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Trial registered on ANZCTR

Registration number

ACTRN12611000824965

Ethics application status

Approved

Date submitted

19/07/2011

Date registered

4/08/2011

Date last updated

7/03/2012

Type of registration

Prospectively registered

Titles & IDs

Public title

A comparison of the immune response to two different oral polio vaccine regimes in Pakistan

Scientific title

Comparison of immunogenicity of Monovalent oral polio vaccine (mOPVI) administered at short intervals with Monovalent (mOPVI) and Bivalent (bOPV1,3) oral polio vaccine given at standard intervals in healthy infants in Pakistan: a randomized trial

Secondary ID [1]

Nil known

Universal Trial Number (UTN)

Trial acronym

OPV Short Interval Trial

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Poliomyelitis

Condition category

Condition code

Public Health

Epidemiology

Infection

Other infectious diseases

Oral and Gastrointestinal

Normal oral and gastrointestinal development and function

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

1. Standard trivalent oral poliovirus vaccine (tOPV), in a 10:1:6 formulation, containing at least 1 000 000 TCID50 per dose of Sabin -strain poliovirus type 1, at least 100 000 TCID50 per dose of Sabin-strain poliovirus type 2
and at least 600 000 TCID50 per dose of Sabin-strain poliovirus type 3 is given at birth to all 4 groups of subjects.
2. Monovalent type 1 oral poliovirus vaccine (mOPV1) containing at least1 000 000 TCID50 per dose of Sabin- strain poliovirus type 1 is given at 42 days (6 weeks of age) and 7 days later (group 1) or 14 days later (group 2) or 30 days later (group 3).
3. The oral bivalent vaccine containing at least 1 000 000 CCID50 per dose of Sabin poliovirus type 1 and 600 000 CCID50 per dose of Sabin poliovirus type 3 is given to group 4 at 42 days (6 weeks of age) and 30 days later .

Intervention code [1]

Prevention

Comparator / control treatment

The control group 1 will receive tOPV at birth, mOPV1 at 42 days (6 weeks of age) and the last dose of mOPV1 30 days later (10 weeks of age).

Control group

Active

Outcomes

Primary outcome [1]

- A schedule of two doses of mOPV1 administered at a 7 or 14 day interval following a previous mOPV1 dose administered at 42 days induces comparable levels of seroconversion against poliovirus type 1 compared to (i) a schedule of two doses of mOPV1; or (ii) two doses of bOPV1,3 administered at a standard interval of 30 days apart.
The principal purpose of the study is to demonstrate the non-inferiority of shorter intervals (7 or 14 days) between two doses of mOPV1 vaccine compared to 2 doses of mOPV1 and bOPV1,3 administered at standard intervals (30 days apart). This is a phase IV study, and the data generated by this clinical trial are intended to guide programmatic action.

Timepoint [1]

Blood sample at birth, 42 days, 79 days, 86 days, and 102 days

Secondary outcome [1]

Safety:
Adverse events following vaccine administration will be monitored. All participants will be informed to contact the study primary investigators or study physicians at the primary care area clinics if the child requires medical care. Should a serious illness arise requiring a physician visit or hospitalization, parents will receive instructions on who to contact.
No serious adverse effect following the use of live-attenuated Sabin strains in this very young study population (<3 months of age) have been reported.
In the unforeseen instance of serious adverse events after routine DPT, free transport and hospital referral to a tertiary care public sector hospital (National Institute of Child Health) will be arranged as well as provision of cost of care during hospital stay.
The methods and timing for assessing, recording, and analyzing safety parameters:
The study questionnaire will record data during each visit, and for the preceding period, if applicable.
Procedures for eliciting reports of and for recording adverse event and intercurrent illnesses:
As discussed above, parents will be encouraged to use the PHCs run by the study staff for reporting adverse events and seeking care for intercurrent illnesses. They also have the mobile phone number of their local CHW to call for any problem. Adverse events will be recorded in the study forms.
The type and duration of follow-up of subjects after adverse events: Should adverse events occur, referral and cost of medical care at a tertiary public sector hospital will be provided.

Timepoint [1]

After the first dose at birth, at 42 days, at 79 days, at 86 days and at 102 days

Eligibility

Key inclusion criteria

Infants born healthy (> 2.5 kg birth weight, immediate cry, no neonatal IMCI danger signs) at the study sites (home or health facility births assisted by study-Trained Birth Attendants/other health personnel) and not planning to travel away during entire the study period (birth-102 days).

Minimum age

0 Days

Maximum age

0 Days

Sex

Both males and females

Can healthy volunteers participate?

Yes

Key exclusion criteria

High-risk newborns will be excluded, as well as newborns requiring hospitalization, birth weight below 2.5 kg, cry >2 minutes, and with any neonatal IMNCI danger signs, residence >30 km from study site, or family is planning to be absent during the birth - 102 day study period. A diagnosis or suspicion of immunodeficiency disorder (either in the participant or in a member of the immediate family - e.g. several early infant deaths, household member on chemotherapy) will render the newborn ineligible for the study. Subjects will be re-screened for eligibility at the 6 week visit before randomization to study arms. Infants with illness requiring hospitalization, weight <2.5 kg, family planning to be away during the next 10 weeks, or unwilling to have another blood draw will be excluded from randomization. The families of babies with exclusion criteria will be informed about immediate treatment options if their baby is sick (hospital referral and in case of refusal centre-based outpatient care), need for receipt of routine immunizations, and reassured about long term continued assessment and primary level care at the PHC.

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)

Expectant mothers and fathers (if available) will be informed about the study and invited to participate. The parents will be asked to give permission for collection of cord blood at birth or baby's peripheral blood through venepuncture within 24 hours of birth. Informed consent for trial participation will be sought by study personnel at any one of the following time points: late pregnancy follow up visits (36-37 week of gestation) closest to expected date of delivery (EDD); within 24 hours of birth in case the first option could not be availed. Good liaison with the family’s identified birth attendant (traditional birth attendant, TBA, or skilled attendant) will be maintained to ensure presence at time of delivery. The birth attendant will be incentivized to inform our study personnel of impending births if family provides informed consent during late pregnancy follow-up.
After delivery, an evaluation will be done to see whether the newborn meets the eligibility criteria for inclusion into the study (weight >2.5kg, immediate cry, no neonatal danger signs as per IMNCI guidelines). If eligible, the blood (1 ml) will be collected in vaccutainer gel tubes and labelled appropriately. A birth dose of tOPV will be administered to all subjects post informed consent and cord/peripheral blood collection. Cord blood will be collected from babies when a study staff member can be present to ensure study procedures are followed. For infants born between the hours of 9pm at night to 9 am in the morning, which is outside our clinic working hours, the following procedure will be in place: the birth attendant will call a trained community health worker residing locally to collect blood from the cord. In cases of failure to collect cord blood for any reason, peripheral blood will be collected the next day within 24 hours of birth, if, the parents consent. A trained phlebotomist will conduct the venepuncture with optimal consideration to maximizing asepsis and minimizing discomfort to the newborn, allowing a maximum of two attempts.
The parents will be advised to return to the local Primary Health Centre (PHC) at day 42 (6 weeks) of life. Local CHWs will accompany the babies and mothers to the centre on day 42. The infants will undergo a physical exam by a study physician at the center and well infants will be randomized to one of four groups, three receiving the first dose of mOPV1 and the fourth, bivalent OPV1,3 at the day 42 (6 weeks) visit. The randomization procedure will be handled by AKU’s Clinical Trials Unit (CTU) who will inform regarding the infant’s study arm assignment through a text message. One ml of peripheral blood will be collected from each subject after vaccination is complete (second blood sampling).

Methods used to generate the sequence in which subjects will be randomised (sequence generation)

Randomization for assignment to a study arm will take place using a random number generator. This is not a blinded study. Assignments for randomization will be done in a blinded manner by staff based at the Clinical Trial Unit of AKU who will inform the study physician about each infant’s assignment.

Masking / blinding

Open (masking not used)

Who is / are masked / blinded?

Intervention assignment

Parallel

Other design features

different groups of participants receive different interventions during the same time span of the study

Phase

Phase 4

Type of endpoint/s

Safety/efficacy

Statistical methods / analysis

Recruitment

Recruitment status

Withdrawn

Reason for early stopping/withdrawal

Date of first participant enrolment

Anticipated

1/10/2011

Actual

Date of last participant enrolment

Anticipated

Actual

Date of last data collection

Anticipated

Actual

Sample size

Target

800

Accrual to date

Final

Recruitment outside Australia

Country [1]

Pakistan

State/province [1]

Funding & Sponsors

Funding source category [1]

Charities/Societies/Foundations

Name [1]

World Health Organization (WHO)

Address [1]

Avenue Appia 20
Geneva CH-1211

Country [1]

Switzerland

Primary sponsor type

University

Name

Department of Paediatrics and Child Health, Aga Khan University

Address

Aga Khan University (AKU)
Stadium road
P.O. Box 3500
Karachi, 74800

Country

Pakistan

Secondary sponsor category [1]

None

Name [1]

Address [1]

Country [1]

Other collaborator category [1]

Government body

Name [1]

Centers for Disease Control and Prevention(CDC)

Address [1]

1600 Clifton Road
NE Mailstop G17,
Atlanta, GA 30 333

Country [1]

United States of America

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

WHO ERC

Ethics committee address [1]

Avenue Appia 20
Geneva CH-1211

Ethics committee country [1]

Switzerland

Date submitted for ethics approval [1]

01/06/2011

Approval date [1]

13/06/2011

Ethics approval number [1]

RPC454

Summary

Brief summary

An Emergency Action Plan for polio eradication in Pakistan in 2011 has recently been launched by the President of Pakistan which incorporates independent monitoring of immunization activities and increased political accountability at national, federal, district and union council levels, in the hope that eradication goals can be met quickly. As part of this effort, national EPI officers, WHO Polio Eradication Initiative, and other concerned partners are exploring ways of urgently suppressing polio virus activity in Pakistan. A proposed method to attain this is by conducting short-interval polio vaccination campaigns using type 1 monovalent oral polio vaccine (mOPV1) against the prevalent serotype (WPV1), particularly in areas with limited access due to security concerns. An earlier clinical trial in Egypt had demonstrated higher birth dose sero-conversion against WPV1, the main circulating global polio strain using mOPV1 compared to trivalent oral polio vaccine (tOPV) in 2006, leading many countries to use mOPV1 in subsequent supplemental immunization activities (SIA). A randomized, double-blinded trial in three centres in India has also established superiority of monovalent vaccines over trivalent and non inferiority of bivalent compared with monovalent OPV1 and OPV3. One of the major lessons learnt since Global Polio Eradication Initiative (GPEI) began, has been optimizing the impact of the new, highly immunogenic monovalent OPVs. This has proven difficult in practice, and in some settings has contributed to alternating outbreaks of the remaining wild poliovirus type 1 (WPV1) and wild poliovirus type 3 (WPV3) serotypes. The fast-tracked development and introduction of a bivalent OPV1&3 formulation in 2009, and its large-scale use in Supplemental Immunization Activities (SIAs) could complement the continued use of trivalent OPV in some SIAs and in routine immunization, as well as of monovalent OPVs in some mop-ups and SIAs where appropriate.
Typically, SIA rounds are separated by an interval of ~30 days. It is possible that the same level of immunogenicity could be attained by shorter interval spacing as compared to the 30 day interval, allowing multiple SIA rounds to be conducted quickly to eradicate WPV circulation from an area in a very short time period of a few weeks instead of the current situation of having to conduct several rounds over a period of months and more children getting infected in areas of high WPV transmission. For example, in Pakistan, in 2010, intervals between SNIDs ranged from 5-9 weeks. Shorter interval SIA rounds would also have the added benefit of allowing multiple "sweep throughs" in areas of high transmission in a short period of time, increasing the chance that children missed on a previous round will get vaccinated in subsequent rounds. However, there is limited knowledge on the effect of shorter intervals of mOPV vaccination on immunogenicity levels in young children and comparative efficacy of mOPV1 versus bivalent oral polio vaccine containing serotypes 1 and 3 (bOPV1&3). It is assumed more vaccinations administered within a shorter period of time would be non-inferior to regular intervals, defined as an immunization round every 30 days. Although shorter interval immunization rounds were carried out in Somalia, Afghanistan, and Kenya, and were successful in eradicating polio from these areas, there was no documentation of immunogenicity levels in these children.
In order to generate data on 2-dose seroconversion with short interval monovalent OPV1 administration, and standard interval monovalent OPV1 and bivalent OPV (1&3) administration, we propose to assess additional programmatic options for short-interval SIA rounds in Pakistan and conduct a clinical trial in Karachi, Pakistan where immunogenicity of supplemental mOPV doses in a naive population (newborns) needs objective evaluation.

Trial website

Trial related presentations / publications

Public notes

Contacts

Principal investigator

Name

Address

Country

Phone

Fax

Contact person for public queries

Name

Dr. Jackie Fournier-Caruana

Address

World Health Organization
Avenue Appia 20
Geneva CH-1211

Country

Switzerland

Phone

+41 794 755519

Fax

[email protected]

Contact person for scientific queries

Name

Dr. Jackie Fournier-Caruana

Address

World Health Organization
Avenue Appia 20
Geneva CH-1211

Country

Switzerland

Phone

+41 794 755519

Fax

[email protected]

No information has been provided regarding IPD availability

What supporting documents are/will be available?

No Supporting Document Provided

Results publications and other study-related documents

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No additional documents have been identified.

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