Adverse events

Solicited Adverse Events Study VAC31518COV3001

In study VAC31518COV3001 solicited adverse events were collected in the safety subset group During the 7-day post-vaccination period, the frequency of solicited AEs was higher in participants in the Ad26.COV2.S group (66%), compared to participants in the placebo group (41.9%) (mainly grade 1 and 2) in the safety subset group.

Table 26: Overall Summary of Solicited Adverse Events; Safety Subset (Study VAC31518COV3001)

Ad26 5e10 Placebo

Analysis set: Safety Subset 3356 3380

Post-dose 3356 3380

Subjects with 1 or more:

Solicited AE 2216 (66.0%) 1417 (41.9%)

Solicited AE of worst grade 3 75 (2.2%) 25 (0.7%)

Solicited AE of worst grade 4 0 0

Solicited local AE 1687 (50.3%) 658 (19.5%)

Solicited local AE of worst grade 3 23 (0.7%) 6 (0.2%)

Solicited local AE of worst grade 4 0 0

Solicited systemic AE 1853 (55.2%) 1188 (35.1%)

Solicited systemic AE of worst

grade 3 61 (1.8%) 21 (0.6%)

Solicited systemic AE of worst

grade 4 0 0

Solicited systemic AEs considered

to be related to study vaccine 1819 (54.2%) 1131 (33.5%) Solicited systemic AEs of grade 3 or

higher considered to be related to

study vaccine 60 (1.8%) 20 (0.6%)

Key: AE = adverse event

Note: Subjects are counted only once within a period for any given event, regardless of the number of times they actually experienced the event in that period. Relationship to vaccine is assessed by the investigator.

Solicited local reactions

During the 7-day post-vaccination period, the frequency of solicited local AEs was higher in participants in the Ad26.COV2.S group (50.3%), compared to participants in the placebo group (19.5%) (table below). The most frequently reported solicited local AE was vaccination site pain with a frequency that was higher in participants in the Ad26.COV2.S group (48.7%), compared to participants in the placebo group (16.7%). Vaccination site erythema (7.3% vs. 3.9%, respectively) and vaccination site swelling (5.3% vs. 1.6%) were also more frequent in participants in the Ad26.COV2.S group.

Local solicited adverse events were mainly grade 1 or 2. The frequency of Grade 3 solicited local AEs was low overall, but higher in participants in the Ad26.COV2.S group compared to participants in the placebo group: vaccination site pain (0.3% vs. 0.1%, respectively), vaccination site erythema (0.2%

vs. 0.1%), and vaccination site swelling (0.2% vs. 0.1%) (no grade 4). All solicited local AEs are considered related to study vaccination by definition. These local solicited AEs are adequately specified, with the appropriate frequencies, in the ADR table in the SmPC.

Table 27: Number of Subjects with Local Solicited Adverse Events by Derived Term and Worst Severity Grade; Safety Subset (Study VAC31518COV3001)

Ad26 5e10 Placebo

Analysis set: Safety Subset 3356 3380

Post-dose 3356 3380

Subjects with 1 or more Local

AEs Any 1687 (50.3%) 658 (19.5%)

Grade 1 1441 (42.9%) 609 (18.0%)

Grade 2 223 (6.6%) 43 (1.3%)

Grade 3 23 (0.7%) 6 (0.2%)

Vaccination Site Erythema

Any 245 (7.3%) 131 (3.9%)

Grade 1 207 (6.2%) 108 (3.2%)

Grade 2 31 (0.9%) 21 (0.6%)

Grade 3 7 (0.2%) 2 (0.1%)

Vaccination Site Pain

Any 1634 (48.7%) 565 (16.7%)

Grade 1 1425 (42.5%) 542 (16.0%)

Grade 2 198 (5.9%) 21 (0.6%)

Grade 3 11 (0.3%) 2 (0.1%)

Vaccination Site Swelling

Any 178 (5.3%) 53 (1.6%)

Grade 1 150 (4.5%) 45 (1.3%)

Grade 2 21 (0.6%) 6 (0.2%)

Grade 3 7 (0.2%) 2 (0.1%)

Key: AE = adverse event

Note: Subjects are counted only once within a period for any given event, regardless of the number of times they actually experienced the event in that period. The event experienced by the subject with the worst severity grade is used. If a subject has missing severity grade for a specific adverse event, the subject is counted in the ‘Any’ row for that adverse event.

The frequencies of solicited local AEs are graphically presented in Figure 22 below.

Figure 21: Presentation of Local Solicited Adverse Events by Worst Severity Grade After any Vaccination; Safety Subset (Study VAC31518COV3001)

All solicited local AEs were transient in nature and reported as resolved. The median time to onset of the selected solicited local AEs was within 2 days after vaccination with Ad26.COV2.S (including day of vaccination), and within 1 to 2 days with placebo.

The median duration for the most frequent solicited local AEs (vaccination site pain, vaccination site erythema) was 2 days after vaccination with Ad26.COV2.S or placebo. The median duration for vaccination site swelling was 3 days after vaccination with Ad26.COV2.S and 1 days after placebo.

Solicited systemic reactions

During the 7-day post-vaccination period, the frequency of solicited systemic AEs was higher in participants in the Ad26.COV2.S group (55.2%), compared to participants in the placebo group (35.1%) (table below). The most frequently solicited systemic AEs were headache (39% in

Ad26.COV2.S group vs. 23.8% in the placebo group), fatigue (38.3% vs. 21.6%, respectively), and myalgia (33.2% vs. 12.8%). Nausea were reported at 14.2% in Ad26.COV2.S group vs. 9.7% in the placebo group. Pyrexia (defined as body temperature ≥38.0°C, as recorded by the participants) was reported in 302 (9.0%) participants in the Ad26.COV2.S group, compared to 20 (0.6%) of participants in the placebo group. These systemic solicited AEs are adequately specified, with the appropriate frequencies, in the ADR table in the SmPC.

Most solicited systemic AEs were Grade 1 or Grade 2 in severity (no grade 4). The frequency of Grade 3 solicited systemic AEs was low overall, but higher in participants in the Ad26.COV2.S group

compared to participants in the placebo group. The most frequently reported Grade 3 solicited systemic AEs reported for fatigue (35 participants – 1%) and myalgia (32 participants – 1%) during the 7-day postvaccination period. Grade 3 headache were reported by 23 subjects (0.7%), and grade 3 nausea by 6 subjects (0.2%). Grade 3 pyrexia was reported in 8 (0.2%) participants in the

Ad26.COV2.S group. Among these 8 participants, 7 participants were in the ≥18 to <60 years age

group and these 7 participants were all <35 years of age. In the ≥60 years age group, 1 participant reported Grade 3 pyrexia. No Grade 3 pyrexia was reported in the placebo group.

Table 28. Number of Subjects With Systemic Solicited Adverse Events by Derived Term and Worst Severity Grade; Safety Subset (Study VAC31518COV3001)

Ad26 5e10 Placebo

Analysis set: Safety Subset 3356 3380

Post-dose 3356 3380

Subjects with 1 or more Systemic

AEs Any 1853 (55.2%) 1188 (35.1%)

Grade 1 1217 (36.3%) 938 (27.8%)

Grade 2 575 (17.1%) 229 (6.8%)

Grade 3 61 (1.8%) 21 (0.6%)

Fatigue

Any 1286 (38.3%) 729 (21.6%)

Grade 1 929 (27.7%) 601 (17.8%)

Grade 2 322 (9.6%) 119 (3.5%)

Grade 3 35 (1.0%) 9 (0.3%)

Headache

Any 1308 (39.0%) 805 (23.8%)

Grade 1 935 (27.9%) 658 (19.5%)

Grade 2 350 (10.4%) 138 (4.1%)

Grade 3 23 (0.7%) 9 (0.3%)

Myalgia

Any 1115 (33.2%) 432 (12.8%)

Grade 1 848 (25.3%) 375 (11.1%)

Grade 2 235 (7.0%) 51 (1.5%)

Grade 3 32 (1.0%) 6 (0.2%)

Nausea

Any 478 (14.2%) 329 (9.7%)

Grade 1 402 (12.0%) 284 (8.4%)

Grade 2 70 (2.1%) 39 (1.2%)

Grade 3 6 (0.2%) 6 (0.2%)

Pyrexia

Any 302 (9.0%) 20 (0.6%)

Grade 1 214 (6.4%) 16 (0.5%)

Grade 2 80 (2.4%) 4 (0.1%)

Grade 3 8 (0.2%) 0

Key: AE = adverse event

Note: Subjects are counted only once within a period for any given event, regardless of the number of times they actually experienced the event in that period. The event experienced by the subject with the worst severity grade is used. If a subject has missing severity grade for a specific adverse event, the subject is counted in the ‘Any’

row for that adverse event.

Figure 22: Graphical Presentation of Systemic Solicited Adverse Events by Worst Severity Grade After any Vaccination; Safety Subset (Study VAC31518COV3001)

Most solicited systemic AEs after vaccination were considered to be related to study vaccine (98.16%

(1819/1853) of the solicited systemic AEs were considered related to the study vaccine, and 95.2%

(1131/1188) to the placebo). In the Ad26.COV2.S group, the most frequently reported solicited systemic AEs related to vaccination were headache (38.2%), fatigue (37.4%), and myalgia (32.6%).

Related nausea was reported by 13.9%, and related pyrexia by 8.9%.

Table 29: Number of Subjects With Systemic Solicited Adverse Events Related to Vaccination by Derived Term; Safety Subset (Study VAC31518COV3001)

Ad26 5e10 Placebo

Analysis set: Safety Subset 3356 3380

Post-dose 3356 3380

Subjects with 1 or more Systemic AEs related to

vaccination 1819 (54.2%) 1131 (33.5%)

Fatigue 1254 (37.4%) 705 (20.9%)

Headache 1282 (38.2%) 750 (22.2%)

Myalgia 1093 (32.6%) 417 (12.3%)

Nausea 465 (13.9%) 310 (9.2%)

Pyrexia 298 (8.9%) 16 (0.5%)

Key: AE = adverse event

Note: Subjects are counted only once within a period for any given event, regardless of the number of times they actually experienced the event in that period. Relationship to vaccine is assessed by the investigator.

Regarding the severity, most Grade 3 solicited systemic AEs were considered as related to

Ade26.COV2.s, there was only one report of grade 3 headache that was not considered related to the study vaccine. In the Ad26.COV2.S group, the most frequently reported grade 3 solicited systemic AEs related to vaccination were fatigue (1%), myalgia (1%) and headache (0.7%). Grade 3 related nausea and pyrexia were reported by 0.2% each.

Table 30: Number of Subjects With Systemic Solicited Adverse Events related to vaccination by Derived Term and Worst Severity Grade of at Least Grade 3; Safety Subset (Study

VAC31518COV3001)

Ad26 5e10 Placebo

Analysis set: Safety Subset 3356 3380

Post-dose 3356 3380

Subjects with 1 or more Systemic AE grade 3 or higher

Any 60 (1.8%) 20 (0.6%)

Grade 3 60 (1.8%) 20 (0.6%)

Fatigue

Any 35 (1.0%) 9 (0.3%)

Grade 3 35 (1.0%) 9 (0.3%)

Headache

Any 22 (0.7%) 9 (0.3%)

Grade 3 22 (0.7%) 9 (0.3%)

Myalgia

Any 32 (1.0%) 5 (0.1%)

Grade 3 32 (1.0%) 5 (0.1%)

Nausea

Any 6 (0.2%) 6 (0.2%)

Grade 3 6 (0.2%) 6 (0.2%)

Pyrexia

Any 8 (0.2%) 0

Grade 3 8 (0.2%) 0

Key: AE = adverse event

Note: Subjects are counted only once within a period for any given event, regardless of the number of times they actually experienced the event in that period. The event experienced by the subject with the worst severity grade is used. If a subject has missing severity grade for a specific adverse event, the subject is counted in the ‘Any’ row for that adverse event.

Most solicited systemic AEs were transient in nature and reported as resolved. Overall, the median duration of the selected solicited systemic AEs was similar in both groups (1 to 2 days after vaccination with Ad26.COV2.S or with placebo), and also the median time to onset (within 2 days after vaccination with Ad26.COV2.S and within 2 to 3 days after vaccination with placebo)

Supportive studies (COV1001, COV1002 and COV2001)

Overall, the solicited and unsolicited AEs in supportive studies were consistent with the pivotal phase 3 COV3001 study.

Solicited AEs after dose 1

In all supportive studies, most solicited local and systemic AEs were Grade 1 or 2. No grade 3 solicited local AEs were reported in COV1001 and COV2001, although, a 2% of the participants reported a Grade 3 vaccination site pain in COV1002. The frequency of subjects with any Grade 3 solicited systemic AE in COV1001 was 9.9% in cohort 1a and 0.6% in cohort 3; it was a 7.8% in COV1002 and a 2.9% in COV2001.

Solicited AEs administered as 2-dose regimen

Safety data of a 2-dose regimen of Ad26.COV2.S (5x10¹⁰ vp) administered at a 56-day interval was available from COV1001 in 77 adults ≥18 to ≤55 years (Cohort 1a) and 81 adults ≥65 years (Cohort 3) of age. In general, no safety concerns were identified after vaccination with two doses of

Ad26.COV2.S (5x10¹⁰ vp) at a 56-day interval, as no apparent difference was observed regarding the frequencies of solicited local and systemic AEs, and unsolicited AEs, when comparing a one dose and

two dose regimens, in adults aged ≥18 to ≤55 and aged ≥65. There were slightly higher frequencies of solicited systemic AEs after post-dose 1 than after post-dose 2. The main difference was regarding pyrexia. All solicited local AEs and the majority of solicited systemic AEs were Grade 1 or 2 in severity.

Lower frequencies of Grade 3 solicited systemic AEs were observed after a second vaccination with Ad26.COV2.S in both age groups.

Unsolicited AEs

Study VAC31518COV3001

As defined in the protocol, for the participants in the safety subset, the investigator was to record systematically all unsolicited AEs, whether serious or non-serious from the time of vaccination until 28 days post-vaccination. Without such a requirement for a systematic collection of all unsolicited events for those participants in the FAS who were not in the safety subset (although spontaneous unsolicited reports were captured in the eCRF), and although a much larger number of subjects have been vaccinated with Ad26.COV2.S in FAS (21,895), the frequencies calculated in the safety subset (3,356 subjects vaccinated with Ad26.COV2.S) is preferred (higher than in the FAS). The selection of

unsolicited AEs to be presented in the ADR table in the SmPC was made applying the following criteria (all criteria had to be met): Event occurred with a frequency of at least 0.1% in the safety subset; The AE was not collected as a solicited AE (to avoid duplication of the event in both solicited and unsolicited sections); The unsolicited AE occurred at a higher frequency (of >0.1%) in the Ad26.COV2.S group compared to the placebo group; A medical review was done to establish plausible connection to the vaccine and to assess confounding factors. Moreover, it has been checked that the unsolicited AEs reported in Ad26.COV2.S FAS (applying the same criteria as for the safety subset) are also present in the ADR table.

In the safety subset, the frequency of unsolicited AEs reported during the 28-days post-vaccination period was similar for participants in the Ad26.COV2.S group (13.1%) compared to participants in the placebo group (12%). In the Ad26.COV2.S group, the most frequently reported unsolicited AEs by PT (≥1.0% of participants) were headache, fatigue, myalgia, and vaccination site pain, which were also recorded as solicited AEs. In the Ad26.COV2.S group, the unsolicited ADRs (not recorded as solicited AEs) selected for the ADR table in the SmPC are chills, arthralgia, malaise, asthenia, muscular weakness and pain in extremity (table below).

Table 31: Unsolicited Adverse Reactions Reported in the 28 Days Following Vaccination - Individuals 18 Years of Age and Older (Safety Subset COV3001)

ADVERSE REACTIONS AD26.COV2.S

N=3,356 N (%)

PLACEBO N=3,380 N (%)

CHILLS 67 (2.0%) 19 (0.6%)

ARTHRALGIA 35 (1.0%) 24 (0.7%)

MALAISE 26 (0.8%) 18 (0.5%)

ASTHENIA 18 (0.5%) 7 (0.2%)

MUSCULAR WEAKNESS 10 (0.3%) 5 (0.1%)

PAIN IN EXTREMITY 9 (0.3%) 3 (0.1%)

NOTE: SUBJECTS ARE COUNTED ONLY ONCE WITHIN A PERIOD FOR ANY GIVEN EVENT, REGARDLESS OF THE NUMBER OF TIMES THEY ACTUALLY EXPERIENCED THE EVENT IN THAT PERIOD. THE EVENT EXPERIENCED BY THE SUBJECT WITH THE WORST SEVERITY GRADE IS USED. IF A SUBJECT HAS MISSING SEVERITY GRADE FOR A SPECIFIC ADVERSE EVENT, THE SUBJECT IS COUNTED IN THE ‘ANY’ ROW FOR THAT ADVERSE EVENT.

Most reported unsolicited AEs were Grade 1 or Grade 2 in severity. There was as similar frequency of participants with unsolicited AEs of at least Grade 3 in both group (0.6% in the Ad26.COV2.S group vs.

0.5% in the placebo group).

The frequency of unsolicited AEs that were considered related to vaccination was higher in participants in the Ad26.COV2.S group (7.2%) compared to participants in the placebo group (4.6%) (table below).

There was an imbalance between vaccine and placebo in related unsolicited AEs (difference ≥ 2 related events in favour of vaccine group) observed for cough (12 related with vaccine vs. 4 in placebo), sneezing (10 vs. 8), oropharyngeal pain (5 vs. 1), tremor (3 vs. 1), back pain (3 vs. 1) and hyperhidrosis (2 vs. 0). These related events have been appropriately added in the ADR table in section 4.8 of the SmPC.

Table 32: Number of Subjects with Unsolicited Adverse Events Related to Vaccination (≥

0.1% in Ad26 5e10 Group) by System Organ Class and Preferred Term; Safety Subset (Study VAC31518COV3001 – post-dose period)

Ad26 5e10 Placebo (N = 3356) (N = 3380) Number (%) of

Participants Number (%) of Participants

Participants with 1 or more AEs 242 (7.2%) 154 (4.6%)

General disorders and administration site conditions 173 (5.2%) 88 (2.6%)

Chills 56 (1.7%) 8 (0.2%)

Fatigue 48 (1.4%) 48 (1.4%)

Vaccination site pain 41 (1.2%) 22 (0.7%)

Malaise 21 (0.6%) 6 (0.2%)

Asthenia 11 (0.3%) 5 (0.1%)

Vaccination site erythema 11 (0.3%) 7 (0.2%)

Vaccination site swelling 11 (0.3%) 2 (0.1%)

Pyrexia 8 (0.2%) 0

Injection site pain 7 (0.2%) 4 (0.1%)

Pain 3 (0.1%) 1 (<0.1%)

Musculoskeletal and connective tissue disorders 52 (1.5%) 40 (1.2%)

Myalgia 28 (0.8%) 31 (0.9%)

Arthralgia 16 (0.5%) 10 (0.3%)

Muscular weakness 5 (0.1%) 2 (0.1%)

Pain in extremity 4 (0.1%) 0

Back pain 3 (0.1%) 1 (<0.1%)

Nervous system disorders 47 (1.4%) 44 (1.3%)

Headache 38 (1.1%) 33 (1.0%)

Dizziness 3 (0.1%) 5 (0.1%)

Tremor 3 (0.1%) 1 (<0.1%)

Gastrointestinal disorders 32 (1.0%) 34 (1.0%)

Nausea 14 (0.4%) 20 (0.6%)

Diarrhoea 9 (0.3%) 8 (0.2%)

Odynophagia 5 (0.1%) 4 (0.1%)

Abdominal pain 4 (0.1%) 5 (0.1%)

Cough 12 (0.4%) 4 (0.1%)

Nasal congestion 10 (0.3%) 9 (0.3%)

Sneezing 10 (0.3%) 8 (0.2%)

Oropharyngeal pain 5 (0.1%) 1 (<0.1%)

Dyspnoea 3 (0.1%) 2 (0.1%)

Lower respiratory tract congestion 2 (0.1%) 0

Rhinorrhoea 2 (0.1%) 4 (0.1%)

Wheezing 2 (0.1%) 2 (0.1%)

Infections and infestations 8 (0.2%) 11 (0.3%)

Rhinitis 7 (0.2%) 7 (0.2%)

Skin and subcutaneous tissue disorder 7 (0.2%) 4 (0.1%)

Hyperhidrosis 2 (0.1%) 0

Metabolism and nutrition disorders 5 (0.1%) 6 (0.2%)

Decreased appetite 5 (0.1%) 6 (0.2%)

Eye disorders 4 (0.1%) 1 (<0.1%)

Eye irritation 2 (0.1%) 1 (<0.1%)

Eye pain 2 (0.1%) 0

Blood and lymphatic system disorders 2 (0.1%) 2 (0.1%)

Lymphadenopathy 2 (0.1%) 1 (<0.1%)

Investigations 2 (0.1%) 1 (<0.1%)

Body temperature increased 2 (0.1%) 0

Five subjects (0.1%) reported 6 unsolicited AEs of at least Grade 3 considered to be related to the study vaccine in the Ad26.COV2.S group (compared to 1 in placebo group): 1 chill, 1 fatigue, 1 malaise, 1 diarrhoea, 1 pain in extremity and 1 headache (none of grade 4) (table below).

Table 33: Number of Subjects With Unsolicited Adverse Events of at Least Grade 3 and Related to Vaccination by System Organ Class and Preferred Term; Safety Subset (Study VAC31518COV3001)

Supportive studies (COV1001, COV1002 and COV2001) Unsolicited AEs after dose 1

In all studies, most solicited local AEs were Grade 1 or 2. No grade 3 unsolicited AEs (related or not) were reported with dose level 5x10¹⁰ vp of Ade26.COV2.S in COV1002 and COV2001. However, in COV1001, only 2 participants in each age group reported severe related unsolicited AEs.

Unsolicited AEs administered as 2-dose regimen

Safety data of a 2-dose regimen of Ad26.COV2.S (5x10¹⁰ vp) administered at a 56-day interval was available from COV1001 in adults ≥18 to ≤55 years (Cohort 1a) and ≥65 years (Cohort 3) of age.

There was no apparent difference in the frequencies of unsolicited AEs after vaccination with 5x10¹⁰ vp Ad26.COV2.S post-dose 1 compared to post-dose 2 in adults ≥18 to ≤55 years of age. There was slightly higher frequency of unsolicited AEs in participants who received 5x10¹⁰ vp Ad26.COV2.S. after dose 1 than after dose 2 in adults ≥65 years of age. Most unsolicited AEs were Grade 1 or 2 in

severity. Lower frequencies of Grade 3 unsolicited AEs were observed after a second vaccination with Ad26.COV2.S in both age groups.

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