Infections, Rotavirus
Conditions
Keywords
Transmission, Gastroenteritis, Shedding, rotavirus, HRV vaccine
Brief summary
The aim of this study is to explore horizontal transmission of the HRV (Human Rotavirus) vaccine strain within a family from the twin vaccinated with Rotarix to the twin receiving placebo. The Protocol Posting has been updated in order to comply with the FDA Amendment Act, Sep 2007.
Detailed description
This is a Phase 3b study. Three doses of Infanrix® hexa will be administered to all subjects at the discretion of the investigator. One complimentary dose of Rotarix will be administered to all infants enrolled in this study (both study groups) who are aged less than 6 months at Visit 3 (Week 13) as a benefit to the placebo group for participation in the study. The study will be conducted in a double-blind manner with respect to Rotarix and placebo administered at Visit 1 and Visit 2. The parents/guardians of the subjects will know that within each pair of twins, one subject will receive the Rotarix vaccine and one subject will receive the placebo. The study will be open label with respect to administration of the Rotarix vaccine dose given at Visit 3 to all subjects in each group who are aged less than 6 months.
Interventions
BIOLOGICALRotarix
Two-dose oral vaccination.
BIOLOGICALPlacebo
Two-dose oral administration.
Sponsors
GlaxoSmithKline
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
6 Weeks to 14 Weeks
Healthy volunteers
Yes
Inclusion criteria
* Subjects with a live twin living in the same household who is also enrolled in this study. * Born after a gestation period of ≥32 weeks, * Discharged from hospital neonatal care stay, * Subjects who the investigator believes that their parents/guardians can and will comply with the requirements of the protocol should be enrolled in the study. * A male or female between, and including, 6 and 14 weeks of age at the time of the first study vaccination. * Healthy subjects as established by medical history and clinical examination before entering into the study. * Written informed consent obtained from the parent or guardian of the subjects.
Exclusion criteria
* Use of any investigational or non-registered product (drug or vaccine) other than the study vaccine(s) within 30 days preceding the first dose of study vaccine, or planned use during the study period. * Any confirmed or suspected immunosuppressive or immunodeficient condition, based on medical history and physical examination (no laboratory testing required). * Any clinically significant history of chronic gastrointestinal disease. * History of allergic disease or reactions likely to be exacerbated by any component of the vaccine. * Acute disease at time of enrolment. * Administration of immunoglobulins and/or any blood products since birth or planned administration during the study period. * Contact with an immunosuppressed individual. * Concurrently participating in another clinical study, at any time during the study period, in which the subject has been or will be exposed to an investigational or a non-investigational product (pharmaceutical product or device). * Chronic administration of immunosuppressants since birth. * Gastroenteritis within 7 days preceding the first study vaccine administration. * Documented HIV-positive subject.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Presence of Rotavirus Vaccine Strain in Any Stool Sample From Twin Receiving Placebo. | On the day of each vaccine/placebo dose, then three times weekly for 6 consecutive weeks starting after each vaccine/placebo dose and on the day of Visit 3. | Number of subjects in the Placebo Group with rotavirus vaccine strain in at least one stool sample. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Genetic Variation Differences Detected by Sequencing of Genomic Mutations in the HRV Vaccine Strain After Transmission. | During the entire study period (up to Visit 4, Week 17). | Dissimilar amino acid substitutions in the HRV vaccine strain isolated from the twin receiving placebo, when compared to the genetic variation of HRV vaccine strain isolated from the Rotarix vaccine recipients, were counted as genetic variation differences. |
| Live Viral Vaccine Load in the Stool of the Twin Receiving Placebo in Case of Transmission. | During the entire study period (up to Visit 4, Week 17). | Number of subjects in the Placebo Group with live virus identified in at least one stool sample in case of transmission. |
| Anti-rotavirus Immunoglobulin A (IgA) Antibody Seroconversion. | At Visit 3 (Week 13). | Number of initially seronegative subjects with anti-rotavirus IgA antibody concentration ≥ 20 Units/milliliter (U/mL), 1 month after the second dose. |
| Duration of Human Rotavirus (HRV) Shedding Per Study Group. | From Day 0 up to Week 13. | Duration of shedding in the Placebo Group= number of days between first and last stool sample positive (+) for rotavirus (RV) antigen and in the Rotarix Group= number of days between the day of vaccination and the date of last stool sample + for RV antigen. |
| Number of Subjects With Gastroenteritis (GE) and Rotavirus Gastroenteritis (RV GE) Episodes. | Until Visit 4 (Week 17) for GE and until Visit 3 (Week 13) for RV GE. | GE episodes were defined as diarrhea (passage of three or more looser than normal stools within a day) with or without vomiting. RV GE episodes were defined as GE episodes for which the stool sample temporally closest to the onset day of the GE episode was positive for rotavirus by Enzyme Linked Immunosorbent Assay (ELISA). |
| Number of Subjects Reporting Unsolicited Adverse Events (AEs). | Within 31 days after any doses. | An AE is any untoward medical occurrence in a clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. |
| Number of Subjects Reporting Any Serious Adverse Events (SAEs). | Up to Visit 4. | A serious adverse event (SAE) is any untoward medical occurrence that: results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect in the offspring of a study subject, or may evolve into one of the outcomes listed above. |
| Anti-rotavirus IgA Antibody Concentration. | At Visit 3 (Week 13). | Anti-rotavirus IgA antibody concentrations are given as geometric mean concentrations (GMC) with 95% Confidence Intervals. |
Countries
Dominican Republic
Participant flow
Pre-assignment details
Within each pair of twins enrolled in the study, one subject was assigned to the Rotarix Group and one to the Placebo Group.
Participants by arm
| Arm | Count |
|---|---|
| Rotarix Group All subjects received 2 oral doses of Rotarix vaccine at Day 0 (Visit 1) and Week 7 (Visit 2).
Subjects aged less than 6 months at Visit 3 received one complimentary Rotarix vaccine dose at Week 13 (Visit 3). | 100 |
| Placebo Group All subjects received 2 oral doses of placebo at Day 0 (Visit 1) and Week 7 (Visit 2).
Subjects aged less than 6 months at Visit 3 received one complimentary Rotarix vaccine dose at Week 13 (Visit 3). | 100 |
| Total | 200 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 1 | 1 |
| Overall Study | Not vaccinated at Visit 3 | 3 | 3 |
| Overall Study | Withdrawal by Subject | 1 | 1 |
Baseline characteristics
| Characteristic | Rotarix Group | Placebo Group | Total |
|---|---|---|---|
| Age, Continuous | 8.2 Weeks STANDARD_DEVIATION 1.8 | 8.2 Weeks STANDARD_DEVIATION 1.8 | 8.2 Weeks STANDARD_DEVIATION 1.8 |
| Sex: Female, Male Female | 56 Participants | 49 Participants | 105 Participants |
| Sex: Female, Male Male | 44 Participants | 51 Participants | 95 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 100 | 0 / 100 |
| other Total, other adverse events | 69 / 100 | 71 / 100 |
| serious Total, serious adverse events | 5 / 100 | 6 / 100 |
Outcome results
Primary
Presence of Rotavirus Vaccine Strain in Any Stool Sample From Twin Receiving Placebo.
Number of subjects in the Placebo Group with rotavirus vaccine strain in at least one stool sample.
Time frame: On the day of each vaccine/placebo dose, then three times weekly for 6 consecutive weeks starting after each vaccine/placebo dose and on the day of Visit 3.
Population: The analyses were performed on the According-To-Protocol (ATP) cohort for immunogenicity.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo Group | Presence of Rotavirus Vaccine Strain in Any Stool Sample From Twin Receiving Placebo. | 15 subjects |
Secondary
Anti-rotavirus IgA Antibody Concentration.
Anti-rotavirus IgA antibody concentrations are given as geometric mean concentrations (GMC) with 95% Confidence Intervals.
Time frame: At Visit 3 (Week 13).
Population: The analyses were performed on the According-To-Protocol (ATP) cohort for immunogenicity.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Placebo Group | Anti-rotavirus IgA Antibody Concentration. | 78.6 U/mL |
| Placebo Group | Anti-rotavirus IgA Antibody Concentration. | 20.5 U/mL |
Secondary
Anti-rotavirus Immunoglobulin A (IgA) Antibody Seroconversion.
Number of initially seronegative subjects with anti-rotavirus IgA antibody concentration ≥ 20 Units/milliliter (U/mL), 1 month after the second dose.
Time frame: At Visit 3 (Week 13).
Population: The analyses were performed on the According-To-Protocol (ATP) cohort for immunogenicity.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo Group | Anti-rotavirus Immunoglobulin A (IgA) Antibody Seroconversion. | 50 subjects |
| Placebo Group | Anti-rotavirus Immunoglobulin A (IgA) Antibody Seroconversion. | 17 subjects |
Secondary
Duration of Human Rotavirus (HRV) Shedding Per Study Group.
Duration of shedding in the Placebo Group= number of days between first and last stool sample positive (+) for rotavirus (RV) antigen and in the Rotarix Group= number of days between the day of vaccination and the date of last stool sample + for RV antigen.
Time frame: From Day 0 up to Week 13.
Population: The analysis was performed on the According To Protocol analysis for immunogenicity, on the twins whose placebo recipient had at least one stool sample positive for the rotavirus strain.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Placebo Group | Duration of Human Rotavirus (HRV) Shedding Per Study Group. | After Dose 1 (n=11, 9) | 17 Number of days |
| Placebo Group | Duration of Human Rotavirus (HRV) Shedding Per Study Group. | After Dose 2 (n=9, 7) | 13 Number of days |
| Placebo Group | Duration of Human Rotavirus (HRV) Shedding Per Study Group. | After Dose 1 (n=11, 9) | 7 Number of days |
| Placebo Group | Duration of Human Rotavirus (HRV) Shedding Per Study Group. | After Dose 2 (n=9, 7) | 1 Number of days |
Secondary
Live Viral Vaccine Load in the Stool of the Twin Receiving Placebo in Case of Transmission.
Number of subjects in the Placebo Group with live virus identified in at least one stool sample in case of transmission.
Time frame: During the entire study period (up to Visit 4, Week 17).
Population: The analysis was performed on the According To Protocol analysis for immunogenicity, on the twins who received placebo in case of transmission.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo Group | Live Viral Vaccine Load in the Stool of the Twin Receiving Placebo in Case of Transmission. | 3 Subjects |
Secondary
Number of Genetic Variation Differences Detected by Sequencing of Genomic Mutations in the HRV Vaccine Strain After Transmission.
Dissimilar amino acid substitutions in the HRV vaccine strain isolated from the twin receiving placebo, when compared to the genetic variation of HRV vaccine strain isolated from the Rotarix vaccine recipients, were counted as genetic variation differences.
Time frame: During the entire study period (up to Visit 4, Week 17).
Population: The analysis was performed on the According To Protocol analysis for immunogenicity, on the twins who received placebo and those who received Rotarix vaccine, in case of transmission.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo Group | Number of Genetic Variation Differences Detected by Sequencing of Genomic Mutations in the HRV Vaccine Strain After Transmission. | 0 Genetic variation difference |
| Placebo Group | Number of Genetic Variation Differences Detected by Sequencing of Genomic Mutations in the HRV Vaccine Strain After Transmission. | 0 Genetic variation difference |
Secondary
Number of Subjects Reporting Any Serious Adverse Events (SAEs).
A serious adverse event (SAE) is any untoward medical occurrence that: results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect in the offspring of a study subject, or may evolve into one of the outcomes listed above.
Time frame: Up to Visit 4.
Population: The analyses were performed on the Total Vaccinated Cohort
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo Group | Number of Subjects Reporting Any Serious Adverse Events (SAEs). | 5 subjects |
| Placebo Group | Number of Subjects Reporting Any Serious Adverse Events (SAEs). | 6 subjects |
Secondary
Number of Subjects Reporting Unsolicited Adverse Events (AEs).
An AE is any untoward medical occurrence in a clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.
Time frame: Within 31 days after any doses.
Population: The analyses were performed on the Total Vaccinated Cohort
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo Group | Number of Subjects Reporting Unsolicited Adverse Events (AEs). | 69 subjects |
| Placebo Group | Number of Subjects Reporting Unsolicited Adverse Events (AEs). | 71 subjects |
Secondary
Number of Subjects With Gastroenteritis (GE) and Rotavirus Gastroenteritis (RV GE) Episodes.
GE episodes were defined as diarrhea (passage of three or more looser than normal stools within a day) with or without vomiting. RV GE episodes were defined as GE episodes for which the stool sample temporally closest to the onset day of the GE episode was positive for rotavirus by Enzyme Linked Immunosorbent Assay (ELISA).
Time frame: Until Visit 4 (Week 17) for GE and until Visit 3 (Week 13) for RV GE.
Population: The analyses were performed on the Total Vaccinated Cohort
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo Group | Number of Subjects With Gastroenteritis (GE) and Rotavirus Gastroenteritis (RV GE) Episodes. | GE episodes | 32 subjects |
| Placebo Group | Number of Subjects With Gastroenteritis (GE) and Rotavirus Gastroenteritis (RV GE) Episodes. | RV GE episodes | 10 subjects |
| Placebo Group | Number of Subjects With Gastroenteritis (GE) and Rotavirus Gastroenteritis (RV GE) Episodes. | GE episodes | 31 subjects |
| Placebo Group | Number of Subjects With Gastroenteritis (GE) and Rotavirus Gastroenteritis (RV GE) Episodes. | RV GE episodes | 6 subjects |