Trial Outcomes & Findings for Efficacy and Safety Study of DiaPep277 in Newly Diagnosed Type 1 Diabetes Adults (NCT NCT01103284)

Last Updated: 2016-05-26

Results Overview

Change in Beta-cell function, measured as stimulated C-peptide secretion 0, 2, 6, 10 and 20 minutes post administration \[area under the curve (AUC), 0-20 minutes\] at baseline and 24 months, during a glucagon stimulation test (GST). The change in AUC was calculated per patient by subtracting the baseline AUC from the 24 month AUC.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

475 participants

Primary outcome timeframe

Baseline and 24 months

Results posted on

2016-05-26

Participant Flow

Patients newly diagnosed with Type 1 diabetes were recruited at medical centers in the US, EU, Argentina, and Israel.

Participant milestones

Participant milestones
Measure	DiaPep277 Administration of 1 mg DiaPep277®, subcutaneously (s.c.) in the upper arm at 0, 1, 3, 6, 9, 12, 15, 18, 21, and 24 months, for a total of 10 administrations. DiaPep277: 1.0 mg dose in 0.5 mL of solution	Placebo Administration of placebo, subcutaneously (s.c.) in the upper arm at 0, 1, 3, 6, 9, 12, 15, 18, 21, and 24 months, for a total of 10 administrations. Placebo: 40 mg mannitol in 0.5 mL of solution. Dosing: 0, 1, 3, 6, 9, 12, 15, 18, 21, 24 months
Overall Study STARTED	236	239
Overall Study Treated	236	238
Overall Study At Least One Post-baseline Visit (FAS)	233	235
Overall Study COMPLETED	194	195
Overall Study NOT COMPLETED	42	44

Reasons for withdrawal

Reasons for withdrawal
Measure	DiaPep277 Administration of 1 mg DiaPep277®, subcutaneously (s.c.) in the upper arm at 0, 1, 3, 6, 9, 12, 15, 18, 21, and 24 months, for a total of 10 administrations. DiaPep277: 1.0 mg dose in 0.5 mL of solution	Placebo Administration of placebo, subcutaneously (s.c.) in the upper arm at 0, 1, 3, 6, 9, 12, 15, 18, 21, and 24 months, for a total of 10 administrations. Placebo: 40 mg mannitol in 0.5 mL of solution. Dosing: 0, 1, 3, 6, 9, 12, 15, 18, 21, 24 months
Overall Study Death	2	0
Overall Study Lost to Follow-up	9	10
Overall Study Pregnancy	3	1
Overall Study Protocol Violation	12	5
Overall Study Adverse Event	0	5
Overall Study Withdrawal by Subject	14	18
Overall Study Dermal Hypersensitivity	0	1
Overall Study Termination by the Sponsor	0	1
Overall Study Not described	2	1
Overall Study Missing CRF entries for study completion	0	2

Baseline Characteristics

Efficacy and Safety Study of DiaPep277 in Newly Diagnosed Type 1 Diabetes Adults

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	DiaPep277 n=236 Participants Administration of 1 mg DiaPep277®, subcutaneously (s.c.) in the upper arm at 0, 1, 3, 6, 9, 12, 15, 18, 21, and 24 months, for a total of 10 administrations. DiaPep277: 1.0 mg dose in 0.5 mL of solution	Placebo n=238 Participants Administration of placebo, subcutaneously (s.c.) in the upper arm at 0, 1, 3, 6, 9, 12, 15, 18, 21, and 24 months, for a total of 10 administrations. Placebo: 40 mg mannitol in 0.5 mL of solution. Dosing: 0, 1, 3, 6, 9, 12, 15, 18, 21, 24 months	Total n=474 Participants Total of all reporting groups
Age, Continuous	28.7 years STANDARD_DEVIATION 6.75 • n=5 Participants	28.5 years STANDARD_DEVIATION 6.56 • n=7 Participants	28.6 years STANDARD_DEVIATION 6.65 • n=5 Participants
Age, Customized	27.0 years n=5 Participants	27.0 years n=7 Participants	27.0 years n=5 Participants
Sex: Female, Male Female	79 Participants n=5 Participants	73 Participants n=7 Participants	152 Participants n=5 Participants
Sex: Female, Male Male	157 Participants n=5 Participants	165 Participants n=7 Participants	322 Participants n=5 Participants
Race/Ethnicity, Customized Caucasian	224 participants n=5 Participants	225 participants n=7 Participants	449 participants n=5 Participants
Race/Ethnicity, Customized Hispanic	6 participants n=5 Participants	6 participants n=7 Participants	12 participants n=5 Participants
Race/Ethnicity, Customized Black	3 participants n=5 Participants	4 participants n=7 Participants	7 participants n=5 Participants
Race/Ethnicity, Customized Oriental	1 participants n=5 Participants	1 participants n=7 Participants	2 participants n=5 Participants
Race/Ethnicity, Customized Asian	1 participants n=5 Participants	0 participants n=7 Participants	1 participants n=5 Participants
Race/Ethnicity, Customized Other	0 participants n=5 Participants	2 participants n=7 Participants	2 participants n=5 Participants
Race/Ethnicity, Customized Unknown	1 participants n=5 Participants	0 participants n=7 Participants	1 participants n=5 Participants
Daily Insulin Dose	0.305 IU/kg/day STANDARD_DEVIATION 0.1587 • n=5 Participants	0.317 IU/kg/day STANDARD_DEVIATION 0.1649 • n=7 Participants	0.311 IU/kg/day STANDARD_DEVIATION 0.1618 • n=5 Participants
Fasting C-Peptide	0.388 nmol/L STANDARD_DEVIATION 0.1473 • n=5 Participants	0.407 nmol/L STANDARD_DEVIATION 0.1731 • n=7 Participants	0.398 nmol/L STANDARD_DEVIATION 0.1609 • n=5 Participants

PRIMARY outcome

Timeframe: Baseline and 24 months

Population: Full Analysis Set (FAS) All subjects randomized who had a baseline visit and at least one scheduled post-baseline visit

Outcome measures

Outcome measures
Measure	DiaPep277 n=233 Participants Administration of 1 mg DiaPep277®, subcutaneously (s.c.) in the upper arm at 0, 1, 3, 6, 9, 12, 15, 18, 21, and 24 months, for a total of 10 administrations. DiaPep277: 1.0 mg dose in 0.5 mL of solution	Placebo n=235 Participants Administration of placebo, subcutaneously (s.c.) in the upper arm at 0, 1, 3, 6, 9, 12, 15, 18, 21, and 24 months, for a total of 10 administrations. Placebo: 40 mg mannitol in 0.5 mL of solution. Dosing: 0, 1, 3, 6, 9, 12, 15, 18, 21, 24 months
Change From Baseline in Glucagon-Stimulated C-Peptide AUC at 24 Months	-5.20 nmol*min/L Standard Error 0.27	-4.83 nmol*min/L Standard Error 0.30

SECONDARY outcome

Timeframe: 24 and 25 months

Population: Full Analysis Set (FAS) All subjects randomized who had a baseline visit and at least one scheduled post-baseline visit.

The percentage of subjects achieving good glycemic control, i.e. an HbA1c \<7% at study end (Month 25). If HbA1c was missing at Month 25, but the Month 24 value was available, then the Month 24 value was used to calculate the percentage of subjects with an HbA1c ≤ 7% at study end.

Outcome measures

Outcome measures
Measure	DiaPep277 n=233 Participants Administration of 1 mg DiaPep277®, subcutaneously (s.c.) in the upper arm at 0, 1, 3, 6, 9, 12, 15, 18, 21, and 24 months, for a total of 10 administrations. DiaPep277: 1.0 mg dose in 0.5 mL of solution	Placebo n=235 Participants Administration of placebo, subcutaneously (s.c.) in the upper arm at 0, 1, 3, 6, 9, 12, 15, 18, 21, and 24 months, for a total of 10 administrations. Placebo: 40 mg mannitol in 0.5 mL of solution. Dosing: 0, 1, 3, 6, 9, 12, 15, 18, 21, 24 months
Percentage of Subjects That Achieve Good Glycemic Control: HbA1c<7%	47 percentage of subjects Interval 40.0 to 54.0	47 percentage of subjects Interval 40.0 to 55.0

SECONDARY outcome

Timeframe: Baseline to 25 Months

Population: Full Analysis Set (FAS) All subjects randomized who had a baseline visit and at least one scheduled post-baseline visit

Total number of days with at least one hypoglycemic event recorded

Outcome measures

Outcome measures
Measure	DiaPep277 n=233 Participants Administration of 1 mg DiaPep277®, subcutaneously (s.c.) in the upper arm at 0, 1, 3, 6, 9, 12, 15, 18, 21, and 24 months, for a total of 10 administrations. DiaPep277: 1.0 mg dose in 0.5 mL of solution	Placebo n=235 Participants Administration of placebo, subcutaneously (s.c.) in the upper arm at 0, 1, 3, 6, 9, 12, 15, 18, 21, and 24 months, for a total of 10 administrations. Placebo: 40 mg mannitol in 0.5 mL of solution. Dosing: 0, 1, 3, 6, 9, 12, 15, 18, 21, 24 months
Frequency of Hypoglycemic Events	1955 days	3264 days

SECONDARY outcome

Timeframe: Baseline to 25 months

Population: Full Analysis Set (FAS) All subjects randomized who had a baseline visit and at least one scheduled post-baseline visit

Outcome measures

Outcome measures
Measure	DiaPep277 n=233 Participants Administration of 1 mg DiaPep277®, subcutaneously (s.c.) in the upper arm at 0, 1, 3, 6, 9, 12, 15, 18, 21, and 24 months, for a total of 10 administrations. DiaPep277: 1.0 mg dose in 0.5 mL of solution	Placebo n=235 Participants Administration of placebo, subcutaneously (s.c.) in the upper arm at 0, 1, 3, 6, 9, 12, 15, 18, 21, and 24 months, for a total of 10 administrations. Placebo: 40 mg mannitol in 0.5 mL of solution. Dosing: 0, 1, 3, 6, 9, 12, 15, 18, 21, 24 months
Mean Number of Days With at Least One Hypoglycemic Event	13.0 days Standard Error 2.3	35.4 days Standard Error 7.6

OTHER_PRE_SPECIFIED outcome

Timeframe: 24 and 25 months

Population: Full Analysis Set (FAS) All subjects randomized who had a baseline visit and at least one scheduled post-baseline visit.

Percentage of subjects requiring a daily insulin dose ≤ 0.5 IU/kg at end of study (25 Months). If insulin dose was missing at Month 25, but the Month 24 value was available, then the Month 24 value was used to calculate the percentage of subjects with a daily insulin dose ≤ 0.5 IU/kg at study end.

Outcome measures

Outcome measures
Measure	DiaPep277 n=233 Participants Administration of 1 mg DiaPep277®, subcutaneously (s.c.) in the upper arm at 0, 1, 3, 6, 9, 12, 15, 18, 21, and 24 months, for a total of 10 administrations. DiaPep277: 1.0 mg dose in 0.5 mL of solution	Placebo n=235 Participants Administration of placebo, subcutaneously (s.c.) in the upper arm at 0, 1, 3, 6, 9, 12, 15, 18, 21, and 24 months, for a total of 10 administrations. Placebo: 40 mg mannitol in 0.5 mL of solution. Dosing: 0, 1, 3, 6, 9, 12, 15, 18, 21, 24 months
Percentage of Subjects Requiring a Daily Insulin Dose ≤ 0.5 IU/kg at End of Study	63 percentage of subjects Interval 57.0 to 69.0	57 percentage of subjects Interval 50.0 to 63.0

Adverse Events

DiaPep277

Serious events: 15 serious events

Other events: 171 other events

Deaths: 0 deaths

Placebo

Serious events: 10 serious events

Other events: 172 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Dr. Jeanne Novak

CBR International

Phone: 7207461190

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Investigator shall submit any paper or presentation to the Sponsor for review and comments at least 60 days prior to submitting the same to a third party. Upon receiving any request from the Sponsor to delete any Confidential Information or request to delay in publication up to 90 days to allow the filing of any Sponsor application, the Investigator shall take the request action. Investigator shall not be restricted after 18 months from completion of their site's performance in the study.
Publication restrictions are in place

Restriction type: OTHER

Measure	DiaPep277 n=236 participants at risk Administration of 1 mg DiaPep277®, subcutaneously (s.c.) in the upper arm at 0, 1, 3, 6, 9, 12, 15, 18, 21, and 24 months, for a total of 10 administrations. DiaPep277: 1.0 mg dose in 0.5 mL of solution	Placebo n=238 participants at risk Administration of placebo, subcutaneously (s.c.) in the upper arm at 0, 1, 3, 6, 9, 12, 15, 18, 21, and 24 months, for a total of 10 administrations. Placebo: 40 mg mannitol in 0.5 mL of solution. Dosing: 0, 1, 3, 6, 9, 12, 15, 18, 21, 24 months
Metabolism and nutrition disorders Diabetic ketoacidosis	0.85% 2/236 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)	0.00% 0/238 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)
Metabolism and nutrition disorders Hypoglycemia	0.42% 1/236 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)	1.3% 3/238 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)
Metabolism and nutrition disorders Diabetes mellitus inadequate control	0.42% 1/236 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)	0.00% 0/238 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)
Infections and infestations Meningitis viral	0.42% 1/236 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)	0.00% 0/238 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)
Infections and infestations Pneumonia	0.42% 1/236 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)	0.00% 0/238 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)
Infections and infestations Tick-borne viral encephalitis	0.42% 1/236 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)	0.00% 0/238 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)
Infections and infestations Tonsillitis Streptococcal	0.42% 1/236 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)	0.00% 0/238 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)
Infections and infestations Sialoadenitis	0.00% 0/236 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)	0.42% 1/238 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)
Gastrointestinal disorders Abdominal pain	0.42% 1/236 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)	0.00% 0/238 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)
Gastrointestinal disorders Duodenal ulcer hemorrhage	0.42% 1/236 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)	0.00% 0/238 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)
Gastrointestinal disorders Incarcerated inguinal hernia	0.42% 1/236 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)	0.00% 0/238 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)
Gastrointestinal disorders Anal fistula	0.00% 0/236 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)	0.42% 1/238 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)
Injury, poisoning and procedural complications Meniscus inury	0.42% 1/236 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)	0.00% 0/238 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)
Injury, poisoning and procedural complications multiple injuries	0.00% 0/236 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)	0.42% 1/238 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)
Musculoskeletal and connective tissue disorders Muscle disorder	0.00% 0/236 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)	0.42% 1/238 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)
Musculoskeletal and connective tissue disorders Sympathetic posterior cervical syndrome	0.00% 0/236 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)	0.42% 1/238 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)
Nervous system disorders Hypoglycemic seizure	0.42% 1/236 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)	0.00% 0/238 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)
Nervous system disorders Loss of Consciousness	0.00% 0/236 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)	0.42% 1/238 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)
Blood and lymphatic system disorders Lymphadenitis	0.00% 0/236 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)	0.42% 1/238 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Benign muscle neoplasm	0.00% 0/236 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)	0.42% 1/238 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)
Pregnancy, puerperium and perinatal conditions Abortion spontaneous	0.42% 1/236 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)	0.00% 0/238 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)
Psychiatric disorders Depression	0.00% 0/236 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)	0.42% 1/238 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)
Respiratory, thoracic and mediastinal disorders Nasal septum deviation	0.42% 1/236 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)	0.00% 0/238 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)

Measure	DiaPep277 n=236 participants at risk Administration of 1 mg DiaPep277®, subcutaneously (s.c.) in the upper arm at 0, 1, 3, 6, 9, 12, 15, 18, 21, and 24 months, for a total of 10 administrations. DiaPep277: 1.0 mg dose in 0.5 mL of solution	Placebo n=238 participants at risk Administration of placebo, subcutaneously (s.c.) in the upper arm at 0, 1, 3, 6, 9, 12, 15, 18, 21, and 24 months, for a total of 10 administrations. Placebo: 40 mg mannitol in 0.5 mL of solution. Dosing: 0, 1, 3, 6, 9, 12, 15, 18, 21, 24 months
Infections and infestations Nasopharyngitis	22.0% 52/236 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)	25.2% 60/238 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)
Infections and infestations Upper respiratory tract infection	7.6% 18/236 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)	5.5% 13/238 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)
Infections and infestations Influenza	6.4% 15/236 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)	7.1% 17/238 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)
Infections and infestations Sinusitis	4.2% 10/236 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)	1.7% 4/238 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)
Infections and infestations Gastroenteriitis	3.0% 7/236 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)	3.8% 9/238 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)
Infections and infestations Urinary tract infection	3.0% 7/236 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)	3.4% 8/238 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)
Infections and infestations Bronchitis	3.0% 7/236 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)	2.1% 5/238 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)
Infections and infestations Pharyngitis	2.1% 5/236 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)	3.8% 9/238 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)
Infections and infestations Tonsillitis	1.7% 4/236 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)	2.5% 6/238 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)
Infections and infestations Rhinitis	1.3% 3/236 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)	3.8% 9/238 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)
Gastrointestinal disorders Nausea	3.8% 9/236 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)	5.5% 13/238 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)
Gastrointestinal disorders Diarrhea	3.8% 9/236 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)	2.9% 7/238 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)
Gastrointestinal disorders Abdominal Pain	2.1% 5/236 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)	2.5% 6/238 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)
Gastrointestinal disorders Toothache	2.1% 5/236 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)	2.5% 6/238 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)
Gastrointestinal disorders Abdominal pain upper	2.1% 5/236 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)	1.7% 4/238 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)
Gastrointestinal disorders vomiting	1.7% 4/236 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)	2.9% 7/238 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)
General disorders Injection site pain	8.5% 20/236 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)	7.6% 18/238 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)
General disorders Asthenia	1.3% 3/236 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)	2.5% 6/238 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)
General disorders Fatigue	1.3% 3/236 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)	2.1% 5/238 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)
Nervous system disorders Headache	7.2% 17/236 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)	10.5% 25/238 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)
Nervous system disorders Migraine	0.42% 1/236 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)	2.1% 5/238 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)
Musculoskeletal and connective tissue disorders Back pain	4.7% 11/236 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)	2.5% 6/238 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)
Musculoskeletal and connective tissue disorders Arthralgia	2.1% 5/236 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)	1.7% 4/238 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)
Musculoskeletal and connective tissue disorders Pain in extremity	1.3% 3/236 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)	3.4% 8/238 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)
Injury, poisoning and procedural complications Laceration	0.85% 2/236 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)	2.1% 5/238 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)
Injury, poisoning and procedural complications Joint injury	0.00% 0/236 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)	2.1% 5/238 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)
Investigations Blood creatine phosphokinase increased	2.5% 6/236 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)	1.3% 3/238 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)
Investigations Blood thyroid stimulating hormone increased	0.42% 1/236 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)	2.1% 5/238 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)
Respiratory, thoracic and mediastinal disorders Cough	2.1% 5/236 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)	3.4% 8/238 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)
Respiratory, thoracic and mediastinal disorders Oropharyngeal pain	1.7% 4/236 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)	2.9% 7/238 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)
Respiratory, thoracic and mediastinal disorders Respiratory disorder	1.7% 4/236 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)	2.5% 6/238 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)
Skin and subcutaneous tissue disorders Rash	3.0% 7/236 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)	1.3% 3/238 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)
Metabolism and nutrition disorders Hypercholesterolemia	0.00% 0/236 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)	2.1% 5/238 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)
Psychiatric disorders Psychiatric disorders	4.2% 10/236 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)	3.8% 9/238 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)
Blood and lymphatic system disorders Blood and lymphatic system disorders	3.4% 8/236 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)	4.2% 10/238 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)
Cardiac disorders Cardiac disorders	3.4% 8/236 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)	2.5% 6/238 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)
Endocrine disorders Hypothyroidism	0.85% 2/236 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)	2.1% 5/238 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)
Immune system disorders Immune system disorders	2.5% 6/236 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)	2.5% 6/238 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)
Vascular disorders Hypertension	0.85% 2/236 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)	2.1% 5/238 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)
Renal and urinary disorders Renal and urinary disorders	1.7% 4/236 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)	2.9% 7/238 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)
Eye disorders Eye disorders	1.7% 4/236 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)	2.5% 6/238 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)
Reproductive system and breast disorders Reproductive system and breast disorders	2.5% 6/236 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)	1.7% 4/238 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)
Hepatobiliary disorders Hepatobiliary Disorders	0.42% 1/236 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)	2.1% 5/238 • AE data were collected from the time of subject enrollment through one month after the final product administrations (Total of 25 months after first study product administration)