Safety of Nasal Influenza Immunisation in Children With Asthma - The SNIFFLE-4 Study
Phase: PHASE4
Conditions: Asthma
Sponsor: Imperial College London

	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  SNIFFLE-­‐4	  Study	  Protocol	  	  
Confidential	  
	  
SNIFFLE-­‐4	  Protocol	  	  Version	  2.2,	  5	  September	  2016	  	  
	  
Page	  1	  of	  48	  
	  
	  
Safety	  of	  Nasal	  Influenza	  Immunisation	  
in	  Children	  with	  Asthma:	  
The	  SNIFFLE	  4	  study	  
	  
VERSION	  2.2,	  5	  September	  2016	  
	  
SPONSOR:	  	  
Imperial	  College	  Healthcare	  NHS	  Trust	  
FUNDING:	  	  	  
Department	  of	  Health	  Policy	  Research	  Programme	  (NVEC039/0031)	  
	  
CONFIDENTIAL	  
This	  document	  is	  confidential	  and	  the	  property	  of	  the	  chief	  investigators.	  No	  part	  of	  it	  may	  be	  transmitted,	  
reproduced,	  published,	  or	  used	  without	  prior	  written	  authorization	  from	  the	  chief	  investigator.	  
	  
STATEMENT	  OF	  COMPLIANCE	  
This	   protocol	   describes	   the	   SNIFFLE	   4	   study	   and	   provides	   information	   about	   procedures	   for	   entering	  
participants.	  The	  protocol	  should	  not	  be	  used	  as	  a	  guide	  for	  the	  treatment	  of	  other	  participants;	  every	  care	  
was	  taken	  in	  its	  drafting,	  but	  corrections	  or	  amendments	  may	  be	  necessary.	  These	  will	  be	  circulated	  to	  
investigators	  in	  the	  study,	  but	  centres	  entering	  participants	  for	  the	  first	  time	  are	  advised	  to	  contact	  the	  
trials	  centre	  to	  confirm	  they	  have	  the	  most	  recent	  version.	  	  
Problems	  relating	  to	  this	  trial	  should	  be	  referred,	  in	  the	  first	  instance,	  to	  the	  study	  coordination	  centre.	  	  
This	  trial	  will	  adhere	  to	  the	  principles	  outlined	  in	  the	  Medicines	  for	  Human	  Use	  (Clinical	  Trials)	  Regulations	  
2004	   (SI	   2004/1031),	   amended	   regulations	   (SI	   2006/1928)	   and	   the	   International	   Conference	   on	  
Harmonisation	   Good	   Clinical	   Practice	   (ICH	   GCP)	   guidelines.	   It	   will	   be	   conducted	   in	   compliance	   with	   the	  
protocol,	  the	  Data	  Protection	  Act	  and	  other	  regulatory	  requirements	  as	  appropriate.	  
Protocol	  authorised	  by:	  
Name	  &	  Role	  
Date	  
Signature	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  

	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  SNIFFLE-­‐4	  Study	  Protocol	  	  
Confidential	  
	  
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AMENDMENT	  HISTORY	  
	  
Amendment	  
No.	  
Protocol	  
Version	  
No.	  
Date	  issued	  
Author(s)	  of	  
changes	  
Details	  of	  Changes	  made	  
1	  
2.1	  
14	  Aug	  2016	  
Approved	  by:	  
	  REC:	  2	  Sept	  16	  
HRA:	  pending	  
	  
Paul	  Turner	  
1) Following	  discussions	  with	  PHE	  and	  DoH,	  
remove	  “surveillance	  nasal	  swabs”	  during	  
influenza	  season,	  and	  instead	  take	  nasal	  
swabs	  during	  the	  7	  days	  post	  vaccination	  
to	  assess	  for	  viral	  shedding.	  
2) Update	  PILs	  and	  consents	  to	  incorporate	  
nasal	  swabbing	  as	  in	  (1)	  above.	  
3) Update	  PILs	  and	  consents	  to	  include	  
IRAS/HRA	  reference	  numbers	  as	  requested	  
by	  HRA	  
2	  
2.2	  
5	  Sept	  	  2016	  
Approved	  by:	  
	  REC:	  pending	  
HRA:	  pending	  	  
	  
Paul	  Turner	  
1. Clarify	  consent	  procedure	  to	  be	  followed	  
for	  participants	  who	  turn	  16	  years	  in	  the	  4	  
weeks	  following	  vaccination.	  
2. Clarify	  eligibility	  criteria	  in	  line	  with	  
analysis	  plan	  as	  outlined	  in	  section	  9.	  	  
3. Include	  further	  details	  regarding	  statistical	  
analysis	  [section	  9.2]	  
4. Minor	  clarifications	  and	  corrections:	  
i. Correct	  name/title	  of	  PIS	  16-­‐17	  year	  
olds	  to	  PIS	  16+years	  (to	  remove	  
confusion	  over	  which	  PIS	  to	  be	  used	  in	  
young	  people	  age	  18	  yrs	  and	  ensure	  
consistency	  with	  consent	  forms).	  
ii. Clarify	  exclusion	  regarding	  ICU	  
admission	  (that	  this	  relates	  to	  
intubation+ventilation)	  
iii. Clarify	  “hospitalisation”	  in	  children	  age	  
2-­‐4	  years	  means	  observation	  in	  hospital	  
>	  4hrs.	  
	  
	  
	  

	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  SNIFFLE-­‐4	  Study	  Protocol	  	  
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PROTOCOL	  SYNOPSIS	  
	  
	  
Title	  
Safety	  of	  Nasal	  Influenza	  Immunisation	  in	  Children	  with	  Asthma	  
Abbreviated	  title	  
SNIFFLE	  4	  study	  
Eudra	  CT	  registration	  no.	  
2016-­‐002352-­‐24	  
HRA	  NREC	  Number	  
16/WM/0276	  
Sponsor	  R&D	  Number	  
16SM3348	  
Clinicaltrials.gov	  registration	  no.	  
NCT02866942	  
HRA	  IRAS	  /	  UKCRN	  reference	  
207822	  
Primary	  objective	  
To	  assess	  changes	  in	  asthma	  symptoms	  /	  symptom	  control	  following	  
LAIV	  in	  children	  with	  asthma	  /	  recurrent	  wheezing,	  including	  
children	  with	  difficult/severe	  asthma.	  
Intervention	  and	  key	  procedures	  
Single	  dose	  of	  intranasal	  LAIV	  
(To	  fulfil	  a	  duty	  of	  care,	  influenza	  vaccine-­‐naïve	  individuals	  under	  9	  
years	  of	  age	  AND	  at	  high	  risk	  for	  severe	  influenza	  infection	  will	  be	  
eligible	  for	  a	  second	  dose	  4	  weeks	  later,	  as	  per	  DoH	  guidelines).	  
Nasal	  swab	  (collected	  by	  parent)	  in	  the	  event	  of	  flu	  like	  illness	  from	  
January	  2017	  until	  end	  of	  Influenza	  season	  (approx.	  April	  2017)	  
Safety	  
Participants	  will	  be	  immunised	  in	  the	  hospital	  environment,	  by	  
personnel	  qualified	  in	  the	  recognition	  and	  treatment	  of	  anaphylaxis,	  
and	  observed	  for	  at	  least	  20	  minutes	  following	  a	  dose.	  	  
	  
Families	  will	  be	  contacted	  at	  72	  hours	  after	  immunisation	  to	  
establish	  the	  occurrence	  of	  any	  delayed	  effects.	  
	  
Completion	  of	  validated	  questionnaire	  at	  4	  weeks	  after	  LAIV.	  
Patient	  group	  
Children	  and	  young	  people	  with	  asthma	  /	  recurrent	  wheezing	  
attending	  paediatric	  outpatients,	  aged	  2-­‐18	  years	  old	  (inclusive).	  
Target	  recruitment	  of	  840	  subjects.	  
Primary	  outcome	  
Change	  in	  asthma	  symptoms	  and	  control	  pre	  and	  4	  weeks	  post	  LAIV,	  
as	  assessed	  by	  validated	  questionnaire:	  
• 
Age	  2-­‐4	  years:	  TRACK	  questionnaire	  
• 
Age	  5-­‐11	  years:	  C-­‐ACT	  score	  
• 
Age	  12+	  years:	  ACT	  score	  
Secondary	  outcomes	  
1. Incidence	  of	  adverse	  events	  (AEs)	  and	  serious	  adverse	  events	  
(SAEs)	  following	  LAIV	  
2. To	  document	  influenza	  virus	  shedding	  in	  the	  week	  following	  
vaccination	  with	  LAIV	  	  
Sponsor	  
Imperial	  College	  Healthcare	  NHS	  Trust	  
Funding	  
Department	  of	  Health	  Policy	  Research	  Programme	  (NVEC039/0031)	  

	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  SNIFFLE-­‐4	  Study	  Protocol	  	  
Confidential	  
	  
SNIFFLE-­‐4	  Protocol	  	  Version	  2.2,	  5	  September	  2016	  	  
	  
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TABLE	  OF	  CONTENTS	  
STATEMENT	  OF	  COMPLIANCE	  ...........................................................................................................................	  1	  
PROTOCOL	  SYNOPSIS	  ........................................................................................................................................	  2	  
GLOSSARY	  OF	  ABBREVIATIONS	  .........................................................................................................................	  7	  
INVESTIGATORS	  AND	  FACILITIES	  .......................................................................................................................	  8	  
Lead	  Study	  Centre	  and	  National	  Coordinating	  Centre	  ..................................................................................	  8	  
Study	  Management	  .......................................................................................................................................	  8	  
Co-­‐investigators	  ...............................................................................................................................	  9	  
Sites	  and	  Principle	  Investigators	  ......................................................................................................	  9	  
Trial	  Study	  Committee	  (TSC)	  ..........................................................................................................	  12	  
Independent	  Data	  Monitoring	  Committee	  ....................................................................................	  12	  
Sponsor	  .......................................................................................................................................................	  12	  
Funding	  and	  resources	  ................................................................................................................................	  12	  
1.	  INTRODUCTION	  ...........................................................................................................................................	  13	  
1.1	  BACKGROUND	  .......................................................................................................................................	  13	  
1.2	  Research	  Question	  ................................................................................................................................	  16	  
1.3	  STUDY	  RATIONALE	  &	  JUSTIFICATION	  ....................................................................................................	  16	  
2.	  	  STUDY	  OBJECTIVES	  .....................................................................................................................................	  17	  
2.1	  Primary	  objective	  ..................................................................................................................................	  17	  
2.2	  Secondary	  objective	  ..............................................................................................................................	  17	  
3.	  	  STUDY	  DESIGN	  ............................................................................................................................................	  17	  
3.1	  Study	  outcomes	  measures	  ....................................................................................................................	  18	  
3.1.1	  Primary	  study	  outcome	  ........................................................................................................	  18	  
3.1.2.	  Secondary	  study	  outcomes	  ..................................................................................................	  18	  
3.1.3.	  OTher	  study	  outcomes	  ........................................................................................................	  18	  
4.	  STUDY	  POPULATION	  ....................................................................................................................................	  18	  
4.1	  Recruitment	  ..........................................................................................................................................	  19	  
4.2	  Eligibility	  Criteria:	  Children	  to	  receive	  LAIV	  ...........................................................................................	  19	  
4.2.1	  Inclusion	  Criteria	  ...................................................................................................................	  19	  
4.2.2	  Exclusion	  Criteria	  ..................................................................................................................	  19	  

	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  SNIFFLE-­‐4	  Study	  Protocol	  	  
Confidential	  
	  
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4.3	  Subject	  Withdrawal	  ...............................................................................................................................	  20	  
5.	  Study	  TREATMENT	  .......................................................................................................................................	  21	  
5.1	  Description	  ............................................................................................................................................	  21	  
5.2	  Dosage	  and	  Route	  of	  Administration	  ....................................................................................................	  21	  
5.3	  Dose	  modification	  .................................................................................................................................	  21	  
5.4	  Preparation	  and	  administration	  of	  study	  drug	  ......................................................................................	  21	  
5.5	  Dispensing	  and	  Product	  Accountability	  ................................................................................................	  22	  
6	  STUDY	  VISITS,	  PROCEDURES	  SCHEDULE	  and	  Patient	  Flow	  Diagram	  ............................................................	  23	  
6.1	  STUDY	  PROCEDURES	  .............................................................................................................................	  24	  
6.1.1	  POST	  VACCINATION	  SCHEDULE	  ............................................................................................	  24	  
6.1.2	  Second	  dose	  of	  LAIV	  .............................................................................................................	  24	  
6.2	  CONSENT	  ...............................................................................................................................................	  26	  
7	  ADVERSE	  EVENT	  REPORTING	  ........................................................................................................................	  27	  
7.1	  Definitions	  .............................................................................................................................................	  27	  
7.1.1	  Documentation	  of	  Adverse	  Events	  .......................................................................................	  28	  
7.2	  Grading	  and	  attribution	  of	  adverse	  events	  ...........................................................................................	  28	  
7.2.1	  Non-­‐allergic	  reactions	  ...........................................................................................................	  28	  
7.2.2	  Grading	  and	  attribution	  of	  adverse	  events:	  Allergic	  reaction	  ...............................................	  29	  
7.3	  Reporting	  Procedures	  ...........................................................................................................................	  30	  
7.3.1	  Non	  serious	  AR/AEs	  ..............................................................................................................	  30	  
7.3.2	  Serious	  AR/AEs	  ......................................................................................................................	  30	  
8.	  ASSESSMENT	  AND	  FOLLOW-­‐UP	  ...................................................................................................................	  32	  
8.1	  CLINICAL	  ASSESSMENTS	  ........................................................................................................................	  32	  
8.1.1	  Allergy	  testing	  .......................................................................................................................	  32	  
8.1.2	  Clinical	  observation	  /	  monitoring	  of	  patients	  by	  clinical	  staff	  ..............................................	  32	  
8.1.3	  AstHMA	  CONTROL	  ASSESSMENT	  PRE	  and	  4	  weeks	  post	  vaccination	  ...................................	  32	  
8.2	  Telephone	  follow	  up	  .............................................................................................................................	  33	  
8.3	  Additional	  clinical	  assessments	  (Royal	  Brompton	  site	  only)	  .................................................................	  33	  
8.4	  NASAL	  SWABBING	  and	  SAMPLE	  MANAGEMENT	  ..................................................................................	  34	  
8.4.1	  Collection	  of	  nasal	  swab	  .......................................................................................................	  34	  
8.4.2	  Labelling,	  despatch,	  and	  storage	  of	  samples	  ........................................................................	  34	  

	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  SNIFFLE-­‐4	  Study	  Protocol	  	  
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8.4.3	  Handling	  of	  residual	  samples	  on	  completion	  of	  testing	  .......................................................	  35	  
8.5	  Loss	  to	  Follow-­‐up	  ..................................................................................................................................	  35	  
8.6	  Trial	  Closure	  ..........................................................................................................................................	  35	  
9.	  STATISTICS	  AND	  DATA	  ANALYSIS	  .................................................................................................................	  36	  
9.1	  Definitions	  .............................................................................................................................................	  36	  
9.2	  Sample	  Size	  Estimation	  .........................................................................................................................	  36	  
Population	  to	  be	  analysed	  .............................................................................................................	  36	  
9.3	  Statistical	  Analysis	  Plan	  .........................................................................................................................	  37	  
10	  DATA	  MANAGEMENT	  .................................................................................................................................	  39	  
10.1	  Data	  Collection	  ....................................................................................................................................	  39	  
10.2	  Data	  RECORDS	  .....................................................................................................................................	  39	  
11	  ADMINISTRATIVE	  AND	  REGULATORY	  ISSUES	  .............................................................................................	  40	  
11.1	  CLINICAL	  TRIALS	  AUTHORISATION	  ......................................................................................................	  40	  
11.2	  Ethics	  approval	  ....................................................................................................................................	  40	  
11.3	  Informed	  consent	  and	  participant	  assent	  ...........................................................................................	  40	  
11.4	  Confidentiality	  .....................................................................................................................................	  40	  
11.5	  INDEMNITY	  ..........................................................................................................................................	  40	  
11.6	  SPONSOR	  .............................................................................................................................................	  40	  
11.7	  FUNDING	  .............................................................................................................................................	  41	  
11.8	  AUDITS	  ................................................................................................................................................	  41	  
11.9	  Monitoring	  ..........................................................................................................................................	  41	  
12	  STUDY	  MANAGEMENT	  ...............................................................................................................................	  41	  
13	  PUBLICATION	  POLICY	  .................................................................................................................................	  41	  
APPENDIX	  1:	  TRACK	  QUESTIONNAIRE	  .............................................................................................................	  42	  
APPENDIX	  2a:	  ASTHMA	  CONTROL	  TEST	  –	  for	  children	  age	  5-­‐11	  years	  ............................................................	  43	  
APPENDIX	  2b:	  ASTHMA	  CONTROL	  TEST	  –	  YOUNG	  PEOPLE	  age	  12+	  years	  ......................................................	  44	  
APPENDIX	  3:	  ASTHMA	  CONTROL	  Questionnaire	  .............................................................................................	  45	  
APPENDIX	  4:	  Brighton	  Collaboration	  case	  definition	  of	  anaphylaxis	  ..............................................................	  46	  
APPENDIX	  5:	  Topic	  Guide	  for	  72hr	  telephone	  follow-­‐up	  .................................................................................	  47	  
APPENDIX	  6:	  Topic	  Guide	  for	  telephone	  follow-­‐up	  at	  4	  weeks	  .......................................................................	  48	  
	  
	  
	  

	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  SNIFFLE-­‐4	  Study	  Protocol	  	  
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GLOSSARY	  OF	  ABBREVIATIONS	  
	  
ABBREVIATION	  
TERM	  
ACQ	  
Asthma	  Control	  Questionnaire	  
ACT	  
Asthma	  Control	  Test	  
AE	  
Adverse	  Event	  
AEFI	  
Adverse	  Event	  Following	  Immunisation	  
BDP	  
Beclomethasone	  dipropionate	  
BDR	  
Bronchodilator	  responsiveness	  
BTS	  /	  SIGN	  
British	  Thoracic	  Society	  /	  	  
Scottish	  Intercollegiate	  Guidelines	  Network	  
C-­‐ACT	  
Childhood	  Asthma	  Control	  Test	  
CRF	  
Case	  report	  form	  
DoH	  
Department	  of	  Health	  (England)	  
FeNO	  
Fractional	  exhaled	  nitric	  oxide	  
GCP	  
Good	  Clinical	  Practice	  
IDMC	  
Independent	  Data	  Monitoring	  Committee	  
LAIV	  
Live	  Attenuated	  Influenza	  Vaccine	  (Intranasal,	  live)	  
LRTA	  
Leukotriene	  Receptor	  Antagonist	  
PAQLQ	  
Paediatric	  Asthma	  Quality	  of	  Life	  Questionnaire	  
PHE	  
Public	  Health	  England	  
PSW	  
Preschool	  wheeze	  
SAE	  
Serious	  adverse	  event	  
SAR	  
Serious	  adverse	  reaction	  
SOP	  
Standard	  Operating	  Procedure	  
SUSAR	  
Suspected	  Unexpected	  Serious	  Adverse	  Reaction	  
TIV	  
Trivalent	  Influenza	  Vaccine	  (Intramuscular,	  killed)	  
TRACK	  
Test	  for	  Respiratory	  and	  Asthma	  Control	  in	  Kids	  
TSC	  
Trial	  Study	  Committee	  
	  
	  

	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  SNIFFLE-­‐4	  Study	  Protocol	  	  
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INVESTIGATORS	  AND	  FACILITIES	  
LEAD	  STUDY	  CENTRE	  AND	  NATIONAL	  COORDINATING	  CENTRE	  
Imperial	  College	  Healthcare	  NHS	  Trust	  /	  Imperial	  College	  London	  
Paediatric	  Research	  Unit,	  7th	  Floor	  QEQM	  Building,	  St	  Mary’s	  Hospital,	  Praed	  Street,	  London	  W2	  1NY	  
T:	  020	  3312	  7754	  
STUDY	  MANAGEMENT	  	  
CHIEF	  INVESTIGATOR	  
Name	  
Dr	  Paul	  Turner	  	  
BM	  BCh	  FRACP	  MRCPCH	  PhD	  
Position	  
MRC	  Clinician	  Scientist	  &	  Hon	  Consultant	  in	  Paediatric	  Allergy	  &	  Immunology	  
Institution	  
Imperial	  College	  Healthcare	  NHS	  Trust	  /	  Imperial	  College	  London	  
Address	  
Paediatric	  Research	  Unit,	  7th	  Floor	  QEQM	  Building,	  St	  Mary’s	  Hospital,	  Praed	  Street	  
City	  
London	  
Postcode	  
W2	  1NY	  
Phone	  
020	  3312	  7754	  
Email	  
p.turner@imperial.ac.uk	  
TRIAL	  STATISTICIAN	  
	  
	  
Name	  
Prof	  Nick	  Andrews	  
Position	  
Deputy	  Head	  of	  the	  Statistics	  Unit	  
Institution	  
Public	  Health	  England	  
Address	  
61	  Colindale	  Avenue	  
City	  
London	  
Postcode	  
NW9	  5EQ	  
Phone	  
Switchboard	  0044	  208	  200	  6868	  
Email	  
Nick.Andrews@phe.gov.uk	  
STUDY	  COORDINATOR	  AND	  CLINICAL	  ENQUIRIES	  
Name	  
Ms	  Heather	  Hanna	  
Position	  
Senior	  Research	  Nurse	  
Institution	  
Imperial	  College	  London	  
Address	  
Paediatric	  Research	  Unit,	  7th	  Floor	  QEQM	  Building,	  St	  Mary’s	  Hospital,	  Praed	  Street	  
City	  
London	  
Postcode	  
W2	  1NY	  
Phone	  
020	  3312	  7754	  
Fax	  
020	  3312	  7571	  
Email	  
h.hanna@imperial.ac.uk	  
	  
	  

	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  SNIFFLE-­‐4	  Study	  Protocol	  	  
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CO-­‐INVESTIGATORS	  
IMPERIAL	  COLLEGE	  LONDON	  
Name	  
Dr	  Sejal	  Saglani	  
Position	  
Reader	  and	  Hon	  Consultant	  in	  Paediatric	  Respiratory	  Medicine	  
Institution	  
Imperial	  College	  London	  /	  Royal	  Brompton	  &	  Harefield	  NHS	  Foundation	  Trust	  
Address	  
Royal	  Brompton	  Hospital,	  Sydney	  Street,	  London	  SW3	  6NP	  
Phone	  
020	  7594	  3167	  
Email	  
s.saglani@imperial.ac.uk	  
	  
Name	  
Dr	  Louise	  Fleming	  
Position	  
Clinical	  Senior	  Lecturer	  and	  Hon	  Consultant	  in	  Paediatric	  Respiratory	  Medicine	  
Institution	  
Imperial	  College	  London	  /	  Royal	  Brompton	  &	  Harefield	  NHS	  Foundation	  Trust	  
Address	  
Royal	  Brompton	  Hospital,	  Sydney	  Street,	  London	  SW3	  6NP	  
Phone	  
020	  7352	  8121	  ext	  2938	  
Email	  
L.Fleming@rbht.nhs.uk	  
PUBLIC	  HEALTH	  ENGLAND	  
Name	  
Professor	  Elizabeth	  Miller	  
Position	  
Consultant	  Epidemiologist	  	  
Institution	  
Immunisation	  Hepatitis	  and	  Blood	  Safety	  Department,	  Public	  Health	  England	  
Address	  
61	  Colindale	  Avenue,	  London	  NW9	  5EQ	  
Phone	  
020	  8327	  7430	  
Email	  
liz.miller@phe.gov.uk	  
	  
Name	  
Dr	  Jo	  Southern	  MSc	  PhD	  MICR	  CSci	  MFPH	  
Position	  
Senior	  Clinical	  Scientist,	  Epidemiology	  
Institution	  
Immunisation	  Hepatitis	  and	  Blood	  Safety	  Department,	  Public	  Health	  England	  
Address	  
61	  Colindale	  Avenue,	  London	  NW9	  5EQ	  
Phone	  
020	  8327	  6021	  
Email	  
jo.southern@phe.gov.uk	  
	  
SITES	  AND	  PRINCIPLE	  INVESTIGATORS	  
BIRMINGHAM	  
Name	  
Dr	  Prasad	  Nagakumar	  &	  Dr	  Satish	  Rao	  
Position	  
Consultant	  in	  Paediatric	  Respiratory	  Medicine	  
Institution	  
Birmingham	  Children's	  Hospital	  NHS	  Foundation	  Trust	  
Address	  
Steelhouse	  Lane	  ,	  Birmingham,	  B4	  6NH	  
Phone	  
0121	  333	  8199	  	  
Email	  
Prasad.Nagakumar@bch.nhs.uk	  /	  satish.rao@bch.nhs.uk	  
BRIGHTON	  
Name	  
Dr	  Paul	  Seddon	  &	  Dr	  Katy	  Fiddler	  
Position	  
Consultant	  in	  Paediatric	  Respiratory	  Medicine	  
Institution	  
Brighton	  &	  Sussex	  University	  Hospitals	  NHS	  Trust	  
Address	  
Royal	  Alexandra	  Children's	  Hospital,	  Eastern	  Road,	  Brighton	  BN2	  5BE	  
Phone	  
01273	  696955	  
Email	  
seddop@gmail.com	  

	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  SNIFFLE-­‐4	  Study	  Protocol	  	  
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BRISTOL	  
Name	  
Dr	  Huw	  Thomas	  
Position	  
Consultant	  Paediatrician	  
Institution	  
Bristol	  Royal	  Hospital	  for	  Children	  
Address	  
Upper	  Maudlin	  Street,	  Bristol	  BS2	  8BJ	  
Phone	  
0117	  342	  8655	  
Email	  
Huw.Thomas@UHBristol.nhs.uk	  
LEEDS	  
Name	  
Dr	  Alexandra	  Adams	  
Position	  
Consultant	  in	  Paediatric	  Respiratory	  Medicine	  
Institution	  
Leeds	  Children’s	  Hospital	  
Address	  
Leeds	  General	  Infirmary,	  Great	  George	  Street,	  Leeds,	  LS1	  3EX	  
Phone	  
0113	  392	  7125	  
Email	  
Alexandra.adams2@nhs.net	  
LEICESTER	  
Name	  
Dr	  Gary	  Stiefel	  &	  Dr	  Hitesh	  Pandya	  
Position	  
Consultant	  in	  Paediatric	  Allergy	  &	  Consultant	  in	  Paediatric	  Respiratory	  Medicine	  
Institution	  
Leicester	  Royal	  Infirmary	  
Address	  
Infirmary	  Square	  Leicester	  LE1	  5WW	  
Phone	  
0116	  258	  6914	  
Email	  
Gary.GHS.Stiefel@uhl-­‐tr.nhs.uk	  
LIVERPOOL	  
Name	  
Dr	  Ian	  Sinha	  	  
Position	  
Consultant	  in	  Respiratory	  Medicine	  
Institution	  
Alder	  Hey	  Children’s	  Hospital	  NHS	  Foundation	  Trust	  
Address	  
Eaton	  Road,	  West	  Derby,	  Liverpool	  L12	  2AP	  
Phone	  
0151	  228	  4811	  x2777	  
Email	  
Ian.Sinha@alderhey.nhs.uk	  
LONDON:	  KING’S	  COLLEGE	  HOSPITAL	  
Name	  
Dr	  Atul	  Gupta	  
Position	  
Consultant	  in	  Paediatric	  Respiratory	  Medicine	  
Institution	  
Kings	  College	  Hospital	  NHS	  Foundation	  Trust	  
Address	  
Denmark	  Hill,	  London	  SE5	  9RS	  
Phone	  
020	  3299	  4574	  
Email	  
Atulgupta1@nhs.net	  
LONDON:	  ROYAL	  BROMPTON	  HOSPITAL	  
Name	  
Dr	  Sejal	  Saglani	  /	  Dr	  Louise	  Fleming	  
Position	  
Hon	  Consultants	  in	  Paediatric	  Respiratory	  Medicine	  
Institution	  
Imperial	  College	  London	  /	  Royal	  Brompton	  &	  Harefield	  NHS	  Foundation	  Trust	  
Address	  
Royal	  Brompton	  Hospital,	  Sydney	  Street,	  London	  SW3	  6NP	  
Phone	  
020	  7594	  3167	  
Email	  
s.saglani@imperial.ac.uk	  /	  L.Fleming@rbht.nhs.uk	  
	  

	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  SNIFFLE-­‐4	  Study	  Protocol	  	  
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LONDON:	  ST	  MARY’S	  HOSPITAL	  
Name	  
Paul	  Turner	  
Position	  
MRC	  Clinician	  Scientist	  &	  Hon	  Consultant	  in	  Paediatric	  Allergy	  &	  Immunology	  
Institution	  
Imperial	  College	  London	  
Address	  
Paed.	  Research	  Unit,	  7th	  Floor	  QEQM,	  St	  Mary’s	  Hospital,	  Praed	  Street	  London	  W2	  1NY	  
Phone	  
020	  3312	  7754	  
Email	  
p.turner@imperial.ac.uk	  
MANCHESTER	  
Name	  
Dr	  Stephen	  Hughes	  &	  Dr	  Clare	  Murray	  
Position	  
Consultant	  Paediatric	  Immunologist	  /	  Consultant	  in	  Paed	  Respiratory	  Medicine	  
Institution	  
Royal	  Manchester	  Children’s	  Hospital	  
Address	  
Oxford	  Road,	  Manchester,	  M13	  9WL	  
Phone	  
0161	  701	  0678	  
Email	  
stephen.hughes@cmft.nhs.uk	  /	  Clare.murray@manchester.ac.uk	  
NEWCASTLE	  
Name	  
Dr	  Sam	  Moss	  	  
Position	  
Consultant	  in	  Paediatric	  Allergy	  
Institution	  
The	  Newcastle	  upon	  Tyne	  Hospitals	  NHS	  Foundation	  Trust	  
Address	  
Freeman	  Hospital,	  Freeman	  Road,	  High	  Heaton	  Newcastle	  upon	  Tyne	  NE7	  7DN	  
Phone	  
0191	  282	  0673	  
Email	  
Samantha.Moss@nuth.nhs.uk	  
OXFORD	  
Name	  
Dr	  Andrew	  Ives	  
Position	  
Consultant	  in	  Paediatric	  Respiratory	  Medicine	  
Institution	  
Oxford	  University	  Hospitals	  NHS	  Foundation	  Trust	  
Address	  
Children’s	  Hospital,	  John	  Radcliffe	  Hospital,	  Headley	  Way,	  OX3	  9DU	  	  
Phone	  
01865	  234194	  
Email	  
andrew.ives@ouh.nhs.uk	  
SHEFFIELD	  
Name	  
Dr	  Nicola	  Jay	  /	  Dr	  Sonal	  Kansra	  
Position	  
Consultant	  Paediatrician	  /	  Consultant	  in	  Paediatric	  Respiratory	  Medicine	  
Institution	  
Sheffield	  Children’s	  Hospital	  NHS	  Foundation	  Trust	  
Address	  
Clinical	  Research	  Facility,	  D	  Floor,	  Stephenson	  Wing,	  Sheffield	  Children's	  Hospital	  
Sheffield	  S10	  2TH	  
Phone	  
0114	  271	  7559	  /	  7672	  
Email	  
Nicola.jay@sch.nhs.uk	  /	  sonal.kansra@sch.nhs.uk	  
SOUTHAMPTON	  
Name	  
Prof	  Graham	  Roberts	  &	  Dr	  Mich	  Erlewyn-­‐Lajeunesse	  
Position	  
Professor	  and	  Hon	  Consultant	  Paediatrician	  in	  Paediatric	  Allergy	  and	  Respiratory	  Medicine	  
/	  Consultant	  Paediatric	  Immunologist	  and	  Hon.	  Senior	  Clinical	  Lecturer	  
Institution	  
University	  Hospital	  Southampton	  NHS	  Foundation	  Trust	  
Address	  
Southampton	  General	  Hospital	  Southampton	  SO16	  6YD	  
Phone	  
023	  8120	  6160	  /	  023	  8120	  4335	  
Email	  
g.c.roberts@soton.ac.uk	  /	  Mich.Lajeunesse@soton.ac.uk	  

	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  SNIFFLE-­‐4	  Study	  Protocol	  	  
Confidential	  
	  
SNIFFLE-­‐4	  Protocol	  	  Version	  2.2,	  5	  September	  2016	  	  
	  
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TRIAL	  STUDY	  COMMITTEE	  (TSC)	  
The	  ISC	  is	  the	  main	  decision	  making	  body,	  with	  overall	  responsibility	  for	  ensuring	  the	  project’s	  aims	  are	  
delivered	  to	  schedule	  and	  within	  budget.	  The	  TSC	  will	  consist	  of:	  
• 
Dr	  Paul	  Turner	  (CI)	  
• 
Prof	  Liz	  Miller	  (Co-­‐investigator)	  
• 
Dr	  Jo	  Southern	  (Co-­‐investigator)	  
• 
Dr	  Louise	  Fleming	  (Co-­‐investigator)	  
• 
Dr	  Sejal	  Saglani	  (Co-­‐investigator)	  
INDEPENDENT	  DATA	  MONITORING	  COMMITTEE	  
A	  data	  monitoring	  committee	  (IDMC)	  will	  be	  appointed,	  consisting	  of	  three	  members	  independent	  of	  the	  
study	  team.	  They	  will	  review	  safety	  data	  on	  an	  on	  going	  basis	  and	  review	  severe	  events	  reported	  by	  PIs.	  The	  
IDMC	  will	  provide	  advice	  to	  the	  TSC.	  The	  following	  membership	  has	  been	  confirmed:	  
• Dr	  Glenis	  Scadding	  [Chairperson]	  (Consultant	  in	  Rhinology	  and	  Allergy,	  London)	  
• Prof.	  Jürgen	  Schwarze	  (Edward	  Clark	  Chair	  of	  Child	  Life	  and	  Health,	  University	  of	  Edinburgh)	  
• Dr	  Andrew	  Riordan	  (Consultant	  in	  Paediatric	  Immunology	  and	  Infectious	  Diseases,	  Liverpool)	  
• Dr	  Andre	  Charlett	  (Director	  of	  Statistics	  Unit,	  Public	  Health	  England)	  
	  
SPONSOR	  
Imperial	  College	  Healthcare	  NHS	  Trust,	  Sponsor	  number:	  16SM3348	  
CONTACT:	  
Name	  
Joanne	  Siwoniku	  
Position	  
Clinical	  Trials	  Manager,	  Joint	  Research	  Compliance	  Office	  
Institution	  
Imperial	  College	  London	  and	  Imperial	  College	  Healthcare	  NHS	  Trust	  
Address	  
Room	  221,	  Medical	  School	  Building,	  Norfolk	  Place	  
City	  
London	  
Postcode	  
W2	  1PG	  
Phone	  
020	  7594	  6245	  
Email	  
j.siwoniku@imperial.ac.uk	  
	  
FUNDING	  AND	  RESOURCES	  
Funding	  has	  been	  obtained	  from	  the	  Department	  of	  Health	  Policy	  Research	  Programme	  (NVEC039/0031)	  
awarded	  to	  Prof	  Elizabeth	  Miller,	  Public	  Health	  England.	  
	  
	  
	  

	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  SNIFFLE-­‐4	  Study	  Protocol	  	  
Confidential	  
	  
SNIFFLE-­‐4	  Protocol	  	  Version	  2.2,	  5	  September	  2016	  	  
	  
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1.	  INTRODUCTION	  
	  
1.1	  BACKGROUND	  
	  
Data	  collected	  during	  previous	  pandemic	  situations,	  as	  well	  as	  mathematical	  modelling	  of	  mixing	  patterns	  
and	  infectivity,	  have	  shown	  that	  children	  serve	  as	  the	  most	  important	  reservoir	  for	  influenza	  infection	  and	  
transmission.1,2	  	  
Vaccinating	  children	  may	  therefore	  provide	  the	  most	  effective	  method	  for	  interrupting	  the	  chain	  of	  
transmission	  and	  so	  achieving	  disease	  control.	  This	  was	  recognised	  by	  the	  Joint	  Committee	  for	  Vaccination	  
and	  Immunisation	  (JCVI),	  who	  at	  its	  meeting	  in	  June	  2012	  recommended	  the	  annual	  vaccination	  of	  all	  
children	  aged	  2-­‐16	  years	  of	  age	  with	  the	  live	  attenuated	  influenza	  vaccine	  (LAIV).	  LAIV	  has	  been	  shown	  to	  
be	  more	  effective	  in	  this	  age	  group	  than	  the	  inactivated	  trivalent	  influenza	  vaccine	  (TIV)	  which,	  though	  
recommended	  for	  annual	  vaccination	  children	  with	  specific	  risk	  factors,	  has	  variable	  efficacy	  in	  young	  
children	  depending	  on	  the	  match	  between	  vaccine	  and	  circulating	  strains.3	  
The	  safety	  of	  LAIV	  in	  non-­‐atopic	  children	  has	  been	  demonstrated	  in	  a	  number	  of	  published	  studies,4	  and	  to	  
date	  over	  1	  million	  doses	  have	  been	  given.	  However,	  LAIV	  contains	  very	  small	  amounts	  of	  egg	  protein	  
(ovalbumin)	  and	  until	  recently	  has	  been	  contraindicated	  in	  children	  with	  egg	  allergy.	  	  The	  SNIFFLE-­‐15	  and	  
SNIFFLE-­‐2	  studies6,	  commissioned	  by	  Public	  Health	  England,	  demonstrated	  the	  safety	  of	  LAIV	  in	  children	  
with	  egg	  allergy.	  A	  total	  of	  1237	  doses	  were	  administered	  in	  887	  children,	  with	  no	  systemic	  allergic	  or	  
anaphylactic	  reactions	  observed.	  Administration	  of	  LAIV	  in	  children	  with	  a	  history	  of	  asthma	  or	  recurrent	  
wheezing	  did	  not	  affect	  asthma	  control.6	  This	  is	  important,	  because	  USA	  guidelines	  currently	  recommend	  
against	  the	  use	  of	  LAIV	  in	  children	  with	  a	  history	  of	  wheezing	  in	  the	  preceding	  12	  months,7	  although	  the	  
evidence	  for	  this	  recommendation	  is	  poor.5,6	  However,	  due	  to	  the	  small	  numbers	  of	  children	  on	  high-­‐dose	  
inhaled	  corticosteroids	  (BTS/SIGN	  step	  4+	  treatment),	  only	  limited	  conclusions	  could	  be	  drawn	  regarding	  
the	  safety	  of	  LAIV	  in	  children	  with	  “severe	  asthma”	  (defined	  as	  BTS/SIGN	  step	  4+	  therapy).	  
We	  now	  wish	  to	  assess	  the	  safety	  of	  LAIV	  in	  children	  with	  asthma,	  including	  those	  children	  with	  “severe	  
asthma”	  or	  “difficult-­‐to-­‐control”	  symptoms,	  to	  increase	  the	  safety	  data	  in	  this	  sub-­‐population.	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  
1JCVI	  Statement	  on	  the	  Routine	  Annual	  Influenza	  Vaccination	  Programme	  –	  Extension	  of	  the	  Programme	  to	  Children,	  
2012.	  https://www.gov.uk/government/publications/jcvi-­‐statement-­‐on-­‐the-­‐routine-­‐annual-­‐influenza-­‐vaccination-­‐
programme	  
2Baguelin	  M,	  Flasche	  S,	  Camacho	  A,	  Demiris	  N,	  Miller	  E,	  Edmunds	  WJ.	  Assessing	  optimal	  target	  populations	  for	  influenza	  
vaccination	  programmes:	  an	  evidence	  synthesis	  and	  modelling	  study.	  PLoS	  Med.	  2013	  Oct;10(10):e1001527.	  doi:	  
10.1371/journal.pmed.1001527.	  	  
3Heikkinen	  T,	  Heinonen	  S.	  Effectiveness	  and	  Safety	  of	  Influenza	  Vaccination	  in	  Children:	  European	  Perspective.	  Vaccine.	  
2011	  Oct	  6;29(43):7529-­‐34	  
4Tennis	  P,	  Toback	  SL,	  Andrews	  E,	  McQuay	  LJ,	  Ambrose	  CS.	  A	  postmarketing	  evaluation	  of	  the	  frequency	  of	  use	  and	  
safety	  of	  live	  attenuated	  influenza	  vaccine	  use	  in	  nonrecommended	  children	  younger	  than	  5	  years.	  Vaccine.	  
2011;29(31):4947-­‐52.	  
Ambrose	  CS,	  Yi	  T,	  Falloon	  J.	  An	  integrated,	  multistudy	  analysis	  of	  the	  safety	  of	  Ann	  Arbor	  strain	  live	  attenuated	  
influenza	  vaccine	  in	  children	  aged	  2-­‐17	  years.	  Influenza	  and	  other	  respiratory	  viruses.	  2011;5(6):389-­‐97.	  
Baxter	  R,	  Toback	  SL,	  Sifakis	  F,	  Hansen	  J,	  Bartlett	  J,	  Aukes	  L,	  et	  al.	  A	  postmarketing	  evaluation	  of	  the	  safety	  of	  Ann	  Arbor	  
strain	  live	  attenuated	  influenza	  vaccine	  in	  children	  5	  through	  17	  years	  of	  age.	  Vaccine.	  2012;30(19):2989-­‐98.	  
Kelso	  JM.	  Safety	  of	  influenza	  vaccines.	  Current	  opinion	  in	  allergy	  and	  clinical	  immunology.	  2012;12(4):383-­‐8.	  
Tennis	  P,	  Toback	  SL,	  Andrews	  EB,	  McQuay	  LJ,	  Ambrose	  CS.	  A	  US	  postmarketing	  evaluation	  of	  the	  frequency	  and	  safety	  
of	  live	  attenuated	  influenza	  vaccine	  use	  in	  nonrecommended	  children	  younger	  than	  5	  years:	  2009-­‐2010	  season.	  
Vaccine.	  2012;30(42):6099-­‐102.	  
5	  Turner	  PJ,	  Southern	  J,	  Andrews	  NJ,	  Miller	  E,	  Erlewyn-­‐Lajeunesse	  M;	  on	  behalf	  of	  the	  SNIFFLE	  Study	  Investigators.	  
Safety	  of	  live	  attenuated	  influenza	  vaccine	  in	  atopic	  children	  with	  egg	  allergy.	  J	  Allergy	  Clin	  Immunol.	  2015;136:376-­‐81.	  
6Turner	  PJ,	  Southern	  J,	  Andrews	  NJ,	  Miller	  E,	  Erlewyn-­‐Lajeunesse	  M;	  SNIFFLE-­‐2	  Study	  Investigators.	  Safety	  of	  live	  
attenuated	  influenza	  vaccine	  in	  young	  people	  with	  egg	  allergy:	  multicentre	  prospective	  cohort	  study.	  BMJ.	  2015;	  
351:h6291.	  
7	  Grohskopf,	  L.A.,	  Olsen,	  S.J.,	  Sokolow,	  L.Z.,	  Bresee,	  J.S.,	  Cox,	  N.J.,	  Broder,	  K.R.	  et	  al.	  Prevention	  and	  control	  of	  seasonal	  
influenza	  with	  vaccines:	  recommendations	  of	  the	  Advisory	  Committee	  on	  Immunization	  Practices	  (ACIP)—United	  
States,	  2014-­‐15	  Influenza	  Season.	  MMWR	  Morb	  Mortal	  Wkly	  Rep.	  2014;	  63:	  691–697	  

	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  SNIFFLE-­‐4	  Study	  Protocol	  	  
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Figure	  1a:	  BTS/SIGN	  Management	  steps:	  Children	  /	  young	  people	  aged	  over	  12	  years:	  
	  
	  
	  
Figure	  1b:	  BTS/SIGN	  Management	  steps:	  Children	  aged	  5-­‐12	  years:	  
	  
	  
	  

	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  SNIFFLE-­‐4	  Study	  Protocol	  	  
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Figure	  1c:	  BTS/SIGN	  Management	  steps:	  Children	  aged	  under	  5	  years:	  
	  
LAIV	  results	  in	  nasal	  viral	  shedding	  for	  7-­‐10	  days	  after	  administration,8	  an	  effect	  more	  predominant	  in	  
younger	  children.	  It	  is	  this	  which	  has	  resulted	  in	  the	  recommendation	  for	  LAIV	  not	  be	  administered	  in	  the	  
context	  of	  a	  close	  relative	  with	  immunodeficiency,	  although	  the	  viral	  components	  in	  LAIV	  are	  attenuated	  so	  
that	  the	  risk	  of	  causing	  infection	  is	  negligible.	  	  
Data	  from	  the	  USA	  over	  recent	  years	  has	  demonstrated	  reduce	  vaccine	  efficacy	  (VE)	  for	  LAIV;	  this	  was	  
initially	  attributed	  to	  vaccine	  lability	  with	  inappropriate	  temperature-­‐controlled	  handling,	  and	  resulted	  in	  a	  
change	  in	  strains	  included	  in	  the	  vaccine.	  However,	  despite	  this,	  VE	  reported	  for	  North	  America	  has	  
dropped	  further,	  and	  the	  vaccine	  is	  no	  longer	  recommended	  in	  the	  USA.9	  In	  contrast,	  VE	  in	  the	  UK	  and	  
other	  countries	  continues	  to	  be	  high,	  around	  60%	  (slightly	  greater	  than	  the	  injected	  influenza	  vaccine	  in	  
children)	  with	  up	  to	  80%	  efficacy	  against	  influenza	  B	  strains.10	  These	  data	  continue	  to	  support	  the	  use	  of	  
LAIV	  in	  children	  in	  the	  UK.	  
However,	  it	  is	  unclear	  as	  to	  why	  vaccine	  efficacy	  is	  so	  different	  between	  UK	  and	  USA.	  One	  hypothesis	  is	  that	  
underlying	  LAIV	  immunity,	  induced	  by	  previous	  LAIV	  vaccination	  in	  individuals,	  can	  reduce	  the	  ability	  of	  
subsequent	  vaccine	  to	  induce	  an	  immune	  response.	  It	  is	  noteworthy	  that	  LAIV	  has	  been	  used	  in	  the	  USA	  
since	  2003,	  a	  decade	  earlier	  than	  in	  the	  UK.	  In	  order	  to	  obtain	  data	  relating	  to	  support	  or	  refute	  this	  
hypothesis,	  we	  intend	  to	  study	  vaccine	  shedding	  in	  the	  10	  days	  following	  LAIV	  administration	  in	  this	  study.	  
We	  will	  also	  correlate	  vaccine	  shedding	  with	  reported	  adverse	  events	  following	  vaccination,	  to	  see	  if	  there	  
is	  an	  association	  present.	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  
8	  Block	  SL,	  Yogev	  R,	  Hayden	  FG,	  Ambrose	  CS,	  Zeng	  W,	  Walker	  RE.	  Shedding	  and	  immunogenicity	  of	  live	  attenuated	  
influenza	  vaccine	  virus	  in	  subjects	  5-­‐49	  years	  of	  age.	  Vaccine	  2008;26(38):4940-­‐6.	  	  
Mallory	  RM,	  Yi	  T,	  Ambrose	  CS.	  Shedding	  of	  Ann	  Arbor	  strain	  live	  attenuated	  influenza	  vaccine	  virus	  in	  children	  6-­‐59	  
months	  of	  age.	  Vaccine	  2011;29(26):4322-­‐7.	  	  
9	  http://www.cdc.gov/media/releases/2016/s0622-­‐laiv-­‐flu.html	  
10https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/530756/Influenza_vaccine_effectiv
eness_in_primary_care_in_children.pdf	  

	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  
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1.2	  RESEARCH	  QUESTION	  
To	  assess	  the	  safety	  of	  LAIV	  (Fluenz®,	  Astra	  Zeneca)	  in	  children	  with	  asthma	  or	  a	  history	  of	  recurrent	  
wheezing,	  age	  2-­‐18	  years.	  
	  
1.3	  STUDY	  RATIONALE	  &	  JUSTIFICATION	  
The	  JCVI	  has	  recommended	  annual	  influenza	  vaccination	  for	  all	  children	  2-­‐16	  years	  of	  age.	  The	  programme	  
commenced	  using	  Fluenz	  in	  the	  2013/2014	  influenza	  season,	  was	  initially	  restricted	  to	  children	  under	  4	  
years	  of	  age	  for	  logistic	  reasons,	  but	  is	  subsequently	  being	  expanded	  over	  the	  next	  few	  years	  to	  include	  all	  
children	  under	  16	  years.	  
To	  date,	  there	  are	  only	  limited	  data	  available	  regarding	  the	  safety	  of	  LAIV	  in	  children	  with	  “severe”	  asthma	  
requiring	  high	  dose	  inhaled	  corticosteroid	  therapy	  (or	  more	  intensive	  treatment).	  In	  the	  SNIFFLE-­‐1	  and	  -­‐2	  
studies,	  only	  49	  children	  were	  included	  requiring	  BTS	  Step	  4+	  treatment.	  This	  lack	  of	  data	  is	  reflected	  in	  the	  
current	  guidance	  from	  Department	  of	  Health:	  
“There	  is	  limited	  safety	  data	  on	  children	  who	  are	  currently	  taking	  a	  high	  dose	  of	  an	  inhaled	  steroid	  
–	  Budesonide	  >800	  mcg/day	  or	  equivalent	  (e.g.	  Fluticasone	  >500	  mcgs/day)	  –	  such	  children	  should	  
only	  be	  given	  LAIV	  on	  the	  advice	  of	  their	  specialist.”	  
This	  study	  will	  enrol	  840	  children	  with	  a	  history	  of	  asthma	  or	  recurrent	  wheezing	  (target	  420	  at	  BTS	  4+	  or	  
greater,	  the	  remaining	  420	  participants	  at	  lesser	  levels	  of	  treatment),	  to	  obtain	  further	  safety	  data	  relating	  
to	  the	  administration	  of	  LAIV	  in	  this	  group	  of	  children	  and	  thus	  inform	  UK	  guidance	  with	  regard	  to	  LAIV.	  
The	  study	  includes	  an	  assessment	  of	  influenza	  virus	  shedding	  following	  LAIV.	  Though	  efficacy	  of	  the	  vaccine	  
has	  been	  maintained	  in	  the	  first	  few	  years	  of	  LAIV	  use	  in	  the	  UK,	  this	  is	  not	  so	  in	  the	  USA	  where	  it	  has	  been	  
used	  for	  the	  last	  decade.	  The	  unique	  cohort	  included	  in	  this	  study	  provide	  an	  opportunity	  to	  assess	  viral	  
shedding	  in	  the	  period	  immediately	  after	  vaccination,	  through	  parental	  collection	  of	  nasal	  swabs	  at	  three	  
time	  points	  in	  the	  week	  following	  vaccination,	  which	  will	  be	  posted	  in	  prepaid	  bags	  directly	  to	  the	  testing	  
laboratory	  at	  PHE	  Colindale.	  This	  will	  likely	  be	  24	  hours,	  72	  hours	  and	  6	  days	  after	  vaccination	  but	  these	  
time	  points	  will	  be	  confirmed	  nearer	  the	  start	  of	  the	  study	  based	  on	  international	  data	  which	  is	  being	  
gathered	  and	  published	  now.	  There	  may	  be	  a	  correlation	  between	  vaccine	  shedding	  and	  adverse	  events	  
following	  vaccination.	  The	  data	  will	  also	  help	  inform	  as	  to	  whether	  there	  is	  a	  link	  between	  vaccine	  shedding	  
and	  previous	  exposure	  to	  influenza	  vaccines	  including	  previous	  LAIV,	  an	  issue	  which	  might	  explain	  the	  
apparent	  lower	  efficacy	  of	  LAIV	  in	  the	  USA	  compared	  to	  UK	  and	  Finland.	  	  
	  
	  

	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  
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2.	  	  STUDY	  OBJECTIVES	  
2.1	  PRIMARY	  OBJECTIVE	  
To	  assess	  changes	  in	  symptoms	  and	  symptom	  control	  pre-­‐	  and	  4	  weeks	  after	  LAIV	  administration	  in	  
children	  with	  asthma	  /	  recurrent	  wheezing,	  including	  children	  with	  difficult-­‐to-­‐control/severe	  asthma.	  
2.2	  SECONDARY	  OBJECTIVE	  
1. To	  assess	  the	  safety	  of	  LAIV	  in	  children	  with	  a	  past	  medical	  history	  of	  asthma	  or	  recurrent	  wheeze,	  
documentation	  of:	  
• 
AEs	  occurring	  up	  to	  72	  hours	  after	  LAIV	  in	  participants.	  
• 
Wheezing	  /	  asthma	  symptoms	  in	  subjects	  given	  LAIV	  in	  the	  4	  weeks	  prior	  to	  vaccine	  
administration	  vs	  the	  4	  week	  period	  after	  LAIV.	  
2. To	  document	  influenza	  virus	  shedding	  in	  the	  week	  following	  vaccination	  with	  LAIV	  
	  
	  
3.	  	  STUDY	  DESIGN	  
Type	  of	  Study:	  
Multicentre,	  observational	  study	  of	  the	  safety	  of	  LAIV	  in	  children	  with	  asthma	  or	  
recurrent	  wheezing	  
Number	  of	  Subjects:	  
840	  children:	  420	  on	  BTS/SIGN	  STEP	  4+	  treatment	  (the	  remainder	  on	  lesser	  levels	  
of	  treatment)	  attending	  Paediatric	  Outpatients	  for	  routine	  clinic	  visits	  from	  
September-­‐January	  2017	  (see	  power	  calculation	  below)	  
Expected	  Duration:	  
Recruitment	  to	  commence	  1st	  September	  2016	  
	  
Clinical	  interventions	  to	  commence	  from	  mid-­‐September	  2016	  for	  5	  months.	  
	  
	  
	  

	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  SNIFFLE-­‐4	  Study	  Protocol	  	  
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3.1	  STUDY	  OUTCOMES	  MEASURES	  
3.1.1	  PRIMARY	  STUDY	  OUTCOME	  	  
	  
• 
Change	  in	  symptom/disease	  control	  assessment	  through	  validated	  questionnaire	  pre-­‐	  and	  4	  weeks	  
after	  LAIV	  in	  children	  with	  asthma	  /	  recurrent	  wheezing:	  
o 
In	  children	  age	  2-­‐4	  years	  inclusive:	  TRACK	  score11	  	  	  (Appendix	  1)	  
o 
In	  children	  age	  5-­‐11	  years:	  Children’s	  Asthma	  Control	  Test	  (C-­‐ACT)	  	  score12	  	  	  (Appendix	  2a)	  
o 
In	  children	  age	  12+	  years:	  Asthma	  Control	  Test	  (ACT)	  score14	  (Appendix	  2b)	  
	  
3.1.2.	  SECONDARY	  STUDY	  OUTCOMES	  	  
	  
1. Incidence	  of	  adverse	  events	  (AE)	  and	  serious	  adverse	  events	  (SAEs)	  in	  children	  receiving	  LAIV:	  
• 
AEs	  occurring	  up	  to	  72	  hours	  after	  LAIV.	  
• 
SAEs	  unrelated	  to	  asthma	  symptoms	  with	  onset	  up	  to	  72	  hours	  after	  LAIV	  
• 
Incidence	  of	  a	  ‘significant	  exacerbation’	  in	  asthma,	  defined	  as:	  
i. At	  least	  3	  day	  course	  of	  oral	  steroids	  following	  an	  unscheduled	  contact	  with	  a	  
healthcare	  professional;	  OR	  
ii. Unscheduled	  visit	  to	  an	  Emergency	  department	  or	  admission	  to	  hospital	  for	  
treatment	  of	  asthma	  symptoms,	  requiring	  systemic	  corticosteroids13	  
2. Incidence	  and	  extent	  of	  viral	  shedding	  in	  children	  and	  young	  people	  receiving	  LAIV	  during	  the	  2016/17	  
influenza	  season,	  using	  quantitative	  analysis	  of	  consecutive	  nasal	  swabs	  obtained	  up	  to	  10	  days	  
following	  LAIV.	  These	  data	  will	  be	  correlated	  with	  the	  incidence	  of	  adverse	  events	  related	  to	  asthma	  
over	  the	  same	  time	  period.	  
	  
3.1.3.	  OTHER	  STUDY	  OUTCOMES	  	  
	  
Other	  outcome	  data	  collected	  during	  the	  study	  will	  include:	  
• 
Asthma	  Control	  Questionnaire	  (ACQ)	  prior	  to	  LAIV	  (see	  section	  8.1.3)	  
• 
For	  participants	  at	  the	  Royal	  Brompton	  Hospital	  site:	  
o 
Paediatric	  Asthma	  Quality	  of	  Life	  Questionnaire	  data	  (see	  section	  8.3)	  
o 
Inflammatory	  biomarkers,	  including	  Fractional	  exhaled	  nitric	  oxide	  and	  assessment	  of	  
induced	  sputum.	  
	  
4.	  STUDY	  POPULATION	  
Subjects	  will	  not	  be	  randomised	  in	  this	  Phase	  IV	  study.	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  
11Murphy	  KR,	  Zeiger	  RS,	  Kosinski	  M,	  et	  al.	  Test	  for	  respiratory	  and	  asthma	  control	  in	  kids	  (TRACK):	  a	  caregiver-­‐
completed	  questionnaire	  for	  preschool-­‐aged	  children.	  J	  Allergy	  Clin	  Immunol.	  2009;123(4):833-­‐9.e9.	  
12Jia	  CE,	  Zhang	  HP,	  Lv	  Y,	  et	  al.	  The	  Asthma	  Control	  Test	  and	  Asthma	  Control	  Questionnaire	  for	  assessing	  asthma	  control:	  
systematic	  review	  and	  meta-­‐analysis.	  J	  Allergy	  Clin	  Immunol	  2013;131:695-­‐703.	  
13	  Reddel	  HK,	  Taylor	  DR,	  Bateman	  ED,	  et	  al.;	  American	  Thoracic	  Society/European	  Respiratory	  Society	  Task	  Force	  on	  
Asthma	  Control	  and	  Exacerbations.	  An	  official	  American	  Thoracic	  Society/European	  Respiratory	  Society	  statement:	  
asthma	  control	  and	  exacerbations:	  standardizing	  endpoints	  for	  clinical	  asthma	  trials	  and	  clinical	  practice.	  Am	  J	  Respir	  
Crit	  Care	  Med.	  2009	  Jul	  1;180(1):59-­‐99.	  	  
	  

	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  SNIFFLE-­‐4	  Study	  Protocol	  	  
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4.1	  RECRUITMENT	  
Subjects	  will	  be	  recruited	  through	  2	  routes:	  
1. Children	  currently	  managed	  within	  the	  existing	  paediatric	  services	  at	  participating	  study	  sites.	  
Recruitment	  will	  be	  via	  publicity	  (posters,	  flyers),	  email	  and	  postal	  mailing	  (with	  an	  option	  for	  a	  follow-­‐
up	  contact	  by	  post,	  email	  or	  telephone*	  where	  there	  is	  no	  response	  to	  the	  initial	  invite).	  	  
2. Children	  who	  received	  the	  LAIV	  vaccine	  in	  2014-­‐16	  as	  part	  of	  the	  SNIFFLE	  studies,	  who	  have	  a	  diagnosis	  
of	  asthma	  or	  recurrent	  wheezing	  and	  are	  currently	  cared	  for	  by	  the	  clinical	  team	  at	  participating	  study	  
sites.	  Families	  will	  receive	  a	  separate	  letter	  of	  invitation	  (by	  post	  or	  email),	  from	  their	  clinical	  team.	  
*Telephone	  calling	  will	  only	  take	  place	  where	  the	  child/family	  is	  already	  under	  the	  care	  of	  the	  local	  
clinical	  team,	  and	  the	  clinician	  thus	  has	  an	  established	  relationship	  with	  the	  family.	  
4.2	  ELIGIBILITY	  CRITERIA:	  CHILDREN	  TO	  RECEIVE	  LAIV	  
4.2.1	  INCLUSION	  CRITERIA	  
1. Aged	  2	  –	  18	  years	  old	  (inclusive)	  
2. Physician	  diagnosis	  of	  asthma	  or	  recurrent	  wheezing	  (by	  the	  hospital	  specialist)	  AND:	  
i. 
In	   children	   age	   2-­‐4	   years:	   ≥2	   exacerbations	   in	   the	   past	   year	   requiring	   oral	   steroids	   or	  
observation	  in-­‐hospital	  beyond	  4	  hours	  duration	  OR	  receiving	  regular	  inhaled	  corticosteroids.	  
ii. 
In	  children	  ≥	  5	  years	  of	  age,	  receiving	  treatment	  equivalent	  to	  at	  least	  BTS/SIGN	  step	  2	  
therapy.	  
3. Written	  informed	  consent	  from	  parent/guardian	  (or	  the	  patient	  themselves	  from	  age	  16	  years),	  
with	  assent	  from	  children	  aged	  8	  years	  and	  above	  wherever	  possible.	  In	  the	  event	  of	  either	  parent	  
or	  child	  being	  unwilling	  to	  give	  consent/assent	  as	  appropriate,	  enrolment	  will	  not	  proceed.	  
4.2.2	  EXCLUSION	  CRITERIA	  
1. Admission	  to	  PICU	  for	  invasive	  ventilation	  due	  to	  a	  respiratory	  illness	  in	  the	  preceding	  2	  years.	  
	  
2. Contraindications	  to	  LAIV	  (notwithstanding	  allergy	  to	  egg	  protein),	  which	  include:	  
a. 
Hypersensitivity	  to	  the	  active	  ingredients,	  gelatin	  or	  gentamicin	  (a	  possible	  trace	  residue)	  
b. Previous	  systemic	  allergic	  reaction	  to	  LAIV	  
c. 
Previous	  allergic	  reaction	  to	  an	  influenza	  vaccine	  (not	  LAIV)	  is	  a	  relative	  contra-­‐indication,	  
which	  must	  be	  discussed	  with	  the	  site	  PI	  to	  confirm	  patient	  suitability	  
d. Children/adolescents	   who	   are	   clinically	   immunodeficient	   due	   to	   conditions	   or	  
immunosuppressive	   therapy	   such	   as:	   acute	   and	   chronic	   leukaemias;	   lymphoma;	  
symptomatic	  
HIV	  
infection;	  
cellular	  
immune	  
deficiencies;	  
and	  
high-­‐dose	  
corticosteroids**.	  	  
**High-­‐dose	  steroids	  is	  defined	  as	  a	  treatment	  course	  for	  at	  least	  one	  month,	  equivalent	  
to	  a	  dose	  greater	  than	  20mg	  prednisolone	  per	  day	  (any	  age),	  or	  for	  children	  under	  20kg,	  a	  
dose	  greater	  than	  1mg/kg/day.	  	  
NB:	  LAIV	  is	  not	  contraindicated	  for	  use	  in	  individuals	  with	  asymptomatic	  HIV	  infection;	  or	  
individuals	   who	   are	   receiving	   topical/inhaled/low-­‐dose	   oral	   systemic	   corticosteroids	   or	  
those	  receiving	  corticosteroids	  as	  replacement	  therapy,	  e.g.	  for	  adrenal	  insufficiency.	  
e. Children	  /	  adolescents	  younger	  than	  18	  years	  of	  age	  receiving	  salicylate	  therapy	  because	  
of	  the	  association	  of	  Reye's	  syndrome	  with	  salicylates	  and	  wild-­‐type	  influenza	  infection.	  
f. 
Pregnancy	  

	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  
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3. Contraindications	  to	  vaccination	  on	  that	  occasion,	  e.g.	  due	  to	  child	  being	  acutely	  unwell:	  
a. 
Febrile	  ≥38.0oC	  in	  last	  72	  hours	  	  
b. *Acute	  wheeze	  in	  last	  72	  hours	  requiring	  treatment	  beyond	  that	  normally	  prescribed	  for	  
regular	  use	  by	  the	  child’s	  treating	  healthcare	  professional	  
c. 
*Recent	  admission	  to	  hospital	  in	  last	  2	  weeks	  for	  acute	  asthma	  
d. *Current	  oral	  steroid	  for	  asthma	  exacerbation	  or	  course	  completed	  within	  last	  2	  weeks	  
e. Any	  other	  significant	  condition	  or	  circumstance	  which,	  in	  the	  opinion	  of	  the	  investigator,	  
may	   either	   put	   the	   participant	   at	   risk	   because	   of	   participation	   in	   the	   study,	   or	   may	  
influence	  the	  result	  of	  the	  study,	  or	  the	  participant’s	  ability	  to	  participate	  in	  the	  study.	  
*Items	  3b-­‐3d	  are	  relative	  contra-­‐indications:	  Many	  children	  with	  “difficult-­‐to-­‐control”	  symptoms	  may	  
meet	  fail	  to	  meet	  these	  criteria	  on	  a	  routine	  basis.	  Where	  these	  are	  present,	  the	  study	  centre	  PIs	  are	  
able	  to	  authorise	  participation	  on	  a	  case-­‐by-­‐case	  basis,	  after	  assessing	  the	  child	  and	  their	  lung	  function	  
at	  the	  time	  of	  enrolment.	  
Recent	   antihistamine	   use	   is	   not	   a	   contra-­‐indication	   to	   LAIV	   administration,	   but	   use	   of	   any	  
antihistamine	  in	  the	  96	  hours	  prior	  to	  LAIV	  will	  be	  logged	  on	  the	  CRF.	  
Administration	  of	  another	  live	  vaccine	  (e.g.	  MMR)	  within	  the	  previous	  4	  weeks	  is	  no	  longer	  a	  contra-­‐
indication	  to	  LAIV	  administration,	  according	  to	  updated	  DoH	  guidelines.	  
NB:	  	  See	  Summary	  of	  Product	  Characteristics	  for	  full	  details	  of	  contra-­‐indications	  to	  LAIV.	  	  
4.3	  SUBJECT	  WITHDRAWAL	  
Parents/guardians	  may	  withdraw	  their	  child	  at	  any	  time	  without	  giving	  a	  reason.	  In	  accordance	  with	  
the	  current	  revision	  of	  the	  Declaration	  of	  Helsinki	  and	  any	  other	  applicable	  regulations,	  the	  parents	  or	  
legal	  representatives	  of	  the	  child	  have	  the	  right	  to	  withdraw	  the	  participant	  from	  the	  study	  at	  any	  
time	  and	  for	  any	  reason,	  without	  prejudice	  to	  his	  or	  her	  future	  medical	  care,	  and	  are	  not	  obliged	  to	  
give	  his	  or	  her	  reasons	  for	  doing	  so.	  
	  
The	  investigator	  may	  withdraw	  a	  participant	  from	  the	  study	  at	  any	  time	  if,	  in	  the	  investigator’s	  clinical	  
judgment,	   it	   is	   in	   the	   best	   interests	   of	   the	   participant’s	   health	   and	   well-­‐being.	   In	   addition	   the	  
participant	  may	  be	  withdrawn	  for	  any	  of	  the	  following	  reasons:	  
• 
Decision	  by	  the	  Investigator	  
• 
Ineligibility	  (either	  newly	  arising	  during	  the	  study,	  or	  retrospective	  having	  been	  overlooked	  at	  
screening)	  
• 
Significant	  protocol	  deviation	  
• 
Participant	  non-­‐compliance	  with	  study	  requirements	  
• 
An	  adverse	  event	  which	  requires	  discontinuation	  of	  the	  study	  treatment,	  or	  results	  in	  inability	  
to	  continue	  to	  comply	  with	  study	  procedures.	  
If	  known,	  the	  reason	  for	  withdrawal	  should	  be	  recorded	  in	  a	  CRF.	  If	  the	  participant	  is	  withdrawn	  due	  
to	  an	  adverse	  event,	  the	  Investigator	  will	  arrange	  for	  appropriate	  follow-­‐up	  through	  telephone	  calls	  
(and/or	  visits	  if	  necessary)	  until	  the	  adverse	  event	  has	  resolved	  or	  stabilised.	  	  
	  
All	  safety	  data	  for	  any	  participants	  withdrawn	  after	  receiving	  the	  study	  vaccination	  will	  be	  included	  in	  
the	  data	  analyses,	  unless	  specific	  instruction	  for	  their	  destruction	  is	  received	  from	  the	  participant	  or	  
their	  parent/guardian.	  Withdrawn	  participants	  will	  not	  be	  replaced.	  
	  

	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  SNIFFLE-­‐4	  Study	  Protocol	  	  
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5.	  STUDY	  TREATMENT	  
5.1	  DESCRIPTION	  	  
Live	  Attenuated	  Intranasal	  Vaccine	  (LAIV)	  Quadrivalent	  vaccine	  (Fluenz-­‐Tetra,	  Astra	  Zeneca),	  as	  provided	  for	  
use	  by	  the	  Department	  of	  Health	  as	  part	  of	  the	  UK	  National	  Immunisation	  Schedule	  
5.2	  DOSAGE	  AND	  ROUTE	  OF	  ADMINISTRATION	  
0.2	  ml	  (administered	  as	  0.1	  ml	  per	  nostril).	  Immunisation	  will	  be	  carried	  out	  by	  nasal	  administration,	  as	  per	  
the	  SmPC	  provided.	  
	  5.3	  DOSE	  MODIFICATION	  
No	  dose	  modification	  proposed.	  
	  5.4	  PREPARATION	  AND	  ADMINISTRATION	  OF	  STUDY	  DRUG	  
FLUENZ	  IS	  FOR	  NASAL	  USE	  only.	  	  
•	  DO	  NOT	  USE	  WITH	  A	  NEEDLE.	  Do	  not	  inject.	  	  
	  
•	  FLUENZ	  is	  administered	  as	  a	  divided	  dose	  in	  both	  nostrils.	  	  
•	  After	  administering	  half	  of	  the	  dose	  in	  one	  nostril,	  administer	  the	  other	  half	  of	  the	  dose	  in	  the	  other	  
nostril	  immediately	  or	  shortly	  thereafter.	  	  
•	  The	  patient	  can	  breathe	  normally	  while	  the	  vaccine	  is	  being	  administered	  –	  there	  is	  no	  need	  to	  actively	  
inhale	  or	  sniff.	  	  
•	  Refer	  to	  the	  FLUENZ	  administration	  diagram	  (Figure	  2)	  for	  step-­‐by-­‐step	  administration	  instructions.	  	  
Figure	  2	  FLUENZ	  Administration	  
	  

	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  SNIFFLE-­‐4	  Study	  Protocol	  	  
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Any	  unused	  product	  will	  be	  disposed	  of	  in	  accordance	  with	  local	  requirements	  for	  medical	  waste.	  
5.5	  DISPENSING	  AND	  PRODUCT	  ACCOUNTABILITY	  
Fluenz	  Tetra	  (quadrivalent	  LAIV)	  is	  approved	  by	  the	  European	  Medicines	  Agency	  and	  distribution	  and	  
administration	  to	  selected	  children	  will	  take	  place	  during	  the	  influenza	  season	  2016-­‐17.	  Provision	  of	  doses	  
of	  vaccine	  will	  be	  through	  the	  Department	  of	  Health	  vaccine	  supply	  network	  as	  part	  of	  the	  national	  
immunisation	  programme,	  with	  no	  additional	  requirements	  (e.g.	  cold	  chain	  monitoring)	  beyond	  that	  
provided	  by	  the	  normal	  UK	  vaccine	  supply	  system.	  Vaccine	  will	  be	  delivered	  via	  existing	  systems	  to	  on-­‐site	  
pharmacists	  at	  study	  sites	  (all	  NHS	  hospitals).	  Doses	  will	  then	  be	  released	  according	  to	  local	  procedure,	  
using	  existing	  hospital	  pharmacy	  systems	  and	  logging	  (rather	  than	  CTIMP-­‐specific	  documentation).	  	  
	  
The	  application	  for	  a	  clinical	  trials	  authority	  will	  include	  an	  exemption	  for	  study	  specific	  labelling.	  
	  
	  
	  
	  

	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  SNIFFLE-­‐4	  Study	  Protocol	  	  
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6	  STUDY	  VISITS,	  PROCEDURES	  SCHEDULE	  and	  Patient	  Flow	  Diagram	  
The	  study	  schedule	  is	  summarised	  in	  the	  following	  flow	  chart	  and	  table:	  
	  
	  
	  
Visit	  1	  
24	  
hours	  
later	  
72	  
hours	  
later	  
6-­‐7	  days	  
later	  
Follow-­‐up	  
4	  weeks	  
later	  
Written	  Informed	  Consent	  (parent/	  guardian)	  
Written	  assent	  (child)	  
X	  
X	  
	  
	  
	  
	  
Medical	  assessment	  
X	  
	  
	  
	  
	  
Asthma	  control/symptom	  questionnaire:	  
• 
Age	  2-­‐4	  years:	  TRACK	  score	  
(Appendix	  1)	  
• 
Age	  5-­‐11	  years:	  C-­‐ACT	  score	  
(Appendix	  2a)	  
• 
Age	  12+	  years:	  ACT	  score	  	  
(Appendix	  2b)	  
X	  
	  
	  
	  
X	  
Vaccine	  administration	  	  
followed	  by	  20	  mins	  observation	  
X	  
	  
	  
	  
	  
Nasal	  swab	  at	  home	  
	  
X	  
X	  
X	  
	  
Delayed	  effects	  telephone	  questionnaire	  at	  
72hrs	  
	  
	  
X	  
	  
	  
Asthma	  assessment	  4	  weeks	  post	  LAIV	  	  
	  
	  
	  
	  
X	  
2nd	  dose	  in	  children	  <9	  years	  
	  	  	  	  	  who	  meet	  DoH	  critieria	  (see	  6.1.2)	  
	  
	  
	  
	  
X	  
	  
Subject	  
screening	  
• Complete	  eligibility	  
determination	  on	  Patient	  
CRF	  
Pt	  deemed	  
to	  be	  
eligible	  
• Obtain	  consent	  
• Complete	  remainder	  of	  Patient	  CRF	  
• Log	  patient	  and	  obtain	  Subject	  ID	  code	  
Administer	  
vaccine	  
• ConAirm	  suitability	  for	  vaccine	  today	  
• Baseline	  obs	  	  →	  Give	  vaccine	  →	  Post	  vaccine	  
observation	  (20mins)	  
• Arrange	  telephone	  F/U	  
• Submit	  patient	  details	  on	  online	  data	  system	  
Follow-­‐up	  
• Nasal	  swabs	  at	  home	  around	  24	  and	  72hrs	  
post	  LAIV,	  with	  a	  third	  swab	  1	  week	  later.	  
• Telephone	  F/U	  at	  72hrs	  to	  monitor	  AEs	  
Four	  week	  
asthma	  F/U	  
• Preferably	  by	  email	  

	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  SNIFFLE-­‐4	  Study	  Protocol	  	  
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6.1	  STUDY	  PROCEDURES	  
	  
Following	  consent	  (see	  6.1.2),	  subjects	  will	  be	  assessed	  for	  suitability	  for	  vaccine	  administration.	  Baseline	  
observations	  (temperature,	  heart	  rate,	  respiratory	  rate,	  oxygen	  saturations	  in	  air	  and	  lung	  function)	  will	  be	  
documented	  on	  the	  paper	  CRF.	  Asthma	  control	  will	  be	  assessed	  as	  per	  section	  8.1.3.	  
	  
LAIV	  will	  be	  administered	  according	  to	  the	  SmPC	  (see	  section	  5.4)	  and	  the	  child	  observed	  for	  20	  minutes	  
afterwards	  to	  confirm	  no	  acute	  adverse	  event.	  The	  observation	  time	  will	  be	  extended	  if	  there	  is	  any	  clinical	  
concern.	  Vaccine	  will	  be	  administered	  in	  a	  clinical	  area	  where	  facilities	  exist	  to	  manage	  any	  adverse	  
reaction,	  should	  this	  occur.	  Additional	  surveillance	  and	  monitoring	  will	  be	  performed	  in	  participants	  at	  the	  
Royal	  Brompton	  Hospital	  site	  (see	  section	  8.6).	  
	  
Following	  vaccination,	  the	  CRF	  will	  be	  completed	  and	  patient	  details	  entered	  on	  to	  a	  secure	  encrypted	  
server	  run	  by	  Public	  Health	  England,	  confirming	  vaccine	  administration	  and	  providing	  the	  required	  contact	  
details	  for	  follow-­‐up.	  
6.1.1	  POST	  VACCINATION	  SCHEDULE	  
	  
Parents	  will	  be	  asked	  to	  take	  up	  to	  3	  nasal	  swabs	  from	  their	  child/young	  person	  at	  home,	  in	  the	  week	  
following	  vaccination.	  The	  nasal	  swab,	  which	  looks	  like	  a	  large	  cotton	  bud,	  will	  be	  passed	  into	  the	  nostril	  
and	  moved	  around	  for	  a	  minute.	  The	  exact	  timing	  of	  these	  will	  be	  confirmed	  prior	  to	  study	  
commencement,	  once	  international	  efforts	  to	  assess	  vaccine	  shedding	  have	  been	  reported.	  However,	  it	  is	  
likely	  these	  will	  be	  at	  24	  and	  72	  hours,	  and	  at	  6-­‐7	  days	  following	  vaccination.	  Parents	  will	  be	  provided	  with	  
three	  test	  kits,	  full	  instructions	  and	  Royal-­‐Mail	  approved	  kits	  (for	  Category	  B	  specimens)	  will	  be	  provided	  for	  
each	  child,	  along	  with	  postage-­‐paid	  envelopes	  for	  posting	  back	  to	  PHE	  through	  the	  normal	  post	  network.	  
	  
Parents	  will	  be	  shown	  the	  process	  by	  their	  study	  nurse	  at	  the	  vaccination	  visit.	  The	  swab	  may	  be	  collected	  
up	  to	  24	  hours	  after	  the	  stated	  time.	  
	  
From	  72	  hours	  after	  LAIV	  (and	  up	  to	  7	  days	  later,	  to	  allow	  for	  weekends),	  families	  will	  be	  contacted	  to	  
document	  any	  potential	  adverse	  events	  which	  have	  occurred	  since	  vaccination.	  This	  will	  be	  done	  by	  
telephone	  contact	  by	  staff	  at	  the	  study	  site.	  A	  guide	  for	  this	  telephone	  call	  is	  found	  in	  Appendix	  5.	  Families	  
will	  be	  reminded	  about	  the	  nasal	  swab	  at	  this	  time.	  	  
	  
One	  month	  later,	  families	  will	  receive	  an	  email	  invite	  from	  Public	  Health	  England	  to	  complete	  a	  brief	  online	  
questionnaire	  to	  assess	  asthma	  control.	  Where	  families	  do	  not	  have	  access	  to	  email,	  this	  can	  be	  completed	  
through	  telephone	  contact	  by	  staff	  at	  the	  local	  study	  site	  (as	  per	  the	  72	  hour	  follow-­‐up,	  using	  the	  telephone	  
guide	  in	  Appendix	  6).	  
	  
	  
6.1.2	  SECOND	  DOSE	  OF	  LAIV	  
	  
Children	  who	  meet	  DoH	  criteria	  for	  specified	  ‘clinical	  risk	  categories’	  (Table	  1)	  and	  are	  under	  9	  years	  of	  age	  
and	  have	  not	  received	  prior	  seasonal	  influenza	  vaccination	  will	  be	  offered	  a	  second	  dose	  of	  LAIV	  at	  least	  4	  
weeks	  later.	  We	  expect	  very	  few	  children	  to	  meet	  this	  criteria,	  as	  most	  would	  have	  received	  prior	  influenza	  
vaccination	  (in	  SNIFFLE	  1,	  no	  child	  would	  have	  required	  a	  second	  dose).	  However,	  there	  is	  a	  duty	  of	  care	  to	  
our	  participants	  and	  we	  are	  therefore	  including	  provision	  for	  a	  second	  dose	  in	  this	  protocol.	  	  
	  
Data	  pertaining	  to	  second	  visits	  will	  be	  collected	  on	  a	  separate	  CRF,	  but	  not	  used	  in	  the	  primary	  analysis.	  
	  

	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  SNIFFLE-­‐4	  Study	  Protocol	  	  
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Table	  1:	  Clinical	  risk	  categories	  requiring	  a	  second	  dose	  of	  LAIV	  in	  vaccine-­‐naïve	  children	  under	  age	  9	  yrs:	  
Chronic	  respiratory	  
disease	  	  
• 
Asthma	  requiring	  continuous	  or	  repeated	  use	  of	  inhaled	  or	  systemic	  
steroids	  or	  with	  previous	  exacerbations	  requiring	  hospital	  admission.	  
• 
Chronic	  obstructive	  pulmonary	  disease	  (COPD)	  including	  chronic	  bronchitis	  
and	  emphysema;	  bronchiectasis,	  cystic	  fibrosis,	  interstitial	  lung	  fibrosis,	  
pneumoconiosis	  and	  bronchopulmonary	  dysplasia	  (BPD).	  	  
• 
Children	  who	  have	  previously	  been	  admitted	  to	  hospital	  for	  lower	  
respiratory	  tract	  disease.	  
Chronic	  heart	  disease	  	  
Congenital	  heart	  disease,	  hypertension	  with	  cardiac	  complications,	  chronic	  
heart	  failure.	  	  
Chronic	  kidney	  
disease	  	  
Chronic	  kidney	  disease	  at	  stage	  3,	  4	  or	  5,	  chronic	  kidney	  failure,	  nephrotic	  
syndrome,	  kidney	  transplantation.	  	  
Chronic	  liver	  disease	  	  
Cirrhosis,	  biliary	  atresia,	  chronic	  hepatitis	  	  
Chronic	  neurological	  
disease	  
Stroke,	  transient	  ischaemic	  attack	  (TIA).	  	  Conditions	  in	  which	  respiratory	  
function	  may	  be	  compromised	  due	  to	  neurological	  disease	  (e.g.	  polio	  
syndrome	  sufferers).	  	  
Clinicians	  should	  consider	  on	  an	  individual	  basis	  the	  clinical	  needs	  of	  patients	  
including	  individuals	  with	  cerebral	  palsy,	  multiple	  sclerosis	  and	  related	  or	  
similar	  conditions;	  or	  hereditary	  and	  degenerative	  disease	  of	  the	  nervous	  
system	  or	  muscles;	  or	  severe	  neurological	  or	  severe	  learning	  disability.	  
Diabetes	  	  
Type	  1	  diabetes,	  type	  2	  diabetes	  requiring	  insulin	  or	  oral	  hypoglycaemic	  drugs,	  
diet	  controlled	  diabetes.	  	  
Immunosuppression	  	  
Immunosuppression	  due	  to	  disease	  or	  treatment.	  Patients	  undergoing	  
chemotherapy	  leading	  to	  immunosuppression.	  Asplenia	  or	  splenic	  dysfunction.	  	  
HIV	  infection	  at	  all	  stages.	  
	  
Individuals	  treated	  with	  or	  likely	  to	  be	  treated	  with	  systemic	  steroids	  for	  more	  
than	  a	  month	  at	  a	  dose	  greater	  than	  20mg	  prednisolone	  per	  day	  (any	  age);	  or	  
for	  children	  under	  20kg,	  a	  dose	  greater	  than	  1mg	  per	  kg	  per	  day.	  	  
	  
It	  is	  difficult	  to	  define	  at	  what	  level	  of	  immunosuppression	  a	  patient	  could	  be	  
considered	  to	  be	  at	  a	  greater	  risk	  of	  the	  serious	  consequences	  of	  influenza	  and	  
should	  be	  offered	  influenza	  vaccination.	  This	  decision	  is	  best	  made	  on	  an	  
individual	  basis	  and	  left	  to	  the	  patient’s	  clinician.	  	  
	  
Some	  immunocompromised	  patients	  may	  have	  a	  suboptimal	  immunological	  
response	  to	  the	  vaccine.	  
	  
NB:	  LAIV	  is	  not	  contraindicated	  for	  use	  in	  individuals	  with	  asymptomatic	  HIV	  
infection;	  or	  individuals	  who	  are	  receiving	  topical/inhaled	  corticosteroids	  or	  
low-­‐dose	  systemic	  corticosteroids	  or	  those	  receiving	  corticosteroids	  as	  
replacement	  therapy,	  e.g.	  for	  adrenal	  insufficiency.	  
	  
	  
	  
	  

	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  SNIFFLE-­‐4	  Study	  Protocol	  	  
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6.2	  CONSENT	  
We	  will	  endeavour	  to	  provide	  the	  Patient	  Information	  Leaflets	  prior	  to	  visit	  to	  hospital,	  but	  
this	  may	  not	  always	  be	  possible.	  Patients	  may	  therefore	  be	  consented	  (according	  to	  Good	  
Clinical	  Practice)	  without	  a	  requirement	  for	  a	  ‘cooling-­‐off’	  period	  following	  receipt	  of	  the	  
study	  information	  leaflets,	  where	  this	  is	  specifically	  requested	  by	  the	  family.	  In	  this	  case,	  at	  
least	  30	  minutes	  will	  be	  allowed	  for	  participants	  and	  their	  carers	  to	  read	  the	  patient	  
information	  provided	  and	  consider	  the	  contents.	  
The	  reasons	  for	  this	  were	  highlighted	  in	  the	  PPI	  discussions	  during	  the	  development	  of	  the	  
previous	  SNIFFLE	  protocols	  and	  include:	  
• 
Many	  families	  travel	  significant	  distances	  to	  specialist	  allergy/respiratory	  clinics,	  
often	  requiring	  the	  child	  to	  miss	  school	  and	  their	  parents/carers	  to	  miss	  work.	  In	  
SNIFFLE-­‐1,	  families	  frequently	  requested	  vaccination	  at	  the	  same	  time	  as	  their	  
routine	  outpatient	  appointment,	  to	  avoid	  having	  to	  make	  a	  second	  trip	  to	  hospital.	  
Many	  families	  declined	  to	  return	  to	  hospital	  for	  vaccination	  at	  a	  separate	  visit,	  and	  
were	  thus	  left	  unvaccinated	  and	  at	  risk	  of	  infection.	  
• 
The	  vaccine	  to	  be	  administered	  in	  this	  study	  is	  part	  of	  the	  routine	  UK	  National	  
Immunisation	  Schedule.	  The	  study	  allows	  children	  to	  participate	  in	  this	  programme	  
in	  a	  safe	  environment,	  utilising	  a	  vaccine	  delivery	  route	  (intranasal)	  which	  minimises	  
discomfort	  to	  the	  child.	  	  
• 
The	  proposed	  consent	  process	  has	  been	  trialled	  successfully	  in	  the	  SNIFFLE-­‐2	  and	  -­‐3	  
studies,	  with	  positive	  feedback	  from	  both	  eligible	  young	  people	  and	  their	  families.	  
Following	  discussion	  with	  the	  Research	  Ethics	  Committee,	  it	  has	  been	  agreed	  that	  in	  
participants	  under	  16	  years	  at	  the	  time	  of	  consent	  and	  vaccination,	  but	  who	  will	  turn	  16	  
years	  of	  age	  prior	  to	  the	  4	  week	  follow-­‐up	  assessment,	  the	  participant	  does	  not	  need	  to	  be	  
formally	  consented	  as	  it	  can	  be	  assumed	  that	  in	  voluntarily	  answering	  the	  questionnaire,	  the	  
participant	  provides	  consent.	  	  
However,	  for	  participants	  at	  the	  Royal	  Brompton	  site	  undergoing	  further	  assessment	  at	  the	  4	  
week	  follow-­‐up	  (as	  outlined	  in	  section	  8.3),	  formal	  consent	  will	  need	  to	  be	  taken	  from	  the	  
young	  person	  prior	  to	  the	  assessments	  being	  performed.	  
	  
	  

	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  SNIFFLE-­‐4	  Study	  Protocol	  	  
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7	  ADVERSE	  EVENT	  REPORTING	  
7.1	  DEFINITIONS	  
Adverse	  Event	  (AE):	  any	  untoward	  medical	  occurrence	  in	  a	  patient	  or	  clinical	  trial	  subject	  administered	  a	  
medicinal	  product	  and	  which	  does	  not	  necessarily	  have	  a	  causal	  relationship	  with	  this	  treatment.	  	  An	  AE	  
can	  therefore	  be	  any	  unfavourable	  and	  unintended	  sign	  (including	  an	  abnormal	  laboratory	  finding),	  
symptom,	  or	  disease	  temporally	  associated	  with	  the	  use	  of	  an	  investigational	  medicinal	  product	  (IMP),	  
whether	  or	  not	  considered	  related	  to	  the	  IMP.	  
	  
An	  adverse	  event	  will	  be	  followed	  until	  it	  resolves	  or	  until	  30	  days	  after	  a	  participant	  terminates	  from	  the	  
study,	  whichever	  comes	  first.	  
	  
Adverse	  Reaction	  (AR):	  all	  untoward	  and	  unintended	  responses	  to	  an	  IMP	  related	  to	  any	  dose	  
administered.	  	  All	  AEs	  judged	  by	  either	  the	  reporting	  investigator	  or	  the	  sponsor	  as	  having	  reasonable	  
causal	  relationship	  to	  a	  medicinal	  product	  qualify	  as	  adverse	  reactions.	  	  The	  expression	  reasonable	  causal	  
relationship	  means	  to	  convey	  in	  general	  that	  there	  is	  evidence	  or	  argument	  to	  suggest	  a	  causal	  relationship.	  
	  
Unexpected	  Adverse	  Reaction:	  an	  AR,	  the	  nature	  or	  severity	  of	  which	  is	  not	  consistent	  with	  the	  applicable	  
product	  information	  (eg	  investigator’s	  brochure	  for	  an	  unapproved	  investigational	  product	  or	  summary	  of	  
product	  characteristics	  (SmPC)	  for	  an	  authorised	  product).	  	  When	  the	  outcome	  of	  the	  adverse	  reaction	  is	  
not	  consistent	  with	  the	  applicable	  product	  information	  this	  adverse	  reaction	  should	  be	  considered	  as	  
unexpected.	  	  Side	  effects	  documented	  in	  the	  SmPC	  which	  occur	  in	  a	  more	  severe	  form	  than	  anticipated	  are	  
also	  considered	  to	  be	  unexpected.	  
	  
Serious	  Adverse	  Event	  (SAE)	  or	  Serious	  Adverse	  Reaction:	  any	  untoward	  medical	  occurrence	  or	  effect	  that:	  	  
• 
Results	  in	  death	  
• 
Is	  life-­‐threatening	  –	  refers	  to	  an	  event	  in	  which	  the	  subject	  was	  at	  risk	  of	  death	  at	  the	  time	  of	  the	  event;	  
it	  does	  not	  refer	  to	  an	  event	  which	  hypothetically	  might	  have	  caused	  death	  if	  it	  were	  more	  severe	  
• 
Requires	  hospitalisation,	  or	  prolongation	  of	  existing	  inpatients’	  hospitalisation	  
• 
Results	  in	  persistent	  or	  significant	  disability	  or	  incapacity	  
• 
Is	  a	  congenital	  anomaly	  or	  birth	  defect	  
	  
Medical	  judgement	  should	  be	  exercised	  in	  deciding	  whether	  an	  AE/AR	  is	  serious	  in	  other	  situations.	  	  
Important	  AE/ARs	  that	  are	  not	  immediately	  life-­‐threatening	  or	  do	  not	  result	  in	  death	  or	  hospitalisation	  but	  
may	  jeopardise	  the	  subject	  or	  may	  require	  intervention	  to	  prevent	  one	  of	  the	  other	  outcomes	  listed	  in	  the	  
definition	  above,	  should	  also	  be	  considered	  serious.	  
	  
Suspected	  Unexpected	  Serious	  Adverse	  Reaction	  (SUSAR):	  any	  suspected	  adverse	  reaction	  related	  to	  an	  
IMP	  that	  is	  both	  unexpected	  and	  serious.	  
	  
Any	  symptoms	  requiring	  treatment	  for	  anaphylaxis	  (adrenaline,	  steroids,	  salbutamol)	  will	  be	  classified	  as	  
a	  SERIOUS	  ADVERSE	  REACTION	  and	  must	  be	  documented	  on	  both	  the	  CRF	  as	  well	  as	  through	  completion	  
of	  a	  SAE	  form.	  The	  investigator	  should	  also	  make	  a	  notification	  to	  the	  MHRA	  should	  also	  be	  made	  through	  
the	  yellow	  card	  scheme	  (https://yellowcard.mhra.gov.uk/).	  	  
	  
For	  the	  purpose	  of	  this	  study,	  SARs	  and	  SAEs	  not	  related	  to	  asthma/wheezing	  will	  only	  be	  collected	  where	  
onset	  is	  within	  72	  hours	  of	  vaccine	  administration.	  Those	  relating	  to	  respiratory	  symptoms	  will	  be	  collected	  
up	  to	  one	  month	  after	  LAIV	  at	  visit	  1.	  
	  

	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  
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7.1.1	  DOCUMENTATION	  OF	  ADVERSE	  EVENTS	  
Safety	  data	  will	  be	  recorded	  on	  a	  specifically	  designed	  case	  report	  form	  (CRF).	  All	  serious	  adverse	  events	  
(SAEs)	  or	  reactions	  (SARs)	  will	  be	  reported	  on	  a	  SAE	  report	  form	  in	  addition	  to	  CRFs.	  Throughout	  the	  study,	  
the	  investigator	  will	  record	  all	  adverse	  events	  on	  the	  appropriate	  CRF	  regardless	  of	  their	  severity	  or	  relation	  
to	  study	  medication	  or	  study	  procedure.	  The	  investigator	  will	  treat	  participants	  experiencing	  adverse	  
events	  appropriately	  and	  observe	  them	  at	  suitable	  intervals	  until	  their	  symptoms	  resolve	  or	  their	  status	  
stabilizes.	  	  
SAEs	  will	  be	  reported	  within	  24	  hours	  of	  the	  Site	  Study	  Team	  becoming	  aware	  of	  the	  event.	  All	  SUSARs	  will	  
be	  reported	  by	  the	  CI	  to	  the	  relevant	  Competent	  Authority	  and	  to	  the	  REC	  and	  other	  parties	  as	  applicable.	  
For	  fatal	  and	  life-­‐threatening	  SUSARs,	  this	  will	  be	  done	  no	  later	  than	  7	  calendar	  days	  after	  the	  Sponsor	  or	  
delegate	  is	  first	  aware	  of	  the	  reaction.	  Any	  additional	  relevant	  information	  will	  be	  reported	  within	  8	  
calendar	  days	  of	  the	  initial	  report.	  All	  other	  SUSARs	  will	  be	  reported	  within	  15	  calendar	  days.	  All	  SAE	  
information	  must	  be	  recorded	  on	  an	  SAE	  form	  and	  faxed,	  or	  scanned	  and	  emailed,	  to	  the	  JRCO	  (Fax	  
number:	  0203	  311	  0203	  or	  via	  email	  to	  jrco.ctimp.team@imperial.ac.uk).	  
Both	  SAEs	  and	  SARs	  will	  be	  reported	  to	  the	  Independent	  Data	  Monitoring	  Committee	  (IDMC).	  The	  IDMC	  has	  
the	  authority	  to	  recommend	  termination	  of	  the	  trial	  because	  of	  safety	  findings.	  SARs	  will	  also	  be	  reported	  
to	  MHRA	  through	  the	  yellow	  card	  system.	  
7.2	  GRADING	  AND	  ATTRIBUTION	  OF	  ADVERSE	  EVENTS	  
7.2.1	  NON-­‐ALLERGIC	  REACTIONS	  
The	  study	  site	  will	  grade	  the	  severity	  of	  adverse	  events	  experienced	  by	  study	  participants	  according	  to	  the	  
criteria	  set	  forth	  in	  the	  NCI-­‐CTCAE	  Version	  3.0	  
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev3.pdf).	  
This	  document	  provides	  a	  common	  language	  to	  describe	  levels	  of	  severity,	  to	  analyse	  and	  interpret	  data,	  
and	  to	  articulate	  the	  clinical	  significance	  of	  all	  adverse	  events.	  
Adverse	  events	  will	  be	  graded	  on	  a	  scale	  from	  1	  to	  5	  according	  to	  the	  following	  standards	  in	  the	  NCI-­‐CTCAE	  
manual:	  	  
Grade	  1	  =	  mild	  adverse	  event.	  	  
Grade	  2	  =	  moderate	  adverse	  event.	  	  
Grade	  3	  =	  severe	  and	  undesirable	  adverse	  event.	  	  
Grade	  4	  =	  life-­‐threatening	  or	  disabling	  adverse	  event.	  	  
Grade	  5	  =	  death.	  	  
All	  adverse	  events	  will	  be	  recorded	  and	  graded	  whether	  they	  are	  or	  are	  not	  related	  to	  disease	  progression	  
or	  treatment.	  The	  NCI-­‐CTCAE	  grades	  will	  be	  the	  primary	  source	  for	  scoring.	  
The	  relation,	  or	  attribution,	  of	  an	  adverse	  event	  to	  study	  participation	  will	  be	  determined	  by	  the	  
investigator	  and	  recorded	  on	  CRF	  and/or	  SAE	  reporting	  form.	  The	  assignment	  of	  the	  causality	  should	  be	  
made	  by	  the	  investigator	  responsible	  for	  the	  care	  of	  the	  participant	  using	  the	  definitions	  below	  (Table	  2).	  If	  
any	  doubt	  about	  the	  causality	  exists	  the	  local	  investigator	  should	  inform	  the	  study	  coordination	  centre	  who	  
will	  notify	  the	  Chief	  Investigators.	  	  The	  pharmaceutical	  companies	  and/or	  other	  clinicians	  may	  be	  asked	  to	  
advise	  in	  some	  cases.	  

	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  
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In	  the	  case	  of	  discrepant	  views	  on	  causality	  between	  the	  investigator	  and	  others,	  all	  parties	  will	  discuss	  the	  
case.	  	  In	  the	  event	  that	  no	  agreement	  is	  made	  relating	  to	  a	  SUSAR,	  the	  MHRA	  will	  be	  informed	  of	  both	  
points	  of	  view.	  	  
Table	  2:	  Assignment	  of	  causality	  for	  adverse	  events	  
Relationship	  
Description	  
Unrelated	  
There	  is	  no	  evidence	  of	  any	  causal	  relationship	  
Unlikely	  
There	  is	  little	  evidence	  to	  suggest	  there	  is	  a	  causal	  relationship	  (e.g.	  the	  
event	  did	  not	  occur	  within	  a	  reasonable	  time	  after	  administration	  of	  the	  
trial	  medication).	  	  There	  is	  another	  reasonable	  explanation	  for	  the	  event	  
(e.g.	  the	  participant’s	  clinical	  condition,	  other	  concomitant	  treatment).	  
Possible	  
There	  is	  some	  evidence	  to	  suggest	  a	  causal	  relationship	  (e.g.	  because	  
the	  event	  occurs	  within	  a	  reasonable	  time	  after	  administration	  of	  the	  
trial	  medication).	  	  However,	  the	  influence	  of	  other	  factors	  may	  have	  
contributed	  to	  the	  event	  (e.g.	  the	  participant’s	  clinical	  condition,	  other	  
concomitant	  treatments).	  
Probable	  
There	  is	  evidence	  to	  suggest	  a	  causal	  relationship	  and	  the	  influence	  of	  
other	  factors	  is	  unlikely.	  
Definitely	  
There	  is	  clear	  evidence	  to	  suggest	  a	  causal	  relationship	  and	  other	  
possible	  contributing	  factors	  can	  be	  ruled	  out.	  
Not	  assessable	  
There	  is	  insufficient	  or	  incomplete	  evidence	  to	  make	  a	  clinical	  
judgement	  of	  the	  causal	  relationship.	  
	  
7.2.2	  GRADING	  AND	  ATTRIBUTION	  OF	  ADVERSE	  EVENTS:	  ALLERGIC	  REACTION	  
Allergic	  reactions	  to	  LAIV	  will	  be	  determined	  using	  the	  World	  Allergy	  Organisation	  (WAO)	  criteria	  for	  allergic	  
reactions	  to	  immunotherapy	  (Table	  3).	  For	  the	  purpose	  of	  this	  study,	  mild	  symptoms	  of	  an	  allergic	  reaction	  
(ie.	  non-­‐anaphylactic	  symptoms)	  will	  be	  classified	  as	  non-­‐serious	  adverse	  event,	  and	  should	  be	  documented	  
on	  the	  CRF.	  
Anaphylaxis	  will	  be	  defined	  as	  per	  the	  case	  definition	  and	  guidelines	  as	  described	  by	  the	  Brighton	  
Collaboration	  Anaphylaxis	  Working	  Group	  (see	  appendix	  4).	  
Any	  symptoms	  requiring	  treatment	  for	  anaphylaxis	  (adrenaline,	  steroids,	  salbutamol)	  will	  be	  classified	  as	  
a	  SERIOUS	  ADVERSE	  REACTION	  and	  will	  be	  documented	  on	  both	  the	  CRF	  and	  a	  SAE	  form.	  The	  local	  
investigator	  should	  also	  make	  a	  notification	  to	  the	  MHRA	  through	  the	  MHRA	  yellow	  card	  scheme.	  

	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  SNIFFLE-­‐4	  Study	  Protocol	  	  
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Table	  3:	  World	  Allergy	  Organisation	  (WAO)	  Grading	  System	  for	  allergic	  reactions	  to	  immunotherapy	  
7.3	  REPORTING	  PROCEDURES	  
	  
All	  adverse	  events	  should	  be	  reported.	  	  Depending	  on	  the	  nature	  of	  the	  event	  the	  reporting	  procedures	  
below	  should	  be	  followed.	  	  Any	  questions	  concerning	  adverse	  event	  reporting	  should	  be	  directed	  to	  the	  
study	  coordination	  centre	  in	  the	  first	  instance.	  	  A	  flowchart	  is	  provided	  overleaf	  to	  aid	  the	  reporting	  
procedure.	  
7.3.1	  NON	  SERIOUS	  AR/AES	  
	  
All	  such	  events,	  whether	  expected	  or	  not,	  should	  be	  recorded	  in	  the	  adverse	  event	  section	  of	  the	  relevant	  
case	  report	  form	  and	  reported	  to	  the	  study	  CI	  within	  one	  month	  of	  the	  form	  being	  due.	  	  	  
7.3.2	  SERIOUS	  AR/AES	  
	  
Fatal	  or	  life	  threatening	  SAEs	  and	  SUSARs	  should	  be	  reported	  on	  the	  same	  day	  as	  the	  site	  is	  made	  aware	  of	  
the	  event.	  	  The	  SAE	  form	  asks	  for	  nature	  of	  event,	  date	  of	  onset,	  severity,	  corrective	  therapies	  given,	  
outcome	  and	  causality	  (i.e.	  unrelated,	  unlikely,	  possible,	  probably,	  definitely).	  	  The	  responsible	  investigator	  
should	  determine	  the	  causality	  of	  the	  event.	  	  Additional	  information	  should	  be	  sent	  to	  the	  CI	  within	  5	  days	  
if	  the	  reaction	  has	  not	  resolved	  at	  the	  time	  of	  reporting.	  	  Any	  expected	  SAR	  will	  also	  be	  reported	  via	  the	  
MHRA	  yellow	  card	  system.	  
	  
SAEs:	  An	  SAE	  form	  should	  be	  completed	  and	  emailed	  to	  the	  study	  CI	  immediately,	  who	  will	  in	  turn	  inform	  
the	  JRCO	  (Fax	  number:	  0203	  311	  0203	  or	  via	  email	  to	  jrco.ctimp.team@imperial.ac.uk)	  within	  24	  hours.	  
	  
SUSARs:.	  All	  SUSARs	  will	  be	  reported	  by	  the	  CI	  to	  the	  relevant	  Competent	  Authority	  (MHRA)	  and	  to	  the	  REC	  
and	  other	  parties	  as	  applicable.	  For	  fatal	  and	  life-­‐threatening	  SUSARs,	  this	  will	  be	  done	  no	  later	  than	  7	  
calendar	  days	  after	  the	  Sponsor	  or	  delegate	  is	  first	  aware	  of	  the	  reaction.	  Any	  additional	  relevant	  
information	  will	  be	  reported	  within	  8	  calendar	  days	  of	  the	  initial	  report.	  All	  other	  SUSARs	  will	  be	  reported	  
within	  15	  calendar	  days.	  	  

	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  SNIFFLE-­‐4	  Study	  Protocol	  	  
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Contact	  details	  for	  reporting	  SAEs	  and	  SUSARs:	  
Study	  CI:	  	  
	  
Fax	  020	  3312	  7571	  	  	  	  	  	  	  	  	  	  Email:	  p.turner@imperial.ac.uk	  
Compliance	  Office:	  	  
Fax:	  020	  3311	  0203	  	  	  	  	  	  	  	  	  Email:	  jrco.ctimp.team@imperial.ac.uk	  

	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  
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8.	  ASSESSMENT	  AND	  FOLLOW-­‐UP	  
8.1	  CLINICAL	  ASSESSMENTS	  	  
	  8.1.1	  ALLERGY	  TESTING	  
No	  allergy	  testing	  will	  be	  performed	  as	  part	  of	  this	  protocol.	  
8.1.2	  LUNG	  FUNCTION	  TESTING	  
Where	  study	  participants	  are	  able	  to	  comply,	  lung	  function	  will	  be	  performed	  prior	  to	  LAIV	  
using	  the	  system	  in	  use	  at	  each	  centre	  and	  according	  to	  local	  protocol.	  Data	  relating	  to	  
bronchodilator	  responsiveness	  (BDR)	  will	  be	  collected	  if	  performed	  for	  routine	  clinical	  
assessment.	  For	  children	  with	  non-­‐severe	  symptoms,	  an	  assessment	  of	  peak	  flow	  using	  a	  
peak	  flow	  meter	  will	  suffice,	  although	  formal	  lung	  function	  is	  preferable.	  
8.1.2	  CLINICAL	  OBSERVATION	  /	  MONITORING	  OF	  PATIENTS	  BY	  CLINICAL	  STAFF	  
Patients	  will	  have	  baseline	  observations	  (temperature,	  heart	  rate,	  respiratory	  rate,	  oxygen	  
saturations,	  lung	  function	  (FEV1	  and/or	  PEFR))	  performed	  prior	  to	  LAIV	  administration,	  with	  
clinical	  respiratory	  and	  dermatological	  assessment	  at	  the	  same	  time.	  
	  
Children	  will	  be	  observed	  for	  at	  least	  20	  minutes	  after	  LAIV	  in	  a	  safe	  environment	  with	  
appropriate	  clinical	  supervision	  and	  access	  to	  paediatric	  resuscitation	  facilities	  and	  trained	  
staff,	  in	  the	  event	  of	  a	  severe	  allergic	  reaction.	  
8.1.3	  ASTHMA	  CONTROL	  ASSESSMENT	  PRE	  AND	  4	  WEEKS	  POST	  VACCINATION	  
Participants’	  families	  will	  be	  asked	  to	  complete	  a	  questionnaire	  to	  determine	  their	  child’s	  
asthma	  symptoms	  and	  control,	  using	  a	  validated	  tool	  at	  visit	  1:	  
• 
In	  children	  age	  2-­‐4	  years:	  TRACK	  questionnaire	  (Appendix	  1)	  
• 
In	  children	  age	  5-­‐11	  years:	  C-­‐ACT	  questionnaire	  (Appendix	  2a)	  
• 
In	  children	  age	  12+	  years:	  ACT	  questionnaire	  (Appendix	  2b)	  
As	  part	  of	  the	  CRF,	  the	  questions	  on	  the	  Asthma	  Control	  Questionnaire14	  (ACQ,	  Appendix	  3)	  
will	  also	  be	  completed.	  While	  the	  (C-­‐)ACT	  and	  TRACK	  questionnaires	  assess	  asthma	  
symptoms	  over	  the	  preceding	  4	  weeks,	  the	  ACQ	  assesses	  symptoms	  and	  control	  over	  the	  
preceding	  7	  days	  and	  also	  includes	  lung	  function;15	  the	  ACQ	  may	  therefore	  be	  more	  
representative	  of	  asthma	  control	  at	  the	  time	  of	  vaccination.	  The	  (C-­‐)ACT	  will	  be	  completed	  
first,	  before	  the	  ACQ.	  
Families	  will	  be	  asked	  to	  complete	  a	  further	  questionnaire	  4	  weeks	  after	  vaccination.	  In	  
general,	  this	  will	  be	  done	  using	  an	  online	  questionnaire.	  Families	  will	  be	  asked	  at	  their	  first	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  
14	  Juniper	  	  EF,	  	  O’Byrne	  	  PM,	  	  Guyatt	  	  GH,	  et	  	  al.	  Development	  	  and	  validation	  of	  a	  questionnaire	  to	  measure	  asthma	  
control.	  Eur	  Respir	  J	  1999;	  14:	  902–907.	  
15	  Juniper	  EF,	  Gruffydd-­‐Jones	  K,	  Ward	  S,	  Svensson	  K.	  Validation,	  measurement	  properties	  and	  interpretation	  of	  the	  
Asthma	  Control	  Questionnaire	  in	  children.	  Eur	  Respir	  J	  2010:	  36:	  1410-­‐1416	  

	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  
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visit	  as	  to	  whether	  they	  prefer	  to	  be	  contacted	  by	  telephone	  by	  the	  study	  team,	  or	  receive	  an	  
email	  request	  with	  a	  link	  to	  a	  secure,	  online	  survey.	  Either	  way,	  the	  survey	  will	  take	  2-­‐3	  
minutes	  to	  complete.	  A	  guide	  for	  the	  telephone	  call	  is	  provided	  in	  Appendix	  6.	  These	  data	  will	  
be	  recorded	  on	  a	  CRF.	  
If	  the	  family	  fails	  to	  respond	  to	  the	  email	  request,	  the	  local	  study	  team	  will	  attempt	  to	  contact	  
the	  family	  by	  telephone.	  If,	  after	  three	  attempts	  (on	  three	  separate	  days),	  the	  local	  study	  
team	  is	  unable	  to	  contact	  the	  family,	  the	  child	  will	  be	  deemed	  lost	  to	  follow	  up	  and	  this	  will	  
be	  documented	  on	  the	  CRF,	  which	  will	  then	  be	  closed.	  
At	  the	  Royal	  Brompton,	  participants	  will	  be	  invited	  to	  return	  to	  hospital	  for	  the	  4	  week	  
follow-­‐up	  (which	  will,	  in	  general,	  coincide	  with	  a	  routine	  clinic	  follow-­‐up	  appointment).	  The	  
follow-­‐up	  questionnaires	  will	  be	  completed	  at	  this	  visit,	  along	  with	  some	  further	  repeat	  
assessments	  (section	  8.3).	  
	  
8.2	  TELEPHONE	  FOLLOW	  UP	  
Participants’	  families	  will	  be	  contacted	  by	  the	  local	  research	  team	  at	  least	  72	  hours	  after	  LAIV	  
administration	  (and	  within	  7	  days,	  to	  allow	  for	  weekends),	  to	  determine	  whether	  their	  child	  
has	  experienced	  any	  delayed	  symptoms	  which	  might	  be	  attributable	  to	  the	  vaccine.	  This	  
telephone	  consultation	  will	  take	  approximately	  2	  minutes.	  A	  guide	  for	  this	  telephone	  call	  is	  
provided	  in	  Appendix	  5.	  These	  data	  will	  be	  recorded	  on	  the	  CRF.	  Following	  this,	  the	  CRF	  will	  
be	  deemed	  complete	  and	  forwarded	  to	  the	  coordinating	  centre.	  
If	  after	  three	  attempts	  (on	  three	  separate	  days)	  the	  local	  study	  team	  is	  unable	  to	  contact	  the	  
family,	  the	  child	  will	  be	  deemed	  lost	  to	  follow	  up	  and	  this	  will	  be	  documented	  on	  the	  CRF,	  
which	  will	  then	  be	  closed.	  
	  
8.3	  ADDITIONAL	  CLINICAL	  ASSESSMENTS	  (ROYAL	  BROMPTON	  SITE	  ONLY)	  
	  
Participants	  at	  the	  Royal	  Brompton	  Hospital	  site	  will	  undergo	  further	  clinical	  assessments,	  immediately	  
prior	  to	  and	  4	  weeks	  after	  LAIV.	  Thus,	  participants	  at	  the	  Royal	  Brompton	  will	  be	  asked	  to	  return	  4	  weeks	  
later	  for	  these	  repeat	  assessments.	  Data	  will	  be	  collected	  on	  a	  supplementary	  clinical	  record	  form.	  
The	  planned	  additional	  assessments	  are	  as	  follows:	  
1. Measurement	  of	  fractional	  exhaled	  nitric	  oxide	  (FeNO)	  
Exhaled	  nitric	  oxide	  is	  a	  marker	  thought	  to	  represent	  inflammation	  in	  the	  airways.	  This	  non-­‐
invasive	  technique	  is	  approved	  by	  NICE	  for	  the	  diagnosis	  and	  monitoring	  of	  asthma	  in	  both	  
children	  and	  adults.16	  For	  most	  children	  at	  this	  site,	  FeNO	  is	  measured	  as	  part	  of	  routine	  clinical	  
care.	  For	  school-­‐aged	  children,	  exhaled	  nitric	  oxide	  will	  be	  measured	  according	  to	  local	  protocol.	  
For	  preschool	  children,	  exhaled	  breath	  will	  be	  collected	  during	  normal	  tidal	  breathing	  into	  a	  bag	  
and	  nitric	  oxide	  measured	  in	  the	  collected	  gas	  (“offline”	  method).	  This	  technique	  has	  been	  
established	  as	  a	  routine	  test	  at	  the	  Royal	  Brompton	  Hospital.	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  
16	  Measuring	  fractional	  exhaled	  nitric	  oxide	  concentration	  in	  asthma:	  NIOX	  MINO,	  NIOX	  VERO	  and	  NObreath	  
NICE	  diagnostics	  guidance	  [DG12]	  Published	  date:	  April	  2014.	  

	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  
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2. Induced	  Sputum	  
This	  is	  also	  a	  routine	  clinical	  test	  in	  the	  severe	  asthma	  clinic.	  Hypertonic	  saline	  will	  be	  given	  via	  a	  
nebuliser	  and	  the	  child	  asked	  to	  cough	  any	  phlegm	  into	  a	  universal	  container.	  In	  preschool	  
children,	  the	  sputum	  sample	  can	  be	  obtained	  using	  a	  combination	  of	  chest	  physiotherapy	  and	  
suction.	  The	  procedure	  will	  only	  be	  undertaken	  where	  children	  are	  clinical	  well	  (and	  thus	  eligible	  
for	  LAIV).	  The	  sample	  will	  be	  assessed	  in	  the	  laboratory	  for	  inflammatory	  cells	  and	  any	  excess	  
stored	  at	  -­‐80°C	  for	  analysis	  of	  inflammatory	  cytokines.	  Where	  consent	  is	  provided,	  any	  residual	  
sample	  will	  be	  stored	  for	  future	  research.	  
	  
3. Paediatric	  Asthma	  Quality	  of	  Life	  Questionnaire	  (PAQLQ)	  
Children	  aged	  7+	  years	  and	  their	  caregiver	  will	  be	  asked	  to	  complete	  the	  PAQLQ,	  a	  validated	  
assessment	  of	  health-­‐related	  quality	  of	  life	  in	  asthma.17	  
	  
	  
8.4	  NASAL	  SWABBING	  AND	  SAMPLE	  MANAGEMENT	  
8.4.1	  COLLECTION	  OF	  NASAL	  SWAB	  
Parents	  will	  be	  asked	  to	  collect	  up	  to	  3	  nasal	  swabs	  in	  the	  week	  following	  LAIV	  administration.	  
This	  will	  involve	  putting	  a	  swab,	  which	  looks	  like	  a	  large	  cotton	  bud,	  into	  the	  nostril	  and	  
moving	  it	  around	  for	  up	  to	  a	  minute.	  	  
8.4.2	  LABELLING,	  DESPATCH,	  AND	  STORAGE	  OF	  SAMPLES	  
Each	  participant	  will	  be	  assigned	  a	  unique	  identifying	  number	  during	  the	  enrolment	  process,	  
according	  to	  the	  Standard	  Operating	  Protocol	  in	  respect	  of	  participant	  identification	  for	  the	  
study.	  The	  participant	  number	  will	  be	  linked	  to	  a	  pre-­‐generated	  sample	  barcode	  for	  every	  
clinical	  sample	  taken,	  which	  can	  be	  scanned	  at	  the	  testing	  laboratory.	  
	  
Samples	  will	  be	  sent	  to	  the	  receiving	  laboratory	  at	  the	  Virus	  Reference	  Division,	  PHE	  Colindale	  
by	  Royal	  Mail	  using	  approved	  packaging	  which	  will	  be	  supplied	  to	  each	  family.	  A	  brief	  paper	  
form	  will	  be	  completed	  by	  parents	  to	  confirm	  date	  of	  sampling.	  All	  samples	  will	  be	  logged	  
locally,	  to	  enable	  the	  identification	  of	  any	  lost	  or	  delayed	  samples	  and	  provide	  a	  log	  of	  where	  
samples	  are	  currently	  stored.	  
	  
Samples	  arriving	  at	  the	  receiving	  laboratory	  at	  the	  Virus	  Reference	  Division,	  PHE	  Colindale	  
without	  accompanying	  paperwork	  will	  be	  initially	  processed	  (given	  that	  consent	  has	  already	  
been	  obtained)	  but	  any	  results	  embargoed	  until	  confirmatory	  paperwork	  has	  been	  received	  
from	  the	  family.	  
	  
Samples	  will	  be	  initially	  processed	  from	  the	  administrative	  perspective	  and	  stored	  until	  
formal	  processing	  in	  batches.	  Not	  all	  swabs	  received	  will	  undergo	  viral	  detection	  and	  
quantification:	  swabs	  will	  be	  selected	  from	  representative	  cohorts	  of	  individuals,	  by	  previous	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  
17	  Juniper	  EF,	  Guyatt	  GH,	  Feeny	  DH,	  Ferrie	  PJ,	  Griffith	  LE,	  Townsend	  M.	  Measuring	  quality	  of	  life	  in	  children	  with	  
asthma.	  Qual	  Life	  Res	  1996;	  5:	  35	  -­‐46.	  

	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  SNIFFLE-­‐4	  Study	  Protocol	  	  
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influenza	  vaccination	  status:	  no	  previous	  vaccination,	  previous	  LAIV	  only,	  previous	  injected	  
influenza	  vaccine	  only.	  This	  will	  allow	  an	  assessment	  of	  the	  impact	  of	  previous	  LAIV	  receipt	  on	  
viral	  shedding,	  something	  necessary	  to	  determine	  the	  effect	  of	  prior	  influenza	  immunisation	  
on	  viral	  shedding.	  Any	  swabs	  not	  included	  in	  the	  viral	  quantification	  will	  be	  handled	  as	  per	  
section	  8.4.3.	  
	  
8.4.3	  HANDLING	  OF	  RESIDUAL	  SAMPLES	  ON	  COMPLETION	  OF	  TESTING	  
During	  the	  consent	  process,	  parents/guardians	  will	  be	  asked	  for	  consent	  to	  keep	  their	  child’s	  
residual	  samples	  (if	  any)	  to	  be	  used	  for	  further	  research	  to	  improve	  understanding	  of	  vaccines	  
and	  how	  they	  work.	  Lack	  of	  consent	  to	  this	  will	  not	  preclude	  participation	  in	  the	  study.	  Where	  
consent	  is	  given,	  any	  residual	  samples	  will	  be	  archived	  at	  -­‐70	  ºC	  or	  below	  at	  PHE	  Colindale.	  
Residual	  samples	  from	  participants	  who	  do	  not	  give	  such	  consent	  will	  be	  destroyed.	  
	  
8.5	  LOSS	  TO	  FOLLOW-­‐UP	  	  
All	  data	  for	  any	  participants	  withdrawn	  after	  receiving	  the	  study	  vaccination	  will	  be	  included	  in	  the	  data	  
analyses,	  unless	  specific	  instruction	  for	  their	  destruction	  is	  received	  from	  the	  participant	  or	  their	  
parent/guardian.	  Withdrawn	  participants	  will	  not	  be	  replaced	  (allowance	  for	  modest	  attrition	  is	  built	  into	  
the	  sample	  size	  calculation).	  	  
	  
8.6	  TRIAL	  CLOSURE	  	  
The	  study	  will	  be	  considered	  complete	  following	  enrolment	  of	  the	  last	  patient	  and	  completion	  of	  the	  study	  
procedures	  in	  that	  patient.	  Upon	  review	  by	  the	  TSC,	  recruitment	  may	  be	  extended	  if	  target	  recruitment	  is	  
achieved	  prior	  to	  end	  of	  the	  vaccination	  period	  for	  influenza	  and	  additional	  funding	  is	  available.	  
	  
The	  study	  will	  be	  placed	  on	  hold	  and,	  upon	  review	  of	  study	  data	  and	  discussion	  with	  the	  IDMC,	  may	  be	  
terminated	  early	  if	  any	  of	  the	  following	  occur:	  
• 
One	  patient	  suffers	  an	  allergic	  reaction	  or	  asthma	  episode	  that	  warrants	  admission	  to	  the	  
ICU	  and	  use	  of	  mechanical	  ventilation	  
• 
Death	  of	  a	  participant	  during	  the	  study	  period,	  from	  any	  cause	  
• 
Two	  similar	  SUSARs	  (Suspected	  Unexpected	  Serious	  Adverse	  Reactions)	  or	  the	  repetition	  of	  
one	  SUSAR	  
	  
A	  teleconference	  will	  be	  scheduled	  within	  72	  hours	  if	  any	  of	  the	  aforementioned	  situations	  occur.	  This	  
conference	  will	  be	  attended	  by	  the	  members	  of	  the	  IDMC	  and	  the	  TSC.	  At	  this	  teleconference	  the	  clinical	  
relevance	  of	  the	  findings	  will	  be	  determined	  and	  recommendations	  may	  be	  made	  by	  the	  IDMC	  which	  may	  
include:	  
• 
requesting	  further	  information	  
• 
modifying	  the	  protocol	  
• 
stopping	  enrolment	  
• 
institute	  more	  frequent	  monitoring	  guidelines	  
	  
	  

	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  SNIFFLE-­‐4	  Study	  Protocol	  	  
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9.	  STATISTICS	  AND	  DATA	  ANALYSIS	  
9.1	  DEFINITIONS	  
	  
For	  the	  purpose	  of	  analyses,	  severity	  will	  be	  defined	  as	  follows:	  
	  
• 
Age	  2-­‐4	  years	  (preschool	  wheezers,	  PSW):	  
o 
Step	  3/4	  BTS	  management:	  ≥400mcg	  beclomethasone	  dipropionate	  /day	  or	  200mcg/FP,	  
AND	  LRTA	  (either	  continuous	  or	  intermittent	  or	  previous	  failed	  trial)	  
	  
OR	  
	  
o 
≥2	  exacerbations	  in	  the	  past	  year	  requiring	  oral	  steroids	  or	  observation	  in-­‐hospital	  beyond	  
4	  hours	  duration	  	  
	  
• 
Age	  5+	  years:	  
o 
Requiring	  Step	  4+	  management	  according	  to	  BTS	  Guidelines	  
	  
A	  ‘significant	  exacerbation’	  in	  asthma	  is	  defined	  as:	  
i. 
At	  least	  3	  day	  course	  of	  oral	  steroids	  following	  an	  unscheduled	  contact	  with	  a	  healthcare	  
professional;	  OR	  
ii. 
Unscheduled	  visit	  to	  an	  Emergency	  department	  or	  admission	  to	  hospital	  for	  treatment	  of	  
asthma	  symptoms,	  requiring	  systemic	  corticosteroids	  
	  
9.2	  SAMPLE	  SIZE	  ESTIMATION	  
Sample	  size	  is	  based	  on	  the	  primary	  objective	  of	  comparing	  the	  proportion	  of	  participants	  who	  experience	  
a	  significant	  change	  in	  asthma	  control,	  as	  measured	  by	  a	  change	  in	  at	  least	  3	  points	  and	  from	  >=20	  on	  the	  
(C-­‐)ACT	  (good	  control)	  to	  <20	  (sub-­‐optimal	  control)	  in	  each	  group	  (BTS	  ≤3	  vs	  BTS	  4/5),	  or	  vice	  versa.	  In	  the	  
SNIFFLE-­‐2	  study,	  such	  a	  change	  (one	  way	  or	  the	  other)	  was	  seen	  in	  about	  20%	  of	  children	  (10%	  worse,	  10%	  
better).	  	  
A	  sample	  of	  400	  children	  in	  each	  group	  will	  provide	  sufficient	  power	  (5%	  significance	  level,	  80%	  power)	  to	  
detect	  an	  improvement	  in	  10%	  vs	  deterioration	  in	  17.5%,	  allowing	  for	  10%	  attrition.	  In	  SNIFFLE-­‐2,	  follow-­‐up	  
at	  four	  weeks	  was	  89%.	  If	  the	  proportion	  of	  participants	  with	  a	  change	  in	  ACT	  score	  is	  less	  than	  this,	  with	  
only	  5%	  improving	  and	  10%	  getting	  worse,	  a	  sample	  size	  of	  about	  420	  would	  provide	  a	  similar	  level	  of	  
power.	  This	  would	  represent	  a	  conservative	  assumption	  in	  the	  proportions	  changing.	  For	  comparing	  the	  
average	  change	  pre	  to	  post	  vaccination	  in	  ACT	  score	  between	  the	  severe	  and	  non-­‐severe	  groups,	  the	  
standard	  deviation	  of	  change	  from	  SNIFFLE-­‐2	  was	  used	  (about	  3	  units).	  With	  a	  sample	  size	  of	  400	  in	  each	  
group	  the	  detectable	  difference	  is	  0.6	  units	  between	  the	  groups	  (80%	  power,	  5%	  significance).	  
Assuming	  that	  about	  1%	  of	  participants	  experience	  a	  significant	  deterioration	  in	  asthma	  control	  (as	  defined	  
in	  3.1.2	  above),	  then	  the	  95%	  CI	  for	  a	  significant	  deterioration	  will	  be	  from	  0.027%	  to	  2.54%.	  	  If	  0/400	  are	  
observed	  the	  upper	  95%	  CI	  is	  0.92%.	  
POPULATION	  TO	  BE	  ANALYSED	  
CHILDREN	  AGED	  2-­‐18	  YEARS	  (INCLUSIVE)	  WITH	  A	  PHYSICIAN-­‐DIAGNOSIS	  OF	  ASTHMA	  
OR	  RECURRENT	  WHEEZING,	  REQUIRING	  REGULAR	  MAINTENANCE	  THERAPY	  OR,	  IF	  

	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  SNIFFLE-­‐4	  Study	  Protocol	  	  
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AGE	  2-­‐4	  YEARS,	  ≥2	  EXACERBATIONS	  IN	  THE	  PAST	  YEAR	  AS	  DEFINED	  IN	  SECTION	  9.1	  .	  
9.3	  STATISTICAL	  ANALYSIS	  PLAN	  
	  
In	  brief,	  a	  per-­‐protocol	  analysis	  will	  be	  completed	  for	  all	  individuals	  with	  at	  least	  one	  safety	  measurement.	  
Proportions	  with	  AEs	  will	  be	  estimated	  with	  95%	  CIs.	  
	  
For	  the	  primary	  outcome,	  the	  change	  in	  TRACK	  or	  ACT	  score	  pre-­‐	  and	  4	  weeks	  post	  LAIV	  will	  be	  assessed	  by	  
McNemar’s	  test	  for	  paired	  data.	  The	  minimum	  important	  difference	  (MID)	  for	  the	  ACT	  score	  is	  around	  2	  
points	  in	  children18	  and	  3	  points	  in	  adults,19	  and	  10	  points	  for	  TRACK.20	  For	  the	  purpose	  of	  this	  analysis,	  a	  
change	  in	  ACT	  of	  at	  least	  3	  points,	  or	  10	  points	  for	  TRACK	  will	  be	  determined	  to	  be	  a	  significant	  change,	  
where	  this	  results	  in	  an	  ACT	  score	  below	  20	  or	  TRACK	  score	  below	  80	  points.	  
	  
For	  secondary	  outcomes,	  the	  incidence	  of	  reactions	  to	  LAIV	  (both	  immediate	  and	  delayed)	  and	  significant	  
exacerbation	  in	  asthma	  will	  be	  estimated	  with	  95%	  confidence	  intervals.	  Comparison	  to	  historical	  rates	  will	  
be	  by	  Fisher’s	  exact	  test.	  
	  
Sub-­‐group	  analyses	  will	  be	  performed	  using	  the	  following	  criteria:	  
• 
Age:	  2-­‐4,	  5-­‐11,	  12-­‐17	  years	  
• 
Severity	  of	  respiratory	  symptoms:	  “severe”	  vs	  “non-­‐severe”	  
• 
Children	  who	  have	  previously	  received	  influenza	  vaccine	  
• 
Children	  receiving	  high	  dose	  inhaled	  corticosteroids	  (≥800	  mcg/day	  beclomethasone	  dipropionate,	  
or	  equivalent)21	  vs	  those	  who	  are	  not.	  This	  cut-­‐off	  will	  be	  applied	  to	  all	  participants	  age	  6+	  years.	  
	  
	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  
18	  Voorend-­‐van	  Bergen	  S,	  Vaessen-­‐Verberne	  AA,	  Landstra	  AM,	  Brackel	  HJ,	  van	  den	  Berg	  NJ,	  Caudri	  D,	  de	  Jongste	  JC,	  
Merkus	  PJ,	  Pijnenburg	  MW.	  Monitoring	  childhood	  asthma:	  web-­‐based	  diaries	  and	  the	  asthma	  control	  test.	  J	  Allergy	  Clin	  
Immunol.	  2014	  Jun;133(6):1599-­‐605.e2.	  
19	  Schatz	  M,	  Kosinski	  M,	  Yarlas	  AS,	  Hanlon	  J,	  Watson	  ME,	  Jhingran	  P.	  The	  minimally	  important	  difference	  of	  the	  Asthma	  
Control	  Test.	  J	  Allergy	  Clin	  Immunol.	  2009	  Oct;124(4):719-­‐23.e1.	  
20	  Zeiger	  RS,	  Mellon	  M,	  Chipps	  B,	  Murphy	  KR,	  Schatz	  M,	  Kosinski	  M,	  Lampl	  K,	  Ramachandran	  S.	  Test	  for	  Respiratory	  and	  Asthma	  
Control	  in	  Kids	  (TRACK):	  clinically	  meaningful	  changes	  in	  score.	  J	  Allergy	  Clin	  Immunol.	  2011	  Nov;128(5):983-­‐8.	  
21	  Chung	  KF,	  Wenzel	  SE,	  Brozek	  JL,	  et	  al.	  International	  ERS/ATS	  guidelines	  on	  definition,	  evaluation	  and	  treatment	  of	  severe	  asthma.	  
Eur	  Respir	  J.	  2014	  Feb;43(2):343-­‐73.	  

	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  SNIFFLE-­‐4	  Study	  Protocol	  	  
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A	  further	  analysis	  will	  also	  be	  taken	  to	  generate	  Receiver	  Operating	  Characteristic	  (ROC)	  curves	  to	  
determine	  if	  a	  cut-­‐off	  of	  high	  specificity	  and	  sensitivity	  can	  be	  determined	  for	  the	  (C-­‐)ACT	  and	  ACQ	  in	  
predicting	  which	  children	  are	  likely	  to	  experience	  a	  significant	  exacerbation	  in	  asthma	  following	  LAIV.	  The	  
ACQ	  is	  only	  validated	  for	  children	  age	  6	  and	  over:	  thus,	  this	  analysis	  will	  be	  performed	  using	  both	  the	  
complete	  dataset	  and	  also	  after	  excluding	  children	  under	  age	  6	  years.	  
	  
Data	  analysis	  will	  be	  undertaken	  by	  PHE	  Immunisation	  Department	  Statistician	  and	  members	  of	  the	  Clinical	  
Trial	  Team	  where	  appropriate.	  
	  
The	  results	  of	  the	  study	  will	  be	  submitted	  for	  peer-­‐reviewed	  journal	  publication(s).	  If	  requested,	  
anonymised	  data	  will	  be	  provided	  to	  the	  vaccine	  manufacturers,	  and	  comparative	  analysis	  of	  results	  may	  
be	  performed.	  
No	  interim	  analyses	  are	  planned.	  
	  
	  
	  

	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  SNIFFLE-­‐4	  Study	  Protocol	  	  
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10	  DATA	  MANAGEMENT	  
10.1	  DATA	  COLLECTION	  	  
The	  following	  data	  will	  be	  collected:	  
• 
Patient	  demographics	  
• 
Current	  health	  to	  establish	  safety	  of	  immunisation	  
• 
Vaccination	  history:	  	  
! 
previous	  exposure	  to	  influenza	  vaccine	  
! 
previous	  reactions	  to	  vaccines	  
• 
Past	  medical	  history:	  
! 
Medical	  indication	  for	  influenza	  vaccination	  or	  routine	  
! 
Asthma	  status	  
! 
Active	  Allergic	  rhinitis	  
! 
Current	  Medication	  
! 
Other	  atopy:	  allergic	  rhinitis,	  eczema,	  other	  food	  allergies	  
Data	  will	  be	  collected	  by	  paper	  CRF	  and	  then	  transferred	  to	  Public	  Health	  England,	  with	  
participants	  identified	  by	  study	  number.	  Patient	  identifiable	  information	  (e.g.	  names,	  email	  
addresses)	  will	  be	  transferred	  to	  Public	  Health	  England	  via	  a	  GSI	  gateway	  secure	  server.	  This	  
is	  necessary	  to	  facilitate	  the	  swabbing	  phase	  of	  the	  study.	  Specific	  consent	  to	  share	  patient	  
identifiable	  information	  with	  Public	  Health	  England	  will	  be	  included	  on	  the	  study	  consent	  
form.	  
	  
10.2	  DATA	  RECORDS	  
Paper	  records	  will	  be	  maintained	  at	  local	  sites	  for	  all	  participants	  enrolled	  in	  the	  study.	  CRFs	  
will	  be	  completed	  at	  each	  visit,	  reviewed	  by	  the	  coordinating	  centre	  and	  then	  sent	  to	  PHE	  
Colindale.	  A	  database	  will	  be	  constructed	  at	  PHE	  Colindale	  to	  record	  the	  information	  
collected	  in	  the	  CRFs.	  As	  the	  data	  are	  being	  entered,	  the	  CRFs	  will	  be	  monitored	  for	  
completion	  errors	  or	  omissions.	  When	  such	  a	  problem	  is	  identified	  the	  card	  will	  be	  
photocopied	  and	  the	  field	  for	  correction	  marked.	  Any	  corrections	  necessary	  will	  be	  made	  by	  
the	  study	  team	  according	  to	  GCP	  and	  returned	  to	  PHE	  Colindale,	  where	  the	  database	  will	  be	  
updated	  accordingly	  and	  the	  photocopy	  filed	  with	  the	  original	  CRF.	  	  
Information	  from	  CRFs	  will	  be	  entered	  at	  PHE	  Colindale	  into	  an	  Access	  database.	  Data	  will	  be	  
entered	  twice	  by	  different	  members	  of	  staff	  into	  identical	  Access	  study	  databases	  which	  will	  
be	  compared	  using	  an	  Access	  programme	  which	  compares	  the	  data	  in	  the	  two	  databases	  and	  
identifies	  data	  entry	  errors.	  These	  will	  then	  be	  corrected.	  
Study	  data	  will	  be	  kept	  for	  10	  years	  following	  the	  child’s	  18th	  birthday,	  and	  then	  disposed	  of	  
securely.	  Local	  paperwork	  will	  be	  kept	  as	  part	  of	  the	  patient	  notes/CRF	  as	  per	  local	  policy.	  
	  
	  

	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  SNIFFLE-­‐4	  Study	  Protocol	  	  
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11	  ADMINISTRATIVE	  AND	  REGULATORY	  ISSUES	  
11.1	  CLINICAL	  TRIALS	  AUTHORISATION	  
This	  study	  has	  Clinical	  Trials	  Authorisation	  from	  the	  UK	  Competent	  Authority;	  MHRA,	  Eudra	  CT	  registration	  
no.	  2016-­‐002352-­‐24.	  The	  study	  is	  also	  registered	  at	  Clinicaltrials.gov,	  reference:	  NCT02866942.	  
11.2	  ETHICS	  APPROVAL	  
The	  Chief	  Investigator	  has	  obtained	  the	  required	  approvals	  from	  the	  West	  Mildands-­‐Edgbaston	  Research	  
Ethics	  Committee.	  	  The	  study	  will	  be	  submitted	  for	  Site	  Specific	  Assessment	  (SSA)	  at	  each	  participating	  NHS	  
Trust.	   	   The	   Chief	   Investigator	   will	   require	   a	   copy	   of	   the	   Trust	   R&D	   approval	   letters	   before	   accepting	  
participants	   into	   the	   study.	   	   The	   study	   will	   be	   conducted	   in	   accordance	   with	   the	   recommendations	   for	  
physicians	  involved	  in	  research	  on	  human	  subjects	  adopted	  by	  the	  18th	  World	  Medical	  Assembly,	  Helsinki	  
1964	  and	  later	  revisions.	  
11.3	  INFORMED	  CONSENT	  AND	  PARTICIPANT	  ASSENT	  
Consent	  to	  enter	  the	  study	  must	  be	  sought	  for	  each	  participant	  only	  after	  a	  full	  explanation	  has	  been	  given,	  
an	  information	  leaflet	  offered	  and	  time	  allowed	  for	  consideration.	  Signed	  consent	  from	  the	  parent/legal	  
guardian	  should	  be	  obtained.	  	  In	  children	  over	  8	  years	  of	  age,	  participant	  assent	  will	  also	  be	  sought.	  The	  
right	  of	  the	  parent/guardian	  to	  refuse	  to	  participate	  without	  giving	  reasons	  must	  be	  respected.	  	  After	  the	  
participant	  has	  entered	  the	  trial	  the	  clinician	  remains	  free	  to	  give	  alternative	  treatment	  to	  that	  specified	  in	  
the	  protocol	  at	  any	  stage	  if	  he/she	  feels	  it	  is	  in	  the	  participant’s	  best	  interest,	  but	  the	  reasons	  for	  doing	  so	  
should	  be	  recorded.	  	  In	  these	  cases	  the	  participants	  remain	  within	  the	  study	  for	  the	  purposes	  of	  follow-­‐up	  
and	  data	  analysis.	  	  All	  participants	  are	  free	  to	  withdraw	  at	  any	  time	  from	  the	  protocol	  treatment	  without	  
giving	  reasons	  and	  without	  prejudicing	  further	  treatment.	  
11.4	  CONFIDENTIALITY	  
Participants’	   identification	   data	   will	   be	   required	   for	   the	   registration	   process.	   Both	   Imperial	   College	  
Healthcare	  NHS	  Trust	  /	  Imperial	  College	  London	  and	  Public	  Health	  England	  are	  registered	  under	  the	  Data	  
Protection	   Act.	   The	   Chief	   Investigator	   will	   preserve	   the	   confidentiality	   of	   participants	   taking	   part	   in	   the	  
study	  under	  the	  Data	  Protection	  Act.	  
	  
11.5	  INDEMNITY	  
Imperial	  College	  Healthcare	  NHS	  Trust	  holds	  standard	  NHS	  Hospital	  Indemnity	  and	  insurance	  cover	  with	  
NHS	  Litigation	  Authority	  for	  NHS	  Trusts	  in	  England,	  which	  apply	  to	  this	  study.	  
11.6	  SPONSOR	  
Imperial	  College	  Healthcare	  NHS	  Trust	  will	  act	  as	  the	  main	  Sponsor	  for	  this	  study.	  Delegated	  responsibilities	  
will	  be	  assigned	  to	  the	  NHS	  trusts	  taking	  part	  in	  this	  study.	  
	  
	  
	  

	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  SNIFFLE-­‐4	  Study	  Protocol	  	  
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11.7	  FUNDING	  
Funding	  has	  been	  secured	  from	  the	  Department	  of	  Health	  Policy	  Research	  Programme	  (NVEC039/0031)	  
awarded	  to	  Prof	  Elizabeth	  Miller,	  Public	  Health	  England.	  
11.8	  AUDITS	  
The	  study	  may	  be	  subject	  to	  inspection	  and	  audit	  by	  Imperial	  College	  Healthcare	  NHS	  Trust	  under	  their	  
remit	   as	   sponsor	   and	   other	   regulatory	   bodies	   to	   ensure	   adherence	   to	   GCP	   and	   the	   NHS	   Research	  
Governance	  Framework	  for	  Health	  and	  Social	  Care	  (2nd	  edition).	  
11.9	  MONITORING	  
The	   JRCO	   Clinical	   Trial	   Monitor	   will	   be	   responsible	   for	   monitoring	   this	   study	   throughout	   its	   duration,	  
including	  site	  initiation	  visit	  and	  close	  out	  visit.	  The	  monitor	  will	  conduct	  a	  risk	  assessment	  and	  compile	  a	  
monitoring	   plan	   accordingly.	   After	   each	   monitoring	   visit	   the	   monitoring	   report	   will	   be	   sent	   to	   the	   chief	  
investigator	  and	  any	  action	  point	  that	  needs	  to	  be	  completed	  will	  be	  done	  so	  by	  the	  study	  team.	  
	  
12	  STUDY	  MANAGEMENT	  
The	  day-­‐to-­‐day	  management	  of	  the	  study	  will	  be	  co-­‐ordinated	  through	  Dr	  Paul	  Turner	  (CI).	  	  
	  
13	  PUBLICATION	  POLICY	  	  
All	  publications	  and	  presentations	  relating	  to	  the	  study	  will	  be	  authorised	  by	  the	  Trial	  Steering	  Committee	  
and	   the	   Department	   of	   Health.	   If	   there	   are	   named	   authors,	   these	   will	   include	   at	   least	   the	   trial’s	   Chief	  
Investigator,	  Statistician	  and	  Trial	  Coordinator.	  Where	  the	  journal’s	  policy	  allows,	  all	  site	  PIs	  will	  be	  listed	  as	  
collaborators	  for	  any	  publications	  generated	  from	  the	  study.	  
Members	   of	   the	   Data	   Monitoring	   Committee	   will	   be	   listed	   and	   contributors	   will	   be	   cited	   by	   name	   if	  
published	  in	  a	  journal	  where	  this	  does	  not	  conflict	  with	  the	  journal’s	  policy.	  	  
	  
	  

	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  SNIFFLE-­‐4	  Study	  Protocol	  	  
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APPENDIX	  1:	  TRACK	  QUESTIONNAIRE	  
	  
	  
	  
TRACK
™Test for Respiratory
and Asthma Control in Kids 
Who should use TRACK?
This simple test can help determine if your child’s breathing problems are not under control. 
The test was designed for children who
• Are under 5 years of age AND
• Have a history of 2 or more episodes of wheezing, shortness of breath, or cough lasting
   more than 24 hours AND
• Have been previously prescribed bronchodilator medicines, also known as quick-relief medications 
   (eg, albuterol, Ventolin®, Proventil®, Maxair®, ProAir®, or Xopenex®), for respiratory problems 
   OR have been diagnosed with asthma
How to take TRACK
Step 1: Make a check mark in the box below each of your selected answers.
Step 2: Write the number of your answer in the score box provided to the right of each question.
Step 3: Add up the numbers in the individual score boxes to obtain your child’s total score.
Step 4: Take the test to your child’s health care provider to talk about your child’s total TRACK score.
For kids 
under
5 years 
of age
During the past 4 weeks, how often was your child bothered by breathing problems, such as 
wheezing, coughing, or shortness of breath?
During the past 4 weeks, how often did your child’s breathing problems (wheezing, coughing, 
shortness of breath) wake him or her up at night? 
During the past 4 weeks, to what extent did your child’s breathing problems, such as wheezing, 
coughing, or shortness of breath, interfere with his or her ability to play, go to school, or engage 
in usual activities that a child should be doing at his or her age?
During the past 3 months, how often did you need to treat your child’s breathing problems 
(wheezing, coughing, shortness of breath) with quick-relief medications (albuterol, Ventolin®, 
Proventil®, Maxair®, ProAir®, Xopenex®, or Primatene® Mist)?
Not at all                       Once or twice                  Once every week          2 or 3 times a week         4 or more times a week
Not at all                       Once or twice                  Once every week          2 or 3 times a week         4 or more times a week
Not at all                       Once or twice                  Once every week          2 or 3 times a week         4 or more times a week
Not at all                            Slightly                          Moderately                       Quite a lot                         Extremely
Score
Total
1
2
3
4
20
20
20
20
15
15
15
15
10
10
10
10
5
5
5
5
0
0
During the past 12 months, how often did your child need to take oral corticosteroids 
(prednisone, prednisolone, Orapred®, Prelone®, or Decadron®) for breathing problems 
not controlled by other medications?
5
  Never                                Once                                Twice                            3 times                       4 or more times
20
15
10
5
0
0
0
Please see reverse side for an explanation of what your child’s total TRACK score means.
The brands mentioned herein are trademarks of their respective owners and are not trademarks of the AstraZeneca group 
of companies. The makers of these brands are not afﬁ liated with and do not endorse AstraZeneca or its products.

	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  SNIFFLE-­‐4	  Study	  Protocol	  	  
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APPENDIX	  2A:	  ASTHMA	  CONTROL	  TEST	  –	  FOR	  CHILDREN	  AGE	  5-­‐11	  YEARS	  
CHILDHOOD	  ASTHMA	  CONTROL	  TEST	  
For	  children	  age	  5-­‐12	  years	  of	  age	  
How	  to	  take	  the	  Childhood	  Asthma	  Control	  Test:	  
1. Let	  your	  child	  respond	  to	  the	  first	  four	  questions	  (1	  to	  4),	  by	  CIRCLING	  THEIR	  ANSWER.	  If	  your	  child	  
needs	  help	  reading	  or	  understanding	  the	  question,	  you	  may	  help,	  but	  let	  your	  child	  select	  the	  
response.	  	  
	  
2. Complete	  the	  remaining	  three	  questions	  (5	  to	  7)	  on	  your	  own	  by	  CIRCLING	  YOUR	  ANSWER.	  Try	  not	  to	  
let	  your	  child’s	  responses	  influence	  your	  answers.	  There	  are	  no	  right	  or	  wrong	  answers.	  
	  
	  
	  

	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  SNIFFLE-­‐4	  Study	  Protocol	  	  
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APPENDIX	  2B:	  ASTHMA	  CONTROL	  TEST	  –	  YOUNG	  PEOPLE	  AGE	  12+	  YEARS	  
ASTHMA	  CONTROL	  TEST	  
For	  young	  people	  over	  12	  years	  of	  age	  
	  
	  
	  
Why take the Asthma Control Test™?
The Asthma Control Test™will provide you with a snapshot of how well your asthma has been controlled over the last four
weeks, giving you a simple score out of 25. Asthma symptoms can vary from month to month, so it is worth keeping the test
handy to see if your score changes. You can also share your results with your doctor or asthma nurse to help explain just how
your asthma affects you.
Are you in control of your asthma? Or is your asthma in control of you? Here’s how to find out
Step 1: Read each question below carefully, circle your score and write it in the box.
Step 2: Add up each of your five scores to get your total Asthma Control Test™score.
Step 3: Use the score guide to learn how well you are controlling your asthma.
What does your score mean?
Q1
Score:
During the past 4 weeks, how often did your asthma prevent you from getting as much done at
work, school or home?
Most of the time 
2
Some of the time 
3
A little of the time
4
None of the time 
5
All of the time
1
During the past 4 weeks, how often have you had shortness of breath?
1
2
3
More than once 
a day
Once a day
3-6 times a week
1-2 times a week
4
Not at all
5
2
3
2-3 nights a week 
Once a week 
Once or twice 
4
Not at all
5
1
2
3
3 or more times 
a day
1-2 times a day
2-3 times a week
Once a week or less
4
Not at all
5
During the past 4 weeks, how often have you used your reliever inhaler (usually blue)?
1
2
3
Poorly controlled
Somewhat controlled
Well controlled
4
Completely controlled 5
How would you rate your asthma control during the past 4 weeks?
Score: 25 – WELL DONE
• Your asthma appears to have been
UNDER CONTROL over the last 
4 weeks. 
• However, if you are experiencing 
any problems with your asthma, 
you should see your doctor or nurse.
Score: less than 20– OFF TARGET
• Your asthma may NOT HAVE BEEN 
CONTROLLED during the past 4 weeks.
• Your doctor or nurse can recommend 
an asthma action plan to help 
improve your asthma control.
Score: 20 to 24 – ON TARGET
• Your asthma appears to have been 
REASONABLY WELL CONTROLLED 
during the past 4 weeks. 
• However, if you are experiencing 
symptoms your doctor or nurse may 
be able to help you.
Not controlled
1
4 or more times 
a week
During the past 4 weeks, how often did your asthma symptoms (wheezing, coughing, chest
tightness, shortness of breath) wake you up at night or earlier than usual in the morning?
Total Score
Q2
Q3
Q4
Q5
Score:
Score:
Score:
Score:

	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  SNIFFLE-­‐4	  Study	  Protocol	  	  
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APPENDIX	  3:	  ASTHMA	  CONTROL	  QUESTIONNAIRE	  
	  
	  
	  
	  
	  
	  

	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  SNIFFLE-­‐4	  Study	  Protocol	  	  
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APPENDIX	  4:	  BRIGHTON	  COLLABORATION	  CASE	  DEFINITION	  OF	  ANAPHYLAXIS	  
Anaphylaxis	  is	  a	  clinical	  syndrome	  characterized	  by:	  
• 
sudden	  onset	  	  
	  
	  
	  
	  
	  
AND	  
• 
rapid	  progression	  of	  signs	  and	  symptoms	  	  
	  
	  
AND	  
• 
involving	  multiple	  (≥2)	  organ	  systems,	  as	  follows:	  
Level	  1	  of	  diagnostic	  certainty	  	  
• 
≥1	  major	  cardiovascular	  AND/OR	  ≥1	  major	  respiratory	  criterion	  	  AND	  
• 
≥1	  major	  dermatological	  criterion	  
Level	  2	  of	  diagnostic	  certainty	  	  
• 
≥1	  major	  cardiovascular	  AND	  ≥1	  major	  respiratory	  criterion	  OR	  	  
• 
≥1	  major	  cardiovascular	  OR	  respiratory	  criterion	  AND	  	  
• 
≥1	  minor	  criterion	  involving	  ≥1	  different	  system	  (other	  than	  cardiovascular	  or	  respiratory	  systems)	  
OR	  	  
• 
(≥1	  major	  dermatologic)	  AND	  (≥1	  minor	  cardiovascular	  AND/OR	  minor	  respiratory	  criterion)	  	  
Level	  3	  of	  diagnostic	  certainty	  	  
• 
≥1	  minor	  cardiovascular	  OR	  respiratory	  criterion	  AND	  	  
• 
≥1	  minor	  criterion	  from	  each	  of	  ≥2	  different	  systems/categories	  	  
Note	  that	  all	  levels	  of	  diagnostic	  certainty	  require	  the	  involvement	  the	  cardiovascular	  and/or	  respiratory	  
systems.	  
Organ	  System	  
Major	  Criteria	  
Minor	  Criteria	  
Skin	  or	  mucosal	  
• generalized	  urticaria	  (hives)	  or	  erythema	  
• angioedema,	  localized	  or	  generalized	  
• generalized	  pruritus	  with	  skin	  rash	  
• generalized	  pruritus	  without	  skin	  rash	  
• generalized	  prickle	  sensation	  
• localized	  injection	  site	  urticaria	  
• red	  and	  itchy	  eyes	  
Cardiovascular	  
• measured	  hypotension	  OR	  
• shock	  (at	  least	  3	  of	  the	  following):	  
! tachycardia	  
! capillary	  refill	  time	  (CRT)	  >3	  sec	  
! reduced	  central	  pulse	  volume	  
! decreased	  level	  or	  loss	  of	  consciousness	  
• Reduced	  peripheral	  circulation	  (at	  least	  2	  
of:	  
• Tachycardia	  
• CRT	  >3	  sec	  without	  hypotension	  
• Decreased	  level	  of	  consciousness	  
Respiratory	  
• Bilateral	  wheeze	  (bronchospasm)	  
• Stridor	  
• Swelling	  of	  upper	  airways	  
• Respiratory	  distress	  (at	  least	  2	  of	  
tachypnoea;	  use	  of	  accessory	  respiratory	  
muscles;	  recession;	  cyanosis;	  grunting)	  
• Persistent	  dry	  cough	  
• Hoarse	  voice	  
• Difficulty	  breathing	  without	  wheeze	  or	  
stridor	  
• Sensation	  of	  throat	  closure	  
	  
Gastrointestinal	  
	  
• Diarrhoea	  
• Abdominal	  pain	  
• Nausea	  
• Vomiting	  
Laboratory	  
	  
Mast	  cell	  tryptase	  >	  upper	  normal	  limit	  
NB:	  For	  the	  purposes	  of	  this	  study,	  local	  rhinitis	  and	  oropharyngeal	  symptoms	  will	  be	  classed	  as	  LOCAL	  
symptoms	  and	  not	  indicative	  of	  a	  systemic	  allergy	  response.	  
	  
	  

	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  SNIFFLE-­‐4	  Study	  Protocol	  	  
Confidential	  
	  
SNIFFLE-­‐4	  Protocol	  	  Version	  2.2,	  5	  September	  2016	  	  
	  
Page	  47	  of	  48	  
	  
APPENDIX	  5:	  TOPIC	  GUIDE	  FOR	  72HR	  TELEPHONE	  FOLLOW-­‐UP	  
Participants’	  families	  will	  be	  contacted	  by	  the	  local	  research	  team	  at	  least	  72	  hours	  after	  LAIV	  
administration	  (and	  within	  7	  days,	  to	  allow	  for	  weekends),	  to	  determine	  whether	  their	  child	  has	  experienced	  
any	  delayed	  symptoms	  which	  might	  be	  attributable	  to	  the	  vaccine.	  This	  telephone	  consultation	  will	  take	  
approximately	  2-­‐3	  minutes.	  If	  after	  three	  attempts	  (on	  three	  separate	  days)	  the	  local	  study	  team	  is	  unable	  
to	  contact	  the	  family,	  the	  child	  will	  be	  deemed	  lost	  to	  follow	  up.	  
	  
Guide	  to	  telephone	  interview:	  
	  
1. Confirm	  interviewee’s	  identity	  
	  
2. Introduce	  yourself:	  
“I	  am	  <name>,	  from	  the	  SNIFFLE-­‐4	  Study.	  We	  arranged	  to	  speak	  briefly	  today	  to	  find	  how	  <participant’s	  
name>	  is	  going	  after	  his/her	  ‘flu	  vaccine	  on	  <date>”	  
	  
3. “Have	  you	  noticed	  any	  health	  problems	  since	  the	  vaccine?”	  
	  
4. For	  each	  symptom	  reported:	  	  
• 
When	  did	  this	  start?	  
• 
How	  long	  did	  this	  last?	  
• 
Did	  you	  do	  anything	  as	  a	  result?	  
	  
5. “Since	  the	  vaccine,	  	  
	  
i. Have	  you	  needed	  to	  give	  your	  child	  more	  reliever	  medicine	  (e.g.	  ventolin)	  than	  normal?	  
	  
ii. Have	  you	  had	  to	  take	  <participant’s	  name>	  to	  see	  a	  Doctor	  because	  of	  his/her	  breathing?	  
iii. (If	  YES)	  –	  did	  you	  have	  to	  take	  them	  to	  hospital?	  
iv. (If	  YES)	  –	  did	  <participant’s	  name>	  have	  to	  stay	  in	  hospital	  overnight?	  
	  
v. Did	  <participant’s	  name>	  have	  to	  start	  any	  medicines,	  like	  an	  oral	  steroid?	  If	  so,	  for	  how	  long?	  
	  
FINALLY:	  Remind	  family	  to	  take	  nasal	  swab	  at	  72	  hours	  and	  6	  days	  after	  LAIV.	  
	  
	  

	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  SNIFFLE-­‐4	  Study	  Protocol	  	  
Confidential	  
	  
SNIFFLE-­‐4	  Protocol	  	  Version	  2.2,	  5	  September	  2016	  	  
	  
Page	  48	  of	  48	  
	  
APPENDIX	  6:	  TOPIC	  GUIDE	  FOR	  TELEPHONE	  FOLLOW-­‐UP	  AT	  4	  WEEKS	  
**	  For	  patients	  with	  asthma/recurrent	  wheeze	  only	  **	  
Participants’	  families	  will	  be	  contacted	  by	  the	  local	  research	  team	  4	  weeks	  after	  LAIV	  administration,	  to	  
determine	  whether	  their	  child	  has	  experienced	  any	  change	  in	  their	  lower	  respiratory	  symptoms	  which	  might	  
be	  attributable	  to	  the	  vaccine.	  This	  telephone	  consultation	  will	  take	  approximately	  2-­‐3	  minutes.	  If	  after	  
three	  attempts	  (on	  three	  separate	  days)	  the	  local	  study	  team	  is	  unable	  to	  contact	  the	  family,	  the	  child	  will	  
be	  deemed	  lost	  to	  follow	  up.	  
	  
Guide	  to	  telephone	  interview:	  
1.	  
Confirm	  interviewee’s	  identity	  
2.	  
Introduce	  yourself:	  
“I	  am	  <name>	  from	  the	  SNIFFLE-­‐4	  Study.	  Your	  child	  <participant’s	  name>	  had	  the	  ‘flu	  vaccine	  with	  
us	  one	  month	  ago,	  and	  we	  arranged	  to	  speak	  to	  find	  out	  if	  you	  had	  needed	  to	  do	  anything	  different	  
with	  his	  asthma/wheezing”	  
3.	  
Complete	  appropriate	  TRACK	  /	  C-­‐ACT	  /	  ACT	  Questionnaire	  over	  the	  telephone	  	  
(see	  separate	  questionnaires)	  
4.	  
Finally,	  ask	  the	  following	  questions:	  
Since	  the	  vaccine,	  	  
i) 
Have	  you	  had	  to	  take	  <participant’s	  name>	  to	  see	  a	  Doctor	  because	  of	  his/her	  breathing?	  
ii) (If	  YES)	  –	  did	  you	  have	  to	  take	  them	  to	  hospital?	  
iii) (If	  YES)	  –	  did	  <participant’s	  name>	  have	  to	  stay	  in	  hospital	  overnight?	  
iv) Did	  <participant’s	  name>	  have	  to	  start	  any	  medicines,	  like	  an	  oral	  steroid?	  If	  so,	  for	  how	  long?