Summary Background Rotavirus gastroenteritis is a significant cause of morbidity and mortality. Objective To perform an integrated safety analysis of data from the Phase III studies of the ...pentavalent rotavirus vaccine (PRV). Methods Healthy 6- to 12-week-old infants received 3 doses of PRV or placebo at 4- to 10-week intervals in 3 Phase III, blinded, randomized, placebo-controlled trials. Active surveillance for serious adverse events (AE), including intussusception, was performed at 7, 14, and 42 days after each dose. Other AEs occurring within 42 days after each dose were documented on Vaccination Report Cards. Fecal shedding of vaccine-virus strains was evaluated by plaque assay and electropherotyping. Results Intussusception and other serious AEs were evaluated among 71 799 vaccinated sub- jects. Within 42 days after any dose, intussusception occurred among 6 PRV and 5 placebo recipients. All AEs were evaluated among 11 722 vaccinated subjects. Within the week following the first dose, the incidences of fever and irritability were similar among PRV and placebo recipients, although diarrhea and vomiting occurred more frequently among PRV recipients versus placebo recipients (10.4% vs. 9.1% and 6.7% vs. 5.4%, respectively). Fecal shedding of vaccine-virus strains occurred in 8.9% of 360 PRV recipients after the first dose. Conclusions Across the 3 Phase III clinical trials, PRV was well tolerated, with no increased clinical risk of intussusception. Fecal shedding of vaccine-virus strains occurred infrequently and in low amounts, suggesting the risk of transmission is unlikely.
The pentavalent human-bovine reassortant rotavirus vaccine is indicated as a 3-dose series with first dose administered orally at 6 to 12 weeks with subsequent doses at 4 to 10 week intervals. In ...pre-licensure phase III trials, the majority followed this schedule, but there were 2956 instances where infants received a dose of pentavalent human-bovine reassortant rotavirus vaccine/placebo >10 weeks after the previous dose. Among this subset, the efficacy against any severity of disease, the reduction in utilization of healthcare resources and the safety profile after vaccination were comparable with overall results.
Highlights ► The methodology and lessons-learned of a clinical trial with pentavalent rotavirus vaccine (RotaTeq® ) are described. ► The study was conducted following good clinical practices. ► ...Inclement weather, difficult transportation, and movement of study participants were some of the challenges identified. ► The study was well accepted in the community and was completed successfully.
Upon termination of a clinical trial that uses interim evaluations to determine whether the trial can be stopped, a proper statistical analysis must account for the interim evaluations. For example, ...in a group-sequential design where the efficacy of a treatment regimen is evaluated at interim stages, and the opportunity to stop the trial based on positive efficacy findings exists, the terminal p-value, point estimate, and confidence limits of the outcome of interest must be adjusted to eliminate bias. While it is standard practice to adjust terminal statistical analyses due to opportunities to stop for "positive" findings, adjusting due to opportunities to stop for "negative" findings is also important. Stopping rules for negative findings are particularly useful when monitoring a specific rare serious adverse event in trials designed to show safety with respect to the event. In these settings, establishing conservative stopping rules are appropriate, and therefore accounting for the interim monitoring can have a substantial effect on the final results. Here I present a method to account for interim safety monitoring and illustrate its usefulness. The method is demonstrated to have advantages over methodology that does not account for interim monitoring.
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BFBNIB, DOBA, GIS, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
During the vaccination phase of the Rotavirus Efficacy and Safety Trial (REST), the period between the administration of dose 1 through 13 days after the administration of dose 3, there were more ...wild-type rotavirus gastroenteritis (RVGE) cases among vaccine recipients compared with placebo recipients using the protocol-specified microbiological plaque assay in the clinical-efficacy cohort, a subset of subjects where vaccine efficacy against RVGE of any severity was assessed. In this study, a rotavirus genome segment 6-based reverse transcriptase-polymerase chain reaction assay was applied post hoc to clarify the accuracy of type categorization of all these RVGE cases in vaccine recipients during the vaccination phase of REST. The assay characterized 147 (90%) of 163 re-assayed RVGE cases or rotavirus-associated health care contacts as type-determinable: either wild-type or vaccine-type rotavirus strains. In the clinical-efficacy cohort (N = 5673), 19 (18.8%) of 101 samples from RVGE cases contained wild-type rotavirus, 70 (69.3%) vaccine virus, and 12 (11.9%) were indeterminable. In the large-scale cohort (N = 68,038), 10 (34.5%) of 29 samples from RVGE-related health care contacts contained wild-type rotavirus strains, 15 (51.7%) vaccine-type rotavirus strains, and 4 (13.8%) were indeterminable. Of the 33 samples from RVGE cases in placebo recipients, all were confirmed to contain wild-type rotaviruses. Altogether, this post-hoc re-evaluation showed that the majority (75%) of type-determinable RVGE cases or health care contacts that occurred during the vaccination phase of REST in vaccine recipients were associated with vaccine-type rotavirus strains rather than wild-type rotavirus strains.
BACKGROUND:A live pentavalent rotavirus vaccine (PRV) containing 5 human-bovine (WC3) reassortants expressing human serotypes G1, G2, G3, G4 and P1A8 was evaluated in a blinded, placebo-controlled ...study. Possible interactions between PRV and concomitantly administered licensed pediatric vaccines were investigated in a United States-based nested substudy (Concomitant Use Study) of the Rotavirus Efficacy and Safety Trial.
METHODS:From 2002 to 2003, healthy infants approximately 6 to 12 weeks of age at entry were randomized to receive either 3 oral doses of PRV or placebo at 4- to 10-week intervals. Subjects were also to receive combined Haemophilus influenzae type b and hepatitis B vaccine (2 doses), diphtheria and tetanus toxoids and acellular pertussis vaccine (3 doses), inactivated poliovirus vaccine (2 doses) and pneumococcal conjugate vaccine (3 doses) on the same day; oral poliovirus vaccine was not administered. Immunogenicity was assessed by measuring antibody responses to PRV and antigens contained in the licensed vaccines. Cases of rotavirus gastroenteritis were defined by forceful vomiting and/or ≥3 watery or looser-than-normal stools within a 24-hour period, and detection of rotavirus antigen in the stool. Safety was assessed by reporting of adverse events using diary cards.
RESULTS:The Concomitant Use Study enrolled 662 subjects in the PRV group and 696 subjects in the placebo group. For the 17 antigens in the concomitantly administered vaccines, antibody responses were similar in PRV and placebo recipients, except for moderately diminished antibody responses to the pertactin component of pertussis vaccine. Efficacy of PRV against rotavirus gastroenteritis of any severity was 89.5% (95% CI = 26.5–99.8%). PRV was generally well tolerated when given concomitantly with the prespecified vaccines.
CONCLUSIONS:In this study, antibody responses to the concomitantly administered vaccines were generally similar in PRV and placebo recipients. PRV was efficacious and well tolerated when given concomitantly with pediatric vaccines licensed in the United States.
The Rotavirus Efficacy and Safety Trial (REST) was a blinded, placebo-controlled
study of the live pentavalent human-bovine vaccine, RotaTeq® (Merck &
Co. Inc., West Point, PA). REST was noteworthy ...because its primary objective was to
evaluate the safety of RotaTeq® with regard to intussusception, a rare
intestinal illness that occurs with a background incidence of approximately 50 cases
per 100 000 infant years. The study involved approximately 70 000 infants at over 500
study sites in 11 countries. The study demonstrated that the risk of intussusception
was similar in vaccine and placebo recipients and that the vaccine prevented
rotavirus gastroenteritis, ameliorated the severity of disease in those who had any
disease, and substantially reduced rotavirus-associated hospitalizations and other
health care contacts. This report provides an in-depth review of the background,
statistical and regulatory considerations, and execution of REST. We describe the
rationale and methods used for sample size, continuous safety monitoring, group
sequential design, and detailed study execution. The results of the study have been
reported elsewhere. The design and conduct of this study may serve as a useful model
for planning other future large-scale clinical trials, especially those evaluating
uncommon adverse events. Clinical Trials 2008; 5: 131—139. http://
ctj.sagepub.com
In this randomized trial, the clinical efficacy of an oral, live pentavalent human–bovine reassortant vaccine was estimated to be 98.0 percent against severe gastroenteritis due to rotavirus. In the ...safety study, which included 68,038 infants, the rates of intussusception were similar in the vaccine and placebo groups (relative risk, 0.8; 95 percent confidence interval, 0.3 to 1.8).
In this randomized trial, the clinical efficacy of an oral, live pentavalent human–bovine reassortant vaccine was estimated to be 98.0 percent against severe gastroenteritis due to rotavirus.
Rotavirus is the leading cause of hospitalization and death from acute gastroenteritis among infants and young children worldwide. More than 2 million hospitalizations and nearly half a million deaths are attributed to this infection annually.
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The strategy of preventing rotavirus through vaccination derives from studies demonstrating that wild-type rotavirus infection induces immunity against subsequent rotavirus gastroenteritis.
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Primary rotavirus infection provides substantial protection against gastroenteritis caused by the same serotype and against severe disease regardless of serotype. The four most prevalent serotypes, which account for more than 80 percent of cases of human rotavirus disease worldwide, are G1P8, G2P4, . . .
BACKGROUND.A refrigerator-stable rotavirus (RV) vaccine that withstands gastric acid is anticipated to permit more widespread use of RV vaccine.
OBJECTIVE.We investigated for the first time in ...infants an oral, liquid formulation of G1 and G2 human bovine reassortant rotavirus vaccine (HRRV) with a new stabilizer/buffer (S/B) containing sucrose, sodium phosphate and sodium citrate.
METHODS.During 1997 through 1998, 731 healthy infants ∼2 to 4 months of age were enrolled at 19 US sites to receive 3 HRRV or placebo doses ∼6 to 8 weeks apart in a partially double blinded study. Infants were randomized to(1) HRRV with no S/B but with prefeeding; (2) HRRV plus 1 of 3 different concentrations/volumes of S/B; or (3) placebo.
RESULTS.No serious vaccine-related adverse experiences or intussusception cases were reported. No statistically significant differences were observed between vaccine and placebo recipients for fever (≥38.1°C) 0 to 7 days after any dose, irritability, vomiting or diarrhea incidence 0 to 42 days after any dose. Vaccine virus shedding among vaccine recipients was uncommon. Among S/B vaccine groups, proportions of infants with a ≥3-fold titer rise from baseline to Postdose 3 for G1 serum-neutralizing antibody (SNA), G2 SNA, WC3 SNA, serum anti-RV IgA, serum anti-RV IgG and stool anti-RV IgA were generally similar to those of the prefed non-S/B group.
CONCLUSIONS.HRRV with a new S/B was generally well-tolerated; immunogenicity was generally similar to the prefed non-S/B group. No intussusception cases were reported, but the small sample size precluded a definitive conclusion. A large international clinical study is under way to address safety and efficacy of an S/B formulation of a pentavalent version of HRRV.
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