Infections, Rotavirus
Conditions
Brief summary
This study is planned to evaluate the safety (in terms of occurrence of any serious adverse events), reactogenicity (any side effects) and immunogenicity (ability of the vaccine to develop antibodies that fight infection) of the HRV vaccine when used in pre-term infants aged between 6 and 14 weeks at the time of the first dose in Portugal, France and Poland and in pre-term infants aged between 6 and 12 weeks at the time of first dose in Spain. The study will be performed in four European countries (France, Poland, Spain, and Portugal). 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. Each study group is further stratified into two sub-groups depending on the gestational age at birth of the subject: * Stratum I: very pre-term infants, born after a gestational period of 27-30 weeks (189-216 days) (20% of enrolment). * Stratum II: mild pre-term infants born after a gestational period of 31-36 weeks (217-258 days) (80% of enrolment). The study will be conducted in a double-blind manner with respect to the HRV vaccine and placebo. The study will not be blinded with respect to the type of concomitantly administered routine infant vaccination. In accordance with the local National Plan of Immunisation schedule in each of the respective participating countries, GSK Biologicals' Infanrix Hexa™ (DTPa-HBV-IPV/Hib), Infanrix Quinta™ (DTPa-IPV-Hib), Infanrix™+IPV+Hib (DTPa+IPV+Hib) and/or Engerix-B™ (HBV) will be co-administered (at a maximum interval of two days from each other) with each HRV vaccine or placebo dose. Hepatitis B and Bacille Calmette-Guérin vaccines (BCG) at birth are allowed if included in the local National Plan of Immunisation schedule in participating countries. At the discretion of the investigator the following vaccines may be administered during each subject's study participation: * Vaccine against Streptococcus pneumoniae (Prevenar®) in France and Spain (concomitantly with HRV vaccine/Placebo). * Vaccine against Neisseria meningitidis (Neis Vacc C®) is allowed if there is at least 14-days interval with respect to the administration of the HRV vaccine/Placebo.
Interventions
BIOLOGICALRotarix™
Two-dose oral vaccination.
BIOLOGICALPlacebo
Two-dose oral administration
Sponsors
GlaxoSmithKline
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
6 Weeks to 14 Weeks
Healthy volunteers
Yes
Inclusion criteria
* 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. * Healthy male or female infant between, and including, 6 and 14 weeks (42 - 104 days) of age at the time of first study vaccination in Portugal, France and Poland. A male or female infant between, and including, 6 and 12 weeks of age at the time of first study vaccination in Spain. * Medically stable pre-term infants, born within a gestational period of 27 -36 weeks. * Written informed consent obtained from the parent or guardian of the subject. * Planned to be discharged from hospital's neonatal stay on or before the day of the first HRV vaccine/Placebo administration.
Exclusion criteria
* Use of any investigational or non-registered product (drug or vaccine) other than the HRV vaccine within 30 days preceding the first dose of HRV vaccine, or planned use during the study period. * Chronic administration of immunosuppressants or other immune-modifying drugs since birth. * Planned administration/ administration of a vaccines not foreseen by the study protocol from birth till study end. * 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). * Any clinically significant history of chronic gastrointestinal disease. * Any confirmed or suspected immunosuppressive or immunodeficient condition, based on medical history and physical examination (no laboratory testing required). * History of allergic disease or reactions likely to be exacerbated by any component of the vaccine. * Major congenital defects or serious chronic illness (subjects with severe broncho-pulmonary dysplasia requiring persistent oxygen-therapy will be excluded). * History of any neurologic disorders or seizures. Grade I and II intra-ventricular bleeding are allowed. * Acute disease at the time of enrolment. * Administration of immunoglobulins, and/or any blood products within one month (30 days) preceding the first dose of study vaccines or planned administration during the study period. Monoclonal anti-RSV therapy/prophylaxis and recombinant erythropoietin are allowed.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects Reporting Any Serious Adverse Events (SAEs). | From Day 0 up to 1 month after Dose 2 of Rotarix vaccine/Placebo | An 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects Reporting Unsolicited Adverse Events (AEs), According to Medical Dictionary for Regulatory Activities (MedDRA) Classification. | Within 31 days after any Rotarix vaccine/Placebo dose. | 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 for Whom Each Type of Solicited Symptom Was Reported. | Within 15 days after each Rotarix vaccine/Placebo dose. | Solicited symptoms included Diarrhea (3 or more looser than normal stools/day), Fever (axillary temperature ≥ 37.5 degrees Celsius (°C)), Irritability, Loss of appetite, and Vomiting |
| Number of Subjects for Whom Presence of Rotavirus (RV) Gastroenteritis (GE) Was Detected in Stools. | From Dose 1 up to 1 month after Dose 2 of Rotarix vaccine/Placebo | Gastroenteritis (GE): diarrhoea with or without vomiting. Rotavirus (RV) GE: A GE episode was a RV GE if a stool sample taken during or not later than 7 days after the episode was RV positive by Enzyme Linked Immunosorbent Assay. |
| Seroconversion to Anti-rotavirus Immunoglobulin A (IgA) Antibody. | At Visit 3, 1 month after Dose 2 of Rotarix vaccine/Placebo | Number of subjects with anti-rotavirus IgA antibody concentration ≥ 20 Units/milliliter (U/mL). |
| Serum Anti-Rotavirus IgA Antibody Concentration. | At Visit 3, 1 month after Dose 2 of Rotarix vaccine/Placebo | Anti-rotavirus IgA antibody concentrations are given as geometric mean concentrations (GMC) with 95% Confidence Intervals, calculated on all subjects. |
Countries
France, Poland, Portugal, Spain
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Rotarix Group All subjects received 2 oral doses of Rotarix vaccine, 1 dose at Day 0 and 1 dose at Month 1 or 2 depending on the country. | 670 |
| Placebo Group All subjects received 2 oral doses of placebo, 1 dose at Day 0 and 1 dose at Month 1 or 2 depending on the country. | 339 |
| Total | 1,009 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 2 |
| Overall Study | Age limit exceeded for Dose 2 | 1 | 0 |
| Overall Study | Lost to Follow-up | 10 | 2 |
| Overall Study | Physician Decision | 1 | 1 |
| Overall Study | Protocol Violation | 1 | 0 |
| Overall Study | Recurrent pneumonia & bronchitis | 0 | 1 |
Baseline characteristics
| Characteristic | Rotarix Group | Placebo Group | Total |
|---|---|---|---|
| Age, Continuous | 8.5 weeks STANDARD_DEVIATION 1.77 | 8.5 weeks STANDARD_DEVIATION 1.78 | 8.5 weeks STANDARD_DEVIATION 1.77 |
| Sex: Female, Male Female | 327 Participants | 167 Participants | 494 Participants |
| Sex: Female, Male Male | 343 Participants | 172 Participants | 515 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 199 / 670 | 110 / 339 |
| serious Total, serious adverse events | 34 / — | 23 / — |
Outcome results
Primary
Number of Subjects Reporting Any Serious Adverse Events (SAEs).
An 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: From Day 0 up to 1 month after Dose 2 of Rotarix vaccine/Placebo
Population: The analyses were performed on the Total Vaccinated Cohort that included all the subjects with at least one study vaccine or placebo administration documented.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rotarix Group | Number of Subjects Reporting Any Serious Adverse Events (SAEs). | 34 subjects |
| Placebo Group | Number of Subjects Reporting Any Serious Adverse Events (SAEs). | 23 subjects |
Secondary
Number of Subjects for Whom Each Type of Solicited Symptom Was Reported.
Solicited symptoms included Diarrhea (3 or more looser than normal stools/day), Fever (axillary temperature ≥ 37.5 degrees Celsius (°C)), Irritability, Loss of appetite, and Vomiting
Time frame: Within 15 days after each Rotarix vaccine/Placebo dose.
Population: The analyses were performed on the Total vaccinated cohort for the safety and the immunogenicity subset that included all subjects with at least one study vaccine or placebo administered and for whom solicited symptoms were collected.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Rotarix Group | Number of Subjects for Whom Each Type of Solicited Symptom Was Reported. | Fever | 54 subjects |
| Rotarix Group | Number of Subjects for Whom Each Type of Solicited Symptom Was Reported. | Loss of appetite | 81 subjects |
| Rotarix Group | Number of Subjects for Whom Each Type of Solicited Symptom Was Reported. | Irritability | 133 subjects |
| Rotarix Group | Number of Subjects for Whom Each Type of Solicited Symptom Was Reported. | Vomiting | 52 subjects |
| Rotarix Group | Number of Subjects for Whom Each Type of Solicited Symptom Was Reported. | Diarrhea | 9 subjects |
| Placebo Group | Number of Subjects for Whom Each Type of Solicited Symptom Was Reported. | Vomiting | 27 subjects |
| Placebo Group | Number of Subjects for Whom Each Type of Solicited Symptom Was Reported. | Diarrhea | 5 subjects |
| Placebo Group | Number of Subjects for Whom Each Type of Solicited Symptom Was Reported. | Fever | 29 subjects |
| Placebo Group | Number of Subjects for Whom Each Type of Solicited Symptom Was Reported. | Irritability | 66 subjects |
| Placebo Group | Number of Subjects for Whom Each Type of Solicited Symptom Was Reported. | Loss of appetite | 45 subjects |
Secondary
Number of Subjects for Whom Presence of Rotavirus (RV) Gastroenteritis (GE) Was Detected in Stools.
Gastroenteritis (GE): diarrhoea with or without vomiting. Rotavirus (RV) GE: A GE episode was a RV GE if a stool sample taken during or not later than 7 days after the episode was RV positive by Enzyme Linked Immunosorbent Assay.
Time frame: From Dose 1 up to 1 month after Dose 2 of Rotarix vaccine/Placebo
Population: The analyses were performed on the Total Vaccinated Cohort that included all the subjects with at least one study vaccine or placebo administration documented.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rotarix Group | Number of Subjects for Whom Presence of Rotavirus (RV) Gastroenteritis (GE) Was Detected in Stools. | 3 subjects |
| Placebo Group | Number of Subjects for Whom Presence of Rotavirus (RV) Gastroenteritis (GE) Was Detected in Stools. | 2 subjects |
Secondary
Number of Subjects Reporting Unsolicited Adverse Events (AEs), According to Medical Dictionary for Regulatory Activities (MedDRA) Classification.
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 Rotarix vaccine/Placebo dose.
Population: The analyses were performed on the Total Vaccinated Cohort that included all the subjects with at least one study vaccine or placebo administration documented.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rotarix Group | Number of Subjects Reporting Unsolicited Adverse Events (AEs), According to Medical Dictionary for Regulatory Activities (MedDRA) Classification. | 196 subjects |
| Placebo Group | Number of Subjects Reporting Unsolicited Adverse Events (AEs), According to Medical Dictionary for Regulatory Activities (MedDRA) Classification. | 138 subjects |
Secondary
Seroconversion to Anti-rotavirus Immunoglobulin A (IgA) Antibody.
Number of subjects with anti-rotavirus IgA antibody concentration ≥ 20 Units/milliliter (U/mL).
Time frame: At Visit 3, 1 month after Dose 2 of Rotarix vaccine/Placebo
Population: The analyses were performed on the According-to-Protocol immunogenicity cohort that included all subjects with at least one study vaccine or placebo administered, for whom immunogenicity data were collected and available and who complied with the inclusion criteria defined in the protocol.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rotarix Group | Seroconversion to Anti-rotavirus Immunoglobulin A (IgA) Antibody. | 126 subjects |
| Placebo Group | Seroconversion to Anti-rotavirus Immunoglobulin A (IgA) Antibody. | 13 subjects |
Secondary
Serum Anti-Rotavirus IgA Antibody Concentration.
Anti-rotavirus IgA antibody concentrations are given as geometric mean concentrations (GMC) with 95% Confidence Intervals, calculated on all subjects.
Time frame: At Visit 3, 1 month after Dose 2 of Rotarix vaccine/Placebo
Population: The analyses were performed on the According-to-Protocol immunogenicity cohort. The anti-rotavirus IgA antibody GMC for Placebo Group was below the assay cut-off (\<20 U/mL), so could not be computed.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Rotarix Group | Serum Anti-Rotavirus IgA Antibody Concentration. | 202.2 U/mL |