Background • Chronic suppurative lung diseases (CSLD) in children are important causes of morbidity and recurrent acute exacerbations are associated with long term lung function decline. • Non-­‐typeable H. influenzae (NTHi) and S. pneumoniae are commonly isolated from the lower airways of both children and adults with CSLD. • The potential clinical impact of a non-­‐typeable Haemophilus influenzae (NTHi) vaccine in children with CSLD has not been investigated. • We aimed to determine the clinical efficacy of the 10-­‐valent pneumococcal-­‐Protein D conjugate vaccine (10vPHiD-­‐CV) in children aged 18-­‐months to <18-­‐years with CSLD (Immunogenicity data are presented in Poster xxx). Primary clinical objective. • Determine the efficacy of 10vPHiD-­‐CV in reducing the incidence of acute exacerbations in the 12-­‐months following the 2nd dose of study vaccine. Secondary clinical objectives. • Determine the efficacy of 10vPHiD-­‐CV in reducing the incidence of any parent/carer-­‐reported respiratory symptoms in the 12 months following the second dose of study vaccine. • Determine the efficacy of 10vPHiD-­‐CV in reducing antibiotic use in the 12 months following the second dose of study vaccine

Chang, Anne B.

Connor, Anne

Cripps, Allan W.

Danchin, Margaret

Goyal, Vikas

Grimwood, Keith

Morris, Peter

Mulholland, E. Kim

O'Grady, Kerry-Ann

Perrett, Kirsten

Rablin, Sheree

Richmond, Peter

Smith-Vaughan, Heidi

Stoney, Tanya

Thornton, Ruth

Torzillo, Paul J.

Wilson, Andrew

Wood, Nicholas

Queensland University of Technology ePrints Archive

Potential	  clinical	  eﬃcacy	  of	  the	  10-­‐valent	  pneumococcal-­‐Protein	  D	  conjugate	  vaccine	  in	  children	  with	  	  chronic	  suppurative	  lung	  diseases:	  a	  double-­‐blind	  randomised	  controlled	  trial	  Kerry-­‐Ann	  	  O’Grady,1	  Keith	  Grimwood,2	  Allan	  Cripps,2	  Kim	  Mulholland,3,4	  Heidi	  Smith-­‐Vaughan,5	  Margaret	  Danchin,4,6	  Nicholas	  Wood,7	  Andrew	  Wilson,8	  Ruth	  Thornton,9	  	  Paul	  J	  Torzillo,10	  Peter	  Morris,5	  Peter	  Richmond,9	  Kirsten	  Perrett,4	  Sheree	  Rablin,1	  Anne	  Connor,11	  	  Vikas	  Goyal,11,12	  Tanya	  Stoney,9	  Anne	  B	  Chang,1,5,12	  on	  behalf	  of	  the	  CHiRRP	  Study	  Team	  	  1.	  Institute	  of	  Health	  &	  Biomedical	  Innovation,	  Queensland	  University	  of	  Technology,	  Sth	  Brisbane,	  Australia;	  2.	  Menzies	  Health	  Institute	  Queensland,	  Griﬃth	  University	  and	  Gold	  Coast	  Health,	  Gold	  Coast,	  Australia;	  3.	  London	  School	  of	  Hygiene	  &	  	  Tropical	  Medicine,	  London,	  United	  Kingdom;	  4.	  Murdoch	  Children’s	  Research	  Institute,	  Parkville,	  Australia;	  5.	  Menzies	  School	  of	  Health	  Research,	  Charles	  Darwin	  University,	  Casuarina,	  Australia;	  6.	  Royal	  Children’s	  Hospital,	  Parkville,	  Australia;	  7.	  National	  Centre	  for	  Immunisation	  Research	  &	  Surveillance,	  University	  of	  Sydney,	  Westmead,	  Australia;	  8.	  Princess	  Margaret	  Hospital	  for	  Children,	  Perth,	  Australia;	  Telethon	  Kids	  Institute,	  Subiaco,	  Australia;	  School	  of	  Medicine,	  University	  of	  Sydney,	  Newtown,	  Australia;	  11.	  Child	  Health	  Research	  Centre,	  The	  University	  of	  Queensland,	  Sth	  Brisbane,	  Australia;	  12.	  Queensland	  Children’s	  Respiratory	  Centre,	  Lady	  Cilento	  Children’s	  Hospital,	  Sth	  Brisbane,	  Australia.	  Background	  •  Chronic	   suppurative	   lung	   diseases	   (CSLD)	   in	   children	   are	   important	   causes	   of	   morbidity	   and	   recurrent	   acute	  exacerbations	  are	  associated	  with	  long	  term	  lung	  function	  decline.1	  	  •  Non-­‐typeable	  H.	  inﬂuenzae	  (NTHi)	  and	  S.	  pneumoniae	  are	  commonly	  isolated	  from	  the	  lower	  airways	  of	  both	  children	  and	  adults	  with	  CSLD.2	  	  •  The	  potential	  clinical	  impact	  of	  a	  non-­‐typeable	  Haemophilus	  inﬂuenzae	  (NTHi)	  vaccine	  in	  children	  with	  CSLD	  has	  not	  been	  investigated.	  	  •  We	  aimed	  to	  determine	  the	  clinical	  eﬃcacy	  of	  the	  10-­‐valent	  pneumococcal-­‐Protein	  D	  conjugate	  vaccine	  (10vPHiD-­‐CV)	  in	  children	  aged	  18-­‐months	  to	  <18-­‐years	  with	  CSLD	  (Immunogenicity	  data	  are	  presented	  in	  Poster	  xxx).	  	  Primary	  clinical	  objective	  •  Determine	  the	  eﬃcacy	  of	  10vPHiD-­‐CV	  in	  reducing	  the	  incidence	  of	  acute	  exacerbations	  in	  the	  12-­‐months	  following	  the	  2nd	  dose	  of	  study	  vaccine.	  	  Secondary	  clinical	  objectives	  •  Determine	  the	  eﬃcacy	  of	  10vPHiD-­‐CV	  in	  reducing	  the	  incidence	  of	  any	  parent/carer-­‐reported	  respiratory	  symptoms	  in	  the	  12	  months	  following	  the	  second	  dose	  of	  study	  vaccine.	  	  •  Determine	  the	  eﬃcacy	  of	  10vPHiD-­‐CV	  in	  reducing	  antibiotic	  use	  in	  the	  12	  months	  following	  the	  second	  dose	  of	  study	  vaccine.	  Methods	  	  •  Multi-­‐centre,	  parallel	  group	  (1:1	  allocation),	  double-­‐blind,	  randomised	  controlled	  trial.	  3	  	  •  Children	  received	  2	  doses,	  2-­‐months	  apart	  of	  10vPHiD-­‐CV	  or	  meningococcal-­‐ACYW135	  conjugate	  vaccine	  (Figure	  1).	  	  	  •  Inclusion/exclusion	  criteria	  are	  listed	  in	  Box	  1;	  a	  glossary	  of	  terms	  is	  	  provided	  in	  Box	  	  2.	  	  •  Children	  underwent	  active	  fortnightly	  surveillance	  for	  acute	  exacerbations,	  respiratory	  symptoms	  and	  antibiotic	  use	  for	  12-­‐months	  post	  the	  second	  dose	  of	  vaccine.	  	  •  In	  intention-­‐to-­‐treat	  analyses,	  incidence	  rate	  ratios	  (IRRs)	  were	  calculated	  with	  child-­‐weeks	  at	  risk	  commencing	  14-­‐days	  post	  the	  second	  vaccine	  dose.	  	  •  Child	  time	  at	  risk	  was	  calculated	  in	  weeks	  for	  exacerbations	  and	  antibiotic	  use	  and	  fortnights	  were	  the	  denominator	  for	  parent/carer	  reported	  respiratory	  symptoms.	  	  •  Subanalyses	  were	  performed	  	  to	  determine	  the	  incidence	  of	  clinical	  endpoints	  following	  the	  ﬁrst	  dose	  of	  vaccine.	  Results	  •  The	  required	  sample	  size	  of	  206	  children	  was	  not	  achieved	  given	  recruitment	  diﬃculties.	  	  •  879	  children	  were	  screened	  and	  62	  enrolled;	  481	  (55%)	  were	  ineligible,	  257	  (29%)	  refused	  &	  79	  (9%)	  were	  not	  enrolled	  for	  other	  reasons.	  One	  child	  was	  unblinded	  	  &	  withdrawn	  following	  a	  serious	  adverse	  event	  unrelated	  to	  study	  vaccine	  &	  excluded	  from	  the	  analysis.	  	  •  The	  mean	  age	  of	  enrolled	  children	  7.0-­‐years	  (95%CI	  6.0,	  7.9);	  53.5%	  were	  male	  (Table	  1).	  There	  were	  no	  diﬀerences	  in	  gender	  and	  age	  between	  children	  who	  were	  and	  were	  not	  enrolled.	  	  •  Baseline	  characteristics	  are	  provided	  in	  Table	  1	  and	  incidence	  rates	  of	  clinical	  endpoints	  are	  presented	  in	  Table	  2.	  Discussion	  •  We	  have	  identiﬁed	  a	  potentially	  important	  role	  for	  the	  10vPHiD-­‐CV	  in	  the	  clinical	  management	  of	  children	  with	  CSLD.	  •  While	  the	  sample	  size	  was	  inadequate	  for	  the	  primary	  endpoint,	  children	  who	  received	  10vPHiD-­‐CV	  required	  less	  courses	  of	  antibiotics	  and	  experienced	  less	  time	  with	  respiratory	  symptoms	  than	  those	  in	  the	  control	  group.	  •  Our	  clinical	  data	  are	  supported	  by	  the	  mucosal	  and	  systemic	  antibody	  responses	  to	  vaccine	  presented	  in	  Poster	  xx.	  	  •  Larger	  trials,	  involving	  multiple	  recruitment	  sites,	  are	  now	  required	  to	  conﬁrm	  our	  ﬁndings.	  Acknowledgements	  The	   authors	  would	   like	   to	   thank:	   the	   study	   staﬀ,	   particularly	   	  Stephanie	   Jeﬀares,	   Laura	  Rost,	   Marita	   Keﬀord,	   Jane	   Ryrie,	   Janet	   Briggs,	   Daniel	   Arnold	   and	   Rebecca	   Doyle;	   the	  participating	  families	  and	  children;	  the	  Departments	  of	  Respiratory	  Medicine	  at	  each	  site;	  our	   study	   monitors	   (Clare	   Brophy,	   Annmarie	   McEvory);	   members	   of	   the	   Data	   Safety	  Monitoring	  Committee	   (Tilman	  Ruﬀ,	  Deborah	   Lehmann,	  Helen	  Marshall,	   Peter	   Jacoby),	  and;	  Terry	  Nolan	  at	  the	  University	  of	  Melbourne	  for	  his	  support	  for	  the	  study.	  	  Funding	  sources	  The	  study	  was	  funded	  by	  an	  Australian	  National	  Health	  and	  Medical	  Research	  Council	  Project	  Grant	  (1019904).	  KO	  is	  supported	  by	  a	  Queensland	  Government	  Smart	  Futures	  Fellowship	  (51008)	  and	  NHMRC	  Career	  Development	  Award	  (1045157).	  The	  vaccine	  manufacturers	  have	  not	  had	  (and	  will	  not	  have)	  any	  role	  in	  funding	  or	  in	  the	  design	  and	  implementation	  of	  this	  study..  	  Clinical	  Trial	  Registration	  Number:	  ACTRN12612000034831	  	  Combating	  H.	  inﬂuenzae	  Related	  Respiratory	  Pathology	  References	  1.	  Kapur	  N,	  Masters	  IB,	  Chang	  AB:.	  Respir	  Med	  2009,103:1681–1687.	  	  2.	  Grimwood	  K.	  Paediatr	  Respir	  Rev	  2011,	  12:111–118.	  	  3.	  O’Grady	  K,	  et	  al.	  Trials	  Journal,	  2013.	  14;	  doi:	  10.1186/1745-­‐6215-­‐14-­‐282	  	  	  	  	  Inclusion	  Criteria	   Exclusion	  Criteria	  •  Child	  aged	  ≥	  18	  months	  and	  <	  18	  years	  with	  CSLD,	  bronchiectasis	  or	  recurrent	  PBB	  (Box	  2)	  	  •  Chronic	   lung	   condition,	   including	   cystic	   ﬁbrosis,	   other	   than	   those	   under	  investigation	  in	  this	  study	  •  At	  least	  2	  respiratory	  exacerbations	  within	  the	  18-­‐months	  prior	  to	  enrolment	  	  •  Prior	   vaccination	  with	  PHiD-­‐CV	  vaccine;	   contraindication	   to	  PHiD-­‐CV	  and/or	  quadrivalent	  (ACYW135)	  meningococcal	  	  conjugate	  vaccine	  •  Age-­‐appropriately	  immunised	  with	  PCV7	  and/or	  PCV13	   •  Known	  hypersensitivity	  to	  any	  component	  of	  the	  vaccines,	  including	  latex	  	  •  A	   prior	   dose	   of	   Pneumovax	   23	   was	   permitted.	  At	   least	   2-­‐months	   post	   the	  dose	  of	  non-­‐study	  pneumococcal	  vaccine	  was	  required	  prior	  to	  enrolment	  •  Conﬁrmed	  or	   suspected	   immunosuppressive	   condition	  or	   immunodeﬁciency	  disorder	   that	   may	   be	   expected	   to	   interfere	   with	   immune	   response	   to	  vaccination	  	  •  If	  vaccinated	  with	  a	  meningococcal	  C	  conjugate	  vaccine,	  a	  period	  of	  at	  least	  6	  months	  post	  vaccination	  was	  required	  prior	  to	  enrolment.	  	  •  Current	  (or	  within	  90	  days	  prior	  to	  receiving	  study	  vaccine)	  or	  planned	  (during	  the	   active	   study	   period)	   immunosuppressive	   therapy,	   including	   systemic	  corticosteroids	  (≥14	  days).	  Inhaled	  steroids	  were	  allowed	  	  •  Negative	  urine	  pregnancy	  test	  if	  post-­‐menarcheal	  female	  	  •  Administration	   of	   immunoglobulins	   and/or	   blood	   products	   within	   90	   days	  prior	   to	   receiving	   study	  vaccine,	  or	  planned	  administration	  of	   such	  products	  during	  the	  study	  period	  	  •  Provision	   of	   written	   informed	   consent	   from	   parent/guardian	   (assent	   from	  child	  as	  per	  local	  HREC	  requirements)	  •  Active	  participation	  in	  a	  clinical	  trial	  of	  another	  investigational	  drug/vaccine	  or	  interventional	  therapy	  •  Parent/child	  willing	  and	  able	  to	  meet	  the	  requirements	  of	  the	  protocol	   •  Acute	   disease	   at	   the	   time	   of	   enrolment.	   Acute	   disease	   was	   deﬁned	   as	   a	  moderate	   or	   severe	   illness	   with	   or	   without	   fever	   (axillary	   temperature	   ≥	  38.0oC)	  at	  the	  time	  of	  enrolment.	  A	  temperature	  greater	  than	  or	  equal	  to	  this	  cut-­‐oﬀ	   warrants	   deferral	   of	   the	   vaccination	   pending	   recovery	   of	   the	  participant	  	  •  Not	  planning	  to	  move	  from	  the	  study	  area	  in	  the	  14	  months	  post	  enrolment	   •  Other	   medical/psychosocial	   condition	   that	   the	   investigators	   considered	  warranted	   exclusion	   from	   the	   trial	   to	   prevent	   potential	   harm/risk	   to	   the	  subject	  or	  may	  adversely	  aﬀect	  study	  outcomes	  Term	   Deﬁnition	  Chronic	  suppurative	  lung	  disease	  (CSLD)	  A	  clinical	  syndrome	  where	  there	  are	  signs/symptoms	  indicating	  chronic	  endobronchial	  suppuration	  with	  or	  without	  HRCT	  evidence	  of	  radiological	  bronchiectasis.	  This	  includes	  chronic	  wet	  or	  productive	  cough	  and	  either	  failure	  of	  cough	  to	  respond	  to	  oral	  antibiotics	  or	  presence	  of	  additional	  respiratory	  symptoms	  or	  signs	  (eg.	  clubbing,	  chest	  wall	  deformity	  or	  crackles)	  Bronchiectasis	   Features	  of	  CSLD	  plus	  conﬁrmed	  bronchiectasis	  by	  chest	  HRCT	  scan	  in	  last	  5	  years	  	  Recurrent	  protracted	  bacterial	  bronchitis	  (PBB)	  The	  presence	  of	  isolated	  chronic	  (>4	  weeks)	  of	  wet/moist	  cough	  that	  resolves	  with	  antibiotics	  in	   the	   absence	   of	   pointers	   suggestive	   of	   an	   alternative	   speciﬁc	   cause	   of	   cough.	   3	   prior	  episodes	  deﬁned	  recurrent	  PBB.	  Respiratory	  exacerbation	   An	  increase	  in	  sputum	  volume	  or	  purulence	  or	  ≥	  3-­‐days	  of	  change	  in	  cough	  (>20%	  increase	  in	  cough	   score	   or	   type	   [dry	   to	   wet]).	   A	   cough	   must	   have	   been	   wet	   to	   be	   considered	   an	  exacerbation.	  The	   ‘baseline-­‐state’	   for	  each	  child	  was	  established	  at	  enrolment,	  prior	   to	  any	  exacerbations.	  This	   consisted	   of	   a	   combination	   of	   symptoms	   [daily	   cough	   (yes/no),	   cough	  quality	   (wet/dry/none),	   cough	   score	   averaged	  over	   2	  days	   and	   signs	   [sputum	  colour	   (if	   any	  present),	  crackles	  on	  chest	  auscultation].	  	  Respiratory	  symptoms	  under	  surveillance	  cough,	  sputum	  production,	  sputum	  colour,	  rhinorrhoea,	  fever,	  wheeze,	  shortness	  of	  breath,	  tachypnoea,	  dyspnoea,	  stridor,	  headache,	  sore	  throat,	  earache.	  Endpoint	   PHiD-­‐CV	  	  N	  =	  	  31	  	  MenACYW135	  	  N	  =	  30	  n/time	  at	  risk	  (IR)	  n/time	  at	  risk	  (IR)	  	  IRR	  (95%CI)	   P-­‐value	  Exacerbations	  post	  dose	  2	   71	  /	  1698	  weeks	  (4.2	  /	  100	  weeks)	  73	  /	  1549	  week	  (4.7	  /	  100	  weeks)	  0.88	  (0.64	  –	  1.23)	   0.237	  Exacerbations	  post	  dose	  1	   106	  /	  1877	  weeks	  (5.6	  /	  100	  weeks)	  106	  /	  1637	  weeks	  (6.5	  /	  100	  weeks)	  0.87	  (0.67	  –	  1.14)	   0.160	  Fortnights	  with	  respiratory	  symptoms	  post	  dose	  2	   213/849	  fortnights	  (25/100	  fortnights)	  260	  /	  775	  fortnights	  (36/100	  fortnights)	  0.75	  (0.62	  –	  0.90)	   0.002	  Fortnights	  with	  respiratory	  symptoms	  post	  dose	  1	   266	  /	  939	  fortnights	  (28/100	  fortnights)	  320	  /	  818	  fortnights	  (39/100	  fortnights)	  0.72	  (0.62	  –	  0.85)	   <0.001	  Antibiotic	  courses	  	  <	  14	  days	  post	  dose	  2	   77	  /	  1692	  weeks	  (4.5/100	  weeks)	  94	  /	  1528	  weeks	  (6.2/100	  weeks)	  0.74	  (0.55	  –	  0.99)	   0.025	  Antibiotic	  courses	  	  <	  14	  days	  post	  dose	  1	   109	  /	  2094	  weeks	  (5.2/100	  weeks)	  123	  /	  1961	  weeks	  (6.3/100	  weeks)	  0.83	  (0.64	  –	  1.07)	   0.078	  Antibiotic	  courses	  <	  28	  days	  post	  dose	  2	   92	  /	  1657	  weeks	  (5.5/100	  weeks)	  102	  /	  1515	  weeks	  (6.7	  /	  100	  weeks)	  0.82	  (0.62	  –	  1.09)	   0.091	  Antibiotic	  courses	  <	  28	  days	  post	  dose	  1	  	   127/2051	  weeks	  (6.2/100	  weeks)	  133/1938	  weeks	  (6.9/100	  weeks)	  0.90	  (0.71	  –	  1.15)	   0.204	  Antibiotics	  of	  any	  duration	  post	  dose	  2	   92	  /	  1647	  weeks	  (6.8	  /	  100	  weeks)	  102	  /	  1505	  weeks	  (5.6	  /	  100	  weeks)	  0.82	  (0.62	  –	  1.09)	   0.086	  Antibiotics	  of	  any	  duration	  post	  dose	  1	  	  127	  /	  2035	  weeks	  (6.9	  /	  100	  weeks)	  133	  /	  1926	  weeks	  (6.2	  /	  100	  weeks)	  0.90	  (0.71	  –	  1.15)	   0.207	  Child	  characteristic	   PHiD-­‐CV	  	  n	  =	  31	  	  MenACYW135	  	  n	  =	  30	  	  p	  value	  Age	  group	  <	  6	  years	  ≥	  6	  years	  	  15	  (48.4%)	  16	  (51.6%)	  	  12	  (40.0%)	  18	  (60.0%)	  	  0.510	  Gender	  Male	  Female	  	  18	  (58.1%)	  13	  (41.9%)	  	  14	  (46.7%)	  16	  (53.3%)	  	  0.373	  Respiratory	  diagnosis	  PBB	  CSLD	  Bronchiectasis	  	  14	  (45.2%)	  9	  (29.0%)	  8	  (25.8%)	  	  18	  (59.7%)	  7	  (23.3%)	  5	  (16.7%)	  	  0.529	  Age	  appropriately	  immunised	  with	  PCV7	  Yes	  Not	  applicable	  Unknown	  	  	  29	  (93.6%)	  1	  (3.3%)	  1	  (3.1%)	  	  24	  (80.0%)	  6	  (20.0%)	  0	  (0.0%)	  	  0.141	  Age	  appropriately	  immunised	  with	  PCV13	  Yes	  Not	  applicable	  Unknown	  	  8	  (25.8%)	  20	  (64.5%)	  3	  (9.7%)	  	  9	  (30.0%)	  19	  (63.3%)	  2	  (6.7%)	  	  0.121	  Prior	  23-­‐valent	  pneumococcal	  polysaccharide	  vaccine	  Yes	  Unknown	  	  10	  (32.3%)	  2	  (6.5%)	  	  4	  (13.3%)	  2	  (6.7%)	  	  0.068	  Mean	  #	  parent	  reported	  respiratory	  exacerbations	  in	  past	  18	  months	  (95%CI)	  7.7	  (6.1	  –	  9.4)	   8.2	  (6.1	  –	  10.2)	   0.725	  Box	  2:	  Glossary	  of	  study	  deﬁnitions	  Figure	  1.	  Overview	  of	  trial	  design	  Box	  1.	  Trial	  eligibility	  criteria	  Table	  1.	  Baseline	  characteristics	  of	  CHiRRP	  children	  Table	  2:	  Incidence	  rates	  (IR)	  /	  child	  time	  at	  risk	  and	  Incidence	  Rate	  Ratios	  (IRR)	  for	  clinical	  endpoints	  

Potential clinical efficacy of the 10-valent pneumococcal-Protein D conjugate vaccine in children with chronic suppurative lung diseases: A double-blind randomised controlled trial

https://eprints.qut.edu.au/96412/1/CHiRRP_ISSPD16_Poster_Draft_3June.pdf

Potential clinical efficacy of the 10-valent pneumococcal-Protein D conjugate vaccine in children with chronic suppurative lung diseases: A double-blind randomised controlled trial

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