Potential Mechanisms for Intussusception After Rotavirus Vaccine-Pilot Study

• Sponsor: Children's Hospital Medical Center, Cincinnati (Other)
• Overall Status: Completed
• CT.gov ID: NCT02542462
• Collaborator: Centers for Disease Control and Prevention (U.S. Fed)
• Enrollment: 144
• Location: 1
• Arms: 4
• Actual Duration (Months): 18
• Patients Per Site Per Month: 8

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Intussusception; Rotavirus Infections	Drug: Rotarix®,; Drug: Rotarix®, with other routine vaccines; Drug: RotaTeq®,; Drug: RotaTeq®, with other routine vaccines	Phase 4

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 144 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Care Provider, Outcomes Assessor)
• Primary Purpose: Other
• Official Title: Potential Mechanisms for Intussusception After Rotavirus Vaccine-Pilot Study
• Actual Study Start Date: Nov 1, 2015
• Actual Primary Completion Date: May 1, 2017
• Actual Study Completion Date: May 1, 2017

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Rotarix® alone monovalent rotavirus vaccine (Rotarix®, RV1)	Drug: Rotarix®,; Single oral dose of licensed rotavirus vaccine given alone; Other Names: Rotavirus vaccine
Active Comparator: Rotarix®,with other routine vaccines monovalent rotavirus vaccine (Rotarix®, RV1), plus additional immunizations	Drug: Rotarix®, with other routine vaccines; Single oral dose of licensed rotavirus vaccine given with other routine vaccines; Other Names: Rotavirus vaccine
Active Comparator: RotaTeq®, alone pentavalent rotavirus vaccine (RotaTeq®, RV5)	Drug: RotaTeq®,; Single oral dose of licensed rotavirus vaccine given alone; Other Names: Rotavirus vaccine
Active Comparator: RotaTeq®,with other routine vaccines pentavalent rotavirus vaccine (RotaTeq®,RV5) plus additional immunizations	Drug: RotaTeq®, with other routine vaccines; Single oral dose of licensed rotavirus vaccine given with other routine vaccines; Other Names: Rotavirus vaccine

Outcome Measures

Primary Outcome Measures

1. 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)

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

3. 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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 42 Days to 90 Days
• Sexes Eligible for Study: All
• Accepts 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

6. Severe Combined Immune Deficiency

7. history of intussusception

8. precautions for either RV1 or RV5 (may interfere with study outcomes)

1. 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)

1. sensitivity to latex (latex rubber is contained in the RV1 oral applicator)

2. febrile illness within previous 14 days (axillary temperature of 100.4◦ F or higher)

3. history of vomiting (forceful expulsion of partially digested milk/food) and/or diarrhea (3 watery stools) within 14 days of Visit 1

4. receipt of any steroids, immunoglobulins, other blood products/transfusion

5. receipt of non-steroidal anti-inflammatory drugs in previous 72 hours (may affect cytokine response)

6. 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)

7. is enrolled or plans to enroll in another clinical trial with an investigational product while participating in this study (observational studies are allowed)

8. 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

9. currently receiving medication for gastroesophageal reflux (GERD) or any other gastrointestinal condition including colic

10. infant who is a relative of any research study personnel

11. allergy to barium

12. failed newborn hearing screening

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Cincinnati Children's Hosptital Medical Center	Cincinnati	Ohio	United States	45219

Sponsors and Collaborators

• Children's Hospital Medical Center, Cincinnati
• Centers for Disease Control and Prevention

Investigators

• Principal Investigator: Mary A. Staat, MD, MPH, Children's Hospital Medical Center, Cincinnati
• Principal Investigator: Karen Broder, MD, Centers for Disease Control and Prevention

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Sep 15, 2017

More Information

Publications

None provided.

• Responsible Party: Children's Hospital Medical Center, Cincinnati
• ClinicalTrials.gov Identifier: NCT02542462
• Other Study ID Numbers: 2015-2754
• First Posted: Sep 7, 2015
• Last Update Posted: Jul 12, 2018
• Last Verified: Jul 1, 2018

• Keywords provided by Children's Hospital Medical Center, Cincinnati: mechanisms for intussusception; rotavirus vaccine
• Additional relevant MeSH terms: Rotavirus Infections; Intussusception; Vaccines

Study Results

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 Detail	43 of 144 enrolled participants withdrew prior to randomization

Arm/Group Title	Rotarix® Alone	Rotarix®,With Other Routine Vaccines	RotaTeq®, Alone	RotaTeq®,With Other Routine Vaccines
Arm/Group Description	monovalent rotavirus vaccine (Rotarix®, RV1) Rotarix®,: Single oral dose of licensed rotavirus vaccine given alone	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	pentavalent rotavirus vaccine (RotaTeq®, RV5) RotaTeq®,: Single oral dose of licensed rotavirus vaccine given alone	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
Period Title: Overall Study
STARTED	25	25	25	26
COMPLETED	25	25	25	25
NOT COMPLETED	0	0	0	1

Baseline Characteristics

Arm/Group Title	Rotarix® Alone	Rotarix®,With Other Routine Vaccines	RotaTeq®, Alone	RotaTeq®,With Other Routine Vaccines	Total
Arm/Group Description	monovalent rotavirus vaccine (Rotarix®, RV1) Rotarix®,: Single oral dose of licensed rotavirus vaccine given alone	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	pentavalent rotavirus vaccine (RotaTeq®, RV5) RotaTeq®,: Single oral dose of licensed rotavirus vaccine given alone	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	Total of all reporting groups
Overall Participants	25	25	25	26	101
Age (weeks) [Mean (Full Range) ]
Mean (Full Range) [weeks]	8.5	8	8.2	8.4	8.2
Sex: Female, Male (Count of Participants)
Female	12 48%	8 32%	13 52%	12 46.2%	45 44.6%
Male	13 52%	17 68%	12 48%	14 53.8%	56 55.4%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	2 8%	0 0%	1 4%	0 0%	3 3%
Not Hispanic or Latino	23 92%	25 100%	24 96%	26 100%	98 97%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	21 84%	23 92%	21 84%	23 88.5%	88 87.1%
White	1 4%	0 0%	3 12%	3 11.5%	7 6.9%
More than one race	3 12%	2 8%	1 4%	0 0%	6 5.9%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%
Region of Enrollment (Count of Participants)
United States	25 100%	25 100%	25 100%	26 100%	101 100%
Gestational age at birth (weeks) (weeks) [Mean (Full Range) ]
Mean (Full Range) [weeks]	38.6	38.8	38.9	38.8	38.8
Birthweight (kilograms) [Mean (Full Range) ]
Mean (Full Range) [kilograms]	3	3	3	3	3

Outcome Measures

1. Primary Outcome

Title	The Effects of RV1 and RV5 With or Without Other Routine Immunizations on Gastrointestinal Anatomy
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Rotarix® Alone	Rotarix®,With Other Routine Vaccines	RotaTeq®, Alone	RotaTeq®,With Other Routine Vaccines
Arm/Group Description	monovalent rotavirus vaccine (Rotarix®, RV1) Rotarix®,: Single oral dose of licensed rotavirus vaccine given alone	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	pentavalent rotavirus vaccine (RotaTeq®, RV5) RotaTeq®,: Single oral dose of licensed rotavirus vaccine given alone	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
Measure Participants	25	25	25	25
Terminal Ileum increase	2 8%	1 4%	0 0%	1 3.8%
Lymph node increase	11 44%	9 36%	5 20%	10 38.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Rotarix® Alone, Rotarix®,With Other Routine Vaccines, RotaTeq®, Alone, RotaTeq®,With Other Routine Vaccines
	Comments	The test is to see a difference among the four groups and the pre to post change of the primary outcomes
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2
	Comments	P value for the number of subjects with an increase of 1 mm or more of terminal ileum from pre to post was 0.2
	Method	Fisher Exact
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Rotarix® Alone, Rotarix®,With Other Routine Vaccines, RotaTeq®, Alone, RotaTeq®,With Other Routine Vaccines
	Comments	The test is to see a difference among the four groups and the pre to post change of the primary outcomes
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3
	Comments	P value for change in the number of subjects with an increase in number of lymph nodes from pre to post was 0.3.
	Method	Fisher Exact
	Comments

2. Primary Outcome

Title	The Feasibility of Conducting a Larger Scale Study as Determined by Study Recruitment Rates (Number of Participants Eligible/Participants Who Enrolled)
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	All Study Participants
Arm/Group Description	Infants were randomized to one of four arms: monovalent rotavirus vaccine (Rotarix(r) RV1) alone, RV1 with other recommended vaccines, pentavalent rotavirus vaccine (RotaTeq(r) RV5) alone, or RV5 with other recommended vaccines
Measure Participants	238
Count of Participants [Participants]	144 576%

3. Primary Outcome

Title	The Feasibility of Conducting a Larger Scale Study as Determined by the Percentage of Participants Who Completed All Study Visits
Description	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

Outcome Measure Data

Analysis Population Description

All randomized subjects, irrespective of arm assignment

Arm/Group Title	All Study Participants
Arm/Group Description	Infants were randomized to one of four arms: monovalent rotavirus vaccine (Rotarix(r) RV1) alone, RV1 with other recommended vaccines, pentavalent rotavirus vaccine (RotaTeq(r) RV5) alone, or RV5 with other recommended vaccines
Measure Participants	101
Count of Participants [Participants]	100 400%

Adverse Events

Time Frame	15 days
Adverse Event Reporting Description	solicited adverse events included fever, diarrhea, vomiting, irritability and hematochezia. Parents of infants filled out a memory aid for 15 days recording any of these events.
Arm/Group Title	Rotarix® Alone		Rotarix®,With Other Routine Vaccines		RotaTeq®, Alone		RotaTeq®,With Other Routine Vaccines
Arm/Group Description	monovalent rotavirus vaccine (Rotarix®, RV1) Rotarix®,: Single oral dose of licensed rotavirus vaccine given alone		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		pentavalent rotavirus vaccine (RotaTeq®, RV5) RotaTeq®,: Single oral dose of licensed rotavirus vaccine given alone		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
All Cause Mortality
	Rotarix® Alone		Rotarix®,With Other Routine Vaccines		RotaTeq®, Alone		RotaTeq®,With Other Routine Vaccines
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/25 (0%)		0/25 (0%)		0/25 (0%)		0/26 (0%)
Serious Adverse Events
	Rotarix® Alone		Rotarix®,With Other Routine Vaccines		RotaTeq®, Alone		RotaTeq®,With Other Routine Vaccines
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/25 (0%)		0/25 (0%)		0/25 (0%)		0/26 (0%)
Other (Not Including Serious) Adverse Events
	Rotarix® Alone		Rotarix®,With Other Routine Vaccines		RotaTeq®, Alone		RotaTeq®,With Other Routine Vaccines
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	25/25 (100%)		25/25 (100%)		25/25 (100%)		25/26 (96.2%)
Gastrointestinal disorders
Diarrhea	3/25 (12%)	3	3/25 (12%)	3	3/25 (12%)	3	2/26 (7.7%)	2
Vomiting	8/25 (32%)	8	7/25 (28%)	7	5/25 (20%)	5	8/26 (30.8%)	8
Infections and infestations
Fever	4/25 (16%)	4	1/25 (4%)	1	6/25 (24%)	6	1/26 (3.8%)	1
Nervous system disorders
Irritability	17/25 (68%)	17	15/25 (60%)	15	13/25 (52%)	13	16/26 (61.5%)	16

Limitations/Caveats

This was a pilot study to assess the feasibility of conducting the outlined study and was not powered to detect differences in the anatomy pre-versus post immunization.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.