Trial Outcomes & Findings for Long-term Safety and Efficacy Study of DX-2930 (SHP643) to Prevent Acute Angioedema Attacks in Patients With Type I and Type II HAE (NCT NCT02741596)

Last Updated: 2021-06-08

Results Overview

An adverse event (AE) was any untoward medical occurrence in a clinical trial Participant whether or not it appeared to have a causal relationship with the treatment administered. Treatment-emergent AEs were defined as AEs with onset at the time of or following the first exposure to open-label DX-2930 in this study, or medical conditions present prior to the start of treatment but increasing in severity or relationship at the time of or following the start of treatment.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

212 participants

Primary outcome timeframe

From start of the study up to follow-up (Day 952)

Results posted on

2021-06-08

Participant Flow

The study was conducted at 43 sites across United States, Canada, Europe and Jorden between 26 May 2016 (first participant first visit) and 31 October 2019 (last participant last visit).

A total of 212 participants were enrolled and received treatment in two groups (Rollover participants \[109\] and Non-rollover participants \[103\]). Participants who rolled from the DX-2930-03 (NCT02586805) study were in Rollover group and participants who were directly enrolled into this DX-2930-04 study were in Non-rollover group.

Participant milestones

Participant milestones
Measure	Rollover Participants Participants who rolled from the DX-2930-03 (NCT02586805) study received 300 milligrams (mg) of DX-2930 subcutaneous (SC) injection on Day 0 followed by a second dose after participants reported their first HAE attack and continued to receive repeated SC administrations of 300 mg DX-2930 every 2 weeks (q2wks) throughout the treatment period (up to 924 days). A wash-out period of a minimum of 10 days and a maximum of 18 days were required between subsequent administrations.	Non-rollover Participants Participants who directly entered in to this DX-2930-04 study received 300 mg of DX-2930 SC injection on Day 0 and continued to receive SC administrations of 300 mg DX-2930 every 2 weeks throughout the treatment period (up to 924 days).
Overall Study STARTED	109	103
Overall Study COMPLETED	31	25
Overall Study NOT COMPLETED	78	78

Reasons for withdrawal

Reasons for withdrawal
Measure	Rollover Participants Participants who rolled from the DX-2930-03 (NCT02586805) study received 300 milligrams (mg) of DX-2930 subcutaneous (SC) injection on Day 0 followed by a second dose after participants reported their first HAE attack and continued to receive repeated SC administrations of 300 mg DX-2930 every 2 weeks (q2wks) throughout the treatment period (up to 924 days). A wash-out period of a minimum of 10 days and a maximum of 18 days were required between subsequent administrations.	Non-rollover Participants Participants who directly entered in to this DX-2930-04 study received 300 mg of DX-2930 SC injection on Day 0 and continued to receive SC administrations of 300 mg DX-2930 every 2 weeks throughout the treatment period (up to 924 days).
Overall Study Adverse Event	1	5
Overall Study Lost to Follow-up	1	1
Overall Study Physician Decision	2	1
Overall Study Pregnancy	3	1
Overall Study Other (Unspecified)	0	3
Overall Study Subject withdrawn-Other	17	4
Overall Study Subject withdrawn-to commercial product	54	63

Baseline Characteristics

Long-term Safety and Efficacy Study of DX-2930 (SHP643) to Prevent Acute Angioedema Attacks in Patients With Type I and Type II HAE

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Rollover Participants n=109 Participants Participants who rolled from the DX-2930-03 (NCT02586805) study received 300 milligrams (mg) of DX-2930 subcutaneous (SC) injection on Day 0 followed by a second dose after participants reported their first HAE attack and continued to receive repeated SC administrations of 300 mg DX-2930 every 2 weeks (q2wks) throughout the treatment period (up to 924 days). A wash-out period of a minimum of 10 days and a maximum of 18 days were required between subsequent administrations.	Non-rollover Participants n=103 Participants Participants who directly entered in to this DX-2930-04 study received 300 mg of DX-2930 SC injection on Day 0 and continued to receive SC administrations of 300 mg DX-2930 every 2 weeks throughout the treatment period (up to 924 days).	Total n=212 Participants Total of all reporting groups
Age, Continuous	41.9 Years STANDARD_DEVIATION 14.74 • n=5 Participants	39.5 Years STANDARD_DEVIATION 16.71 • n=7 Participants	40.7 Years STANDARD_DEVIATION 15.73 • n=5 Participants
Sex: Female, Male Female	75 Participants n=5 Participants	68 Participants n=7 Participants	143 Participants n=5 Participants
Sex: Female, Male Male	34 Participants n=5 Participants	35 Participants n=7 Participants	69 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	8 Participants n=5 Participants	5 Participants n=7 Participants	13 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	101 Participants n=5 Participants	97 Participants n=7 Participants	198 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	2 Participants n=5 Participants	0 Participants n=7 Participants	2 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	8 Participants n=5 Participants	2 Participants n=7 Participants	10 Participants n=5 Participants
Race (NIH/OMB) White	99 Participants n=5 Participants	99 Participants n=7 Participants	198 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants

PRIMARY outcome

Timeframe: From start of the study up to follow-up (Day 952)

Population: Safety population included all participants who received any study drug after entering the DX-2930-04 study.

Outcome measures

Outcome measures
Measure	Rollover Participants n=109 Participants Participants who rolled from the DX-2930-03 (NCT02586805) study received 300 milligrams (mg) of DX-2930 subcutaneous (SC) injection on Day 0 followed by a second dose after participants reported their first HAE attack and continued to receive repeated SC administrations of 300 mg DX-2930 every 2 weeks (q2wks) throughout the treatment period (up to 924 days). A wash-out period of a minimum of 10 days and a maximum of 18 days were required between subsequent administrations.	Non-rollover Participants n=103 Participants Participants who directly entered in to this DX-2930-04 study received 300 mg of DX-2930 SC injection on Day 0 and continued to receive SC administrations of 300 mg DX-2930 every 2 weeks throughout the treatment period (up to 924 days).
Number of Participants With Treatment-emergent Adverse Events (TEAEs)	105 Participants	101 Participants

SECONDARY outcome

Timeframe: Up to Day 924

Population: Safety population included all participants who received any study drug after entering the DX-2930-04 study. Here, the number of participants analyzed signifies participants who were evaluable for this outcome measure.

HAE attack was defined as a discrete episode during which the participant progressed from no angioedema to symptoms of angioedema. The treatment period investigator-confirmed HAE attack rate was calculated for each participant as the number of investigator-confirmed HAE attacks occurring during the treatment period (regular dosing stage of the treatment period for rollover participants) divided by the number of days the participant contributed to the treatment period multiplied by 28 days. Rate of investigator-confirmed HAE attacks during the treatment period was reported.

Outcome measures

Outcome measures
Measure	Rollover Participants n=106 Participants Participants who rolled from the DX-2930-03 (NCT02586805) study received 300 milligrams (mg) of DX-2930 subcutaneous (SC) injection on Day 0 followed by a second dose after participants reported their first HAE attack and continued to receive repeated SC administrations of 300 mg DX-2930 every 2 weeks (q2wks) throughout the treatment period (up to 924 days). A wash-out period of a minimum of 10 days and a maximum of 18 days were required between subsequent administrations.	Non-rollover Participants n=103 Participants Participants who directly entered in to this DX-2930-04 study received 300 mg of DX-2930 SC injection on Day 0 and continued to receive SC administrations of 300 mg DX-2930 every 2 weeks throughout the treatment period (up to 924 days).
Rate of Investigator Confirmed Hereditary Angioedema (HAE) Attacks During the Treatment Period	0.27 Attacks per month Standard Deviation 0.581	0.22 Attacks per month Standard Deviation 0.521

SECONDARY outcome

Timeframe: Up to Day 924

Population: Safety population was analyzed, which included all participants who received any study drug after entering the DX-2930-04 study. Here, the number of participants analyzed signifies participants who were evaluable for this outcome measure.

HAE attack was defined as a discrete episode during which the participant progressed from no angioedema to symptoms of angioedema. Rate of investigator-confirmed HAE attacks requiring acute treatment for each participant as the number of investigator-confirmed HAE attacks occurring during the treatment period (regular dosing stage of the treatment period for rollover participants) divided by the number of days the participant contributed to the treatment period multiplied by 28 days. Rate of investigator-confirmed HAE attacks requiring acute treatment during the treatment period was reported.

Outcome measures

Outcome measures
Measure	Rollover Participants n=106 Participants Participants who rolled from the DX-2930-03 (NCT02586805) study received 300 milligrams (mg) of DX-2930 subcutaneous (SC) injection on Day 0 followed by a second dose after participants reported their first HAE attack and continued to receive repeated SC administrations of 300 mg DX-2930 every 2 weeks (q2wks) throughout the treatment period (up to 924 days). A wash-out period of a minimum of 10 days and a maximum of 18 days were required between subsequent administrations.	Non-rollover Participants n=103 Participants Participants who directly entered in to this DX-2930-04 study received 300 mg of DX-2930 SC injection on Day 0 and continued to receive SC administrations of 300 mg DX-2930 every 2 weeks throughout the treatment period (up to 924 days).
Rate of Investigator-Confirmed Hereditary Angioedema (HAE) Attacks Requiring Acute Treatment During the Treatment Period	0.20 Attacks per month Standard Deviation 0.430	0.21 Attacks per month Standard Deviation 0.517

SECONDARY outcome

Timeframe: Up to Day 924

HAE attack was defined as a discrete episode during which the participant progressed from no angioedema to symptoms of angioedema. Moderate and severe investigator-confirmed HAE attacks were the attacks that were moderate or severe as per the HAE attack assessment and reporting procedures (HAARP) defined severity. The overall severity of attack was determined by the investigator using following definitions: mild (transient or mild discomfort), moderate (mild to moderate limitation in activity), severe (marked limitation in activity). Rate of moderate or severe HAE attacks during the treatment period was reported.

Outcome measures

Outcome measures
Measure	Rollover Participants n=106 Participants Participants who rolled from the DX-2930-03 (NCT02586805) study received 300 milligrams (mg) of DX-2930 subcutaneous (SC) injection on Day 0 followed by a second dose after participants reported their first HAE attack and continued to receive repeated SC administrations of 300 mg DX-2930 every 2 weeks (q2wks) throughout the treatment period (up to 924 days). A wash-out period of a minimum of 10 days and a maximum of 18 days were required between subsequent administrations.	Non-rollover Participants n=103 Participants Participants who directly entered in to this DX-2930-04 study received 300 mg of DX-2930 SC injection on Day 0 and continued to receive SC administrations of 300 mg DX-2930 every 2 weeks throughout the treatment period (up to 924 days).
Rate of Moderate or Severe Hereditary Angioedema (HAE) Attacks During the Treatment Period	0.21 Attacks per month Standard Deviation 0.479	0.19 Attacks per month Standard Deviation 0.512

SECONDARY outcome

Timeframe: Up to Day 924

Population: Safety population included all participants who received any study drug after entering the DX-2930-04 study. Here the number of participants analyzed signifies participants who were evaluable for this outcome measure.

HAE attack was defined as a discrete episode during which the participant progressed from no angioedema to symptoms of angioedema. High-morbidity Hereditary Angioedema (HAE) attack was defined as any attack that had at least one of the following characteristics: severe, resulted in hospitalization (except hospitalization for observation lesser than \[\<\] 24 hours), hemodynamically significant (systolic blood pressure \<90 millimeter of mercury \[mmHg\], required intravenous hydration, or associated with syncope or near-syncope) or laryngeal edema. Number of high-morbidity HAE attacks during the treatment period was analyzed and reported using the methods for the overall number of investigator-confirmed HAE attacks with the exception of the monthly line graphs. Rate of high-morbidity HAE attacks during the treatment period was reported.

Outcome measures

Outcome measures
Measure	Rollover Participants n=106 Participants Participants who rolled from the DX-2930-03 (NCT02586805) study received 300 milligrams (mg) of DX-2930 subcutaneous (SC) injection on Day 0 followed by a second dose after participants reported their first HAE attack and continued to receive repeated SC administrations of 300 mg DX-2930 every 2 weeks (q2wks) throughout the treatment period (up to 924 days). A wash-out period of a minimum of 10 days and a maximum of 18 days were required between subsequent administrations.	Non-rollover Participants n=103 Participants Participants who directly entered in to this DX-2930-04 study received 300 mg of DX-2930 SC injection on Day 0 and continued to receive SC administrations of 300 mg DX-2930 every 2 weeks throughout the treatment period (up to 924 days).
Rate of High-Morbidity Hereditary Angioedema (HAE) Attacks During the Treatment Period	0.03 Attacks per month Standard Deviation 0.085	0.04 Attacks per month Standard Deviation 0.103

SECONDARY outcome

Timeframe: Up to Day 924

Population: Rollover Safety Population included subset of participants who participated in the DX-2930-03 (NCT02586805) study and received any study drug after entering the DX-2930-04 study (that is any exposure to open-label DX-2930). Here, data was not planned to be collected and analyzed for Non-rollover participants.

HAE attack was defined as a discrete episode during which the participant progressed from no angioedema to symptoms of angioedema. Time to first investigator-confirmed HAE attack was calculated from the time of first open-label dose to the start time of the first investigator-confirmed HAE attack. Time to the first investigator-confirmed HAE attack was analyzed and reported only in rollover safety population.

Outcome measures

Outcome measures
Measure	Rollover Participants n=109 Participants Participants who rolled from the DX-2930-03 (NCT02586805) study received 300 milligrams (mg) of DX-2930 subcutaneous (SC) injection on Day 0 followed by a second dose after participants reported their first HAE attack and continued to receive repeated SC administrations of 300 mg DX-2930 every 2 weeks (q2wks) throughout the treatment period (up to 924 days). A wash-out period of a minimum of 10 days and a maximum of 18 days were required between subsequent administrations.	Non-rollover Participants Participants who directly entered in to this DX-2930-04 study received 300 mg of DX-2930 SC injection on Day 0 and continued to receive SC administrations of 300 mg DX-2930 every 2 weeks throughout the treatment period (up to 924 days).
Time to First Investigator-Confirmed Hereditary Angioedema (HAE) Attacks in Rollover Participants	43 Days Interval 18.0 to 97.0	—

Adverse Events

Rollover

Serious events: 12 serious events

Other events: 100 other events

Deaths: 0 deaths

Non-Rollover

Serious events: 9 serious events

Other events: 96 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Study Director

Shire

Phone: +1 866 842 5335

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee If a multicenter publication is not submitted within twelve (12) months after conclusion, abandonment or termination of the Study at all sites, or after Sponsor confirms there shall be no multicenter Study publication, the Institution and/or such Principal Investigator may publish the results from the Institution site individually.
Publication restrictions are in place

Restriction type: OTHER

Measure	Rollover n=109 participants at risk Participants who rolled from the DX-2930-03 (NCT02586805) study received 300 milligrams (mg) of DX-2930 subcutaneous (SC) injection on Day 0 followed by a second dose after participants reported their first HAE attack and continued to receive repeated SC administrations of 300 mg DX-2930 every 2 weeks (q2wks) throughout the treatment period (up to 924 days). A wash-out period of a minimum of 10 days and a maximum of 18 days were required between subsequent administrations.	Non-Rollover n=103 participants at risk Participants who directly entered in to this DX-2930-04 study received 300 mg of DX-2930 SC injection on Day 0 and continued to receive SC administrations of 300 mg DX-2930 every 2 weeks throughout the treatment period (up to 924 days).
Blood and lymphatic system disorders Hypochromic anaemia	0.92% 1/109 • Number of events 1 • From start of the study up to follow-up (Day 952)	0.00% 0/103 • From start of the study up to follow-up (Day 952)
Musculoskeletal and connective tissue disorders Cervical spinal stenosis	0.92% 1/109 • Number of events 1 • From start of the study up to follow-up (Day 952)	0.00% 0/103 • From start of the study up to follow-up (Day 952)
Musculoskeletal and connective tissue disorders Lumbar spinal stenosis	0.92% 1/109 • Number of events 1 • From start of the study up to follow-up (Day 952)	0.00% 0/103 • From start of the study up to follow-up (Day 952)
Musculoskeletal and connective tissue disorders Rheumatoid arthritis	0.92% 1/109 • Number of events 1 • From start of the study up to follow-up (Day 952)	0.00% 0/103 • From start of the study up to follow-up (Day 952)
Musculoskeletal and connective tissue disorders Systemic lupus erythematosus	0.00% 0/109 • From start of the study up to follow-up (Day 952)	0.97% 1/103 • Number of events 1 • From start of the study up to follow-up (Day 952)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Fibrosarcoma	0.00% 0/109 • From start of the study up to follow-up (Day 952)	0.97% 1/103 • Number of events 1 • From start of the study up to follow-up (Day 952)
Vascular disorders Lymphoedema	0.92% 1/109 • Number of events 1 • From start of the study up to follow-up (Day 952)	0.00% 0/103 • From start of the study up to follow-up (Day 952)
Gastrointestinal disorders Anal fissure	0.00% 0/109 • From start of the study up to follow-up (Day 952)	0.97% 1/103 • Number of events 1 • From start of the study up to follow-up (Day 952)
Gastrointestinal disorders Gastric ulcer	0.92% 1/109 • Number of events 1 • From start of the study up to follow-up (Day 952)	0.00% 0/103 • From start of the study up to follow-up (Day 952)
Gastrointestinal disorders Gastrointestinal haemorrhage	0.92% 1/109 • Number of events 1 • From start of the study up to follow-up (Day 952)	0.00% 0/103 • From start of the study up to follow-up (Day 952)
Gastrointestinal disorders Upper gastrointestinal haemorrhage	0.92% 1/109 • Number of events 1 • From start of the study up to follow-up (Day 952)	0.00% 0/103 • From start of the study up to follow-up (Day 952)
Cardiac disorders Coronary artery stenosis	0.00% 0/109 • From start of the study up to follow-up (Day 952)	0.97% 1/103 • Number of events 1 • From start of the study up to follow-up (Day 952)
Infections and infestations Breast abscess	0.92% 1/109 • Number of events 2 • From start of the study up to follow-up (Day 952)	0.00% 0/103 • From start of the study up to follow-up (Day 952)
Infections and infestations Gastroenteritis	0.92% 1/109 • Number of events 1 • From start of the study up to follow-up (Day 952)	0.97% 1/103 • Number of events 1 • From start of the study up to follow-up (Day 952)
Infections and infestations Localised infection	0.00% 0/109 • From start of the study up to follow-up (Day 952)	0.97% 1/103 • Number of events 1 • From start of the study up to follow-up (Day 952)
Infections and infestations Meningitis viral	0.00% 0/109 • From start of the study up to follow-up (Day 952)	0.97% 1/103 • Number of events 1 • From start of the study up to follow-up (Day 952)
Infections and infestations Sepsis	0.00% 0/109 • From start of the study up to follow-up (Day 952)	0.97% 1/103 • Number of events 1 • From start of the study up to follow-up (Day 952)
Injury, poisoning and procedural complications Accidental exposure to product	0.92% 1/109 • Number of events 1 • From start of the study up to follow-up (Day 952)	0.00% 0/103 • From start of the study up to follow-up (Day 952)
Injury, poisoning and procedural complications Incision site inflammation	0.00% 0/109 • From start of the study up to follow-up (Day 952)	0.97% 1/103 • Number of events 1 • From start of the study up to follow-up (Day 952)
Injury, poisoning and procedural complications Wound dehiscence	0.00% 0/109 • From start of the study up to follow-up (Day 952)	0.97% 1/103 • Number of events 1 • From start of the study up to follow-up (Day 952)
Hepatobiliary disorders Cholelithiasis	0.92% 1/109 • Number of events 1 • From start of the study up to follow-up (Day 952)	0.00% 0/103 • From start of the study up to follow-up (Day 952)
Metabolism and nutrition disorders Dehydration	0.00% 0/109 • From start of the study up to follow-up (Day 952)	0.97% 1/103 • Number of events 1 • From start of the study up to follow-up (Day 952)
Nervous system disorders Cerebrovascular accident	0.92% 1/109 • Number of events 1 • From start of the study up to follow-up (Day 952)	0.00% 0/103 • From start of the study up to follow-up (Day 952)
Nervous system disorders Transient ischaemic attack	0.00% 0/109 • From start of the study up to follow-up (Day 952)	0.97% 1/103 • Number of events 1 • From start of the study up to follow-up (Day 952)
Psychiatric disorders Anxiety	0.00% 0/109 • From start of the study up to follow-up (Day 952)	0.97% 1/103 • Number of events 1 • From start of the study up to follow-up (Day 952)
Psychiatric disorders Depression	0.92% 1/109 • Number of events 1 • From start of the study up to follow-up (Day 952)	0.00% 0/103 • From start of the study up to follow-up (Day 952)
Psychiatric disorders Major depression	0.92% 1/109 • Number of events 1 • From start of the study up to follow-up (Day 952)	0.00% 0/103 • From start of the study up to follow-up (Day 952)
Psychiatric disorders Suicidal ideation	0.92% 1/109 • Number of events 1 • From start of the study up to follow-up (Day 952)	0.00% 0/103 • From start of the study up to follow-up (Day 952)
Reproductive system and breast disorders Ovarian cyst	0.92% 1/109 • Number of events 1 • From start of the study up to follow-up (Day 952)	0.00% 0/103 • From start of the study up to follow-up (Day 952)

Measure	Rollover n=109 participants at risk Participants who rolled from the DX-2930-03 (NCT02586805) study received 300 milligrams (mg) of DX-2930 subcutaneous (SC) injection on Day 0 followed by a second dose after participants reported their first HAE attack and continued to receive repeated SC administrations of 300 mg DX-2930 every 2 weeks (q2wks) throughout the treatment period (up to 924 days). A wash-out period of a minimum of 10 days and a maximum of 18 days were required between subsequent administrations.	Non-Rollover n=103 participants at risk Participants who directly entered in to this DX-2930-04 study received 300 mg of DX-2930 SC injection on Day 0 and continued to receive SC administrations of 300 mg DX-2930 every 2 weeks throughout the treatment period (up to 924 days).
Musculoskeletal and connective tissue disorders Arthralgia	10.1% 11/109 • Number of events 20 • From start of the study up to follow-up (Day 952)	15.5% 16/103 • Number of events 17 • From start of the study up to follow-up (Day 952)
Musculoskeletal and connective tissue disorders Back pain	14.7% 16/109 • Number of events 29 • From start of the study up to follow-up (Day 952)	9.7% 10/103 • Number of events 12 • From start of the study up to follow-up (Day 952)
Musculoskeletal and connective tissue disorders Musculoskeletal pain	7.3% 8/109 • Number of events 8 • From start of the study up to follow-up (Day 952)	8.7% 9/103 • Number of events 10 • From start of the study up to follow-up (Day 952)
Musculoskeletal and connective tissue disorders Myalgia	6.4% 7/109 • Number of events 10 • From start of the study up to follow-up (Day 952)	2.9% 3/103 • Number of events 5 • From start of the study up to follow-up (Day 952)
Musculoskeletal and connective tissue disorders Pain in extremity	11.0% 12/109 • Number of events 13 • From start of the study up to follow-up (Day 952)	8.7% 9/103 • Number of events 12 • From start of the study up to follow-up (Day 952)
Gastrointestinal disorders Abdominal discomfort	1.8% 2/109 • Number of events 2 • From start of the study up to follow-up (Day 952)	5.8% 6/103 • Number of events 6 • From start of the study up to follow-up (Day 952)
Gastrointestinal disorders Abdominal pain	10.1% 11/109 • Number of events 13 • From start of the study up to follow-up (Day 952)	10.7% 11/103 • Number of events 12 • From start of the study up to follow-up (Day 952)
Gastrointestinal disorders Abdominal pain upper	3.7% 4/109 • Number of events 4 • From start of the study up to follow-up (Day 952)	6.8% 7/103 • Number of events 7 • From start of the study up to follow-up (Day 952)
Gastrointestinal disorders Constipation	5.5% 6/109 • Number of events 6 • From start of the study up to follow-up (Day 952)	3.9% 4/103 • Number of events 4 • From start of the study up to follow-up (Day 952)
Gastrointestinal disorders Diarrhoea	11.9% 13/109 • Number of events 16 • From start of the study up to follow-up (Day 952)	9.7% 10/103 • Number of events 11 • From start of the study up to follow-up (Day 952)
Gastrointestinal disorders Dyspepsia	7.3% 8/109 • Number of events 8 • From start of the study up to follow-up (Day 952)	2.9% 3/103 • Number of events 3 • From start of the study up to follow-up (Day 952)
Gastrointestinal disorders Nausea	11.9% 13/109 • Number of events 16 • From start of the study up to follow-up (Day 952)	8.7% 9/103 • Number of events 14 • From start of the study up to follow-up (Day 952)
Gastrointestinal disorders Toothache	5.5% 6/109 • Number of events 9 • From start of the study up to follow-up (Day 952)	4.9% 5/103 • Number of events 6 • From start of the study up to follow-up (Day 952)
Gastrointestinal disorders Vomiting	6.4% 7/109 • Number of events 8 • From start of the study up to follow-up (Day 952)	3.9% 4/103 • Number of events 4 • From start of the study up to follow-up (Day 952)
General disorders Fatigue	9.2% 10/109 • Number of events 15 • From start of the study up to follow-up (Day 952)	9.7% 10/103 • Number of events 12 • From start of the study up to follow-up (Day 952)
General disorders Injection site bruising	11.9% 13/109 • Number of events 21 • From start of the study up to follow-up (Day 952)	12.6% 13/103 • Number of events 72 • From start of the study up to follow-up (Day 952)
General disorders Injection site erythema	14.7% 16/109 • Number of events 40 • From start of the study up to follow-up (Day 952)	19.4% 20/103 • Number of events 103 • From start of the study up to follow-up (Day 952)
General disorders Injection site pain	41.3% 45/109 • Number of events 736 • From start of the study up to follow-up (Day 952)	53.4% 55/103 • Number of events 992 • From start of the study up to follow-up (Day 952)
General disorders Injection site pruritus	3.7% 4/109 • Number of events 5 • From start of the study up to follow-up (Day 952)	5.8% 6/103 • Number of events 14 • From start of the study up to follow-up (Day 952)
General disorders Injection site swelling	5.5% 6/109 • Number of events 49 • From start of the study up to follow-up (Day 952)	10.7% 11/103 • Number of events 26 • From start of the study up to follow-up (Day 952)
General disorders Peripheral swelling	6.4% 7/109 • Number of events 11 • From start of the study up to follow-up (Day 952)	0.97% 1/103 • Number of events 1 • From start of the study up to follow-up (Day 952)
General disorders Pyrexia	2.8% 3/109 • Number of events 4 • From start of the study up to follow-up (Day 952)	7.8% 8/103 • Number of events 8 • From start of the study up to follow-up (Day 952)
Infections and infestations Acute sinusitis	6.4% 7/109 • Number of events 10 • From start of the study up to follow-up (Day 952)	6.8% 7/103 • Number of events 11 • From start of the study up to follow-up (Day 952)
Infections and infestations Bronchitis	4.6% 5/109 • Number of events 7 • From start of the study up to follow-up (Day 952)	7.8% 8/103 • Number of events 10 • From start of the study up to follow-up (Day 952)
Infections and infestations Gastroenteritis	3.7% 4/109 • Number of events 5 • From start of the study up to follow-up (Day 952)	10.7% 11/103 • Number of events 14 • From start of the study up to follow-up (Day 952)
Infections and infestations Gastroenteritis viral	4.6% 5/109 • Number of events 5 • From start of the study up to follow-up (Day 952)	9.7% 10/103 • Number of events 11 • From start of the study up to follow-up (Day 952)
Infections and infestations Gastrointestinal infection	5.5% 6/109 • Number of events 7 • From start of the study up to follow-up (Day 952)	3.9% 4/103 • Number of events 4 • From start of the study up to follow-up (Day 952)
Infections and infestations Influenza	11.9% 13/109 • Number of events 17 • From start of the study up to follow-up (Day 952)	8.7% 9/103 • Number of events 10 • From start of the study up to follow-up (Day 952)
Infections and infestations Otitis media	5.5% 6/109 • Number of events 7 • From start of the study up to follow-up (Day 952)	3.9% 4/103 • Number of events 4 • From start of the study up to follow-up (Day 952)
Infections and infestations Pharyngitis streptococcal	2.8% 3/109 • Number of events 3 • From start of the study up to follow-up (Day 952)	5.8% 6/103 • Number of events 8 • From start of the study up to follow-up (Day 952)
Infections and infestations Sinusitis	11.9% 13/109 • Number of events 13 • From start of the study up to follow-up (Day 952)	9.7% 10/103 • Number of events 11 • From start of the study up to follow-up (Day 952)
Infections and infestations Upper respiratory tract infection	27.5% 30/109 • Number of events 51 • From start of the study up to follow-up (Day 952)	24.3% 25/103 • Number of events 54 • From start of the study up to follow-up (Day 952)
Infections and infestations Urinary tract infection	9.2% 10/109 • Number of events 12 • From start of the study up to follow-up (Day 952)	12.6% 13/103 • Number of events 21 • From start of the study up to follow-up (Day 952)
Infections and infestations Viral upper respiratory tract infection	46.8% 51/109 • Number of events 119 • From start of the study up to follow-up (Day 952)	36.9% 38/103 • Number of events 87 • From start of the study up to follow-up (Day 952)
Injury, poisoning and procedural complications Contusion	7.3% 8/109 • Number of events 9 • From start of the study up to follow-up (Day 952)	3.9% 4/103 • Number of events 4 • From start of the study up to follow-up (Day 952)
Injury, poisoning and procedural complications Fall	5.5% 6/109 • Number of events 6 • From start of the study up to follow-up (Day 952)	2.9% 3/103 • Number of events 3 • From start of the study up to follow-up (Day 952)
Injury, poisoning and procedural complications Ligament sprain	5.5% 6/109 • Number of events 7 • From start of the study up to follow-up (Day 952)	11.7% 12/103 • Number of events 14 • From start of the study up to follow-up (Day 952)
Injury, poisoning and procedural complications Procedural pain	6.4% 7/109 • Number of events 9 • From start of the study up to follow-up (Day 952)	3.9% 4/103 • Number of events 5 • From start of the study up to follow-up (Day 952)
Investigations Alanine aminotransferase increased	3.7% 4/109 • Number of events 9 • From start of the study up to follow-up (Day 952)	5.8% 6/103 • Number of events 7 • From start of the study up to follow-up (Day 952)
Investigations Aspartate aminotransferase increased	0.92% 1/109 • Number of events 3 • From start of the study up to follow-up (Day 952)	5.8% 6/103 • Number of events 8 • From start of the study up to follow-up (Day 952)
Investigations Blood creatine phosphokinase increased	6.4% 7/109 • Number of events 8 • From start of the study up to follow-up (Day 952)	4.9% 5/103 • Number of events 8 • From start of the study up to follow-up (Day 952)
Nervous system disorders Headache	26.6% 29/109 • Number of events 70 • From start of the study up to follow-up (Day 952)	22.3% 23/103 • Number of events 37 • From start of the study up to follow-up (Day 952)
Psychiatric disorders Anxiety	7.3% 8/109 • Number of events 9 • From start of the study up to follow-up (Day 952)	4.9% 5/103 • Number of events 5 • From start of the study up to follow-up (Day 952)
Respiratory, thoracic and mediastinal disorders Asthma	5.5% 6/109 • Number of events 6 • From start of the study up to follow-up (Day 952)	1.9% 2/103 • Number of events 2 • From start of the study up to follow-up (Day 952)
Respiratory, thoracic and mediastinal disorders Cough	6.4% 7/109 • Number of events 7 • From start of the study up to follow-up (Day 952)	6.8% 7/103 • Number of events 8 • From start of the study up to follow-up (Day 952)
Respiratory, thoracic and mediastinal disorders Nasal congestion	6.4% 7/109 • Number of events 7 • From start of the study up to follow-up (Day 952)	1.9% 2/103 • Number of events 2 • From start of the study up to follow-up (Day 952)
Respiratory, thoracic and mediastinal disorders Oropharyngeal pain	7.3% 8/109 • Number of events 9 • From start of the study up to follow-up (Day 952)	7.8% 8/103 • Number of events 9 • From start of the study up to follow-up (Day 952)
Skin and subcutaneous tissue disorders Dermatitis contact	6.4% 7/109 • Number of events 7 • From start of the study up to follow-up (Day 952)	2.9% 3/103 • Number of events 3 • From start of the study up to follow-up (Day 952)
Skin and subcutaneous tissue disorders Pruritus	5.5% 6/109 • Number of events 7 • From start of the study up to follow-up (Day 952)	0.97% 1/103 • Number of events 1 • From start of the study up to follow-up (Day 952)
Skin and subcutaneous tissue disorders Rash	7.3% 8/109 • Number of events 8 • From start of the study up to follow-up (Day 952)	4.9% 5/103 • Number of events 5 • From start of the study up to follow-up (Day 952)
Skin and subcutaneous tissue disorders Urticaria	6.4% 7/109 • Number of events 8 • From start of the study up to follow-up (Day 952)	2.9% 3/103 • Number of events 3 • From start of the study up to follow-up (Day 952)