adverse events with an interval of onset of Day 1 to Day 7 after any vaccination with either Sci-B-Vac® or Engerix-B®, in adults ≥18 years old.

Outcome measures

Outcome measures
Measure	Sci-B-Vac Lot A Hep B Vaccination n=712 Participants Sci-B-Vac Lot A Hepatitis B Vaccination Sci-B-Vac® Hepatitis B Vaccination, 10ug, intramuscular (IM) injection at Days 0, 28, and 168.	Sci-B-Vac Lot B Hep B Vaccination n=711 Participants Sci-B-Vac Lot B Hepatitis B Vaccination Sci-B-Vac® Hepatitis B Vaccination, 10ug, intramuscular (IM) injection at Days 0, 28, and 168.	Sci-B-Vac Lot C Hep B Vaccination n=708 Participants Sci-B-Vac Lot C Hepatitis B Vaccination Sci-B-Vac® Hepatitis B Vaccination, 10ug, intramuscular (IM) injection at Days 0, 28, and 168.	Sci-B-Vac Lot C Hep B Vaccination n=705 Participants Sci-B-Vac Lot C Hepatitis B Vaccination Sci-B-Vac® Hepatitis B Vaccination, 10ug, intramuscular (IM) injection at Days 0, 28, and 168.
Percentage of Subject-reporting Solicited Local and Systemic Adverse Events (AEs) Headache	268 Participants	255 Participants	275 Participants	281 Participants
Percentage of Subject-reporting Solicited Local and Systemic Adverse Events (AEs) Pain	384 Participants	527 Participants	536 Participants	542 Participants
Percentage of Subject-reporting Solicited Local and Systemic Adverse Events (AEs) Tenderness	391 Participants	519 Participants	535 Participants	541 Participants
Percentage of Subject-reporting Solicited Local and Systemic Adverse Events (AEs) Pruritis/itching	88 Participants	84 Participants	105 Participants	92 Participants
Percentage of Subject-reporting Solicited Local and Systemic Adverse Events (AEs) Redness/erythema	12 Participants	27 Participants	20 Participants	14 Participants
Percentage of Subject-reporting Solicited Local and Systemic Adverse Events (AEs) Swelling/edema	6 Participants	18 Participants	15 Participants	22 Participants
Percentage of Subject-reporting Solicited Local and Systemic Adverse Events (AEs) Nausea/vomiting	86 Participants	85 Participants	87 Participants	79 Participants
Percentage of Subject-reporting Solicited Local and Systemic Adverse Events (AEs) Diarrhea	105 Participants	94 Participants	87 Participants	96 Participants
Percentage of Subject-reporting Solicited Local and Systemic Adverse Events (AEs) Fatigue	284 Participants	266 Participants	296 Participants	290 Participants
Percentage of Subject-reporting Solicited Local and Systemic Adverse Events (AEs) Myalgia	231 Participants	289 Participants	316 Participants	337 Participants

Adverse Events

Comparator: ENGERIX-B Hep B Vaccination

Serious events: 3 serious events

Other events: 381 other events

Deaths: 0 deaths

Sci-B-Vac Lot A Hep B Vaccination

Serious events: 12 serious events

Other events: 376 other events

Deaths: 1 deaths

Sci-B-Vac Lot B Hep B Vaccination

Serious events: 18 serious events

Other events: 392 other events

Deaths: 0 deaths

Sci-B-Vac Lot C Hep B Vaccination

Serious events: 12 serious events

Other events: 399 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Vlad Popovic

VBI Vaccines, Inc.

Phone: 416-418-4713

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Comparator: ENGERIX-B Hep B Vaccination n=712 participants at risk Active Comparator: ENGERIX-B Hepatitis B Vaccination Engerix-B® Hepatitis B Vaccination, 20ug, intramuscular (IM) injection at Days 0, 28, and 168.	Sci-B-Vac Lot A Hep B Vaccination n=711 participants at risk Sci-B-Vac Lot A Hepatitis B Vaccination Sci-B-Vac® Hepatitis B Vaccination, 10ug, intramuscular (IM) injection at Days 0, 28, and 168.	Sci-B-Vac Lot B Hep B Vaccination n=708 participants at risk Sci-B-Vac Lot B Hepatitis B Vaccination Sci-B-Vac® Hepatitis B Vaccination, 10ug, intramuscular (IM) injection at Days 0, 28, and 168.	Sci-B-Vac Lot C Hep B Vaccination n=705 participants at risk Sci-B-Vac Lot C Hepatitis B Vaccination Sci-B-Vac® Hepatitis B Vaccination, 10ug, intramuscular (IM) injection at Days 0, 28, and 168.
Infections and infestations Upper respiratory tract infection	9.6% 68/712 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).	9.6% 68/711 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).	10.9% 77/708 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).	10.9% 77/705 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).
Infections and infestations Nasopharyngitis	7.7% 55/712 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).	5.5% 39/711 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).	5.9% 42/708 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).	7.5% 53/705 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).
Infections and infestations Influenza	2.7% 19/712 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).	2.1% 15/711 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).	1.8% 13/708 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).	2.0% 14/705 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).
Infections and infestations Sinusitis	1.3% 9/712 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).	2.5% 18/711 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).	1.4% 10/708 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).	1.7% 12/705 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).
Infections and infestations Urinary tract infection	1.7% 12/712 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).	1.4% 10/711 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).	0.85% 6/708 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).	1.6% 11/705 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).
Infections and infestations Gastroenteritis	1.4% 10/712 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).	0.98% 7/711 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).	1.1% 8/708 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).	1.4% 10/705 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).
Infections and infestations Rhinitis	0.98% 7/712 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).	0.70% 5/711 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).	1.1% 8/708 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).	0.57% 4/705 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).
Nervous system disorders Headache	12.9% 92/712 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).	11.4% 81/711 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).	14.8% 105/708 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).	11.5% 81/705 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).
Nervous system disorders Dizziness	0.84% 6/712 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).	1.3% 9/711 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).	1.3% 9/708 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).	2.1% 15/705 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).
Musculoskeletal and connective tissue disorders Back pain	2.5% 18/712 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).	2.8% 20/711 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).	2.8% 20/708 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).	3.8% 27/705 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).
Musculoskeletal and connective tissue disorders Myalgia	2.9% 21/712 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).	2.7% 19/711 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).	2.7% 19/708 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).	3.1% 22/705 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).
Musculoskeletal and connective tissue disorders Neck pain	1.3% 9/712 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).	0.98% 7/711 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).	2.0% 14/708 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).	1.4% 10/705 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).
Musculoskeletal and connective tissue disorders Pain in extremity	1.4% 10/712 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).	1.5% 11/711 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).	0.71% 5/708 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).	1.7% 12/705 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).
Musculoskeletal and connective tissue disorders Arthralgia	1.5% 11/712 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).	0.98% 7/711 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).	1.4% 10/708 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).	1.1% 8/705 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).
Musculoskeletal and connective tissue disorders Muscle tightness	1.4% 10/712 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).	0.98% 7/711 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).	0.56% 4/708 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).	0.85% 6/705 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).
Musculoskeletal and connective tissue disorders Musculoskeletal pain	1.3% 9/712 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).	0.70% 5/711 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).	0.42% 3/708 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).	0.71% 5/705 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).
General disorders Fatigue	2.5% 18/712 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).	3.4% 24/711 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).	2.8% 20/708 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).	5.2% 37/705 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).
General disorders Injection site pain	1.8% 13/712 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).	2.4% 17/711 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).	2.5% 18/708 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).	1.6% 11/705 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).
General disorders Pyrexia	1.1% 8/712 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).	1.3% 9/711 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).	0.99% 7/708 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).	0.71% 5/705 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).
General disorders Injection site bruising	0.98% 7/712 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).	0.98% 7/711 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).	1.1% 8/708 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).	0.85% 6/705 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).
Gastrointestinal disorders Diarrhoea	1.1% 8/712 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).	2.0% 14/711 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).	1.6% 11/708 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).	1.4% 10/705 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).
Gastrointestinal disorders Abdominal pain upper	1.3% 9/712 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).	1.4% 10/711 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).	1.4% 10/708 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).	1.7% 12/705 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).
Gastrointestinal disorders Toothache	1.1% 8/712 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).	1.1% 8/711 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).	0.85% 6/708 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).	0.71% 5/705 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).
Gastrointestinal disorders Dyspepsia	0.42% 3/712 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).	0.28% 2/711 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).	1.3% 9/708 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).	0.85% 6/705 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).
Respiratory, thoracic and mediastinal disorders Oropharyngeal pain	3.1% 22/712 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).	3.2% 23/711 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).	3.1% 22/708 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).	3.4% 24/705 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).
Respiratory, thoracic and mediastinal disorders Cough	1.8% 13/712 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).	1.5% 11/711 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).	1.6% 11/708 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).	1.3% 9/705 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).
Reproductive system and breast disorders Dysmenorrhoea	4.5% 32/712 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).	4.1% 29/711 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).	3.7% 26/708 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).	5.7% 40/705 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).
Injury, poisoning and procedural complications Ligament sprain	0.28% 2/712 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).	0.70% 5/711 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).	0.85% 6/708 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).	1.1% 8/705 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).
Psychiatric disorders Depression	0.84% 6/712 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).	0.42% 3/711 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).	1.3% 9/708 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).	1.1% 8/705 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).
Psychiatric disorders Anxiety	0.56% 4/712 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).	0.56% 4/711 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).	1.3% 9/708 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).	0.00% 0/705 • 1 year Number (%) of subject-reporting unsolicited adverse events (AEs) and serious adverse events (SAEs).