A Phase II Dose-ranging Study of Oral RV3-BB Rotavirus Vaccine

A Phase II Randomized, Double Blind, Parallel Group Dose-ranging Study of Oral RV3-BB Rotavirus Vaccine Administered at a High, Mid and Low Titre as a 3 Dose Neonate Schedule or Administered at a High Titre as a 3 Dose Infant Schedule.

The purpose of this study is to determine the serum IgA response of three dose levels of the oral RV3-BB vaccine when administered in a neonatal schedule or when administered as a high dose in an infant schedule.

Study Overview

• Status: Completed
• Conditions: Rotavirus Infections
• Intervention / Treatment: Biological: Placebo; Biological: RV3-BB

Detailed Description

The primary objective of this study is to assess the cumulative anti-rotavirus serum IgA response (defined as a ≥3 fold increase from baseline) 4 weeks after 3 doses of RV3-BB administered in a neonatal schedule at a High, Mid or low vaccine titre. In addition the cumulative anti-rotavirus serum IgA response (defined as a ≥3 fold increase from baseline) 4 weeks after 3 doses of RV3-BB administered in an infant schedule at a high dose of vaccine will be assessed along with cumulative vaccine take and components of vaccine take after 3 doses of RV3-BB administered in a neonatal or infant schedule.

The safety and tolerability of RV3-BB when administered as an infant or as a neonatal schedule will be described.

• Study Type: Interventional
• Enrollment (Actual): 711
• Phase: Phase 2

Contacts and Locations

Study Locations

• Malawi
  • Blantyre, Malawi
    • Malawi-Liverpool-Wellcome Trust Clinical Research Programme

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 second to 4 months (Child)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Neonate is less than 6 days (≤144 hours) of age at the time of first dose.
• Neonate is in good health as determined by clinical judgment, including a medical history and physical exam, which confirms the absence of a current or past disease state considered significant by the investigator.
• Neonate birth weight 2500-4000g inclusive.
• Neonate's parents/guardians expect to be available for the duration of the study, and agree to adhere to all protocol requirements.
• Neonate's parents/guardians have provided written informed consent prior to study-related procedures being performed.

Exclusion Criteria:

• Any medical, psychiatric, or social condition of a parent/guardian that in the opinion of the investigator would prevent the neonate's parents/guardians from giving proper informed consent or from complying with the study protocol.
• Neonates with known or suspected major congenital malformations or genetically determined disease.
• Neonates with intussusception.
• Neonates with a known or suspected bleeding diathesis, or any condition that may be associated with a prolonged bleeding time.
• Neonates who have ever received any blood products, including immunoglobulin, or for whom receipt of any blood product during the course of the study is anticipated.
• Neonates in whom Essential Programme Immunisation (EPI) vaccines or components are contraindicated.
• Neonates who have received or who expect to receive during the study period, any rotavirus vaccine other than those which will be administered as part of this study.
• Neonates who have ever received, or who are anticipated to receive during the study period, any investigational agent other than those which will be administered as part of this study.
• Neonates with a previous anaphylactic reaction to any drug, vaccine or vaccine component.
• Neonates with a significant evolving neurological disorder.
• Neonates whose parents/guardians are site team employees with direct involvement with the investigators, or who are working on the study.
• Neonates who have been exposed to immunosuppressive courses of glucocorticosteroids, cytotoxic drugs or blood products through prenatal exposure and/or breast milk in the four weeks prior to randomization.
• Neonates with diarrhoea or vomiting in the 24 hours preceding randomisation.
• Neonates with any moderate or severe illness, and/or who have a temperature of ≥37.5˚C axillary/oral or ≥38˚C rectal/tympanic within the 48 hours preceding randomization.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: High dose RV3-BB neonatal schedule; High dose neonatal RV3-BB vaccine schedule. RV3-BB Vaccine for Investigational product doses 1 (0-5 days), 2 (week 6) and 3 (week 10) and placebo for Investigational product dose 4 (week 14)	Biological: Placebo; Oral administration; Biological: RV3-BB; Oral administration
Experimental: Mid dose RV3-BB neonatal schedule; Mid dose neonatal RV3-BB vaccine schedule. RV3-BB Vaccine for Investigational product doses 1 (0-5 days), 2 (week 6) and 3 (week 10) and placebo for Investigational product dose 4 (week 14)	Biological: Placebo; Oral administration; Biological: RV3-BB; Oral administration
Experimental: Low dose RV3-BB neonatal schedule; Low dose neonatal RV3-BB vaccine schedule. RV3-BB Vaccine for Investigational product doses 1 (0-5 days), 2 (week 6) and 3 (week 10) and placebo for Investigational product dose 4 (week 14)	Biological: Placebo; Oral administration; Biological: RV3-BB; Oral administration
Experimental: High dose RV3-BB infant schedule; High dose infant RV3-BB vaccine schedule. Placebo for Investigational product dose 1 (0-5 days) and RV3-BB Vaccine for Investigational product doses 2 (week 6) 3 (week 10) and dose 4 (week 14)	Biological: Placebo; Oral administration; Biological: RV3-BB; Oral administration

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With a Cumulative Anti Rotavirus Serum Immunoglobulin A (IgA) Response (≥3 Fold Increase From Baseline) in Neonatal Vaccine Schedule at High Mid and Low Dose of RV3-BB	Cumulative anti rotavirus serum Immunoglobulin A (IgA) response is defined as a ≥3 fold increase from baseline at each serum collection time point to 4 weeks after 3 doses of RV3-BB	At serum collection at approximately 14 weeks of age

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With a Cumulative Anti Rotavirus Serum IgA Response (≥3 Fold Increase From Baseline) After 3 Doses in an Infant RV3-BB Schedule	Defined as a ≥3 fold increase from baseline to 4 weeks after 3 doses of RV3-BB at 18 weeks of age	At serum collection visit approximately 18 weeks of age
Serum Anti Rotavirus IgA Titres in Participants Receiving RV3-BB in a Neonatal or Infant Schedule	Expressed as geometric mean titres (GMTs) from baseline to post dose 3 of RV3-BB Minimum 10 Maximum 250,000 Higher score considered to be immunogenic.	At serum collection time points at approximately 14 and 18 weeks of age
Number of Participants With a Cumulative "Vaccine Take" (Serum Anti Rotavirus IgA Response or Shedding of RV3-BB Vaccine Virus) and Components of Vaccine Take After 3 Doses of RV3-BB Administered in a Neonatal or Infant Schedule at a High Dose of RV3-BB.	Vaccine take is defined as at least a threefold increase in serum anti-rotavirus immunoglobulin A (IgA) from baseline to post Investigational product dosing, or detectable RV3 shedding in stools (by ELISA or PCR) any day from day three to day five following administration of Investigational product. Cumulative vaccine take is defined as Vaccine take observed at the current assessment time point or following any previous dose	Sample collections at Week 0 through to approximately 14 and 18 weeks of age
Number of Participants With Cumulative Vaccine Take and Components of Vaccine Take After 3 Doses of RV3-BB Administered in a Neonatal or Infant Schedule at a Mid or Low Dose of RV3-BB	Vaccine take is defined as at least a threefold increase in serum anti-rotavirus immunoglobulin A (IgA) from baseline to post Investigational Product dosing, or detectable RV3 shedding in stools (by ELISA or PCR) any day from day three to day five following administration of Investigational product. Cumulative vaccine take is defined as Vaccine take observed at the current assessment time point or following any previous dose	Sample collections at Week 0 through to approximately 14 and 18 weeks of age
Number of Participants With Cumulative Vaccine Take and Components of Vaccine Take After 2 Doses of RV3-BB Administered in a Neonatal or Infant Schedule at a High, Mid or Low Dose of RV3-BB	Vaccine take is defined as at least a threefold increase in serum anti-rotavirus immunoglobulin A (IgA) from baseline to post Investigational product dosing, or detectable RV3 shedding in stools (by ELISA or PCR) any day from day three to day five following administration of Investigational product. Cumulative vaccine take is defined as Vaccine take observed at the current assessment time point or following any previous dose	Sample collections at Week 0 through to approximately 10 and 14 weeks of age
Number of Participants With Cumulative Vaccine Take and Components of Vaccine Take After 1 Dose of RV3-BB Administered in a Neonatal or Infant Schedule at a High, Mid or Low Dose of RV3-BB	Vaccine take is defined as at least a threefold increase in serum anti-rotavirus immunoglobulin A (IgA) from baseline to post Investigational product dosing, or detectable RV3 shedding in stools (by ELISA or PCR) any day from day three to day five following administration of Investigational product. Cumulative vaccine take is defined as Vaccine take observed at the current assessment time point or following any previous dose	Sample collections at Week 0 through to approximately 6 and 10 weeks of age
Occurrence of Adverse Events (AE)	Number of Participants with Adverse Events	First dose of investigational product to Study End at approximately 18 weeks of age
Occurrence of Serious Adverse Events (SAEs)	Number of participants with Serious Adverse Events (SAEs)	First dose of investigational product to Study End at approximately 18 weeks of age
Occurrence of Diarrhea. Severe	Diarrhea will be described according to severity and detection of wild type rotavirus in diarrhea samples collected. Severity defined using a modified version of the Vesikari clinical score for gastroenteritis. Severed is modified Vesikari score of greater than or equal to 11. The Vesikari scale is a 20-point scale based on duration and peak frequency of diarrhea and vomiting, degree of temperature, severity of dehydration, and treatment provided to the patient (i.e., rehydration or hospitalization). This scale is divided into three ranges: mild <7, moderate 7-10, and severe ≥11	First dose of Investigational product to Study End at approximately 18 weeks of age

Collaborators and Investigators

• Sponsor: Murdoch Childrens Research Institute
• Investigators: Principal Investigator: Desiree Witte, MD MTropPaed, Malawi-Liverpool-Wellcome Trust Clinical Research Programme

Publications and helpful links

General Publications

• Witte D, Handley A, Jere KC, Bogandovic-Sakran N, Mpakiza A, Turner A, Pavlic D, Boniface K, Mandolo J, Ong DS, Bonnici R, Justice F, Bar-Zeev N, Iturriza-Gomara M, Ackland J, Donato CM, Cowley D, Barnes G, Cunliffe NA, Bines JE. Neonatal rotavirus vaccine (RV3-BB) immunogenicity and safety in a neonatal and infant administration schedule in Malawi: a randomised, double-blind, four-arm parallel group dose-ranging study. Lancet Infect Dis. 2022 May;22(5):668-678. doi: 10.1016/S1473-3099(21)00473-4. Epub 2022 Jan 20.

Study record dates

Study Major Dates

• Study Start (Actual): June 15, 2018
• Primary Completion (Actual): January 27, 2020
• Study Completion (Actual): January 27, 2020

Study Registration Dates

• First Submitted: March 23, 2018
• First Submitted That Met QC Criteria: March 23, 2018
• First Posted (Actual): March 30, 2018

Study Record Updates

• Last Update Posted (Actual): July 10, 2023
• Last Update Submitted That Met QC Criteria: July 6, 2023
• Last Verified: July 1, 2023

More Information

Terms related to this study

• Keywords: Dose ranging; Neonatal vaccine; RV3-BB vaccine
• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Reoviridae Infections; Rotavirus Infections
• Other Study ID Numbers: MCRI-RV3-BB-004

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Deidentified group data may be available for sharing on application to the Sponsor. This application must include the relevant proposal detailing the intended use of the data, the Ethics approval for this proposal and requires a signed data sharing agreement. Additional study documents including the study protocol, statistical analysis plan and informed consent are available on application to the Sponsor.
• IPD Sharing Time Frame: For 24 months from publication of the primary outcome.
• IPD Sharing Access Criteria: Data access agreement; Approval by local Ethics committee
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes