Vaccine Information: RotaTeq (Page 3 of 4)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

RotaTeq has not been evaluated for its carcinogenic or mutagenic potential or its potential to impair fertility.

14 CLINICAL STUDIES

Overall, 73,086 infants were randomized in 4 placebo-controlled, phase 3 studies conducted in 12 countries on 4 continents. The data demonstrating the efficacy of RotaTeq in preventing rotavirus gastroenteritis come from 7,744 of these infants from the US (including Navajo and White Mountain Apache Nations), Finland, and Japan who were enrolled in 3 of these studies: Study 006, Study 007, and Study 029. A fourth trial, Study 009, provided clinical evidence supporting the consistency of manufacture and contributed data to the overall safety evaluation.

The racial distribution of the efficacy subset was as follows: White (RotaTeq 61%, placebo 62%); Hispanic-American (RotaTeq 9%, placebo 8%); Black (2% in both groups); Multiracial (4% in both groups); Asian (10% in both groups); Native American (13% in both groups); and Other (<1% in both groups). The gender distribution was 52% male and 48% female in both vaccination groups.

The efficacy evaluations in these studies included: 1) Prevention of any grade of severity of rotavirus gastroenteritis; 2) Prevention of severe rotavirus gastroenteritis, as defined by a clinical scoring system; and 3) Reduction in hospitalizations due to rotavirus gastroenteritis.

The vaccine was given as a three-dose series to healthy infants with the first dose administered between 6 and 12 weeks of age and followed by two additional doses administered at 4- to 10-week intervals. The age of infants receiving the third dose was 32 weeks of age or less. Oral polio vaccine administration was not permitted; however, other childhood vaccines could be concomitantly administered. Breast-feeding was permitted in all studies.

The case definition for rotavirus gastroenteritis used to determine vaccine efficacy required that a subject meet both of the following clinical and laboratory criteria: (1) greater than or equal to 3 watery or looser-than-normal stools within a 24-hour period and/or forceful vomiting; and (2) rotavirus antigen detection by enzyme immunoassay (EIA) in a stool specimen taken within 14 days of onset of symptoms. The severity of rotavirus acute gastroenteritis was determined by a clinical scoring system that took into account the intensity and duration of symptoms of fever, vomiting, diarrhea, and behavioral changes.

The primary efficacy analyses included cases of rotavirus gastroenteritis caused by types G1, G2, G3, G4 (and G types containing P1A8 (in Study 029 only)) that occurred at least 14 days after the third dose through the first rotavirus season post vaccination.

Analyses were also done to evaluate the efficacy of RotaTeq against rotavirus gastroenteritis caused by any of types G1, G2, G3, and G4 (and G types containing P1A8 (in Study 029 only)) at any time following the first dose through the first rotavirus season postvaccination among infants who received at least one vaccination (Intent-to-treat, ITT).

14.1 Rotavirus Efficacy and Safety Trial (Study 006)

Primary efficacy against any grade of severity of rotavirus gastroenteritis caused by naturally occurring types G1, G2, G3, or G4 through the first rotavirus season after vaccination was 74.0% (95% CI: 66.8, 79.9) and the ITT efficacy was 60.0% (95% CI: 51.5, 67.1). Primary efficacy against severe rotavirus gastroenteritis caused by naturally occurring types G1, G2, G3, or G4 through the first rotavirus season after vaccination was 98.0% (95% CI: 88.3, 100.0), and ITT efficacy was 96.4% (95% CI: 86.2, 99.6). See Table 8.

Table 8: Efficacy of RotaTeq against any grade of severity of and severe * G1-4 rotavirus gastroenteritis through the first rotavirus season postvaccination in Study 006
*
Severe gastroenteritis defined by a clinical scoring system based on the intensity and duration of symptoms of fever, vomiting, diarrhea, and behavioral changes
ITT analysis includes all subjects in the efficacy cohort who received at least one dose of vaccine.
Per Protocol Intent-to-Treat
RotaTeq Placebo RotaTeq Placebo
Subjects vaccinated 2,834 2,839 2,834 2,839
Gastroenteritis cases
Any grade of severity 82 315 150 371
Severe * 1 51 2 55
Efficacy estimate % and (95% confidence interval)
Any grade of severity 74.0(66.8, 79.9) 60.0(51.5, 67.1)
Severe * 98.0(88.3, 100.0) 96.4(86.2, 99.6)

The efficacy of RotaTeq against severe disease was also demonstrated by a reduction in hospitalizations for rotavirus gastroenteritis among all subjects enrolled in Study 006. RotaTeq reduced hospitalizations for rotavirus gastroenteritis caused by types G1, G2, G3, and G4 through the first two years after the third dose by 95.8% (95% CI: 90.5, 98.2). The ITT efficacy in reducing hospitalizations was 94.7% (95% CI: 89.3, 97.3) as shown in Table 9.

Table 9: Efficacy of RotaTeq in reducing G1-4 rotavirus-related hospitalizations in Study 006
*
ITT analysis includes all subjects who received at least one dose of vaccine.
Per Protocol Intent-to-Treat *
RotaTeq Placebo RotaTeq Placebo
Subjects vaccinated 34,035 34,003 34,035 34,003
Number of hospitalizations 6 144 10 187
Efficacy estimate % and(95% confidence interval) 95.8(90.5, 98.2) 94.7(89.3, 97.3)

14.2 Study 007

Primary efficacy against any grade of severity of rotavirus gastroenteritis caused by naturally occurring types G1, G2, G3, or G4 through the first rotavirus season after vaccination was 72.5% (95% CI: 50.6, 85.6) and the ITT efficacy was 58.4% (95% CI: 33.8, 74.5). Primary efficacy against severe rotavirus gastroenteritis caused by naturally occurring types G1, G2, G3, or G4 through the first rotavirus season after vaccination was 100% (95% CI: 13.0, 100.0) and ITT efficacy against severe rotavirus disease was 100% (95% CI: 30.2, 100.0) as shown in Table 10.

Table 10: Efficacy of RotaTeq against any grade of severity of and severe * G1-4 rotavirus gastroenteritis through the first rotavirus season postvaccination in Study 007
*
Severe gastroenteritis defined by a clinical scoring system based on the intensity and duration of symptoms of fever, vomiting, diarrhea, and behavioral change
ITT analysis includes all subjects in the efficacy cohort who received at least one dose of vaccine.
Per Protocol Intent-to-Treat
RotaTeq Placebo RotaTeq Placebo
Subjects vaccinated 650 660 650 660
Gastroenteritis cases
 Any grade of severity 15 54 27 64
 Severe * 0 6 0 7
Efficacy estimate % and (95% confidence interval)
 Any grade of severity 72.5(50.6, 85.6) 58.4(33.8, 74.5)
 Severe * 100.0(13.0, 100.0) 100.0(30.2, 100.0)

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