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Trial registered on ANZCTR

Registration number

ACTRN12610000210077

Ethics application status

Approved

Date submitted

1/06/2009

Date registered

15/03/2010

Date last updated

8/03/2016

Type of registration

Prospectively registered

Titles & IDs

Public title

Preventing pneumococcal disease in people without spleens (asplenia) and with poorly functioning spleens (hyposplenia)

Scientific title

In patient without spleens or with poorly functioning ones does a newly licensed paediatric pneumococcal conjugate vaccine assist with preventing pneumococcal sepsis in preventing deaths or severe impairments (which are very costly) from overwhelming post splenectomy sepsis

Universal Trial Number (UTN)

Trial acronym

PAPI Prevention of Asplenic Pneumococcal infection

Linked study record

Health condition

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

Improving and sustaining pneumococcal antibodies in asplenic patients

Better understanding of pneumococcal vaccine regimes in asplenic/hyposplenic patients

Asplenia and Hyposplenia

Condition category

Condition code

Infection

Other infectious diseases

Public Health

Health service research

Infection

Studies of infection and infectious agents

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

Asplenic adults and children aged over 10 years will be administered a licensed pneumococcal 10 valent conjugate vaccine (Synflorix). This is a 10 valent polysaccharide-protein conjugate vaccine containing saccharides of the capsular antigen of Streptococcus pneumoniae (pneumococcus) serotypes 1,4, 5 6B, 7F, 9V, 14, 18C, 19F and 23F individually conjugated to protein D (PD) carrier protein derived from Non-typable Haemophilus inlfuenzae, serotype 18C conjugated to tetanus toxoid (TT) carrier protein, and 19F conjugated to diphtheria toxoid (DT) carrier protein. It will be given once to patients in 3 arms of the study and omitted from the 4th arm (they will have pneumococcal polysaccharide vaccine only).

Intervention code [1]

Treatment: Drugs

Intervention code [2]

Prevention

Comparator / control treatment

We will be inviting people over 10 years of age and adults, without spleens, to be randomised to have either the pneumococcal conjugate vaccine (Synflorix) or the polysaccharide vaccine (Pneumovax 23). There are 4 arms to the study and they vary according to the times thay are adminstered. Synflorix vaccine is a 10 valent polysaccharide-protein conjugate vaccine containing saccharides of the capsular antigen of Streptococcus pneumoniae (pneumococcus) serotypes 1,4, 5 6B, 7F, 9V, 14, 18C, 19F and 23F individually conjugated to protein D (PD) carrier protein derived from Non-typable Haemophilus inlfuenzae, serotype 18C conjugated to tetanus toxoid (TT) carrier protein, and 19F conjugated to diphtheria toxoid (DT) carrier protein. Both vaccines are given intramuscular injection (IMI). Patients will have a 1:4 chance of receiving Pneumovax 23 and a 3:4 chance of receiving the pneumococcal conjugate vaccine. Both are licensened vaccines - the Synflorix is only licensed for children.

Control group

Active

Outcomes

Primary outcome [1]

Objectives
Primary
1(a) To describe the serotype specific immune response in Streptococcus pneumoniae (SP) polysaccharide vaccine (PPV23) naive and experienced hyposplenic adults and children >10 years of age 6 weeks following Streptococcus pneumoniae SP conjugate vaccine (PCV10) as measured by quantitative enzyme-linked immunosorbent assay (ELISA) geometric mean titre (GMT)
1(b) To describe the functional serotype specific immune response in SP polysaccharide (PPV23) vaccine naive and experienced hyposplenic adults and children >10 years of age 6 weeks following Streptococcus pneumoniae SP conjugate vaccine (PCV10) as measured by the opsonophagocytic assay (OPA) geometric mean titre (GMT)

2(a) To compare the quantitative serotype specific immune response as measured by the ELISA geometric mean concentration (GMC) 6 weeks after receiving a first dose of PPV23 performed 6 weeks (early) or 6 months (late) after PCV10 vaccination in adults and children who have not previously been exposed to PPV23 vaccine
2(b) To compare the functional serotype specific immune response 6 weeks as measured by the OPA GMT after receiving a first dose of PPV23 performed 6 weeks (early) or 6 months (late) after PCV10 vaccination in adults and children who have not previously been exposed to PPV23 vaccine

3 In PPV23 experienced hyposplenic adults and children, describe the immune persistence prior to revaccination with PCV10 or PPV23 of serotype specific antibodies against 10 serotypes contained in PPV23 prior to revaccination, measured by ELISA.

4(a) In PPV23 experienced hyposplenic adults and children compare quantitative serotype specific ELISA immune responses to (a) PCV10 followed by PPV23, with (b) PPV23, measured 6 weeks following PPV23
4(b) In PPV23 experienced hyposplenic adults and children compare functional serotype specific OPA immune responses to (a) PCV10 followed by PPV23, with (b) PPV23, measured 6 weeks following PPV23

Timepoint [1]

Visit 1 (day 0) The Investigator (or delegate) must obtain the written informed consent of the participant or parent(s)/guardian(s) according to local laws and requirements before any study-related procedures are performed. Once consent has been obtained the full eligibility check list will be assessed.

Participants who meet all of the inclusion and none of the exclusion criteria and have provided written consent will be allocated to one of 4 treatment groups according to their previous exposure to PCV23 (those with previous exposure randomised between Groups 1 and 2 and those with no exposure between Groups 3 and 4).

The following procedures will be conducted prior to randomisation and the results recorded in the participant's case report forms (CRFs): Medical history (including immunisation history), Demographic data (date of birth, gender, weight, height).Vital signs including temperature (using a digital thermometer), (supine, if possible) blood pressure, pulse and respiratory rate.
Blood samples: full blood examination, pneumococcal ELISA, opsonophagocytic assay). Review of prior and concomitant medication. Once randomised, study vaccines will be administered according to group allocation:
Groups 1-3: PCV10
Groups 4: PPV23
At this time concomitant licensed vaccines will also be administered if indicated and requested by treating physician, including any of:Meningococcal vaccine, Haemphilus influenzae type b vaccine, Influenza vaccine
Participants will be required to complete a 7-Day Diary Card (to record and grade the severity of solicited adverse events (AEs)) for the next 6 days following administration of the vaccine (commencing on the evening of the day of administration). The participant will be given a study thermometer along with instructions on its use.
Visit 2 (6 week visit) The following procedures will be conducted and the results recorded in the participant's medical records and CRF: Brief targeted examination by the research nurse noting any changes since previous visit will be conducted. Measurement of vital signs (oral/axillary temperature, blood pressure, pulse and respiratory rate). Record any AEs that have occurred since the last visit
Review of concomitant medication.
Blood samples for: Immunogenicity (pneumococcal ELISA, opsonophagocytic assay).
Groups 1 and 3 only: give pneumococcal polysaccharide vaccine (PPV). Ask participant to complete the 7-Day Diary Cards and provide instruction for their completion. Diary Card completion should commence on the evening of Visit 2. Instruct the participant or parent(s)/guardian(s) to contact the Investigator immediately if any significant illness or any hospitalisation occurs during the study period, or if temperature >37.5 degrees celsius.
Visit 3 (3 months: Groups 1 and 3 only)
A brief targeted examination by the research nurse noting any changes since previous visit will be conducted
Blood samples for Immunogenicity (pneumococcal ELISA, opsonophagocytic assay), Record and review AEs, Collection and review of concomitant medication.
Visit 4 (6 months: Group 2 only)
A brief targeted examination by the research nurse noting any changes since previous visit will be conducted
Blood samples for:Immunogenicity (pneumococcal ELISA, opsonophagocytic assay), Record and review AEs. Collection and review of concomitant medication.
Administer study vaccine: PPV.
Visit 5 (7.5 months: Group 2 only)
A brief targeted examination by the research nurse noting any changes since previous visit will be conducted, Record and review AEs, Collection of 7-Day Diary Card and review of concomitant medication, Blood samples for Immunogenicity (pneumococcal ELISA, opsonophagocytic assay)
Completion visit 6 (18 months): Visit 4 (Group 1 & 3), Visit 6 (Group 2), Visit 3 (Groups 4) A brief targeted examination by the research nurse noting any changes since previous visit will be conducted, Record and review AEs and serious adverse events (SAEs), Review of concomitant medications and vaccines during study period.Blood samples for:
Immunogenicity (pneumococcal ELISA, opsonophagocytic assay)

Secondary outcome [1]

Persistence of serotype specific anti-pneumococcal antibodies as measured by ELISA antibodies

Timepoint [1]

see above in timepoint 1

Eligibility

Key inclusion criteria

People with a histroy of splenectomy (asplenia) and those with a diagnosis of hyposplenism that is confirmed by presence of Howell Jolly bodies (HJBs) on blood film. To participate in trial patients must be over 10 years of age.

Minimum age

10 Years

Maximum age

No limit

Sex

Both males and females

Can healthy volunteers participate?

Key exclusion criteria

STUDY PARTICIPANTS: Patients who (i) could not comply with study commitments (ii) receiving cancer therapy, (iii) received pneumococal polysaccharide vaccine in previous three years

Study design

Purpose of the study

Treatment

Allocation to intervention

Randomised controlled trial

Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)

Asplenic subjects, according to their prior PPV23 experience categories (naive 2 or experienced) in each category will be prospectively randomised to one of two treatment groups (Naive 2 to Groups 1 or 2; Experienced to Groups 3 or 4) in a 1:1 ratio, according to a randomisation schedule generated by the Clinical Epidemiology and Biostatistics Unit, Murdoch Childrens Research Iinstitue/Royal Children's Hospital.

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

Randomisation will be stratified by previous exposure to PPV23, site and participant’s age, giving a total of 12 strata. The randomisation schedule will be computer generated using block randomisation with random block sizes by Clinical Epidemiology and Biostats Unit (CEBU) at RCH who will keep a confidential copy.

Masking / blinding

Open (masking not used)

Who is / are masked / blinded?

Intervention assignment

Parallel

Other design features

Multicentre

Phase

Phase 4

Type of endpoint/s

Pharmacokinetics

Statistical methods / analysis

Recruitment

Recruitment status

Not yet recruiting

Date of first participant enrolment

Anticipated

20/03/2010

Actual

Date of last participant enrolment

Anticipated

Actual

Date of last data collection

Anticipated

Actual

Sample size

Target

250

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

Recruitment postcode(s) [1]

3004

Recruitment postcode(s) [2]

3025

Recruitment postcode(s) [3]

2034

Recruitment postcode(s) [4]

3168

Funding & Sponsors

Funding source category [1]

Government body

Name [1]

National Health and Medical Research

Address [1]

National Health and Medical Research Council
GPO Box 1421
Canberra ACT 2601

Country [1]

Australia

Primary sponsor type

Government body

Name

National Health and Medical Research

Address

National Health and Medical Research Council
GPO Box 1421
Canberra ACT 2601

Country

Australia

Secondary sponsor category [1]

Hospital

Name [1]

Murdoch Childrens Research Institute, Royal Children's Hospital

Address [1]

Flemington Rd, Parkville Victoria 3052,

Country [1]

Australia

Other collaborator category [1]

Hospital

Name [1]

Alfred hospital

Address [1]

Commercial Road
Melbourne Victoria 3004

Country [1]

Australia

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Alfred Health

Ethics committee address [1]

Alfred Hospital, Hospital Research Ethics Committee, Commercial Road, Prahran Victoria 3181

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

20/05/2009

Approval date [1]

11/06/2009

Ethics approval number [1]

HREC 161/09

Summary

Brief summary

Background

There are thousands of Australians who live without a spleen (asplenia) or have a poorly functioning one (hyposplenia). These people are at a significantly increased risk of life-threatening infections (sepsis).The spleen’s main function is to remove bacteria (bugs) from the blood and therefore plays a very important role in the body’s immune system. The most common bacteria that causes problems for people without or with poorly functioning spleens is the pneumococcus bacteria. Asplenic/hyposplenic patients are more than 200 times more likely to develop pneumococcal sepsis than those with normal spleen function. The mortality rate from pneumococcal sepsis for patients without functioning spleens is extremely high at 40-70%. Even if patients do survive they can be left with severe impairment (morbidity). It is well known that this increased risk of acquiring severe sepsis is a lifelong risk with the majority of life-threatening episodes of infection occurring more than 10 years after spleen removal.


Patients that take antibiotics every day have been shown to have some protection against pneumococcal sepsis. Asplenic/hyposplenic patients are also routinely vaccinated against pneumococcus in an attempt to reduce morbidity and mortality. It is currently not very clear to medical practitioners what the optimal vaccine regimes are to protect this group of patients against pneumococcus, either initially, or for repeat immunisations later in life. Newer pneumococcal vaccines have proven safe and effective in reducing pneumococcal sepsis in young children and may also offer promise for asplenic/hyposplenic older children and adults in addition to the existing pneumococcal vaccine. 

2.	What is the purpose of this study?

This study aims to identify the best way to immunise children and adults, who either do not have a spleen or have a poorly functioning one, against pneumococcal disease. There are three main ways to prevent getting bacterial infections in people like you. These are (i) taking antibiotics every day and/or having an emergency supply of antibiotics, (ii) immunisations and (iii) education. However sometimes patients, despite following the recommendations, get pneumococcal infections. Many pneumococcal vaccine research studies in the past have not included people without spleens or poorly functioning ones, so little is known about how these patients respond to the well known vaccinations. 

There are some new pneumococcal vaccines that have been shown to work better in young children than the older type vaccines. The study team is particularly interested in finding out if these newer vaccines might, in addition to using the routine vaccines, provide better antibody levels to protect against pneumococcal disease and will give the researchers information on when is the best time to administer the new vaccine, This vaccine study will not only target older children and adults who have not had any previous doses of pneumococcal vaccines but it will also include those who may have had at least one pneumococcal vaccine and or those who will require further “booster” doses of vaccine. 

3.	How many people are involved in this study?

This study will be conducted in three sites in Melbourne (the Royal Children’s Hospital, Monash Medical Centre and The Alfred hospital) and a further site in Sydney (Prince of Wales Hospital). A total of 220 people will be invited to participate, 110 participants who have previously received the routinely used pneumococcal polysaccharide vaccine (PPV23) and 110 people who have not. Participants will be adults and children aged over 10 years who are asplenic/hyposplenic. 

4.	What type of research is this study?

This is a study comparing different ways of immunising asplenic/hyposplenic children and adults to see which gives the highest and longer lasting levels of protective antibodies against pneumococcus.

Children and adults with asplenia/hyposplenia will be randomly assigned (like flipping a coin) to one of two treatment groups based on whether or not they have previously received the PPV23 vaccine. 

This research study has been reviewed and approved by the Human Research Ethics Committee at each of the four hospital sites. It is the role of this committee to make sure that research participants are protected from harm.

Trial website

No specific website however there will be information about this trial on the Victiorian Spleen Registry (VSR) website - www.spleen.org.au

Trial related presentations / publications

nil yet

Public notes

Contacts

Principal investigator

Name

Address

Country

Phone

Fax

Contact person for public queries

Name

Penelope Jones

Address

Victorian Spleen Registry
85 Commercial Road
Melbourne Victoria 3004

Country

Australia

Phone

61 3 9076 3828

Fax

61 3 9076 2431

[email protected]

Contact person for scientific queries

Name

Dr Jim Buttery

Address

Murdoch Childrens Research Institute, Royal Children’s Hospital, Flemington Road, Parkville Victoria 3052

Country

Australia

Phone

61 3 9345 4772

Fax

61 3 9345 4163

[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

Documents added manually

No documents have been uploaded by study researchers.

Documents added automatically

No additional documents have been identified.

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