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Trial registered on ANZCTR


Registration number
ACTRN12622000929707
Ethics application status
Approved
Date submitted
2/06/2022
Date registered
29/06/2022
Date last updated
7/04/2024
Date data sharing statement initially provided
29/06/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
Comparison of Immunogenicity and Safety of Sabin and Salk Inactivated Poliovirus Vaccine in Infant Immunization
Scientific title
Comparison of immunogenicity and safety between Sabin and Salk inactivated poliovirus vaccine in the combined bivalent oral poliovirus vaccine schedule in infant immunization: A double blind randomized controlled non-inferiority trial
Secondary ID [1] 307262 0
Nil Known
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Poliomyelitis 326524 0
Condition category
Condition code
Infection 323788 323788 0 0
Other infectious diseases
Public Health 323994 323994 0 0
Other public health

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Brief Name:
Sabin inactivated poliovirus vaccine (Sabin IPV)

Intervention:

After obtaining an informed consent and ensuring that the infant is healthy, participants will be randomized to receive the study intervention (Sabin Inactivated Poliovirus Vaccine/ sIPV)- Arm B or the control comparator vaccine/ Arm A.

sIPV will be administered to all intervention group/ Arm B participants at 14 weeks of age and again at 9 months of age by deep intramuscular injection (0.5ml per dose) in thigh at routine immunization clinic in a community hospital by a nurse trained to administer routine immunization under the national immunization program.


The comparator vaccine conventional inactivated poliovirus vaccine (IPV), the Salk IPV, contains all three wild poliovirus strains, Mahoney type 1, MEF-1 (Middle East Forces) type 2 and Saukett type 3. The viruses are grown either in Vero cells or human diploid (MRC-5) cells and then concentrated, purified and inactivated with formaldehyde. The study intervention, Sabin IPV (sIPV) on the other hand is a trivalent inactivated poliovirus vaccine that contains Sabin strains of poliovirus type 1, type 2 and type 3. The Sabin strains are produced on Vero-cells, concentrated, purified and inactivated. This study will use Sabin IPV (Eupolio™) developed by LG Chem, Seoul, South Korea. Eupolio™ is a clear, colorless solution (0.5 mL/dose) and contains 5, 8 and 16 D antigen units of inactivated Sabin poliovirus type 1, 2, and 3 strains respectively.

The vaccine will be directly administered by the immunization nurse involved with the study and will be recorded in the designated study CRF.
Intervention code [1] 323704 0
Treatment: Drugs
Comparator / control treatment
Conventional Salk Inactivated Poliovirus Vaccine (cIPV) will be administered to all Arm A/ control group participants at 14 weeks of age and again at 9 months of age by deep intramuscular injection (0.5ml per dose) in thigh at routine immunization clinic in a community hospital by a nurse trained to administer routine immunization under the national immunization program.

The vaccine will be directly administered by the immunization nurse involved with the study and will be recorded in the designated study CRF.
Control group
Active

Outcomes
Primary outcome [1] 331568 0
Comparative proportion of children seroconverting against type 2 poliovirus following two doses of Salk IPV or Sabin IPV assessed by microneutralization assay for poliovirus antibodies.
Timepoint [1] 331568 0
At 10 months of infant's age (4 weeks after the second dose of Salk or Sabin IPV)
Secondary outcome [1] 410321 0
Comparative seroconversion rates for poliovirus type 1 after two doses of Salk versus Sabin IPV assessed by microneutralization assay for poliovirus antibodies
Timepoint [1] 410321 0
At 10 months of age (4 weeks after the second dose of Sabin or Salk IPV)
Secondary outcome [2] 411152 0
Comparative seroconversion rates for poliovirus types 3 after two doses of Salk versus Sabin IPV assessed by microneutralization assay for poliovirus antibodies
Timepoint [2] 411152 0
At 10 months of age (4 weeks after the second dose of Sabin or Salk IPV)
Secondary outcome [3] 411153 0
Comparative seroconversion rates to poliovirus type 2 after the first dose of Salk or Sabin IPV assessed by microneutralization assay for poliovirus antibodies
Timepoint [3] 411153 0
At 18 weeks of infant's age (4 weeks after the first dose of Salk or Sabin IPV)
Secondary outcome [4] 411154 0
Comparative seroconversion rates to poliovirus type 1 after the first dose of Salk or Sabin IPV assessed by microneutralization assay for poliovirus antibodies
Timepoint [4] 411154 0
At 18 weeks of infant's age (4 weeks after the first dose of Sabin or Salk IPV)
Secondary outcome [5] 411155 0
Comparative seroconversion rates to poliovirus type 3 after the first dose of Salk or Sabin IPV assessed by microneutralization assay for poliovirus antibodies
Timepoint [5] 411155 0
At 18 weeks of age (4 weeks after the first dose of Salk or Sabin IPV at 14 weeks)
Secondary outcome [6] 411156 0
Comparison of numbers of serious adverse events causally associated to the study vaccine assessed by self reported or physician identified solicited and unsolicited events following immunization

Physician identified as well as self reported adverse events via telephone or during a follow up visit will be recorded in a designated CRF. A participant diary card will be provided to record any adverse events following immunization and the card will be reconciled with participant CRF during subsequent follow up visit.

Solicited adverse events that will be recorded include: Redness at injection site, Injection site painful to touch, Swelling at injection site, Fever, Rash, Convulsion, Irritability/ Agitation, Loss of appetite, Vomiting, Diarrhea, Motor weakness/ Paralysis.
Timepoint [6] 411156 0
At 7 days and 28 days following each dose of study intervention at 14 weeks and 9 months of age
Secondary outcome [7] 411157 0
Comparison of number of all adverse events associated with study vaccine assessed by self reported or physician identified solicited and unsolicited events following immunization


Physician identified as well as self reported adverse events via telephone or during a follow up visit will be recorded in a designated CRF. A participant diary card will be provided to record any adverse events following immunization and the card will be reconciled with participant CRF during subsequent follow up visit.

Solicited adverse events that will be recorded include: Redness at injection site, Injection site painful to touch, Swelling at injection site, Fever, Rash, Convulsion, Irritability/ Agitation, Loss of appetite, Vomiting, Diarrhea, Motor weakness/ Paralysis.
Timepoint [7] 411157 0
At 7 days and 28 days following each dose of study intervention at 14 weeks and 9 months of age

Eligibility
Key inclusion criteria
a. Healthy infant as assessed by study physician during the clinic visit for his/her first dose of bivalent Oral Poliovirus Vaccine (bOPV).
b. Infant between 6-8 weeks of age at first contact.
c. Weight at enrolment visit greater than or equal to 3.0 kgs.
d. Children residing nearby at easily accessible distance (approximately around 30 kms distance) so that these parents are able to attend all scheduled study visits and comply with the study procedures for full length of the study.
e. Parents or primary care givers of these infants who provide written informed consent for their children’s participation in the trial.
Minimum age
6 Weeks
Maximum age
8 Weeks
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
a. Parents and infants who are unable to participate for the full length of the study.
b. Infant who has previously received a prior dose of polio vaccine
c. A diagnosis or suspicion of immunodeficiency disorder either in the infant or in an immediate family member.
d. A diagnosis or suspicion of bleeding or a coagulation disorder.
e. Acute infection or illness at the time of enrolment that would require infant’s admission to a hospital.
f. Evidence of a chronic medical condition identified by a study medical officer during physical exam.
g. Known allergy/sensitivity or reaction to polio vaccines.

Study design
Purpose of the study
Prevention
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Sealed opaque envelopes
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Permuted block randomization generated by study independent statistician
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s

The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 3 / Phase 4
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
Sample size estimation:
Sample size is calculated to provide 90% power for the primary outcome as required sample size to show that Sabin IPV administered in two dose schedules at 14 and 36 weeks is non-inferior, with a non- inferiority margin of 10%, to Salk two full doses schedule. With 90% power, 2.5% alpha error, added 15% for attrition due to dropouts, simple size calculation in equal allocation parallel groups yielded 222 subjects in each arm; the sample size is rounded off to the final study size of 230 participants in each arm. Baseline values for type 2 seroconversion for this calculation was taken at 90% from previously published 2 dose Salk IPV studies.


Statistical Analysis plan:
All analyses will be done using SAS 9.4. P value < 0.05 will be considered as statistical significance.

Primary outcome:
The cumulative seroconversion will be presented as percentages with Clopper-Pearson confidence intervals for each arm. The primary outcome will be compared between the arms using Fisher’s exact test. Median titers will also be presented with 95% Bootstrap confidence intervals as appropriate. These median titers will be compared using Kolmogorov Smirnov two sample test. Reverse cumulative distribution will be plotted and compared using Tarone Ware statistic.

Secondary outcomes:
Percentages with 95% confidence intervals will be presented for all major adverse events in each arm. All secondary outcomes will be compared between the arms using Fisher’s exact test and Clopper-Pearson confidence intervals for seroconversion and median titer and its 95% Bootstrap confidence interval will be presented as well.

Procedures for accounting for missing data:
All laboratory samples collected during the trial will be analyzed in the laboratory unless the sample volume is inadequate for valid results. Subjects who complete all study requirements, including all study visits and have adequate serum samples for laboratory analysis, will be included in the per protocol analysis. We will also perform a modified intention to treat analysis (ITT) for all participants in the study irrespective of partial missing data. Participants who have grossly inadequate serum samples so that the laboratory data is missing on type specific poliovirus antibodies for the baseline visit and the 10 months visit (4+1 week after the second dose of IPV will not be included in the analysis of the primary outcome. Any reciprocal titer above 1448 at baseline will be excluded for further analysis.

Recruitment
Recruitment status
Active, not recruiting
Date of first participant enrolment
Anticipated
1/09/2022
Actual
26/03/2023
Date of last participant enrolment
Anticipated
31/07/2023
Actual
21/02/2024
Date of last data collection
Anticipated
28/11/2024
Actual
Sample size
Target
460
Accrual to date
Final
460
Recruitment outside Australia
Country [1] 24815 0
Nepal
State/province [1] 24815 0
Province 3

Funding & Sponsors
Funding source category [1] 311559 0
Other
Name [1] 311559 0
World Health Organization, Polio Research Committee
Country [1] 311559 0
Switzerland
Primary sponsor type
Other
Name
World Health Organization
Address
PRC Secretariat
Avenue Appia 20
1211 Geneva
Switzerland
Country
Switzerland
Secondary sponsor category [1] 312996 0
None
Name [1] 312996 0
Address [1] 312996 0
Country [1] 312996 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 311008 0
Nepal Health Research Council
Ethics committee address [1] 311008 0
Nepal Health Research Council
Ministry of Health, Government of Nepal
Ramshah Path, Kathmandu, Nepal
P.O.Box 7626
Ethics committee country [1] 311008 0
Nepal
Date submitted for ethics approval [1] 311008 0
03/11/2021
Approval date [1] 311008 0
27/12/2022
Ethics approval number [1] 311008 0

Summary
Brief summary
Poliomyelitis was the leading cause of permanent disability before highly effective oral poliovirus vaccine (OPV) and Salk Inactivated Poliovirus vaccine (IPV) became available. Lately polio disease is largely associated with vaccine strains in oral poliovirus vaccine (OPV), Vaccine Associated Paralytic Poliomyelitis (VAPP) outlining the need to introduce strategies to mitigate the risk of VAPP while maintaining population immunity to polioviruses. In 2015, Strategic Advisory Group of Experts (SAGE) recommended staged OPV withdrawal starting with trivalent (tOPV) to bivalent OPV (bOPV) switch and addition of single dose IPV in OPV using countries but supply constraints resulted in delayed implementation. In 2020, SAGE recommended adding another dose of IPV in routine immunization to maintain population immunity to type 2 and reduce continual threat of polio re-emergence. However, conventional Salk-IPV is expensive with limited supply due to high-quality containment requirements of manufacturing. Sabin IPV (sIPV), a trivalent inactivated poliovirus preparation developed from Sabin strains of oral polioviruses type 1, 2 and 3 has shown good immunogenicity against all poliovirus types. Sabin IPV has been shown non-inferior to Salk IPV in head-to-head trials opening feasibility to use this vaccine in national programs. Immunogenicity data on sequential bOPV-Salk IPV with one or two doses of Salk-IPV (both full dose and fractional) are available but similar data is lacking for bOPV-Sabin IPV sequential schedules. Data on bOPV-Sabin IPV sequential schedules may be particularly important for LMIC countries like Nepal that use fIPV schedules for cost and resources management. We intend to generate more evidence on bOPV-Sabin IPV sequential schedule so that Sabin IPV can become a choice or an alternative to Salk IPV in national immunization schedules.

We aim to conduct a double blind, non-inferiority, randomized controlled trial to evaluate immunogenicity of sequential bOPV + 2 dose Sabin IPV polio immunization schedule.

Healthy Nepali infants attending immunization clinics (230 infants in each arm) for their first dose of pentavalent and polio vaccines will be enrolled, randomized to one of the two study arms and followed up till the end of study at 10 months. Routine immunization will be administered to all infants along study intervention of conventional or Sabin IPV at 14 weeks and 9 months. Blood samples will be obtained from infants at 6 weeks, 18 weeks and 10 months. At the end of study, we will compare proportion of children seropositive against type 2 poliovirus following two doses of Salk IPV versus Sabin IPV.

We believe that this study will add evidence on comparability of immunogenicity and safety of 2 doses of Sabin IPV over conventional Salk IPV in sequential schedule following bOPV in routine immunization.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 119678 0
Dr Arun K Sharma
Address 119678 0
Department of Pediatrics
Institute of Medicine
Tribhuvan University
Maharajgunj, Kathmandu, Nepal
GPO Box 1524
Country 119678 0
Nepal
Phone 119678 0
+977014512202
Fax 119678 0
+00977-01-4418186
Email 119678 0
[email protected]
Contact person for public queries
Name 119679 0
Arun K Sharma
Address 119679 0
Department of Pediatrics
Institute of Medicine
Tribhuvan University
Maharajgunj, Kathmandu, Nepal
GPO Box 1524
Country 119679 0
Nepal
Phone 119679 0
+977014512202
Fax 119679 0
+00977-01-4418186
Email 119679 0
[email protected]
Contact person for scientific queries
Name 119680 0
Arun K Sharma
Address 119680 0
Department of Pediatrics
Institute of Medicine
Tribhuvan University
Maharajgunj, Kathmandu, Nepal
GPO Box 1524
Country 119680 0
Nepal
Phone 119680 0
+977014512202
Fax 119680 0
+00977-01-4418186
Email 119680 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
Individual participant data collected during the trial after de-identification
When will data be available (start and end dates)?
Start date: At least 3 months after official publication of the main results
End date: No end date determined
Available to whom?
Case by case basis at the discretion of primary sponsor
Available for what types of analyses?
Data will be available to achieve the aims/ objectives in the approved proposal.
How or where can data be obtained?
Data will be accessible after approval by principal investigator (approvals dependent on PI communication with sponsor)

Contact details:
Dr Arun K Sharma;
Email: [email protected]


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

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No documents have been uploaded by study researchers.

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