Vaccine Information: PREVNAR 13 (Page 2 of 8)

6.2 Clinical Trials Experience With Prevnar 13 in Adults ≥18 Years of Age

The safety of Prevnar 13 was assessed in 7 clinical studies (Studies 6–12) 6–12 conducted in the US and Europe which included 91,593 adults (48,806 received Prevnar 13) ranging in age from 18 through 101 years.

The 48,806 Prevnar 13 recipients included 899 adults who were aged 18 through 49 years, 2,616 adults who were aged 50 through 64 years, 45,291 adults aged 65 years and older. Of the 48,806 Prevnar 13 recipients, 46,890 adults had not previously received Pneumovax® 23 (pneumococcal polysaccharide vaccine [23-valent], PPSV23) (“PPSV23 unvaccinated”) and 1,916 adults were previously vaccinated (“PPSV23 previously vaccinated”) with PPSV23 at least 3 years prior to enrollment.

Safety and Immunogenicity Studies

Safety and immunogenicity of Prevnar 13 is supported by 6 clinical studies. Study 66 evaluated the safety and immunogenicity of Prevnar 13 in adults 18 through 64 years of age who had not received a previous dose of pneumococcal vaccine. Adults 18 through 59 years of age received a single dose of Prevnar 13, and adults 60 through 64 years of age received a single dose of Prevnar 13 or PPSV23.

Study 7 was randomized and compared the safety and immunogenicity of Prevnar 13 with PPSV23 as a single dose in adults ≥70 years vaccinated with PPSV23 (≥5 years prior to enrollment).7 Study 8 was randomized and evaluated the safety and immunogenicity of Prevnar 13 and PPSV23 in different sequential order in PPSV23 naive adults aged 60 through 64 years8.

One clinical safety study9 (Study 9) of Prevnar 13, conducted in PPSV23 previously vaccinated (≥3 years prior to enrollment) adults aged ≥68 years was a single arm study. Two studies, one in the US10 (Study 10) in adults aged 50 through 59 years and the other in Europe11 (Study 11) in adults aged ≥65 years, evaluated the concomitant administration of Prevnar 13 with inactivated influenza vaccine, trivalent (Fluarix ® , A/H1N1, A/H3N2, and B, Fall 2007/Spring 2008: IIV3) in these two age groups in PPSV23 unvaccinated adults.

The total safety population in the 6 safety and immunogenicity studies was 7,097. In 5 of the 6 safety and immunogenicity studies, more females than males were enrolled (50.2% – 61.8%). Across the 6 studies the racial distribution included: >85% White; 0.2%–10.7% Black or African American; 0%–1.7% Asian; <1% Native Hawaiian or other Pacific Islander; ≤1%, American Indian or Alaskan Native. Ethnicity data were not collected in Study 11; in the 5 other studies 0.6%–4.8% were Hispanic or Latino.

In five studies,6–8,10,11 subjects with pre-existing underlying diseases were enrolled if the medical condition was stable (did not require a change in therapy or hospitalization for worsening disease for 12 weeks before receipt of study vaccine) except in Study 9 where subjects were enrolled if the medical condition was stable for 6 or more weeks before receipt of study vaccine.

In the 6 safety and immunogenicity studies,6–11 subjects were excluded from study participation due to prior receipt of diphtheria toxoid-containing vaccines within 6 months of study vaccine. However, the time of prior receipt of a diphtheria toxoid-containing vaccine was not recorded.

Solicited adverse reactions for Prevnar 13 in the safety and immunogenicity studies were monitored by subjects recording local adverse reactions and systemic reactions daily using an electronic diary for 14 consecutive days following vaccination. Unsolicited serious and non-serious adverse events were collected for one month after each vaccination. In addition, serious adverse events were collected for an additional 5 months after each vaccination (at the 6-month follow-up phone contact) in all studies except Study 11.

Following licensure of Prevnar 13 in adults ≥50 years of age, a randomized, double-blind, placebo-controlled US study (Study 13) was conducted to evaluate concomitant administration of Prevnar 13 with inactivated influenza vaccine, quadrivalent (Fluzone ® Quadrivalent, A/H1N1, A/H3N2, B/Brisbane, and B/Massachusetts, Fall 2014/Spring 2015: IIV4) in PPSV23 previously vaccinated adults ≥50 years of age. Unsolicited serious and non-serious adverse events were collected as described above for Studies 6–10.

Efficacy Study

Study 1212 was a randomized double-blind placebo-controlled study conducted in the Netherlands in community-dwelling adults aged 65 years and older with no prior pneumococcal vaccination history. A total of 84,496 subjects received either a single dose of Prevnar 13 (42,240) or placebo (42,256) in a 1:1 randomization. Among the 84,496 subjects, 58,072 (68.7%) were ≥65 to <75 years of age, 23,481 (27.8%) were ≥75 and <85 years of age, and 2,943 (3.5%) were ≥85 years of age. In the total safety population, more males (55.9%) were enrolled than females. The racial distribution was 98.5% White, 0.3% Black, 0.7% Asian, 0.5% Other, with <0.1% having missing data.

Adults with immunocompromising conditions or receiving immunosuppressive therapy and adults residing in a long-term care facility or requiring semiskilled nursing care were excluded. Adults with pre-existing medical conditions, as well as subjects with a history of smoking were eligible for enrollment. In the safety population, 42.3% of subjects had pre-existing medical conditions including heart disease (25.4%), lung disease or asthma (15.1%) and type 1 and type 2 diabetes mellitus (12.5%). Smoking was reported at baseline by 12.3% of the subjects.

For a subset of 2,011 subjects (1,006 Prevnar 13 recipients and 1,005 placebo recipients), solicited adverse reactions were monitored by recording local and systemic events using electronic diaries for 7 days after vaccination; unsolicited adverse events were collected for 28 days after vaccination, and serious adverse events were collected for 6 months after vaccination. For the remaining 41,231 Prevnar 13 and 41,250 placebo vaccinated subjects, serious adverse events were collected for 28 days after vaccination.

Serious Adverse Events in Adult Clinical Studies

Safety and Immunogenicity Studies

Across the 6 safety and immunogenicity studies,6–11 serious adverse events within 1 month of vaccination were reported after an initial study dose in 0.2%–1.4% of 5,057 subjects vaccinated with Prevnar 13, and in 0.4%–1.7% of 1,124 subjects vaccinated after an initial study dose of PPSV23. From 1 month to 6 months after an initial study dose, serious adverse events were reported in 0.2%–5.8% of subjects vaccinated during the studies with Prevnar 13 and in 2.4%–5.5% of subjects vaccinated with PPSV23. One case of erythema multiforme occurred 34 days after receipt of a second dose of Prevnar 13.

Twelve of 5,667 (0.21%) Prevnar 13 recipients and 4 of 1,391 (0.29 %) PPSV23 recipients died. Deaths occurred between Day 3 and Day 309 after study vaccination with Prevnar 13 or PPSV23. Two of 12 deaths occurred within 30 days of vaccination and both deaths were in subjects >65 years of age. One death due to cardiac failure occurred 3 days after receiving placebo. This subject had received Prevnar 13 and IIV3 one month earlier. The other death was due to peritonitis 20 days after receiving Prevnar 13. The reported causes of the 10 remaining deaths occurring greater than 30 days after receiving Prevnar 13 were cardiac disorders (4), neoplasms (4), Mycobacterium avium complex pulmonary infection (1) and septic shock (1).

Efficacy Study

In Study 1212 (subjects 65 years and older), serious adverse events within 1 month of vaccination were reported in 327 of 42,237 (0.8%) Prevnar 13 recipients (352 events) and in 314 of 42,225 (0.7%) placebo recipients (337 events). In the subset of subjects where serious adverse events were monitored for 6 months, 70 of 1,006 (7%) Prevnar 13 vaccinated subjects (90 events) and 60 of 1,005 (6%) placebo vaccinated subjects (69 events) reported serious adverse events.

During the follow-up period (average of 4 years) for case accumulation there were 3,006 deaths (7.1%) in the Prevnar 13 group and 3,005 deaths (7.1%) in the placebo group. There were 10 deaths (<0.1%) in the Prevnar 13 group and 10 deaths (<0.1%) in the placebo group within 28 days of vaccination. There were 161 deaths (0.4%) in the Prevnar 13 group and 144 deaths (0.3%) in the placebo group within 29 days – 6 months following vaccination. These data do not provide evidence for a causal relationship between deaths and vaccination with Prevnar 13.

Solicited Adverse Reactions in Adult Clinical Studies

The incidence and severity of solicited adverse reactions that occurred within 7 or 14 days following each dose of Prevnar 13, PPSV23, or placebo administered to adults in 5 studies are shown in Tables 11, 12, 13, and 14.

The commonly reported local adverse reactions after Prevnar 13 vaccination in PPSV23 unvaccinated and PPSV23 previously vaccinated adults were redness, swelling and pain at the injection site, or limitation of arm movement (Tables 11 and 12). The commonly reported systemic adverse reactions in PPSV23 unvaccinated and PPSV23 previously vaccinated adults were fatigue, headache, chills, rash, decreased appetite, or muscle pain and joint pain (Tables 13 and 14).

Table 11 — Percentage of Subjects With Solicited Local Adverse Reactions Within 7 or 14 Days in PPSV23 Unvaccinated Adults *
Study 6 Study 8 Study 12
Age in Years 18–49 50–59 60–64 60–64 ≥65
Local Reaction Prevnar 13N =266–787% Prevnar 13N =152–322% Prevnar 13N =193–331% PPSV23N =190–301% Prevnar 13N =270–370% PPSV23N =134–175% Prevnar 13N =886–914% PlaceboN =859–865%
*
Studies conducted in US NCT00427895 (Study 6) and NCT00574548 (Study 8) reported local reactions within 14 days. Study conducted in the Netherlands NCT00744263 (Study 12) reported local reactions within 7 days.
Open label administration of Prevnar 13.
Number of subjects with known values (number of subjects reporting yes for at least one day or no for all days).
§
Diameters were measured in caliper units of whole numbers from 1 to 21 or 21+. One caliper unit = 0.5 cm. Measurements were rounded up to the nearest whole number. Intensity of redness and swelling were then characterized as Mild = 2.5 to 5.0 cm, Moderate = 5.1 to 10.0 cm, and Severe is >10.0 cm.
Statistically significant difference p <0.05. No adjustments for multiplicity.
#
Mild = awareness of symptom but easily tolerated, Moderate = discomfort enough to cause interference with usual activity, Severe = incapacitating with inability to do usual activity.
Þ
Mild = some limitation of arm movement, Moderate = unable to move arm above head but able to move arm above shoulder, and Severe = unable to move arm above shoulder.
Redness §
Any 30.5 15.8 20.2 14.2 12.2 11.2 4.9 1.2
Mild 26.4 15.2 15.9 11.2 8.3 9.7 3.7 0.8
Moderate 11.9 5.0 8.6 4.9 6.4 3.9 1.7 0.3
Severe 2.8 0.7 1.7 0.0 1.2 0.8 0.5 0.1
Swelling §
Any 39.4 21.7 19.3 13.1 10.0 10.4 6.8 1.2
Mild 37.2 20.6 15.6 10.1 8.2 6.1 5.5 0.7
Moderate 15.1 4.3 8.2 4.4 3.8 7.6 2.6 0.6
Severe 1.4 0.0 0.6 1.1 0.0 0.0 0.1 0.1
Pain #
Any 96.7 88.8 80.1 73.4 69.2 58.3 36.1 6.1
Mild 93.2 85.9 78.6 68.6 66.1 52.9 32.9 5.6
Moderate 77.1 39.5 23.3 30.0 20.1 21.7 7.7 0.6
Severe 16.0 3.6 1.7 8.6 2.3 0.8 0.3 0.1
Limitation of arm movement Þ
Any 75.2 40.7 28.5 30.8 23.5 28.2 14.1 3.2
Mild 71.5 38.6 26.9 29.3 22.7 26.1 12.4 2.5
Moderate 18.5 2.9 2.2 3.8 1.2 3.1 1.7 0.5
Severe 15.6 2.9 1.7 4.3 1.1 2.3 1.2 0.7
Table 12 — Percentage of Subjects With Solicited Local Adverse Reactions in PPSV23 Previously Vaccinated Adults *
Study 7 Study 9
Age in Years ≥70 ≥68
Local Reaction Prevnar 13N =306–362% PPSV23N =324–383% Prevnar 13N =664–777%
*
Study conducted in US and Sweden NCT00546572 (Study 7) reported local reactions within 14 days. Study conducted in US, Sweden and Germany NCT00500266 (Study 9) reported local reactions within 14 days.
Number of subjects with known values.
Open label administration of Prevnar 13.
§
Diameters were measured in caliper units of whole numbers from 1 to 21 or 21+. One caliper unit = 0.5 cm. Measurements were rounded up to the nearest whole number. Intensity of redness and swelling were then characterized as Mild = 2.5 to 5.0 cm, Moderate = 5.1 to 10.0 cm, and Severe is >10.0 cm.
Statistically significant difference p <0.05. No adjustments for multiplicity.
#
Mild = awareness of symptom but easily tolerated, Moderate = discomfort enough to cause interference with usual activity, Severe = incapacitating with inability to do usual activity.
Þ
Mild = some limitation of arm movement, Moderate = unable to move arm above head but able to move arm above shoulder, and Severe = unable to move arm above shoulder.
Redness §
Any 10.8 22.2 14.3
Mild 9.5 13.5 12.6
Moderate 4.7 11.5 6.5
Severe 1.7 4.8 1.1
Swelling §
Any 10.4 23.1 12.8
Mild 8.9 14.0 10.9
Moderate 4.0 13.6 5.5
Severe 0.0 4.8 0.6
Pain #
Any 51.7 58.5 51.0
Mild 50.1 54.1 49.4
Moderate 7.5 23.6 9.0
Severe 1.3 2.3 0.2
Limitation of arm movement Þ
Any 10.5 27.6 16.2
Mild 10.3 25.2 14.8
Moderate 0.3 2.6 1.6
Severe 0.7 3.0 1.6
Table 13 — Percentage of Subjects With Solicited Systemic Events in PPSV23 Unvaccinated Adults *
Study 6 Study 8 Study 12
Age in Years 18–49 50–59 60–64 60–64 ≥65
Prevnar 13N =221–561% Prevnar 13N =137–248% Prevnar 13N =174–277% PPSV23N =176–273% Prevnar 13N =261–328% PPSV23N =127–173% Prevnar 13N =881–896% PlaceboN =860–878%
*
Studies conducted in US NCT00427895 (Study 6) and NCT00574548 (Study 8) reported systemic events within 14 days. Study conducted in the Netherlands NCT00744263 (Study 12) reported systemic events within 7 days.
Open label administration of Prevnar 13.
Number of subjects with known values (number of subjects reporting yes for at least one day or no for all days).
§
Statistically significant difference p <0.05. No adjustments for multiplicity.
Fevers >40.0°C were confirmed to be data entry errors and remain in the table for the following: 1 case in the 18- to 49- year-old cohort (Study 6), and 7 cases in the Prevnar 13 group and 3 cases in placebo group (Study 12). For the other cohorts in Study 6 and for Study 8, data entry errors were removed.
Systemic Event
Fever
≥38.0°C 7.2 1.5 4.0 1.1 4.2 1.6 2.9§ 1.3
38.0°C to 38.4°C 4.2 1.5 4.0 1.1 3.8 0.8 1.1 0.6
38.5°C to 38.9°C 1.9 0.0 0.6 0.0 0.8 0.0 0.6 0.2
39.0°C to 40.0°C 1.4 0.0 0.0 0.0 0.4 0.8 0.7 0.2
>40.0°C 0.5 0.0 0.0 0.0 0.0 0.0 0.8 0.3
Fatigue 80.5 63.3 63.2 61.5 50.5 49.1 18.8§ 14.8
Headache 81.4 65.9 54.0 54.4 49.7 46.1 15.9 14.8
Chills 38.1 19.6 23.5 24.1 19.9 26.9 9.4 8.4
Rash 21.3 14.2 16.5 13.0 8.6 13.4 3.3§ 0.8
Vomiting 15.0 6.9 3.9 5.4 3.1 3.1 0.3 0.9
Decreased appetite 55.6 25.3 21.3 21.7 14.7 23.0§ 5.3 3.7
Generalized new muscle pain 82.0 61.8 56.2 57.8 46.9 51.5 18.4§ 8.4
Generalized aggravated muscle pain 55.9 39.9 32.6 37.3 22.0 32.5§ 9.1§ 4.4
Generalized new joint pain 41.7 31.5 24.4 30.1 15.5 23.8§ 7.4 5.4
Generalized aggravated joint pain 28.6 25.6 24.9 21.4 14.0 21.1 5.2 4.2
Table 14 — Percentage of Subjects With Systemic Events in PPSV23 Previously Vaccinated Adults *
Study 7 Study 9
Age in Years ≥70 ≥68
Prevnar 13N =299–350% PPSV23N =303–367% Prevnar 13N =635–733%
*
Study conducted in US and Sweden NCT00546572 (Study 7) reported systemic events within 14 days. Study conducted in US, Sweden and Germany NCT00500266 (Study 9) reported systemic events within 14 days.
Number of subjects with known values.
Open label administration of Prevnar 13.
§
Statistically significant difference p <0.05. No adjustments for multiplicity.
Systemic Event
Fever
≥38.0°C 1.0 2.3 1.1
38.0°C to 38.4°C 1.0 2.0 0.8
38.5°C to 38.9°C 0.0 0.0 0.0
39.0°C to 40.0°C 0.0 0.3 0.3
>40.0°C 0.0 0.0 0.0
Fatigue 34.0 43.3§ 34.4
Headache 23.7 26.0 26.1
Chills 7.9 11.2 7.5
Rash 7.3 16.4§ 8.4
Vomiting 1.7 1.3 0.9
Decreased appetite 10.4 11.5 11.2
Generalized new muscle pain 36.8 44.7§ 25.3
Generalized aggravated muscle pain 20.6 27.5§ 12.3
Generalized new joint pain 12.6 14.9 12.8
Generalized aggravated joint pain 11.6 16.5 9.7

Safety Results from Adult Clinical Study of Concomitant Administration of Prevnar 13 and IIV4 (Fluzone Quadrivalent) (Study 13)

The safety profile of Prevnar 13 when administered concomitantly with seasonal inactivated influenza vaccine, quadrivalent, to PPSV23 previously vaccinated adults ≥50 years of age was generally consistent with the known safety profile of Prevnar 13.

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