Intussusception, Rotavirus Infections
Conditions
Keywords
mechanisms for intussusception, rotavirus vaccine
Brief summary
This is a prospective randomized clinical trial that aims to evaluate the potential effects of the first dose of rotavirus vaccines on gastrointestinal motility and anatomy and blood and stool cytokine responses. It will also assess the association between these outcomes and the pattern of the shedding of vaccine strain rotavirus in the stool. Infants will be randomized to one of four arms: monovalent rotavirus vaccine (Rotarix®, RV1) alone, RV1 with other recommended vaccines, pentavalent rotavirus vaccine (RotaTeq®, RV5) alone, or RV5 with other recommended vaccines. Data derived from the pilot study will be used to assess the feasibility of conducting a larger scale study.
Detailed description
Healthy infants 6-13 weeks of age will be randomized (1:1:1:1) to receive either, RV1 alone, RV1 with Advisory Committee on Immunization Practices (ACIP) routinely recommended immunizations (Diphtheria, Tetanus and Pertussis (DTaP), Haemophilus influenza type b (Hib), pneumococcal conjugate (PCV13), Hepatitis B (HBV) and inactivated polio (IPV)), RV5 alone or RV5 with ACIP routinely recommended immunizations. Imaging study personnel and parents will be blinded to the rotavirus vaccine type; parents will be informed about the rotavirus vaccine type at the completion of the study. Up to 100 infants will be enrolled. Recruitment and enrollment will occur prior to the first clinic visit. There will be four study visits including the recruitment/enrollment visit and three clinic visits. Infants will be randomized to either RV1, RV1 plus other immunizations, RV5 alone, or RV5 plus other immunizations. Clinic Visit 1 (day 0) will include blood, saliva, stool and breast milk collection . The MRI and ultrasound will be performed prior to vaccination. Children will receive the immunizations to which they are randomized. Imaging personnel and parents will be blinded to rotavirus vaccine type; they will be informed about other vaccines administered. A second MRI and ultrasound will be performed at Clinic Visit 2 (day 5) and blood and stool samples collected. Parents will be unblinded at the completion of Clinic Visit 3 (day 14). Arrangements will be made to get remaining doses of same rotavirus vaccine. Daily stool samples will be collected at home during the 15 day study period (on vaccination day 0 and for next 14 days). A memory aid will be completed to collect reactogenicity data on days 0 and for the next 14 days. Remaining stools and reactogenicity data from parents will be collected at Visit 3. The investigators will assess blood and stool cytokine responses and intestinal anatomy and motility after rotavirus vaccination by comparing pre-vaccination with post-vaccination responses in the study infants. Cytokines and intestinal anatomy and motility will be assessed at baseline (Visit 1, the day of vaccine receipt) and 5 days after vaccination (Visit 2). For both blood and stool, the following cytokines will be tested: IL-2, IL-6, IL-7, IL-8, IL-15, INF-γ and TNF-α. Additional biomarkers may be studied.
Interventions
DRUGRotarix®,
Single oral dose of licensed rotavirus vaccine given alone
DRUGRotarix®, with other routine vaccines
Single oral dose of licensed rotavirus vaccine given with other routine vaccines
DRUGRotaTeq®,
Single oral dose of licensed rotavirus vaccine given alone
DRUGRotaTeq®, with other routine vaccines
Single oral dose of licensed rotavirus vaccine given with other routine vaccines
Sponsors
Centers for Disease Control and Prevention
Children's Hospital Medical Center, Cincinnati
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
DOUBLE (Caregiver, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
42 Days to 90 Days
Healthy volunteers
Yes
Inclusion criteria
1. healthy infant 6 to 13 weeks (12 weeks and 6 days) of age at day of rotavirus vaccine administration 2. free of obvious health problems as established by medical history and confirmed with infant's primary physician prior to Visit 1 3. parent/legal guardian willing to have infant feed from a bottle for contrast 4. parent/legal guardian willing and capable of signing informed consent 5. parent/legal guardian and infant expected to be available for entire study 6. parent/legal guardian can be reached by telephone 7. parent/legal guardian expresses willingness to complete study procedures and receive 2 month immunizations, according to recommended schedule
Exclusion criteria
1. gestational age of \<37 weeks 2. infant unable to fast for 4 hours prior to MRI procedure 3. receipt of any vaccine except initial HBV (must have at least 28 days between HBV and Visit 1 to be included) 4. history of severe allergic reaction to HBV vaccine 5. contraindications for any of the routine vaccines 1. Severe Combined Immune Deficiency 2. history of intussusception 6. precautions for either RV1 or RV5 (may interfere with study outcomes) a. altered immunocompetence i. infants with primary and acquired immunodeficiency states, cellular immunodeficiency, hypogammaglobulinemic and dysgammaglobulinemic states ii. infants with blood dyscrasias, leukemia, lymphomas, or other malignant neoplasms affecting the bone marrow or lymphatic system iii. infants on immunosuppressive therapy (including high-dose systemic corticosteroids) iv. infants who are HIV-exposed or infected b. acute gastroenteritis c. moderate or severe acute illness with or without fever d. pre-existing chronic gastrointestinal diseases (e.g., congenital malabsorption syndromes, Hirschsprung's disease, or short-gut syndrome) e. infants with spina bifida or bladder exstrophy (latex rubber is contained in the RV1 oral applicator) 7. sensitivity to latex (latex rubber is contained in the RV1 oral applicator) 8. febrile illness within previous 14 days (axillary temperature of 100.4◦ F or higher) 9. history of vomiting (forceful expulsion of partially digested milk/food) and/or diarrhea (3 watery stools) within 14 days of Visit 1 10. receipt of any steroids, immunoglobulins, other blood products/transfusion 11. receipt of non-steroidal anti-inflammatory drugs in previous 72 hours (may affect cytokine response) 12. receipt of an antipyretic medication (acetaminophen or ibuprofen) within 72 hours prior to the first dose of rotavirus vaccine or is already planning to administer a prophylactic antipyretic medication on the day of and the day following vaccination (this exclusion does not apply if the caretaker indicates he/she might administer antipyretics after vaccination to reduce a fever) 13. is enrolled or plans to enroll in another clinical trial with an investigational product while participating in this study (observational studies are allowed) 14. any condition which, in the opinion of the investigators, may post a health risk to the subject or interfere with the MRI or vaccine evaluation 15. currently receiving medication for gastroesophageal reflux (GERD) or any other gastrointestinal condition including colic 16. infant who is a relative of any research study personnel 17. allergy to barium 18. failed newborn hearing screening \-
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Effects of RV1 and RV5 With or Without Other Routine Immunizations on Gastrointestinal Anatomy | 4- 6 days | Number of subjects with an increase in the number of abdominal lymph nodes, as measured by abdominal ultrasound, or an increase of 1 mm or more of terminal ileum wall thickness, as measured by abdominal MRI, from Day 0 (Visit 1) to Day 4-6 (Visit 2) |
| The Feasibility of Conducting a Larger Scale Study as Determined by Study Recruitment Rates (Number of Participants Eligible/Participants Who Enrolled) | 15 months | Study will be determined to be feasible on a larger scale if 10% or more of eligible subjects enroll in the study |
| The Feasibility of Conducting a Larger Scale Study as Determined by the Percentage of Participants Who Completed All Study Visits | 15 months | Study will be determined to be feasible on a larger scale if 70% or more of randomized subjects complete all study visits and remain in the study until completion |
Countries
United States
Participant flow
Recruitment details
During the study period, there were 252 children screened and of these, 238 were eligible for enrollment. These subjects were identified through screening at a primary care clinic and through advertisement
Pre-assignment details
43 of 144 enrolled participants withdrew prior to randomization
Participants by arm
| Arm | Count |
|---|---|
| Rotarix® Alone monovalent rotavirus vaccine (Rotarix®, RV1)
Rotarix®,: Single oral dose of licensed rotavirus vaccine given alone | 25 |
| Rotarix®,With Other Routine Vaccines monovalent rotavirus vaccine (Rotarix®, RV1), plus additional immunizations
Rotarix®, with other routine vaccines: Single oral dose of licensed rotavirus vaccine given with other routine vaccines | 25 |
| RotaTeq®, Alone pentavalent rotavirus vaccine (RotaTeq®, RV5)
RotaTeq®,: Single oral dose of licensed rotavirus vaccine given alone | 25 |
| RotaTeq®,With Other Routine Vaccines pentavalent rotavirus vaccine (RotaTeq®,RV5) plus additional immunizations
RotaTeq®, with other routine vaccines: Single oral dose of licensed rotavirus vaccine given with other routine vaccines | 26 |
| Total | 101 |
Baseline characteristics
| Characteristic | Total | RotaTeq®,With Other Routine Vaccines | Rotarix® Alone | RotaTeq®, Alone | Rotarix®,With Other Routine Vaccines |
|---|---|---|---|---|---|
| Age, Continuous | 8.2 weeks | 8.4 weeks | 8.5 weeks | 8.2 weeks | 8 weeks |
| Birthweight | 3 kilograms | 3 kilograms | 3 kilograms | 3 kilograms | 3 kilograms |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 0 Participants | 2 Participants | 1 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 98 Participants | 26 Participants | 23 Participants | 24 Participants | 25 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Gestational age at birth (weeks) | 38.8 weeks | 38.8 weeks | 38.6 weeks | 38.9 weeks | 38.8 weeks |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 88 Participants | 23 Participants | 21 Participants | 21 Participants | 23 Participants |
| Race (NIH/OMB) More than one race | 6 Participants | 0 Participants | 3 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 7 Participants | 3 Participants | 1 Participants | 3 Participants | 0 Participants |
| Region of Enrollment United States | 101 Participants | 26 Participants | 25 Participants | 25 Participants | 25 Participants |
| Sex: Female, Male Female | 45 Participants | 12 Participants | 12 Participants | 13 Participants | 8 Participants |
| Sex: Female, Male Male | 56 Participants | 14 Participants | 13 Participants | 12 Participants | 17 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 25 | 0 / 25 | 0 / 25 | 0 / 26 |
| other Total, other adverse events | 25 / 25 | 25 / 25 | 25 / 25 | 25 / 26 |
| serious Total, serious adverse events | 0 / 25 | 0 / 25 | 0 / 25 | 0 / 26 |
Outcome results
Primary
The Effects of RV1 and RV5 With or Without Other Routine Immunizations on Gastrointestinal Anatomy
Number of subjects with an increase in the number of abdominal lymph nodes, as measured by abdominal ultrasound, or an increase of 1 mm or more of terminal ileum wall thickness, as measured by abdominal MRI, from Day 0 (Visit 1) to Day 4-6 (Visit 2)
Time frame: 4- 6 days
Population: Subjects had an abdominal MRI followed by an abdominal ultrasound prior to receiving vaccines at Day 0 (Visit 1). They returned 4-6 days later for follow up MRI and Ultrasound post vaccination (Visit 2) Terminal ileum thickness was measured and compared pre-post. Abdominal lymph nodes seen on ultrasound were compared pre-post
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Rotarix® Alone | The Effects of RV1 and RV5 With or Without Other Routine Immunizations on Gastrointestinal Anatomy | Terminal Ileum increase | 2 Participants |
| Rotarix® Alone | The Effects of RV1 and RV5 With or Without Other Routine Immunizations on Gastrointestinal Anatomy | Lymph node increase | 11 Participants |
| Rotarix®,With Other Routine Vaccines | The Effects of RV1 and RV5 With or Without Other Routine Immunizations on Gastrointestinal Anatomy | Lymph node increase | 9 Participants |
| Rotarix®,With Other Routine Vaccines | The Effects of RV1 and RV5 With or Without Other Routine Immunizations on Gastrointestinal Anatomy | Terminal Ileum increase | 1 Participants |
| RotaTeq®, Alone | The Effects of RV1 and RV5 With or Without Other Routine Immunizations on Gastrointestinal Anatomy | Terminal Ileum increase | 0 Participants |
| RotaTeq®, Alone | The Effects of RV1 and RV5 With or Without Other Routine Immunizations on Gastrointestinal Anatomy | Lymph node increase | 5 Participants |
| RotaTeq®,With Other Routine Vaccines | The Effects of RV1 and RV5 With or Without Other Routine Immunizations on Gastrointestinal Anatomy | Terminal Ileum increase | 1 Participants |
| RotaTeq®,With Other Routine Vaccines | The Effects of RV1 and RV5 With or Without Other Routine Immunizations on Gastrointestinal Anatomy | Lymph node increase | 10 Participants |
Comparison: The test is to see a difference among the four groups and the pre to post change of the primary outcomesp-value: 0.2Fisher Exact
Comparison: The test is to see a difference among the four groups and the pre to post change of the primary outcomesp-value: 0.3Fisher Exact
Primary
The Feasibility of Conducting a Larger Scale Study as Determined by Study Recruitment Rates (Number of Participants Eligible/Participants Who Enrolled)
Study will be determined to be feasible on a larger scale if 10% or more of eligible subjects enroll in the study
Time frame: 15 months
Population: During the study period, there were 252 children screened and of these, 238 were eligible for enrollment. These subjects were identified through screening at a primary care clinic and through advertisement.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Rotarix® Alone | The Feasibility of Conducting a Larger Scale Study as Determined by Study Recruitment Rates (Number of Participants Eligible/Participants Who Enrolled) | 144 Participants |
Primary
The Feasibility of Conducting a Larger Scale Study as Determined by the Percentage of Participants Who Completed All Study Visits
Study will be determined to be feasible on a larger scale if 70% or more of randomized subjects complete all study visits and remain in the study until completion
Time frame: 15 months
Population: All randomized subjects, irrespective of arm assignment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Rotarix® Alone | The Feasibility of Conducting a Larger Scale Study as Determined by the Percentage of Participants Who Completed All Study Visits | 100 Participants |