<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT01735084</url>
  </required_header>
  <id_info>
    <org_study_id>1046999</org_study_id>
    <nct_id>NCT01735084</nct_id>
  </id_info>
  <brief_title>Using Pneumococcal Vaccines in Combination for Maximum Protection From Ear and Lung Infections in First 3 Years of Life</brief_title>
  <acronym>PREV-IX_B</acronym>
  <official_title>Pneumococcal Conjugate Vaccine (PCV) Schedules for the Northern Territory (NT): Randomised Controlled Trial of Booster Vaccines to Broaden and Strengthen Protection From Invasive and Mucosal Infections.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Menzies School of Health Research</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Health and Medical Research Council, Australia</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Menzies School of Health Research</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      HYPOTHESES:&#xD;
&#xD;
        1. That infants receiving PHiD-CV10 as a booster at 12 months of age, compared to controls&#xD;
           having no PHiD-CV10 booster (i.e. standard PCV13), will have higher HiD antibody levels,&#xD;
           lower carriage of NTHi, and less tympanic membrane perforation at 18 and 36 months of&#xD;
           age.&#xD;
&#xD;
        2. That infants receiving PCV13 as a booster at 12 months of age, compared to controls&#xD;
           having no PCV13 (i.e. PHiD-CV10 booster) will have higher antibody levels to serotypes&#xD;
           3, 6A and 19A, less carriage of these serotypes, and less tympanic membrane perforation&#xD;
           at 18 and 36 months of age.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      BACKGROUND:&#xD;
&#xD;
      PCV13 is now the recommended PCV in Australia, as 3+0 for non-Indigenous children and as 3+1&#xD;
      for Indigenous children in Western Australia, Queensland and Northern Territory. The decision&#xD;
      to recommend PCV13 over PHiD-CV10 has been primarily driven by the increase in cases of&#xD;
      invasive pneumococcal disease due to serotype 19A(1). However for the NT, in the last 3 years&#xD;
      there has been one case of serotype 3, 6A or 19A invasive pneumococcal disease (IPD) per year&#xD;
      in Indigenous children less than 2 years of age. By contrast, almost 20% of young Indigenous&#xD;
      children have perforated tympanic membranes of which 60% are associated with NTHi, compared&#xD;
      to 3% having serotypes 3, 6A or 19A.&#xD;
&#xD;
      The PREV-IX_COMBO trial is a randomised controlled trial (RCT) of these two pneumococcal&#xD;
      conjugate vaccines currently licensed in Australia. Participating Indigenous infants living&#xD;
      in remote communities in 4 regions of the NT are randomised between 28 and 38 days of age and&#xD;
      allocated to one of three groups: PHiD-CV10 at 2, 4, 6 months or PCV13 at 2,4,6 months, or an&#xD;
      investigational group of a 4-dose combination schedule of PHiD-CV10 at 1,2, and 4 months plus&#xD;
      PCV13 at 6 months.&#xD;
&#xD;
      PREV-IX_BOOST builds on PREV-IX_COMBO to address questions not answerable by a booster trial&#xD;
      in the general population:&#xD;
&#xD;
      The 7 month visit is the final assessment included in the PREV-IX_COMBO trial. In October&#xD;
      2011 the standard PCV schedule for all Indigenous babies in the NT switched from PHiD-CV10 to&#xD;
      PCV13 at 2, 4, 6 and 18 months of age. Thus, all babies in PREV-IX_COMBO will go on to&#xD;
      receive PCV13 at 18 months of age as a part of standard care. An alternative and innovative&#xD;
      option is to take this opportunity to answer these questions: should PCV13 or PHiD-CV10&#xD;
      vaccine be the booster vaccine for infants in the three PREV-IX_COMBO groups, and at what age&#xD;
      should the booster be given? Secondary questions: By randomising the three different primary&#xD;
      course groups to booster dose of either PHiD-CV10 or PCV13, a number of secondary questions&#xD;
      can be proposed. Outputs include the comparative benefit (immune and carriage correlates) of&#xD;
      schedules such as 3+1 PCV13, 3+1 PHiD-CV10, and mixed vaccine schedules such as single dose&#xD;
      PCV13 or single dose PHiD-CV10 boosters following alternate vaccines in the primary course,&#xD;
      and booster options following the early and mixed 4-dose primary course. Furthermore the&#xD;
      design will allow for an evaluation at 18 months of age, of a 12 month boost versus no boost&#xD;
      of specific vaccine components unique to each of these vaccines. For example, a comparison of&#xD;
      the booster effect of HiD (in PHiD-CV10) with no HiD boost (PCV13) on antibody concentration&#xD;
      and nasopharyngeal carriage at 18 months. By combining some of these groups it will be&#xD;
      possible to compare more subtle differences such as differences in immunogenicity of&#xD;
      serotypes shared by the two vaccines (1,4,5,6B,7F,9V,14,18C,19F,23F) but with different&#xD;
      carrier proteins and thus anticipated differences in immunogenicity.&#xD;
&#xD;
      PCVs in the NT: PCV7, PHiD-CV10 (Synflorix) and PCV13 (Prevenar13):&#xD;
&#xD;
      Prevention of invasive pneumococcal disease (IPD) is the primary goal of pneumococcal&#xD;
      conjugate vaccination in infants. Effectiveness against overall IPD has generally remained&#xD;
      high although IPD caused by non-PCV7 types has increased in some high risk groups and&#xD;
      regions, particularly associated with serotypes 19A, 6A, and 33F. These increases have been&#xD;
      described as a 'replacement phenomenon'. In addition there are ongoing outbreaks of IPD due&#xD;
      to non-PCV7 types; in the NT and WA serotypes 1 and 12F account for resurgence in IPD cases&#xD;
      in otherwise low risk groups. Effectiveness of PCVs for all-cause pneumonia and otitis media&#xD;
      has been greatly compromised by replacement serotypes and the broad diversity of&#xD;
      non-pneumococcal respiratory bacterial pathogens which continue to cause high rates of&#xD;
      disease, such as non-typeable H. influenzae (NTHi). Replacement serotypes, particularly&#xD;
      19A(2,3) and NTHi, are the targets of new generation vaccines. In Australia two new PCVs are&#xD;
      licensed: 10-valent pneumococcal-Haemophilus influenzae protein-D conjugate vaccine,&#xD;
      PHiD-CV10 (Synflorix, GSK) and 13-valent PCV, PCV13 (Prevenar13, Pfizer). The two vaccines&#xD;
      have 10 pneumococcal serotypes in common (1,4,5,6B,7F,9V,14,18C,19F,23F), however these are&#xD;
      conjugated to different carrier proteins and immune correlates indicate potential vaccine&#xD;
      differences in efficacy for individual serotypes. PHiD-CV10 has protein D of NTHi as the&#xD;
      carrier for some serotypes and PCV13 is non-toxic diphtheria protein (CRM197)-conjugated, as&#xD;
      was its precursor PCV7, and has three additional serotypes (3, 6A and 19A) but not HiD. There&#xD;
      have been no efficacy trials that directly compare these vaccines; licensure has been based&#xD;
      on immune correlates of protection in comparison with PCV7. Evidence of HiD efficacy has come&#xD;
      from a single RCT in which otitis media was a primary outcome. In that trial of the original&#xD;
      formulation (PHiD-CV11) there was ~55% efficacy for vaccine type AOM, and 35% efficacy for&#xD;
      NTHi AOM following a 3+1 schedule.(3) This trial also demonstrated a 43% (95% Confidence&#xD;
      Interval (CI): -17 to 72, ns) reduction in the carriage of vaccine serotypes and a 43% (95%&#xD;
      CI: 1-67) reduction in the carriage of H. influenzae. This finding has not been replicated in&#xD;
      later trials, partially due to very low baseline rates of NTHi carriage (&lt;10%) and thus low&#xD;
      power to achieve statistical significance. The PREV-IX_COMBO trial will therefore be very&#xD;
      important in providing data on immunological correlates and carriage for different PHiD-CV10&#xD;
      schedules. However, an extended follow-up and comparison of booster dose (this PREV-IX_BOOST&#xD;
      proposal) will provide further evidence for or against inclusion of PHiD-CV10 as a booster&#xD;
      (compared to the NT standard PCV13 at 18 months).&#xD;
&#xD;
      In the NT, booster pneumococcal vaccines are recommended at 18 months of age. This is largely&#xD;
      due to the previous schedule which included 23-valent pneumococcal polysaccharide vaccine&#xD;
      (23PPV) as a booster dose at 18 months. A 3+1 PHiD-CV10 schedule replaced 3+1 PCV7-23PPV in&#xD;
      2009, and the booster age remained at 18 months. In Queensland (QLD) and in Western Australia&#xD;
      (WA) the vaccination schedules allow for PCV13 boost at 12 months of age for high risk and&#xD;
      Indigenous children.&#xD;
&#xD;
      At present there are 4 intra-muscular immunizations (IMIs) at 12 months of age for Indigenous&#xD;
      infants in the Northern Territory childhood vaccination schedule. A combined booster dose&#xD;
      vaccine (e.g. Menitorix) became available in Australia prior to commencement of first&#xD;
      enrolment into the BOOST study. This reduces the number of IMIs at 12 months of age and&#xD;
      provides a 'space' for PCV at 12 months. Administration of PCV booster, originally scheduled&#xD;
      for 13 months of age, will be at 12 months of age for the trial.&#xD;
&#xD;
      Surveillance of otitis media in remote communities shows high rates of disease from weeks&#xD;
      after birth throughout early childhood, particularly tympanic membrane perforations in the&#xD;
      second year of life, and thus supports the need for a booster dose. Between 2008 and 2010, in&#xD;
      PCV7-vaccinated children, mean age of tympanic membrane perforation was 18 months; for&#xD;
      children with AOM with perforation (AOMwiP), the mean age was 13 months and for chronic&#xD;
      suppurative OM (CSOM) 21 months. IPD cases occurring in Indigenous and non-Indigenous&#xD;
      children less than 2 years of age for all serotypes; in 2009 there were 7 cases; in 2011 8&#xD;
      cases. The majority of IPD cases in children under 2 years occurred between 12 and 18 months.&#xD;
&#xD;
      In summary, the precedent of a 12 month PCV booster for Indigenous children in WA and QLD,&#xD;
      and the high incidence of IPD and OM in the first half of the second year of life support the&#xD;
      decision to choose a 12 month booster for this study. The mixed schedules will still allow us&#xD;
      to compare boost versus no boost for HiD, 3,6A and 19A.&#xD;
&#xD;
      Antibody decay post-primary PCV7 to pre-booster:&#xD;
&#xD;
      Furthermore, published data(4) from the PCV7 era which show post-primary antibody levels at&#xD;
      mean age 15 months (range 0.32 to 0.83 microg/mL for all but serotype 14) have declined&#xD;
      almost to those detected in cord blood (range 0.3647 to 1.1797 microg/mL). The clinical&#xD;
      implications of this decay in terms of memory response and duration of protection from&#xD;
      mucosal infections, pneumonia and otitis media, are not known, however vaccine efficacy is&#xD;
      lower for mucosal compared to invasive infection(5). Which vaccine for the booster dose?&#xD;
&#xD;
      Mucosal disease (OM and respiratory illness):&#xD;
&#xD;
      Culture of ear discharge from these perforations shows 60% of specimens from AOMwiP cultured&#xD;
      NTHi and 26% cultured pneumococcus. For CSOM, these figures were 47% and 23% respectively.&#xD;
      Serotyping identified 19A or 6A in 20% of pneumococcal isolates, which translates to 5%&#xD;
      AOMwip and 4% CSOM specimens. NTHi is also associated with exacerbations of chronic&#xD;
      suppurative lung disease (CSLD), or bronchiectasis, in young Indigenous children.(6)&#xD;
      Percentage of ear discharge specimens with OM pathogens pneumococcus (Spn), 19A, NTHi, M.&#xD;
      catarrhalis or neither Spn nor NTHi.&#xD;
&#xD;
      Evidence for efficacy of single dose PHiD-CV10 boost &amp; inclusion in Australian PCV13 3+0&#xD;
      schedule:&#xD;
&#xD;
      A single dose of PHiD-CV10 might be valuable for many Australian children now receiving the&#xD;
      3+0 PCV13 schedule, to provide some immune protection from NTHi. Group 2 of the PREV-IX_COMBO&#xD;
      trial receive either PCV13 at 2,4,6 months and will be randomised in this study to PCV13 (4th&#xD;
      dose) or PHiD-CV10 (1st dose) at 12 months of age. Vesikari et al.(7) evaluated a single dose&#xD;
      of PHiD-CV as catch-up (not booster) in 2 to 5 year old children. Following 1 dose in the 2&#xD;
      to 5 years group ELISA pneumococcal responses were lower than the reference group (reference&#xD;
      group: 3 primary doses with booster at 12 to 15 months) for several serotypes. Responses&#xD;
      following 1 dose in children 2 to 5 years of age suggested that 2 doses may be preferable.&#xD;
      Unfortunately, HiD Geometric Mean Concentrations (GMCs) were not reported. A trial underway&#xD;
      in Queensland will evaluate a double dose of PHiD-CV10 in preventing exacerbations of CSLD in&#xD;
      older children. The BOOST trial in non-CSLD children will complement those data.&#xD;
&#xD;
      Invasive disease due to PCV13 serotypes 3, 6A and 19A:&#xD;
&#xD;
      In 2009, there were 89 cases of IPD in the NT population, 59 in 2010 and 114 in 2011; 25&#xD;
      (10%) of these 262 cases were the unique PCV13 serotypes (3, 6A and 19A) and 17(7%) of these&#xD;
      were Indigenous, four (1.5%) were Aboriginal children &lt; 2 years of age - about one per year&#xD;
      (unpublished, Centre for Disease Control, NT Health).&#xD;
&#xD;
      Episodes of AOM and respiratory illness to 3 years of age:&#xD;
&#xD;
      A very high rate of clinic presentations occurs for babies and young children in remote&#xD;
      communities. Our antibiotic trial for prevention of OM randomised infants at mean age 5&#xD;
      months(9,10) and recorded episodes of illness in placebo and active groups during&#xD;
      approximately 6 months (unpublished). Around 9 episodes of primary respiratory illness or AOM&#xD;
      (8.2 + 0.8) were recorded in notes per child year in the second 6 months of life. There are&#xD;
      no published data for illness in the second and third years of life for this population.&#xD;
      Whilst the BOOST study is unlikely to be sufficiently powered to detect group differences in&#xD;
      rates of illness, these will be measured and reported.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">March 12, 2013</start_date>
  <completion_date type="Actual">October 3, 2019</completion_date>
  <primary_completion_date type="Actual">February 14, 2019</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Prevention</primary_purpose>
    <masking>Single (Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Immune response</measure>
    <time_frame>At 18 months of age</time_frame>
    <description>The primary outcome will be the proportion of subjects with serotype-specific antibody above the level required for protection from IPD in each study group at 18 months of age, 6 months after the booster dose. This will be determined in ELISA assays.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Nasopharyngeal carriage</measure>
    <time_frame>At 12, 18 and 36 months of age</time_frame>
    <description>At baseline (12 mo), 18 and 36 months of age, the proportion of children with a any carriage of serotype 3, 6A and 19A pneumococci b any carriage of any NTHi</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Otitis media</measure>
    <time_frame>At 12, 18 and 36 months of age</time_frame>
    <description>At baseline (12 mo), 18 and 36 months of age, the proportion of children with c any otitis media. d any tympanic membrane perforation</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Episodes of respiratory illness and acute otitis media</measure>
    <time_frame>Between baseline (12 mo) and 36 months of age</time_frame>
    <description>Between baseline (12 mo) and 36 months of age Episodes of respiratory illness and acute otitis media</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">261</enrollment>
  <condition>Otitis Media</condition>
  <condition>Febrile Illness</condition>
  <condition>Cough</condition>
  <condition>Lower Respiratory Tract Infection</condition>
  <condition>Upper Respiratory Tract Infection</condition>
  <arm_group>
    <arm_group_label>Prevenar13</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>The booster dose of Prevenar13 is 0.5 mL given intramuscularly only, with care to avoid injection into or near nerves and blood vessels. The preferred sites are anterolateral aspect of the thigh (vastus lateralis muscle) in infants or the deltoid muscle of the upper arm in young children.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Synflorix</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>The booster vaccination schedule consists of one dose of 0.5 ml with an interval of at least 1 month between doses.</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Prevenar13</intervention_name>
    <description>The vaccine is a ready to use homogeneous white suspension for intramuscular injection, supplied as a pre-filled syringe.&#xD;
Active ingredients&#xD;
Each 0.5 mL dose contains:&#xD;
2.2 μg of pneumococcal purified capsular polysaccharides for serotypes 1, 3, 4, 5, 6A, 7F, 9V, 14, 18C, 19A, 19F and 23F 4.4 μg of pneumococcal purified capsular polysaccharides for serotype 6B. Each serotype is individually conjugated to non-toxic diphtheria CRM197 protein and adsorbed on aluminium phosphate (0.565 mg).</description>
    <arm_group_label>Prevenar13</arm_group_label>
    <other_name>PCV13</other_name>
    <other_name>Prevnar13</other_name>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Synflorix</intervention_name>
    <description>The 10-valent vaccine contains 1 µg of purified capsular polysaccharide of pneumococcal serotypes 1, 5, 6B, 7F, 9V, 14, and 23F conjugated to protein D, 3 µg of serotype 4 conjugated to protein D, 3 µg of serotype 18C conjugated to tetanus toxoid and 3 µg of serotype 19F conjugated to diphtheria toxoid.</description>
    <arm_group_label>Synflorix</arm_group_label>
    <other_name>PHiD-CV</other_name>
    <other_name>PHiD-CV10</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Australian Indigenous infant who was a participant in PREV-IX_COMBO trial of primary&#xD;
             course pneumococcal conjugate vaccines, age at least 2 months post final dose of&#xD;
             primary course. Signed informed consent.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  adverse reaction to Prevenar13 or Synflorix&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>9 Months</minimum_age>
    <maximum_age>3 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Amanda J Leach, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Menzies School of Health Research</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Menzies School of Health Research</name>
      <address>
        <city>Darwin</city>
        <state>Northern Territory</state>
        <zip>0810</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Australia</country>
  </location_countries>
  <reference>
    <citation>Williams SR, Mernagh PJ, Lee MH, Tan JT. Changing epidemiology of invasive pneumococcal disease in Australian children after introduction of a 7-valent pneumococcal conjugate vaccine. Med J Aust. 2011 Feb 7;194(3):116-20. doi: 10.5694/j.1326-5377.2011.tb04192.x.</citation>
    <PMID>21299484</PMID>
  </reference>
  <reference>
    <citation>Miller E, Andrews NJ, Waight PA, Slack MP, George RC. Effectiveness of the new serotypes in the 13-valent pneumococcal conjugate vaccine. Vaccine. 2011 Nov 15;29(49):9127-31. doi: 10.1016/j.vaccine.2011.09.112. Epub 2011 Oct 5.</citation>
    <PMID>21983361</PMID>
  </reference>
  <reference>
    <citation>Weinberger DM, Malley R, Lipsitch M. Serotype replacement in disease after pneumococcal vaccination. Lancet. 2011 Dec 3;378(9807):1962-73. doi: 10.1016/S0140-6736(10)62225-8. Epub 2011 Apr 12.</citation>
    <PMID>21492929</PMID>
  </reference>
  <reference>
    <citation>Leach AJ, Morris PS, Mackenzie G, McDonnell J, Balloch A, Carapetis J, Tang M. Immunogenicity for 16 serotypes of a unique schedule of pneumococcal vaccines in a high-risk population. Vaccine. 2008 Jul 23;26(31):3885-91. doi: 10.1016/j.vaccine.2008.05.012. Epub 2008 May 27.</citation>
    <PMID>18562052</PMID>
  </reference>
  <reference>
    <citation>Black S, Shinefield H, Fireman B, Lewis E, Ray P, Hansen JR, Elvin L, Ensor KM, Hackell J, Siber G, Malinoski F, Madore D, Chang I, Kohberger R, Watson W, Austrian R, Edwards K. Efficacy, safety and immunogenicity of heptavalent pneumococcal conjugate vaccine in children. Northern California Kaiser Permanente Vaccine Study Center Group. Pediatr Infect Dis J. 2000 Mar;19(3):187-95. doi: 10.1097/00006454-200003000-00003.</citation>
    <PMID>10749457</PMID>
  </reference>
  <reference>
    <citation>Hare KM, Grimwood K, Leach AJ, Smith-Vaughan H, Torzillo PJ, Morris PS, Chang AB. Respiratory bacterial pathogens in the nasopharynx and lower airways of Australian indigenous children with bronchiectasis. J Pediatr. 2010 Dec;157(6):1001-5. doi: 10.1016/j.jpeds.2010.06.002. Epub 2010 Jul 24.</citation>
    <PMID>20656297</PMID>
  </reference>
  <reference>
    <citation>Vesikari T, Karvonen A, Korhonen T, Karppa T, Sadeharju K, Fanic A, Dieussaert I, Schuerman L. Immunogenicity of 10-valent pneumococcal nontypeable Haemophilus Influenzae Protein D Conjugate Vaccine when administered as catch-up vaccination to children 7 months to 5 years of age. Pediatr Infect Dis J. 2011 Aug;30(8):e130-41. doi: 10.1097/INF.0b013e31821d1790.</citation>
    <PMID>21540760</PMID>
  </reference>
  <reference>
    <citation>Clucas DB, Carville KS, Connors C, Currie BJ, Carapetis JR, Andrews RM. Disease burden and health-care clinic attendances for young children in remote aboriginal communities of northern Australia. Bull World Health Organ. 2008 Apr;86(4):275-81. doi: 10.2471/blt.07.043034.</citation>
    <PMID>18438516</PMID>
  </reference>
  <reference>
    <citation>Leach AJ, Morris PS, Mathews JD; Chronic Otitis Media Intervention Trial - One (COMIT1) group. Compared to placebo, long-term antibiotics resolve otitis media with effusion (OME) and prevent acute otitis media with perforation (AOMwiP) in a high-risk population: a randomized controlled trial. BMC Pediatr. 2008 Jun 2;8:23. doi: 10.1186/1471-2431-8-23.</citation>
    <PMID>18513453</PMID>
  </reference>
  <reference>
    <citation>Simell B, Nurkka A, Lahdenkari M, Givon-Lavi N, Kayhty H, Dagan R, Jokinen J. Association of serotype-specific antibody concentrations and functional antibody titers with subsequent pneumococcal carriage in toddlers immunized with a 9-valent pneumococcal conjugate vaccine. Clin Vaccine Immunol. 2012 Jan;19(1):96-9. doi: 10.1128/CVI.05369-11. Epub 2011 Nov 9.</citation>
    <PMID>22072724</PMID>
  </reference>
  <reference>
    <citation>Leach AJ, Morris PS, McCallum GB, Wilson CA, Stubbs L, Beissbarth J, Jacups S, Hare K, Smith-Vaughan HC. Emerging pneumococcal carriage serotypes in a high-risk population receiving universal 7-valent pneumococcal conjugate vaccine and 23-valent polysaccharide vaccine since 2001. BMC Infect Dis. 2009 Aug 4;9:121. doi: 10.1186/1471-2334-9-121.</citation>
    <PMID>19650933</PMID>
  </reference>
  <reference>
    <citation>Prymula R, Kriz P, Kaliskova E, Pascal T, Poolman J, Schuerman L. Effect of vaccination with pneumococcal capsular polysaccharides conjugated to Haemophilus influenzae-derived protein D on nasopharyngeal carriage of Streptococcus pneumoniae and H. influenzae in children under 2 years of age. Vaccine. 2009 Dec 10;28(1):71-8. doi: 10.1016/j.vaccine.2009.09.113. Epub 2009 Oct 8.</citation>
    <PMID>19818722</PMID>
  </reference>
  <reference>
    <citation>Prymula R, Peeters P, Chrobok V, Kriz P, Novakova E, Kaliskova E, Kohl I, Lommel P, Poolman J, Prieels JP, Schuerman L. Pneumococcal capsular polysaccharides conjugated to protein D for prevention of acute otitis media caused by both Streptococcus pneumoniae and non-typable Haemophilus influenzae: a randomised double-blind efficacy study. Lancet. 2006 Mar 4;367(9512):740-8. doi: 10.1016/S0140-6736(06)68304-9.</citation>
    <PMID>16517274</PMID>
  </reference>
  <verification_date>March 2020</verification_date>
  <study_first_submitted>November 15, 2012</study_first_submitted>
  <study_first_submitted_qc>November 22, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">November 28, 2012</study_first_posted>
  <last_update_submitted>March 23, 2020</last_update_submitted>
  <last_update_submitted_qc>March 23, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">March 25, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>randomized controlled trial</keyword>
  <keyword>pneumococcal conjugate vaccines</keyword>
  <keyword>booster dose</keyword>
  <keyword>immunogenicity</keyword>
  <keyword>nasopharyngeal carriage</keyword>
  <keyword>Australian Indigenous</keyword>
  <keyword>pediatric</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Infections</mesh_term>
    <mesh_term>Communicable Diseases</mesh_term>
    <mesh_term>Respiratory Tract Infections</mesh_term>
    <mesh_term>Otitis Media</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Heptavalent Pneumococcal Conjugate Vaccine</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT01735084
org study id: 1046999
nct id: NCT01735084
lead sponsor: 
collaborator: 
has dmc: Yes
HYPOTHESES:

        1. That infants receiving PHiD-CV10 as a booster at 12 months of age, compared to controls
           having no PHiD-CV10 booster (i.e. standard PCV13), will have higher HiD antibody levels,
           lower carriage of NTHi, and less tympanic membrane perforation at 18 and 36 months of
           age.

        2. That infants receiving PCV13 as a booster at 12 months of age, compared to controls
           having no PCV13 (i.e. PHiD-CV10 booster) will have higher antibody levels to serotypes
           3, 6A and 19A, less carriage of these serotypes, and less tympanic membrane perforation
           at 18 and 36 months of age.
BACKGROUND:

      PCV13 is now the recommended PCV in Australia, as 3+0 for non-Indigenous children and as 3+1
      for Indigenous children in Western Australia, Queensland and Northern Territory. The decision
      to recommend PCV13 over PHiD-CV10 has been primarily driven by the increase in cases of
      invasive pneumococcal disease due to serotype 19A(1). However for the NT, in the last 3 years
      there has been one case of serotype 3, 6A or 19A invasive pneumococcal disease (IPD) per year
      in Indigenous children less than 2 years of age. By contrast, almost 20% of young Indigenous
      children have perforated tympanic membranes of which 60% are associated with NTHi, compared
      to 3% having serotypes 3, 6A or 19A.

      The PREV-IX_COMBO trial is a randomised controlled trial (RCT) of these two pneumococcal
      conjugate vaccines currently licensed in Australia. Participating Indigenous infants living
      in remote communities in 4 regions of the NT are randomised between 28 and 38 days of age and
      allocated to one of three groups: PHiD-CV10 at 2, 4, 6 months or PCV13 at 2,4,6 months, or an
      investigational group of a 4-dose combination schedule of PHiD-CV10 at 1,2, and 4 months plus
      PCV13 at 6 months.

      PREV-IX_BOOST builds on PREV-IX_COMBO to address questions not answerable by a booster trial
      in the general population:

      The 7 month visit is the final assessment included in the PREV-IX_COMBO trial. In October
      2011 the standard PCV schedule for all Indigenous babies in the NT switched from PHiD-CV10 to
      PCV13 at 2, 4, 6 and 18 months of age. Thus, all babies in PREV-IX_COMBO will go on to
      receive PCV13 at 18 months of age as a part of standard care. An alternative and innovative
      option is to take this opportunity to answer these questions: should PCV13 or PHiD-CV10
      vaccine be the booster vaccine for infants in the three PREV-IX_COMBO groups, and at what age
      should the booster be given? Secondary questions: By randomising the three different primary
      course groups to booster dose of either PHiD-CV10 or PCV13, a number of secondary questions
      can be proposed. Outputs include the comparative benefit (immune and carriage correlates) of
      schedules such as 3+1 PCV13, 3+1 PHiD-CV10, and mixed vaccine schedules such as single dose
      PCV13 or single dose PHiD-CV10 boosters following alternate vaccines in the primary course,
      and booster options following the early and mixed 4-dose primary course. Furthermore the
      design will allow for an evaluation at 18 months of age, of a 12 month boost versus no boost
      of specific vaccine components unique to each of these vaccines. For example, a comparison of
      the booster effect of HiD (in PHiD-CV10) with no HiD boost (PCV13) on antibody concentration
      and nasopharyngeal carriage at 18 months. By combining some of these groups it will be
      possible to compare more subtle differences such as differences in immunogenicity of
      serotypes shared by the two vaccines (1,4,5,6B,7F,9V,14,18C,19F,23F) but with different
      carrier proteins and thus anticipated differences in immunogenicity.

      PCVs in the NT: PCV7, PHiD-CV10 (Synflorix) and PCV13 (Prevenar13):

      Prevention of invasive pneumococcal disease (IPD) is the primary goal of pneumococcal
      conjugate vaccination in infants. Effectiveness against overall IPD has generally remained
      high although IPD caused by non-PCV7 types has increased in some high risk groups and
      regions, particularly associated with serotypes 19A, 6A, and 33F. These increases have been
      described as a 'replacement phenomenon'. In addition there are ongoing outbreaks of IPD due
      to non-PCV7 types; in the NT and WA serotypes 1 and 12F account for resurgence in IPD cases
      in otherwise low risk groups. Effectiveness of PCVs for all-cause pneumonia and otitis media
      has been greatly compromised by replacement serotypes and the broad diversity of
      non-pneumococcal respiratory bacterial pathogens which continue to cause high rates of
      disease, such as non-typeable H. influenzae (NTHi). Replacement serotypes, particularly
      19A(2,3) and NTHi, are the targets of new generation vaccines. In Australia two new PCVs are
      licensed: 10-valent pneumococcal-Haemophilus influenzae protein-D conjugate vaccine,
      PHiD-CV10 (Synflorix, GSK) and 13-valent PCV, PCV13 (Prevenar13, Pfizer). The two vaccines
      have 10 pneumococcal serotypes in common (1,4,5,6B,7F,9V,14,18C,19F,23F), however these are
      conjugated to different carrier proteins and immune correlates indicate potential vaccine
      differences in efficacy for individual serotypes. PHiD-CV10 has protein D of NTHi as the
      carrier for some serotypes and PCV13 is non-toxic diphtheria protein (CRM197)-conjugated, as
      was its precursor PCV7, and has three additional serotypes (3, 6A and 19A) but not HiD. There
      have been no efficacy trials that directly compare these vaccines; licensure has been based
      on immune correlates of protection in comparison with PCV7. Evidence of HiD efficacy has come
      from a single RCT in which otitis media was a primary outcome. In that trial of the original
      formulation (PHiD-CV11) there was ~55% efficacy for vaccine type AOM, and 35% efficacy for
      NTHi AOM following a 3+1 schedule.(3) This trial also demonstrated a 43% (95% Confidence
      Interval (CI): -17 to 72, ns) reduction in the carriage of vaccine serotypes and a 43% (95%
      CI: 1-67) reduction in the carriage of H. influenzae. This finding has not been replicated in
      later trials, partially due to very low baseline rates of NTHi carriage (<10%) and thus low
      power to achieve statistical significance. The PREV-IX_COMBO trial will therefore be very
      important in providing data on immunological correlates and carriage for different PHiD-CV10
      schedules. However, an extended follow-up and comparison of booster dose (this PREV-IX_BOOST
      proposal) will provide further evidence for or against inclusion of PHiD-CV10 as a booster
      (compared to the NT standard PCV13 at 18 months).

      In the NT, booster pneumococcal vaccines are recommended at 18 months of age. This is largely
      due to the previous schedule which included 23-valent pneumococcal polysaccharide vaccine
      (23PPV) as a booster dose at 18 months. A 3+1 PHiD-CV10 schedule replaced 3+1 PCV7-23PPV in
      2009, and the booster age remained at 18 months. In Queensland (QLD) and in Western Australia
      (WA) the vaccination schedules allow for PCV13 boost at 12 months of age for high risk and
      Indigenous children.

      At present there are 4 intra-muscular immunizations (IMIs) at 12 months of age for Indigenous
      infants in the Northern Territory childhood vaccination schedule. A combined booster dose
      vaccine (e.g. Menitorix) became available in Australia prior to commencement of first
      enrolment into the BOOST study. This reduces the number of IMIs at 12 months of age and
      provides a 'space' for PCV at 12 months. Administration of PCV booster, originally scheduled
      for 13 months of age, will be at 12 months of age for the trial.

      Surveillance of otitis media in remote communities shows high rates of disease from weeks
      after birth throughout early childhood, particularly tympanic membrane perforations in the
      second year of life, and thus supports the need for a booster dose. Between 2008 and 2010, in
      PCV7-vaccinated children, mean age of tympanic membrane perforation was 18 months; for
      children with AOM with perforation (AOMwiP), the mean age was 13 months and for chronic
      suppurative OM (CSOM) 21 months. IPD cases occurring in Indigenous and non-Indigenous
      children less than 2 years of age for all serotypes; in 2009 there were 7 cases; in 2011 8
      cases. The majority of IPD cases in children under 2 years occurred between 12 and 18 months.

      In summary, the precedent of a 12 month PCV booster for Indigenous children in WA and QLD,
      and the high incidence of IPD and OM in the first half of the second year of life support the
      decision to choose a 12 month booster for this study. The mixed schedules will still allow us
      to compare boost versus no boost for HiD, 3,6A and 19A.

      Antibody decay post-primary PCV7 to pre-booster:

      Furthermore, published data(4) from the PCV7 era which show post-primary antibody levels at
      mean age 15 months (range 0.32 to 0.83 microg/mL for all but serotype 14) have declined
      almost to those detected in cord blood (range 0.3647 to 1.1797 microg/mL). The clinical
      implications of this decay in terms of memory response and duration of protection from
      mucosal infections, pneumonia and otitis media, are not known, however vaccine efficacy is
      lower for mucosal compared to invasive infection(5). Which vaccine for the booster dose?

      Mucosal disease (OM and respiratory illness):

      Culture of ear discharge from these perforations shows 60% of specimens from AOMwiP cultured
      NTHi and 26% cultured pneumococcus. For CSOM, these figures were 47% and 23% respectively.
      Serotyping identified 19A or 6A in 20% of pneumococcal isolates, which translates to 5%
      AOMwip and 4% CSOM specimens. NTHi is also associated with exacerbations of chronic
      suppurative lung disease (CSLD), or bronchiectasis, in young Indigenous children.(6)
      Percentage of ear discharge specimens with OM pathogens pneumococcus (Spn), 19A, NTHi, M.
      catarrhalis or neither Spn nor NTHi.

      Evidence for efficacy of single dose PHiD-CV10 boost & inclusion in Australian PCV13 3+0
      schedule:

      A single dose of PHiD-CV10 might be valuable for many Australian children now receiving the
      3+0 PCV13 schedule, to provide some immune protection from NTHi. Group 2 of the PREV-IX_COMBO
      trial receive either PCV13 at 2,4,6 months and will be randomised in this study to PCV13 (4th
      dose) or PHiD-CV10 (1st dose) at 12 months of age. Vesikari et al.(7) evaluated a single dose
      of PHiD-CV as catch-up (not booster) in 2 to 5 year old children. Following 1 dose in the 2
      to 5 years group ELISA pneumococcal responses were lower than the reference group (reference
      group: 3 primary doses with booster at 12 to 15 months) for several serotypes. Responses
      following 1 dose in children 2 to 5 years of age suggested that 2 doses may be preferable.
      Unfortunately, HiD Geometric Mean Concentrations (GMCs) were not reported. A trial underway
      in Queensland will evaluate a double dose of PHiD-CV10 in preventing exacerbations of CSLD in
      older children. The BOOST trial in non-CSLD children will complement those data.

      Invasive disease due to PCV13 serotypes 3, 6A and 19A:

      In 2009, there were 89 cases of IPD in the NT population, 59 in 2010 and 114 in 2011; 25
      (10%) of these 262 cases were the unique PCV13 serotypes (3, 6A and 19A) and 17(7%) of these
      were Indigenous, four (1.5%) were Aboriginal children < 2 years of age - about one per year
      (unpublished, Centre for Disease Control, NT Health).

      Episodes of AOM and respiratory illness to 3 years of age:

      A very high rate of clinic presentations occurs for babies and young children in remote
      communities. Our antibiotic trial for prevention of OM randomised infants at mean age 5
      months(9,10) and recorded episodes of illness in placebo and active groups during
      approximately 6 months (unpublished). Around 9 episodes of primary respiratory illness or AOM
      (8.2 + 0.8) were recorded in notes per child year in the second 6 months of life. There are
      no published data for illness in the second and third years of life for this population.
      Whilst the BOOST study is unlikely to be sufficiently powered to detect group differences in
      rates of illness, these will be measured and reported.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Prevention
masking: Single (Outcomes Assessor)
measure: Immune response
time frame: At 18 months of age
description: The primary outcome will be the proportion of subjects with serotype-specific antibody above the level required for protection from IPD in each study group at 18 months of age, 6 months after the booster dose. This will be determined in ELISA assays.
measure: Nasopharyngeal carriage
time frame: At 12, 18 and 36 months of age
description: At baseline (12 mo), 18 and 36 months of age, the proportion of children with a any carriage of serotype 3, 6A and 19A pneumococci b any carriage of any NTHi
measure: Otitis media
time frame: At 12, 18 and 36 months of age
description: At baseline (12 mo), 18 and 36 months of age, the proportion of children with c any otitis media. d any tympanic membrane perforation
measure: Episodes of respiratory illness and acute otitis media
time frame: Between baseline (12 mo) and 36 months of age
description: Between baseline (12 mo) and 36 months of age Episodes of respiratory illness and acute otitis media
arm group label: Prevenar13
arm group type: Experimental
description: The booster dose of Prevenar13 is 0.5 mL given intramuscularly only, with care to avoid injection into or near nerves and blood vessels. The preferred sites are anterolateral aspect of the thigh (vastus lateralis muscle) in infants or the deltoid muscle of the upper arm in young children.
arm group label: Synflorix
arm group type: Experimental
description: The booster vaccination schedule consists of one dose of 0.5 ml with an interval of at least 1 month between doses.
intervention type: Biological
intervention name: Prevenar13
description: The vaccine is a ready to use homogeneous white suspension for intramuscular injection, supplied as a pre-filled syringe.
Active ingredients
Each 0.5 mL dose contains:
2.2 μg of pneumococcal purified capsular polysaccharides for serotypes 1, 3, 4, 5, 6A, 7F, 9V, 14, 18C, 19A, 19F and 23F 4.4 μg of pneumococcal purified capsular polysaccharides for serotype 6B. Each serotype is individually conjugated to non-toxic diphtheria CRM197 protein and adsorbed on aluminium phosphate (0.565 mg).
arm group label: Prevenar13
other name: PCV13
other name: Prevnar13
intervention type: Biological
intervention name: Synflorix
description: The 10-valent vaccine contains 1 µg of purified capsular polysaccharide of pneumococcal serotypes 1, 5, 6B, 7F, 9V, 14, and 23F conjugated to protein D, 3 µg of serotype 4 conjugated to protein D, 3 µg of serotype 18C conjugated to tetanus toxoid and 3 µg of serotype 19F conjugated to diphtheria toxoid.
arm group label: Synflorix
other name: PHiD-CV
other name: PHiD-CV10
criteria: 
gender: All
minimum age: 9 Months
maximum age: 3 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Amanda J Leach, PhD
role: Principal Investigator
affiliation: Menzies School of Health Research
facility: 
country: Australia
citation: Williams SR, Mernagh PJ, Lee MH, Tan JT. Changing epidemiology of invasive pneumococcal disease in Australian children after introduction of a 7-valent pneumococcal conjugate vaccine. Med J Aust. 2011 Feb 7;194(3):116-20. doi: 10.5694/j.1326-5377.2011.tb04192.x.
PMID: 21299484
citation: Miller E, Andrews NJ, Waight PA, Slack MP, George RC. Effectiveness of the new serotypes in the 13-valent pneumococcal conjugate vaccine. Vaccine. 2011 Nov 15;29(49):9127-31. doi: 10.1016/j.vaccine.2011.09.112. Epub 2011 Oct 5.
PMID: 21983361
citation: Weinberger DM, Malley R, Lipsitch M. Serotype replacement in disease after pneumococcal vaccination. Lancet. 2011 Dec 3;378(9807):1962-73. doi: 10.1016/S0140-6736(10)62225-8. Epub 2011 Apr 12.
PMID: 21492929
citation: Leach AJ, Morris PS, Mackenzie G, McDonnell J, Balloch A, Carapetis J, Tang M. Immunogenicity for 16 serotypes of a unique schedule of pneumococcal vaccines in a high-risk population. Vaccine. 2008 Jul 23;26(31):3885-91. doi: 10.1016/j.vaccine.2008.05.012. Epub 2008 May 27.
PMID: 18562052
citation: Black S, Shinefield H, Fireman B, Lewis E, Ray P, Hansen JR, Elvin L, Ensor KM, Hackell J, Siber G, Malinoski F, Madore D, Chang I, Kohberger R, Watson W, Austrian R, Edwards K. Efficacy, safety and immunogenicity of heptavalent pneumococcal conjugate vaccine in children. Northern California Kaiser Permanente Vaccine Study Center Group. Pediatr Infect Dis J. 2000 Mar;19(3):187-95. doi: 10.1097/00006454-200003000-00003.
PMID: 10749457
citation: Hare KM, Grimwood K, Leach AJ, Smith-Vaughan H, Torzillo PJ, Morris PS, Chang AB. Respiratory bacterial pathogens in the nasopharynx and lower airways of Australian indigenous children with bronchiectasis. J Pediatr. 2010 Dec;157(6):1001-5. doi: 10.1016/j.jpeds.2010.06.002. Epub 2010 Jul 24.
PMID: 20656297
citation: Vesikari T, Karvonen A, Korhonen T, Karppa T, Sadeharju K, Fanic A, Dieussaert I, Schuerman L. Immunogenicity of 10-valent pneumococcal nontypeable Haemophilus Influenzae Protein D Conjugate Vaccine when administered as catch-up vaccination to children 7 months to 5 years of age. Pediatr Infect Dis J. 2011 Aug;30(8):e130-41. doi: 10.1097/INF.0b013e31821d1790.
PMID: 21540760
citation: Clucas DB, Carville KS, Connors C, Currie BJ, Carapetis JR, Andrews RM. Disease burden and health-care clinic attendances for young children in remote aboriginal communities of northern Australia. Bull World Health Organ. 2008 Apr;86(4):275-81. doi: 10.2471/blt.07.043034.
PMID: 18438516
citation: Leach AJ, Morris PS, Mathews JD; Chronic Otitis Media Intervention Trial - One (COMIT1) group. Compared to placebo, long-term antibiotics resolve otitis media with effusion (OME) and prevent acute otitis media with perforation (AOMwiP) in a high-risk population: a randomized controlled trial. BMC Pediatr. 2008 Jun 2;8:23. doi: 10.1186/1471-2431-8-23.
PMID: 18513453
citation: Simell B, Nurkka A, Lahdenkari M, Givon-Lavi N, Kayhty H, Dagan R, Jokinen J. Association of serotype-specific antibody concentrations and functional antibody titers with subsequent pneumococcal carriage in toddlers immunized with a 9-valent pneumococcal conjugate vaccine. Clin Vaccine Immunol. 2012 Jan;19(1):96-9. doi: 10.1128/CVI.05369-11. Epub 2011 Nov 9.
PMID: 22072724
citation: Leach AJ, Morris PS, McCallum GB, Wilson CA, Stubbs L, Beissbarth J, Jacups S, Hare K, Smith-Vaughan HC. Emerging pneumococcal carriage serotypes in a high-risk population receiving universal 7-valent pneumococcal conjugate vaccine and 23-valent polysaccharide vaccine since 2001. BMC Infect Dis. 2009 Aug 4;9:121. doi: 10.1186/1471-2334-9-121.
PMID: 19650933
citation: Prymula R, Kriz P, Kaliskova E, Pascal T, Poolman J, Schuerman L. Effect of vaccination with pneumococcal capsular polysaccharides conjugated to Haemophilus influenzae-derived protein D on nasopharyngeal carriage of Streptococcus pneumoniae and H. influenzae in children under 2 years of age. Vaccine. 2009 Dec 10;28(1):71-8. doi: 10.1016/j.vaccine.2009.09.113. Epub 2009 Oct 8.
PMID: 19818722
citation: Prymula R, Peeters P, Chrobok V, Kriz P, Novakova E, Kaliskova E, Kohl I, Lommel P, Poolman J, Prieels JP, Schuerman L. Pneumococcal capsular polysaccharides conjugated to protein D for prevention of acute otitis media caused by both Streptococcus pneumoniae and non-typable Haemophilus influenzae: a randomised double-blind efficacy study. Lancet. 2006 Mar 4;367(9512):740-8. doi: 10.1016/S0140-6736(06)68304-9.
PMID: 16517274
responsible party type: Sponsor
mesh term: Infections
mesh term: Communicable Diseases
mesh term: Respiratory Tract Infections
mesh term: Otitis Media
mesh term: Heptavalent Pneumococcal Conjugate Vaccine