The Effects of Increased Inoculum on Oral Rotavirus Vaccine Take and Immunogenicity

• Sponsor: University of Vermont (Other)
• Overall Status: Completed
• CT.gov ID: NCT02992197
• Collaborator: International Centre for Diarrhoeal Disease Research, Bangladesh (Other), Charles H. Hood Foundation (Other), Thrasher Research Fund (Other)
• Enrollment: 220
• Location: 1
• Arms: 2
• Actual Duration (Months): 11.8
• Patients Per Site Per Month: 18.6

Study Details

Study Description

Brief Summary

Rotavirus is the leading cause of diarrhea in children worldwide. Oral rotavirus vaccines work remarkably well in high-income countries, but for unclear reasons they underperform in low-income countries. A double-blind, randomized control trial will be performed to evaluate whether using a higher dose of a currently licensed vaccine (Rotarix, GlaxoSmithKline) can improve immune responses among infants in Dhaka, Bangladesh.

Infants will be randomized 1:1 to receive either a standard or a double dose of Rotarix at 6 and 10 weeks of life. Infants will be assessed for fecal vaccine shedding and serum rotavirus-specific IgA responses to determine vaccine immunogenicity.

Condition or Disease	Intervention/Treatment	Phase
Rotavirus Infection; Vaccine Response Impaired; Vaccine Virus Shedding	Biological: Rotarix, dose 1; Biological: Rotarix, dose 2; Drug: Placebo (for Rotarix dose 2)	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 220 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Prevention
• Official Title: A Double-blind, Randomized Controlled Trial of the Effect of Vaccine Inoculum on Oral Rotavirus Vaccine (Rotarix, GlaxoSmithKline) Take and Immunogenicity in Dhaka, Bangladesh
• Actual Study Start Date: Jun 12, 2017
• Actual Primary Completion Date: Jun 7, 2018
• Actual Study Completion Date: Jun 7, 2018

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Rotarix, single dose Rotarix 1.5 mL (standard single dose) and 1.5 mL of placebo by mouth (sterile, pharmacy-grade water) at both 6 and 10 weeks of life	Biological: Rotarix, dose 1; Rotarix, dose 1; Drug: Placebo (for Rotarix dose 2); Sterile water to provide volume equivalent as a second dose of Rotarix
Experimental: Rotarix, double dose Rotarix 3 mL by mouth (two standard doses administered simultaneously) at both 6 and 10 weeks of life	Biological: Rotarix, dose 1; Rotarix, dose 1; Biological: Rotarix, dose 2; Rotarix, dose 2

Outcome Measures

Primary Outcome Measures

1. Number (or Percentage) of Infants in Each Study Arm Who Test Positive for Fecal Rotavirus Vaccine-strain Virus Shedding Post-vaccination [Measured through week 12 of life]

   This will be an aggregate measure demonstrating a change from baseline. Infants will have stool collected immediately prior to Rotarix vaccination at weeks 6 and 10 of life, then 4, 7, and 14 days following each dose (i.e. last assessment at week 12 of life). Each specimen will be assessed for vaccine-strain virus (i.e. fecal vaccine shedding) at each time point by polymerase chain reaction. Any child who has a change in fecal vaccine shedding status, from negative at baseline (6 weeks) to positive at any subsequent time point, will be categorized as having met the outcome measure for positive fecal vaccine shedding.

2. Number (or Percentage) of Infants in Each Study Arm With Rotavirus-specific Plasma Immunoglobulin A (IgA) Seroconversion Post-vaccination [Measured at week 14 of life]

   This outcome will measure seroconversion, i.e. the change in plasma rotavirus-specific IgA concentration at week 14 of life compared to week 6 of life (baseline). Blood will be collected from infants prior to the first dose of Rotarix at week 6 of life and again at week 14 of life (4 weeks following the second dose) for measurement of plasma rotavirus-specific IgA by enzyme immunoassay. Infants will be assessed for seroconversion (IgA concentration <=20 U/mL pre-vaccination and >20 post-vaccination). Infants who demonstrate rotavirus-specific IgA seroconversion will be categorized as having met the outcome measure.

3. Number (or Percentage) of Infants in Each Study Arm With Successful Vaccine Take, Defined as Positive Fecal Vaccine Shedding Post-vaccination OR Rotavirus-specific Plasma IgA Seroconversion Post-vaccination [Measured at week 14 of life]

   Vaccine take is an aggregate, dichotomous immunogenicity measure (successful vaccine take vs no vaccine take). Infants positive for either fecal vaccine shedding OR plasma rotavirus-specific IgA seroconversion (as described in Outcomes 1 and 2, respectively) will be categorized as having met the outcome measure of successful vaccine take. Those who met neither outcome will be categorized as no vaccine take.

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A to 15 Weeks
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

1. Generally healthy infant (as determined by medical officers)

2. Age 0-7 days at enrolment

3. Mother willing and able to provide signed informed consent

4. Mother willing to allow infant to be vaccinated according to study schedule

5. Mother willing to allow biological specimens, including blood, stool, and saliva, to be collected from infant according to study protocol

6. Mother willing and able to adhere to study schedule

Exclusion Criteria:

1. Obvious congenital malformation

2. Birth weight (if known) or enrolment weight (if birth weight unknown) < 2000 gm

3. Known immunocompromising condition in infant

4. Enrolment in other vaccine research trials

5. Other household member enrolled in this study

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	International Center for Diarrhoeal Disease Research, Bangladesh (icddr,b)	Dhaka		Bangladesh

Sponsors and Collaborators

• University of Vermont
• International Centre for Diarrhoeal Disease Research, Bangladesh
• Charles H. Hood Foundation
• Thrasher Research Fund

Investigators

• Principal Investigator: Benjamin Lee, M.D., University of Vermont

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jul 24, 2019

More Information

Publications

None provided.

• Responsible Party: Benjamin Lee, Assistant Professor, Department of Pediatrics, University of Vermont
• ClinicalTrials.gov Identifier: NCT02992197
• Other Study ID Numbers: CHRMS 17-0166
• First Posted: Dec 14, 2016
• Last Update Posted: Aug 4, 2020
• Last Verified: Jul 1, 2020

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Benjamin Lee, Assistant Professor, Department of Pediatrics, University of Vermont: Rotavirus; Oral vaccines; Vaccine underperformance; Vaccine shedding
• Additional relevant MeSH terms: Rotavirus Infections

Study Results

Participant Flow

Arm/Group Title	Rotarix, Single Dose	Rotarix, Double Dose
Arm/Group Description	Rotarix 1.5 mL (standard single dose) and 1.5 mL of placebo by mouth (sterile, pharmacy-grade water) at both 6 and 10 weeks of life Rotarix, dose 1: Rotarix, dose 1 Placebo (for Rotarix dose 2): Sterile water to provide volume equivalent as a second dose of Rotarix	Rotarix 3 mL by mouth (two standard doses administered simultaneously) at both 6 and 10 weeks of life Rotarix, dose 1: Rotarix, dose 1 Rotarix, dose 2: Rotarix, dose 2
Period Title: Overall Study
STARTED	110	110
COMPLETED	99	103
NOT COMPLETED	11	7

Baseline Characteristics

Arm/Group Title	Rotarix, Single Dose	Rotarix, Double Dose	Total
Arm/Group Description	Rotarix 1.5 mL (standard single dose) and 1.5 mL of placebo by mouth (sterile, pharmacy-grade water) at both 6 and 10 weeks of life Rotarix, dose 1: Rotarix, dose 1 Placebo (for Rotarix dose 2): Sterile water to provide volume equivalent as a second dose of Rotarix	Rotarix 3 mL by mouth (two standard doses administered simultaneously) at both 6 and 10 weeks of life Rotarix, dose 1: Rotarix, dose 1 Rotarix, dose 2: Rotarix, dose 2	Total of all reporting groups
Overall Participants	97	92	189
Age (Count of Participants)
<=18 years	97 100%	92 100%	189 100%
Between 18 and 65 years	0 0%	0 0%	0 0%
>=65 years	0 0%	0 0%	0 0%
Age (days) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [days]	4.8 (1.8)	5.0 (1.8)	4.9 (1.8)
Sex: Female, Male (Count of Participants)
Female	51 52.6%	41 44.6%	92 48.7%
Male	46 47.4%	51 55.4%	97 51.3%
Race and Ethnicity Not Collected (Count of Participants)
Count of Participants [Participants]	0 0%
Region of Enrollment (participants) [Number]
Bangladesh	97 100%	92 100%	189 100%
Birth place (Count of Participants)
Home birth	19 19.6%	25 27.2%	44 23.3%
Hospital/clinic birth	78 80.4%	67 72.8%	145 76.7%
Mode of delivery (Count of Participants)
Vaginal	55 56.7%	50 54.3%	105 55.6%
Caesarean section	42 43.3%	42 45.7%	84 44.4%
Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	2.81 (0.44)	2.86 (0.38)	2.83 (0.42)
Length (cm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cm]	48.9 (2.6)	48.7 (0.21)	48.8 (2.2)
Head circumference (cm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cm]	34.1 (1.3)	34.2 (1.3)	34.1 (1.3)
Water treatment (Count of Participants)
None	24 24.7%	29 31.5%	53 28%
Water filter	4 4.1%	2 2.2%	6 3.2%
Boil	69 71.1%	61 66.3%	130 68.8%
Type of toilet (Count of Participants)
Septic tank or toilet	52 53.6%	45 48.9%	97 51.3%
Water-sealed or slab latrine	41 42.3%	44 47.8%	85 45%
Pit latrine or open latrine	4 4.1%	3 3.3%	7 3.7%
Open drain beside home	44 45.4%	55 59.8%	99 52.4%
Family demographics (Count of Participants)
Mother's education <= secondary	81 83.5%	74 80.4%	155 82%
Father's education <= secondary	71 73.2%	72 78.3%	143 75.7%
Homeowner	43 44.3%	32 34.8%	75 39.7%
Any food deficit	31 32%	37 40.2%	68 36%
Municipal (piped) water source	93 95.9%	80 87%	173 91.5%
Monthly household income in Taka (Taka) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [Taka]	15000	15000	15000

Outcome Measures

1. Primary Outcome

Title	Number (or Percentage) of Infants in Each Study Arm Who Test Positive for Fecal Rotavirus Vaccine-strain Virus Shedding Post-vaccination
Description	This will be an aggregate measure demonstrating a change from baseline. Infants will have stool collected immediately prior to Rotarix vaccination at weeks 6 and 10 of life, then 4, 7, and 14 days following each dose (i.e. last assessment at week 12 of life). Each specimen will be assessed for vaccine-strain virus (i.e. fecal vaccine shedding) at each time point by polymerase chain reaction. Any child who has a change in fecal vaccine shedding status, from negative at baseline (6 weeks) to positive at any subsequent time point, will be categorized as having met the outcome measure for positive fecal vaccine shedding.
Time Frame	Measured through week 12 of life

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Rotarix, Single Dose	Rotarix, Double Dose
Arm/Group Description	Rotarix 1.5 mL (standard single dose) and 1.5 mL of placebo by mouth (sterile, pharmacy-grade water) at both 6 and 10 weeks of life Rotarix, dose 1: Rotarix, dose 1 Placebo (for Rotarix dose 2): Sterile water to provide volume equivalent as a second dose of Rotarix	Rotarix 3 mL by mouth (two standard doses administered simultaneously) at both 6 and 10 weeks of life Rotarix, dose 1: Rotarix, dose 1 Rotarix, dose 2: Rotarix, dose 2
Measure Participants	97	92
Count of Participants [Participants]	63 64.9%	55 59.8%

2. Primary Outcome

Title	Number (or Percentage) of Infants in Each Study Arm With Rotavirus-specific Plasma Immunoglobulin A (IgA) Seroconversion Post-vaccination
Description	This outcome will measure seroconversion, i.e. the change in plasma rotavirus-specific IgA concentration at week 14 of life compared to week 6 of life (baseline). Blood will be collected from infants prior to the first dose of Rotarix at week 6 of life and again at week 14 of life (4 weeks following the second dose) for measurement of plasma rotavirus-specific IgA by enzyme immunoassay. Infants will be assessed for seroconversion (IgA concentration <=20 U/mL pre-vaccination and >20 post-vaccination). Infants who demonstrate rotavirus-specific IgA seroconversion will be categorized as having met the outcome measure.
Time Frame	Measured at week 14 of life

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Rotarix, Single Dose	Rotarix, Double Dose
Arm/Group Description	Rotarix 1.5 mL (standard single dose) and 1.5 mL of placebo by mouth (sterile, pharmacy-grade water) at both 6 and 10 weeks of life Rotarix, dose 1: Rotarix, dose 1 Placebo (for Rotarix dose 2): Sterile water to provide volume equivalent as a second dose of Rotarix	Rotarix 3 mL by mouth (two standard doses administered simultaneously) at both 6 and 10 weeks of life Rotarix, dose 1: Rotarix, dose 1 Rotarix, dose 2: Rotarix, dose 2
Measure Participants	97	92
Count of Participants [Participants]	41 42.3%	42 45.7%

3. Primary Outcome

Title	Number (or Percentage) of Infants in Each Study Arm With Successful Vaccine Take, Defined as Positive Fecal Vaccine Shedding Post-vaccination OR Rotavirus-specific Plasma IgA Seroconversion Post-vaccination
Description	Vaccine take is an aggregate, dichotomous immunogenicity measure (successful vaccine take vs no vaccine take). Infants positive for either fecal vaccine shedding OR plasma rotavirus-specific IgA seroconversion (as described in Outcomes 1 and 2, respectively) will be categorized as having met the outcome measure of successful vaccine take. Those who met neither outcome will be categorized as no vaccine take.
Time Frame	Measured at week 14 of life

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Rotarix, Single Dose	Rotarix, Double Dose
Arm/Group Description	Rotarix 1.5 mL (standard single dose) and 1.5 mL of placebo by mouth (sterile, pharmacy-grade water) at both 6 and 10 weeks of life Rotarix, dose 1: Rotarix, dose 1 Placebo (for Rotarix dose 2): Sterile water to provide volume equivalent as a second dose of Rotarix	Rotarix 3 mL by mouth (two standard doses administered simultaneously) at both 6 and 10 weeks of life Rotarix, dose 1: Rotarix, dose 1 Rotarix, dose 2: Rotarix, dose 2
Measure Participants	97	92
Count of Participants [Participants]	69 71.1%	62 67.4%

Adverse Events

Time Frame	Enrollment (<7 days of life) through week 14 study visit (4 months) for serious adverse events; week 6 visit (first vaccine dose) through Week 14 visit + 3 days (end of participation) for all other AEs (2 months)
Adverse Event Reporting Description	Serious adverse events were recorded from study enrollment (<7 days of life) but all other adverse events were only recorded starting from the first study intervention (at the week 6 clinic visit), the total numbers of children evaluated for serious adverse events (which is based on study enrollment) differs from those evaluated for adverse events (which is based on the number of children dosed starting at week 6 of life, and is less due to attrition between enrollment and first dosing).
Arm/Group Title	Rotarix, Single Dose		Rotarix, Double Dose
Arm/Group Description	Rotarix 1.5 mL (standard single dose) and 1.5 mL of placebo by mouth (sterile, pharmacy-grade water) at both 6 and 10 weeks of life Rotarix, dose 1: Rotarix, dose 1 Placebo (for Rotarix dose 2): Sterile water to provide volume equivalent as a second dose of Rotarix		Rotarix 3 mL by mouth (two standard doses administered simultaneously) at both 6 and 10 weeks of life Rotarix, dose 1: Rotarix, dose 1 Rotarix, dose 2: Rotarix, dose 2
All Cause Mortality
	Rotarix, Single Dose		Rotarix, Double Dose
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/110 (0%)		0/110 (0%)
Serious Adverse Events
	Rotarix, Single Dose		Rotarix, Double Dose
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/110 (1.8%)		4/110 (3.6%)
Gastrointestinal disorders
Diarrhea	1/110 (0.9%)	2	2/110 (1.8%)	4
Subacute intestinal obstruction	0/110 (0%)	0	1/110 (0.9%)	1
Infections and infestations
Sepsis	1/110 (0.9%)	1	0/110 (0%)	0
Respiratory, thoracic and mediastinal disorders
Diaphragmatic hernia	0/110 (0%)	0	1/110 (0.9%)	1
Other (Not Including Serious) Adverse Events
	Rotarix, Single Dose		Rotarix, Double Dose
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	28/107 (26.2%)		31/106 (29.2%)
Gastrointestinal disorders
Diarrhea	18/107 (16.8%)	20	16/106 (15.1%)	17
Gastroenteritis (vomiting and/or diarrhea)	19/107 (17.8%)	21	18/106 (17%)	21
Infections and infestations
Respiratory tract infection	22/107 (20.6%)	24	21/106 (19.8%)	24
Respiratory, thoracic and mediastinal disorders
Cough or runny nose	12/107 (11.2%)	14	18/106 (17%)	19

Limitations/Caveats

[Not Specified]

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.