Conditions: Influenza
Keywords: Influenza Antiviral treatment Emergency department Influenza therapeutics Rapid influenza testing
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 180
Healthy volunteers: no

Brief summary:
This pilot study is designed to demonstrate the feasibility of utilizing Emergency Departments (EDs) as a primary site for subject enrollment in clinical trials evaluating influenza therapeutics, and to provide pilot data for future clinical trial design and planning.

Primary Objective: To prospectively enroll high-risk subjects with laboratory-confirmed influenza into a randomized, open label study of oral versus IV influenza therapeutic to include symptom evaluation and outcome assessments.

Secondary Objective 1: To identify influenza positive patients utilizing a previously established triage-based assessment and rapid testing algorithm for suspected influenza infection.

Secondary Objective 2: To retrospectively evaluate all potentially eligible patients for potential enrollment biases.

Secondary Objective 3: To create a repository of residual nasopharyngeal samples collected from ED patients with suspected influenza illness.

Detailed description:
Title: A Pilot Randomized Controlled Trial for Feasibility of Enrolling Subjects for Influenza Therapeutic Trials and Administering Influenza Antivirals in the Emergency Department to High Risk Subjects

Population: Adults presenting to the emergency department (ED) with laboratory confirmed influenza who meet Centers for Disease Control and Prevention (CDC) criteria for antiviral treatment

Informed consent: Written informed consent

Number of Sites: 2 - large, urban, academically-affiliated, US EDs

Study Duration: November 2015 - June 2018

Subject Participation Duration: 4 weeks

Description of Agent or Intervention: Subjects will be randomized to either oral (oseltamivir) or intravenous (IV) (peramivir) antiviral treatment.

Description of Study Design: This is an open-label randomized controlled clinical trial in which subjects with influenza are randomized to either oral (oseltamivir) or IV (peramivir) antiviral treatment.

Estimated Time to Complete Enrollment: Subject enrollment will occur over two influenza seasons (November 2015 - April 2016 and November 2016 - April 2017) or longer, at the Principal Investigator's discretion, based on influenza prevalence.

Arms:
arm 1: Subjects randomized to the oral treatment arm will receive 5 days of oral oseltamivir. arm 2: Subjects randomized to the IV treatment group will receive 1 dose of IV peramivir.

Interventions: intervention 1: Oseltamivir intervention 2: Peramivir
Intervention descriptions: intervention 1: Oral intervention 2: IV

Note: Subjects admitted to the hospital directly from the ED Enrollment Visit may receive more doses at the discretion of the treating physician.

Protocol document:
Prot_SAP_ICF_003.pdf: 
Title of study: ED Influenza Therapeutic Pilot Study: Oseltamivir vs. Peramivir 
NCT number: 02609399 
PI name: Richard Rothman, MD, PhD 
Date of protocol: 09/26/16 


Seasons 3 & 4 Protocol 
 
Version: 2.0 
Influenza Therapeutic Pilot 
 
9/26/2016 
1 
 
 
      
 
Influenza Therapeutic Pilot Study 
A Pilot Randomized Controlled Trial for Feasibility of Enrolling Subjects for Influenza 
Therapeutic Trials and Administering Influenza Antivirals in the Emergency Department  
to High Risk Subjects 
 
Protocol Number: 15-001 
Version: 2.0 
 
 
Pharmaceutical Support Provided by: BioCryst Pharmaceuticals, Inc. 
IND Sponsor: Andrea Dugas, MD, PhD 
Lead Co-Principal Investigators: Andrea Dugas, MD, PhD & Richard E. Rothman, 
MD, PhD 
IND #: 127482 
           
09/26/2016 
 
 
 
 


Influenza Therapeutic Pilot Study 
Statistical Analysis Plan 
 
Version 2.0 
 
 
 
IND Sponsor:                                           Richard E. Rothman, MD, PHD 
Study Principle Investigator:    
Richard E. Rothman, MD, PHD 
Study Co-Investigators:     
Andrea Dugas, MD, PHD  
                                                                      and Mustapha Saheed, MD 
 
 
Prepared by: 
 
Qilu Yu, PHD 
 
Westat 
1600 Research Boulevard 
Rockville, MD 20850 
 
5/18/2017 
 
 
 
 
 
 


D o  n ot  us e t his f or m f or  c o ns e nti n g r es e ar c h  
p arti ci p a nts  u nl ess t h e J o h ns  H o p ki ns  M e di ci n e  
L o g o  a p p e ar s  h er e.  
D at e:  S e pt e m b er  2 6,  2 0 1 6  
Pri n ci p al I n v esti g at or:  A n dr e a  D u g as,  M D,  P h D  
A p pli c ati o n  N o.:  I R B 0 0 0 8 0 4 0 5 
 
1  
P a g e  1  of  1 4  
C o m bi n e d I nf or m e d  C o ns e nt/ A ut h ori z ati o n  S e pt e m b er  2 6,  2 0 1 6  
R E S E A R C H  P A R TI CI P A N T I N F O R M E D  C O N S E N T  A N D  P RI V A C Y  A U T H O RI Z A TI O N 
F O R M  
 
Pr ot o c ol  Titl e:   
A  Pil ot  R a n d o mi z e d  C o ntr oll e d  Tri al f or  F e a si bilit y  of 
E nr olli n g  S u bj e ct s f or I nfl u e n z a  T h er a p e uti c  Tri al s  a n d 
A d mi ni st eri n g I nfl u e n z a  A nti vir al s i n t h e  E m er g e n c y 
D e p art m e nt t o  Hi g h  Ri s k  S u bj e ct s  
 
A p pli c ati o n  N o.:      
I R B 0 0 0 8 0 4 0 5 
 
I N D S p o n s or:  
A n dr e a  D u g a s,  M D,  P h D   
 
Pri n ci p al I n v e sti g at or:  
A n dr e a  D u g as,  M D,  P h D  
D e p art m e nt  of  E m er g e n c y  M e di ci n e  
J o h ns  H o p ki ns  M e di c al I nstit uti o ns  
5 8 0 1  S mit h  A v e n u e     
   
  
D a vis  B uil di n g,  S uit e  3 2 2 0  
B alti m or e,  M D  2 1 2 0 9  
P h o n e:     
   
  
4 1 0 -7 3 5 -6 4 0 0  
F a x:        
   
  
4 1 0 -7 3 5 -6 4 2 5  
E m ail:     
   
  
a d u g as 1 @j h mi. e d u    
  
 
 
 


D o  n ot  us e t his f or m f or  c o ns e nti n g r es e ar c h  
p arti ci p a nts  u nl ess t h e J o h ns  H o p ki ns  M e di ci n e  
L o g o  a p p e ar s  h er e.  
D at e:  S e pt e m b er  2 6,  2 0 1 6  
Pri n ci p al I n v esti g at or:  A n dr e a  D u g as,  M D,  P h D  
A p pli c ati o n  N o.:  I R B 0 0 0 8 0 4 0 5 
 
2  
P a g e  2  of  1 4  
C o m bi n e d I nf or m e d  C o ns e nt/ A ut h ori z ati o n  S e pt e m b er  2 6,  2 0 1 6  
1.   
W h at  y o u  s h o ul d  k n o w  a b o ut t hi s  st u d y:  
•  
Y o u   ar e   b ei n g   a s k e d  t o  j oi n   a  r e s e ar c h   st u d y.   T hi s   c o n s e nt  f or m   e x pl ai n s  t h e  
r e s e ar c h  st u d y  a n d  y o ur  p art i n it.  Pl e a s e r e a d it  c ar ef ull y  a n d t a k e  a s  m u c h ti m e  a s 
y o u   n e e d.   A s k   y o ur   st u d y   d o ct or   or  t h e   st u d y  t e a m  t o   e x pl ai n   a n y   w or d s   or  
i nf or m ati o n t h at  y o u  d o  n ot  u n d er st a n d. 
•  
Y o u  ar e  a  v ol u nt e er. If  y o u j oi n t h e  st u d y,  y o u  c a n  c h a n g e  y o ur  mi n d l at er.  T h er e  will 
b e  n o  p e n alt y  or l o s s  of  b e n efit s if  y o u  d e ci d e t o  q uit t h e  st u d y.   
•  
D uri n g  t h e   st u d y,   w e   will  t ell   y o u  if   w e  l e ar n   a n y   n e w i nf or m ati o n  t h at   mi g ht   aff e ct 
w h et h er  y o u  wi s h t o  c o nti n u e t o  p a rti ci p at e. 
•  
If  w e t hi n k  y o ur  p arti ci p ati o n i n t hi s  st u d y  m a y  aff e ct  y o ur  cli ni c al  c ar e, i nf or m ati o n 
a b o ut  y o ur  st u d y  p arti ci p ati o n  will  b e i n cl u d e d i n  y o ur  m e di c al r e c or d,  w hi c h i s  u s e d 
t hr o u g h o ut J o h ns  H o p ki ns.   D o ct or s  o ut si d e  of J o h ns  H o p ki ns m a y  n ot  h a v e  a c c e s s 
t o t hi s i nf or m ati o n.  Y o u  c a n  a s k t h e r e s e ar c h t e a m t o  s e n d t hi s i nf or m ati o n t o  a n y  of 
y o ur  d o ct or s.  
•  
W h e n J o h ns  H o p ki ns  i s   u s e d  i n  t hi s   c o n s e nt  f or m,  it  i n cl u d e s  T h e J o h ns   H o p ki ns 
U ni v ersit y,   T h e  J o h ns   H o p ki ns   H os pit al,  J o h ns   H o p ki ns   B a y vi e w   M e di c al   C e nt er,  
H o w ar d  C o u nt y  G e n er al  H os pit al, J o h ns  H o p ki ns  C o m m u nit y  P h ysi ci a ns,  S u b ur b a n 
H os pit al,  Si bl e y  M e m ori al  H os pit al  a n d  All  C hil dr e n’s  H os pit al.   
•  
Bi o s p e ci m e n s   will   b e   c oll e ct e d  i n  t hi s   st u d y.   Bi o s p e ci m e n s   m a y i n cl u d e   a n y   of  t h e 
f oll o wi n g:   bl o o d,  ti ss u e,   s ali v a,   uri n e,   b o n e   m arr o w,   c ell s,   et c.   M o st   bi o s p e ci m e n s  
c o nt ai n  D N A,  w hi c h i s t h e  g e n eti c  c o d e f or  e a c h  p er s o n.  
•  
A  d e s cri pti o n  of t hi s  cli ni c al tri al  will  b e  a v ail a bl e  o n  htt p:// w w w. Cli ni c al Tri al s. g o v,  a s 
r e q uir e d  b y U S  L a w.  T hi s  W e b  sit e  will  n ot i n cl u d e i nf or m ati o n t h at  c a n i d e ntif y  y o u. 
At  m o st, t h e  W e b  sit e  will i n cl u d e  a  s u m m ar y  of t h e r e s ult s.  Y o u  c a n  s e ar c h t hi s  W e b 
sit e  at  a n y ti m e.   
•  
If  y o u  w o ul d li k e t o r e vi e w t h e i nf or m ati o n f or t hi s  st u d y,  or  a  s u m m ar y  of t h e r e s ult s, 
a s k t h e  st u d y t e a m  d o ct or f or t h e  Cli ni c al Tri al s. g o v  st u d y r e gi str ati o n  n u m b er.  
2.     
Wh y i s t hi s r e s e ar c h  b ei n g  d o n e ?  
T hi s  r e s e ar c h  i s   b ei n g   d o n e  t o   e st a bli s h  t h e   u s e   of  t h e   e m er g e n c y   d e p art m e nt   a s   a  
pri m ar y  sit e f or  p arti ci p a nt  e nr oll m e nt i n r e s e ar c h  st u di e s t h at l o o k  at  dr u g s  u s e d  t o tr e at 
i nfl u e n z a  (“t h e  fl u”).   T hi s   will   h el p   u s   u n d er st a n d  t h e   b e st   w a y  t o   d e si g n   a n d   pl a n  
r e s e ar c h  st u di e s t h at  will  u s e  st u d y  dr u g s t o tr e at  p ati e nt s  w h o  ar e  si c k  wit h t h e fl u.  
W e  will  b e  gi vi n g  o n e  of t w o  dr u g s  u s e d t o tr e at t h e fl u t o  e a c h  st u d y  p a rti ci p a nt,  eit h er 
o s elt a mi vir  or  p er a mi vir . B ot h  o s elt a mi vir  a n d  p er a mi vir  ar e  a p pr o v e d  b y t h e  F o o d  a n d 


D o  n ot  us e t his f or m f or  c o ns e nti n g r es e ar c h  
p arti ci p a nts  u nl ess t h e J o h ns  H o p ki ns  M e di ci n e  
L o g o  a p p e ar s  h er e.  
D at e:  S e pt e m b er  2 6,  2 0 1 6  
Pri n ci p al I n v esti g at or:  A n dr e a  D u g as,  M D,  P h D  
A p pli c ati o n  N o.:  I R B 0 0 0 8 0 4 0 5 
 
3  
P a g e  3  of  1 4  
C o m bi n e d I nf or m e d  C o ns e nt/ A ut h ori z ati o n  S e pt e m b er  2 6,  2 0 1 6  
Dr u g   A d mi ni str ati o n  ( F D A)   t o  tr e at  t h e  fl u  b ut  t h e   u s e   of   o s elt a mi vir   a n d   p er a mi vir  i n  
si c k er  i n di vi d u al s i s  n ot  a p pr o v e d  a n d i s  c o n si d er e d i n v e sti g ati o n al.  T h e  F D A i s  all o wi n g 
o s elt a mi vir  a n d  p er a mi vir t o  b e  u s e d i n t hi s  st u d y .  
P e o pl e  wit h  a  p o siti v e  fl u t e st fr o m t h eir  c urr e nt  e m er g e n c y  d e p art m e nt  vi sit  m a y j oi n. 
H o w  m a n y  p e o pl e  will  b e i n t hi s  st u d y ?  
U p t o  2 2 5  a d ult s  will  b e i n t hi s  st u d y.   
3.   
W h at  will  h a p p e n if  y o u j oi n t hi s  st u d y ?  
If  y o u  a gr e e t o  b e i n t hi s  st u d y,  w e  will  a s k  y o u t o  d o t h e f oll o wi n g t hi n g s: 
O n t h e  D a y  of  E nr oll m e nt:  
S o m e   of  t h e s e  t e st s   a n d   pr o c e d ur e s   ar e  li k el y  t o   b e   p art   of  r e g ul ar   c ar e   a n d   m a y   b e  
d o n e  e v e n if it t ur n s  o ut t h at  y o u  d o  n ot t a k e  p art i n t h e r e s e ar c h  st u d y:  
•   A n s w er  q u e sti o n s  w hil e  y o u  ar e i n t h e  e m er g e n c y  d e p art m e nt  a b o ut  y o ur  c urr e nt 
s y m pt o m s,  a n y  m e di c ati o n s  y o u  m a y  b e t a ki n g,  a n d  y o ur  m e di c al  hi st or y.  W e  wi ll 
al s o  a s k f or  s o m e  b a si c i nf or m ati o n  a b o ut  y o u  s u c h  a s  y o ur  a g e,  s e x , r a c e,  a n d 
t el e p h o n e  n u m b er.  T hi s  will t a k e  a b o ut  1 0  mi n ut e s t o  c o m pl et e. W e  will  al s o  a s k 
y o u t o  si g n  a n  a ut h ori z ati o n f or r el e a s e  of  h e alt h i nf or m ati o n,  w hi c h  will  all o w  o ur 
r e s e ar c h st aff t o r e vi e w  y o ur  m e di c al r e c or d s  at  ot h er  h o s pit al s i n t h e f o ur  w e e k s 
aft er t o d a y’ s  vi sit t o t h e  e m er g e n c y  d e p art m e nt .  
•   H a v e  s o m e l a b or at or y t e st s, if t h e y  h a v e  n ot  b e e n  d o n e i n t h e l a st  2 4  h o ur s .  T hi s 
will t a k e  a b o ut  1  h o ur  t o  c o m pl et e: 
o   Bl o o d:  w e  will  c oll e ct  1 0  m L  or  1 t a bl e s p o o n  of  bl o o d fr o m  y o ur  v ei n . 
o   Pr e g n a n c y  t e st ( Bl o o d  or  Uri n e):  w e  will  c oll e ct  1 0  m L  or  1 t a bl e s p o o n of 
bl o o d  or  uri n e fr o m  w o m e n  of  c hil d b e ari n g  p ot e nti al.  If  y o u  ar e  pr e g n a nt 
y o u  will  n ot  b e  p er mitt e d t o  p arti ci p at e  i n t h e  st u d y.  
T h e r e s ult s  of  y o ur t e st s  will  b e  p art  of  y o ur  m e di c al r e c or d  a n d  pr o vi d e d t o  y o ur 
tr e ati n g  pr o vi d er.  
•   C h e st  x -r a y, if  o n e  w a s  n ot  d o n e  a s  p art  of  y o ur  m e di c al  c ar e i n t h e  e m er g e n c y 
d e p art m e nt.  
•   R e c ei v e  a  dr u g t o tr e at  y o ur fl u .  D e p e n di n g  o n  w hi c h  dr u g y o u  g et , t hi s m a y  t a k e 
u p t o  3 0  mi n ut e s.   
•   Y o u   will  b e  r a n d o ml y   a s si g n e d,   li k e  fli p pi n g   a   c oi n,  t o   o n e   of  t h e  t w o  fl u   dr u g s 
li st e d  b el o w:  
 


D o  n ot  us e t his f or m f or  c o ns e nti n g r es e ar c h  
p arti ci p a nts  u nl ess t h e J o h ns  H o p ki ns  M e di ci n e  
L o g o  a p p e ar s  h er e.  
D at e:  S e pt e m b er  2 6,  2 0 1 6  
Pri n ci p al I n v esti g at or:  A n dr e a  D u g as,  M D,  P h D  
A p pli c ati o n  N o.:  I R B 0 0 0 8 0 4 0 5 
 
4  
P a g e  4  of  1 4  
C o m bi n e d I nf or m e d  C o ns e nt/ A ut h ori z ati o n  S e pt e m b er  2 6,  2 0 1 6  
o   O n e  gr o u p  will  r e c ei v e o s elt a mi vir ( T a mifl u)  b y  m o ut h , w hi c h  will t a k e  n o 
m or e t h a n  5  mi n ut e s . 
o   T h e  s e c o n d  gr o u p  will  r e c ei v e  p er a mi vir ( R a pi v a b)  t hr o u g h   a n I V,  w hi c h 
will t a k e  a b o ut  3 0  mi n ut e s t o  c o m pl et e.  
•   Bi o s p e ci m e n  c oll e cti o n fr o m  y o ur fl u t e st.  A n y l eft o v er  s p e ci m e n fr o m t h e  s w a b 
t h at  w a s t a k e n f or  y o ur fl u t e st  will  b e  st or e d  a n d  m a y  b e  u s e d f or f ut ur e t e sti n g. 
F or  1- 2  w e e k s  aft er  e nr oll m e nt :  
•   C o m pl et e  a  d ail y  di ar y f or  1 4  d a y s.  Y o u  will  a n s w er  q u e sti o n s  a b o ut  h o w  y o u  ar e 
f e eli n g.  
o   Y o u   c a n   c o m pl et e  t h e s e   q u e sti o n s   o n   y o ur   o w n   o v er  t h e  i nt er n et   or   a  
r e s e ar c h   c o or di n at or   will   h el p   y o u  t o  c o m pl et e  t h e   q u e sti o n n air e .  If  y o u 
pr ef er  t o   h a v e   a  r e s e ar c h   c o or di n at or   h el p   y o u   c o m pl et e  t h e  
q u e sti o n n air e, t hi s  will  t a k e  pl a c e  o v er t h e  p h o n e or i f  y o u r e m ai n i n t h e 
h o s pit al, t hi s  m a y t a k e  pl a c e i n  p er s o n. It  will t a k e  a b o ut  1 0  mi n ut e s  e a c h 
d a y . 
•   C o nti n u e t o t a k e  a  dr u g t o tr e at  y o u r fl u, d e p e n di n g  o n  w hi c h  dr u g  y o u r e c ei v e . 
o   If  y o u  ar e t a ki n g  o s elt a mi vir,  y o u  will  b e  a s k e d t o t a k e t h e  dr u g  b y  m o ut h 
o n c e  or t wi c e  a  d a y f or  5  d a y s ( a t ot al  of  5 t o  1 0  d o s e s ).  T hi s  will t a k e l e s s 
t h a n  1  mi n ut e  e a c h  d a y. 
o   If   y o u   ar e  t a ki n g   p er a mi vir  y o u   will   o nl y  r e c ei v e   o n e   d o s e   of  t h e   st u d y  
dr u g   t hr o u g h   a n  I V.  If   y o u   ar e   h o s pit ali z e d   a n d   y o ur   d o ct or   wi s h e s  t o  
c o nti n u e t h e  p er a mi vir, t hi s  dr u g  will  b e  pr o vi d e d t o  y o u fr e e  of  c h ar g e .  
•   St u d y  C h e c k -I n o n  d a y  3  a n d  d a y  7  
o   T h e  st u d y t e a m  will  c all  y o u t o  s e e  h o w  y o u  ar e f e eli n g  a n d if  y o u  h a v e 
a n y   si d e   eff e ct s   fr o m  t h e   dr u g s.   W e   will   al s o   a s k   y o u   a b o ut   a n y   ot h er  
d o ct or   or   h o s pit al   vi sit s   y o u   h a v e   h a d   si n c e   y o u   st art e d  t h e   st u d y.   T hi s 
will t a k e  pl a c e  o v er t h e  p h o n e,  or if  y o u r e m ai n i n t h e  h o s pit al, t hi s  m a y 
t a k e   pl a c e  i n   p er s o n.   T hi s   will  t a k e   a b o ut   5   mi n ut e s   o n   e a c h   d a y.If   y o u  
ar e   a d mitt e d  t o  t h e   h o s pit al,   w e   will   c oll e ct   a   n a s o p h ar y n g e al   s w a b   o n  
t h e s e  d a y s.  We  will i n s ert  a  s w a b i nt o  y o ur  n o s e i n  or d er t o  c oll e ct  a  s m all 
s a m pl e  of  n a s al  s e cr eti o n s.  T hi s i s  a  bi o s p e ci m e n t h at  will  b e  s a v e d f or 
t e sti n g i n t h e f ut ur e t o l o o k  at t h e  a m o u nt  of fl u vir u s t h at  y o u  h a v e i n  y o ur 
b o d y.  
 
 


D o  n ot  us e t his f or m f or  c o ns e nti n g r es e ar c h  
p arti ci p a nts  u nl ess t h e J o h ns  H o p ki ns  M e di ci n e  
L o g o  a p p e ar s  h er e.  
D at e:  S e pt e m b er  2 6,  2 0 1 6  
Pri n ci p al I n v esti g at or:  A n dr e a  D u g as,  M D,  P h D  
A p pli c ati o n  N o.:  I R B 0 0 0 8 0 4 0 5 
 
5  
P a g e  5  of  1 4  
C o m bi n e d I nf or m e d  C o ns e nt/ A ut h ori z ati o n  S e pt e m b er  2 6,  2 0 1 6  
O n  D a y  2 8 ( 4  w e e k s)  aft er  e nr oll m e nt  
•   A n s w er  s o m e  q u e sti o n s  a b o ut  h o w  y o u  h a v e  b e e n f e eli n g  a n d  a b o ut  a n y  ot h er 
d o ct or  or  h o s pit al  vi sit s  y o u  h a v e  h a d i n t h e ti m e  si n c e  y o u  st art e d t h e  st u d y.  T hi s 
will  t a k e   pl a c e   o v er  t h e   p h o n e   or,  if   y o u  r e m ai n  i n  t h e   h o s pit al,  t hi s   m a y  t a k e  
pl a c e i n  p er s o n. It  will t a k e  a b o ut  1 0  mi n ut e s.   
Aft er t hi s, t h e  st u d y i s  c o m pl et e,  a n d  y o u  will  n ot  b e  c o nt a ct e d  a g ai n.   
Aft er   y o u   c o m pl et e  t h e   st u d y,   w e   will  r e vi e w   y o ur   m e di c al  r e c or d  t o   s e e  if   y o u   w er e  
tr e at e d  or  h o s pit ali z e d f or t h e fl u.  
I n ci d e nt al  Fi n di n g s 
If   a c h e st  x -r a y  i s  n ot  d o n e  a s  p art  of  y o ur r e g ul ar  m e di c al  c ar e, y o u  will  h a v e  o n e  a s 
p art  of t hi s r e s e ar c h  st u d y . It will  b e r e vi e w e d  b y  a  q u alifi e d  p er s o n j u st  a s it  w o ul d  b e if 
y o u  w er e  h a vi n g t h e  c h e st  x -r a y  a s  p art  of  y o ur r o uti n e  m e di c al  c ar e. 
T h er e i s  a  p o s si bilit y t h at  w hil e r e vi e wi n g  y o ur  c h e st  x -r a y  w e  m a y  s e e  a n  a b n or m alit y 
th at  w e  di d  n ot  e x p e ct t o  s e e i n t hi s  st u d y.  T hi s i s  w h at i s  c all e d  a n “i n ci d e nt al fi n di n g.”  
W e   will  l et   y o u   k n o w  if   w e   s e e   s u c h   a n  i n ci d e nt al  fi n di n g.   D e p e n di n g   o n  t h e  t y p e   of  
i n ci d e nt al fi n di n g,  w e   m a y  c o nt a ct   y o u   b y  m ail  or   b y  p h o n e.  I n t h e  c a s e   of   a   p ote nti al 
s eri o u s  e m er g e n c y,  s o m e o n e  m a y  g o t o  y o ur  h o m e.  
A  q u alifi e d  p er s o n ( u s u all y  a  m e m b er  of t h e r e s e ar c h t e a m)  will t al k t o  y o u if t h er e i s  a n 
i n ci d e nt al fi n di n g.  Y o u  d o  n ot  h a v e  a n  o pti o n t o  d e cli n e i nf or m ati o n  a b o ut  a n i n ci d e nt al 
fi n di n g. 
If  y o u  w a nt, w e  will  gi v e i nf or m ati o n  a b o ut t hi s i n ci d e nt al fi n di n g t o  y o ur  pri m ar y  d o ct or  or 
w e  will r ef er  y o u t o  a n  a p pr o pri at e  d o ct or f or f urt h er  e v al u ati o n.  
•   A n i n ci d e nt al fi n di n g  m a y  c a u s e  y o u t o f e el  a n xi o u s.   
•   Si n c e  a n i n ci d e nt al fi n di n g  will  b e  p art  of  y o ur  m e di c al r e c or d, it  m a y  aff e ct  y o ur 
c urr e nt  or f ut ur e lif e  or  h e alt h i n s ur a n c e  c o v er a g e.  T hi s ri s k  will  v ar y  d e p e n di n g 
o n t h e t y p e  of i n s ur a n c e  pl a n i n v ol v e d.   
T h e   c o st s  f or   a n y   c ar e  t h at   will   b e   n e e d e d  t o   di a g n o s e   or  tr e at   a n  i n ci d e nt al  fi n di n g  
w o ul d  n ot  b e  p ai d f or  b y t hi s r e s e ar c h  st u d y.  T h e s e  c o st s  w o ul d  b e  y o ur r e s p o n si bilit y.  
R e q u e st t o  c oll e ct  a n d  st or e  bi o s p e ci m e n s f or f ut ur e r e s e ar c h   
A s  p art  of t hi s r e s e ar c h  st u d y,  w e  w o ul d li k e t o  a s k  y o u t o l et  u s  st or e  y o ur  bi o s p e ci m e n s 
a n d  h e alt h i nf or m ati o n f or f ut ur e r e s e ar c h.  T hi s r e s e ar c h  c o ul d i n cl u d e  ot h er  di s e a s e s.  


D o  n ot  us e t his f or m f or  c o ns e nti n g r es e ar c h  
p arti ci p a nts  u nl ess t h e J o h ns  H o p ki ns  M e di ci n e  
L o g o  a p p e ar s  h er e.  
D at e:  S e pt e m b er  2 6,  2 0 1 6  
Pri n ci p al I n v esti g at or:  A n dr e a  D u g as,  M D,  P h D  
A p pli c ati o n  N o.:  I R B 0 0 0 8 0 4 0 5 
 
6  
P a g e  6  of  1 4  
C o m bi n e d I nf or m e d  C o ns e nt/ A ut h ori z ati o n  S e pt e m b er  2 6,  2 0 1 6  
T h e  st u d y  d o ct or  c a n  pr o vi d e  y o u  wit h  a d diti o n al i nf or m ati o n  if  y o u  h a v e  q u e sti o n s.  Al s o, 
furt h er  i nf or m ati o n   a b o ut   o ur   u s e   of   y o ur   bi o s p e ci m e n s   c a n   b e  f o u n d  i n  t hi s   c o n s e nt 
d o c u m e nt   u n d er  t h e   h e a di n g ,  W h at  H a p p e n s   t o   D at a   a n d   Bi o s p e ci m e n s  t h at   ar e  
C oll e ct e d  i n t h e S t u d y ? 
Will  y o u  all o w  u s t o  st or e t h e  bi o s p e ci m e n s  w e  c oll e ct f or t hi s  st u d y  f or  u s e i n f ut ur e 
r e s e ar c h?  Y o u  m a y  p arti ci p at e i n t hi s  st u d y  e v e n if  y o u  d o  n ot  all o w  u s t o  st or e  y o ur 
bi o s p e ci m e n s.  
Y E S      _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _        
   
   
 
Si g n at ur e  of  P arti ci p a nt    
   
   
   
   
 
N O        _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _       
 
Si g n a t ur e  of  P arti ci p a nt   
   
   
   
   
 
 
H o w l o n g  will  y o u  b e i n t h e  st u d y ?  
Y o u  will  b e i n t hi s  st u d y f or  2 8  d a y s ( 4  w e e k s  or  a b o ut  1  m o nt h) . 
4.   
W h at  ar e t h e ri s k s  or  di s c o mf ort s  of t h e  st u d y ?  
 
Q u e sti o n s   
T h e  q u e sti o n s t h at  y o u  will  b e  a s k e d t o  c o m pl et e  d uri n g t h e  st u d y  m a y  c o nt ai n  q u e sti o n s 
t h at  c o ul d  b e  e m b arr a s si n g   a n d/ or  m a k e  y o u f e el  u n c o mf ort a bl e.  Y o u  m a y  g et tir e d  or 
b or e d   w h e n   w e   ar e   a s ki n g   y o u   q u e sti o n s   or   w h e n  y o u   ar e   c o m pl eti n g   q u e sti o n n air e s.  
Y o u  d o  n ot  h a v e t o  a n s w er  a n y  q u e sti o n  y o u  d o  n ot  w a nt t o  a n s w er.   
  
Bl o o d  d r a w   
T o  dr a w  y o ur  bl o o d,  w e  will  pl a c e  a  s m all  n e e dl e i nt o  y o ur  v ei n  a n d  dr a w  1 t a bl e s p o o n  of 
bl o o d.  T hi s  c a n  b e  bri efl y  p ai nf ul,  a n d  c a n r e s ult i n  s o m e  br ui si n g  a n d/ or i nf e cti o n i n  t h at 
ar e a.   
 
T o  mi ni mi z e t h e s e ri s k s  a n d  di s c o mf ort s,  a tr ai n e d  p h y si ci a n,  n ur s e,  st u d y  c o or di n at or, 
or  d e si g n e e  will  c oll e ct t h e  s p e ci m e n s.  C ar e  will  b e t a k e n t o  o bt ai n t h e s e  s p e ci m e n s i n  a 
s af e  a n d  h y gi e ni c  m a n n er.  If  y o u  alr e a d y  h a v e  a n I V li n e  pl a c e d, w e  will  dr a w t h e  bl o o d 
fr o m t h e  e xi sti n g li n e if  p o s si bl e.  
  
Uri n e  c oll e cti o n   
If   y o u   ar e   a   w o m a n   of   c hil d b e ari n g   p ot e nti al   y o u   m a y  b e   a s k e d  t o   gi v e   u s   a   uri n e  
s p e ci m e n f or  a  pr e g n a n c y t e st, if  a  bl o o d  pr e g n a n c y  t e st i s  n ot  d o n e. T h er e  ar e  n o ri s k s 
or  di s c o mf ort s  a s s o ci at e d  wit h t hi s  pr o c e d ur e.   
 
 
 


D o  n ot  us e t his f or m f or  c o ns e nti n g r es e ar c h  
p arti ci p a nts  u nl ess t h e J o h ns  H o p ki ns  M e di ci n e  
L o g o  a p p e ar s  h er e.  
D at e:  S e pt e m b er  2 6,  2 0 1 6  
Pri n ci p al I n v esti g at or:  A n dr e a  D u g as,  M D,  P h D  
A p pli c ati o n  N o.:  I R B 0 0 0 8 0 4 0 5 
 
7  
P a g e  7  of  1 4  
C o m bi n e d I nf or m e d  C o ns e nt/ A ut h ori z ati o n  S e pt e m b er  2 6,  2 0 1 6  
N a s o p h ar y n g e al  s w a b  c oll e cti o n   
T h e  s m all  s w a b  pl a c e d i n  y o ur  n o stril if  y o u  ar e i n  t h e h o s pit al  o n  D a y  3  a n d/ or  D a y  7 , f or 
f ut ur e t e sti n g, m a y  c a u s e  bri ef  p ai n,  a n d  c a u s e  y o ur  n o s e t o it c h,  y o ur  e y e s t o  w at er  or 
y o u  m a y  s n e e z e.  
 
C h e st  x -ra y   
If  a  c h e st  x-r a y i s  n ot  d o n e  a s  p art  of  y o ur  m e di c al  c ar e,  w e  will  d o  o n e f or t hi s  st u d y , 
w hi c h  will  e x p o s e  y o u  t o r a di ati o n fr o m  x-r a y s  or  g a m m a r a y s. X- r a y s  a n d  g a m m a r a y s 
c a n  d a m a g e  c ell s,  b ut  at l o w  d o s e s, t h e  b o d y i s  u s u all y  a bl e t o r e p air t h e s e  c ell s.   
 
T h e r a di ati o n  e x p o s ur e t h at  y o u  will  g et i n t hi s r e s e ar c h  st u d y i s  0. 0 1 r e m ( a r e m i s  a  u nit 
of   a b s or b e d  r a di ati o n).   T hi s  i s  l e s s  t h a n  t h e   0. 3  r e m  t h at  t h e   a v er a g e   p er s o n  i n  t h e  
U nit e d  St at e s  g et s  e a c h  y e ar fr o m  n at ur al  s o ur c e s li k e t h e  s u n,  o ut er  s p a c e,  air, f o o d, 
a n d  s oil.  T h e ri s k fr o m t h e r a di ati o n  e x p o s ur e i n t hi s r e s e ar c h  st u d y i s  v er y  s m all.  
 
T h e r a di ati o n  e x p o s ur e  d e s cri b e d  h er e i s  w h at  y o u  will  g et fr o m t hi s r e s e ar c h  st u d y  o nl y. 
It   d o e s   n ot  i n cl u d e   a n y   e x p o s ur e   y o u   m a y   h a v e  r e c ei v e d   or   will  r e c ei v e  fr o m   ot h er  
m e di c al  t e st s   o ut si d e   of  t hi s   st u d y  t h at   ar e   a   p art   of   y o ur   m e di c al   c ar e.   R a di ati o n  ri s k  
b uil d s   u p   wit h   e a c h   e x p o s ur e.   Y o u   s h o ul d  t hi n k   a b o ut   y o ur   o w n   hi st or y   of  r a di ati o n  
e x p o s ur e  fr o m  t e st s  (li k e   x -r a y s   or   C T   s c a n s)  i n   d e ci di n g   a b o ut  t h e  r a di ati o n  i n  t hi s  
st u d y. If  y o u  h a v e  q u e sti o n s  a b o ut t h e t ot al  a m o u nt  of r a di ati o n  y o u  will  b e r e c ei vi n g,  y o u 
s h o ul d  a s k  y o ur  d o ct or.  
 
I nfl u e n z a d r u g s 
T hi s  i s   a  tr e at m e nt   st u d y.   O s elt a mi vir  ( T a mifl u)  i s  t h e   st a n d ar d   cli ni c al   c ar e  f or  t h e  
tr e at m e nt   of  i nfl u e n z a.  If   y o u  j oi n  t hi s   st u d y   y o u   m a y  r e c ei v e  t h at   dr u g   or   y o u   m a y  
r e c ei v e  a n ot h er  dr u g,  p er a mi vir ( R a pi v a b), w hi c h i s  al s o  u s e d t o tr e at f or i nfl u e n z a.  T h e 
c h a n c e  of r e c ei vi n g t h e  st a n d ar d  of  c ar e  dr u g if  y o u j oi n t h e  st u d y  will  b e  d et er mi n e d  b y 
a  pr o c e s s  c all e d r a n d o mi z ati o n,  w hi c h i s li k e  a  c oi n fli p.  
 
T h er e   ar e   s o m e   k n o w n   si d e   eff e ct s   of  t h e   st u d y   dr u g s,   o s elt a mi vir  ( T a mifl u)   a n d  
p er a mi vir ( R a pi v a b) t h at  s o m e  p e o pl e  h a v e  e x p eri e n c e d,  a n d t h er e  m a y  b e  si d e  eff e ct s 
a n d  di s c o mf ort s t h at  ar e  n ot  y et  k n o w n.  B el o w  ar e  k n o w n  p o s si bl e  si d e  eff e ct s.  
 
•   O s elt a mi vir  
If   y o u  r e c ei v e  t hi s   dr u g   y o u   m a y   e x p eri e n c e   n a u s e a,   v o miti n g,   br o n c hiti s, 
i n s o m ni a  or  v erti g o. 
 
It i s r ar e  b ut  s eri o u s if  y o u  e x p eri e n c e  s ki n/ h y p er s e n siti vit y r e a cti o n s ( a  s ki n r a s h) 
s u c h   a s   St e v e n s -J o h n s o n   S y n dr o m e,  t o xi c   e pi d er m al   n e cr ol y si s,   or   er yt h e m a  
m ultif or m e.   
 


D o  n ot  us e t his f or m f or  c o ns e nti n g r es e ar c h  
p arti ci p a nts  u nl ess t h e J o h ns  H o p ki ns  M e di ci n e  
L o g o  a p p e ar s  h er e.  
D at e:  S e pt e m b er  2 6,  2 0 1 6  
Pri n ci p al I n v esti g at or:  A n dr e a  D u g as,  M D,  P h D  
A p pli c ati o n  N o.:  I R B 0 0 0 8 0 4 0 5 
 
8  
P a g e  8  of  1 4  
C o m bi n e d I nf or m e d  C o ns e nt/ A ut h ori z ati o n  S e pt e m b er  2 6,  2 0 1 6  
It  i s   al s o  r ar e   b ut   s eri o u s  if   y o u   e x p eri e n c e   a n y   n e ur o p s y c hi atri c   e v e nt s  ( e. g.,  
c o n f u si o n  or  a b n or m al  b e h a vi or).  
 
•   P er a mi vir  
I n s erti n g   a n  i ntr a v e n o u s  (I V)   c at h et er  t o   gi v e   y o u   p er a mi vir   m a y   c a u s e   p ai n,  
br ui si n g,  s w elli n g  a n d  bl e e di n g  w h er e t h e  c at h et er i s  pl a c e d.  T h er e i s  al s o  a  ri s k 
of i nf e cti o n.   
 
If  y o u r e c ei v e t hi s  dr u g y o u  m a y  e x p eri e n c e  di arr h e a.  
 
It i s r ar e  b ut  s eri o u s if  y o u  e x p eri e n c e  s ki n/ h y p er s e n siti vit y r e a cti o n s ( a  s ki n r a s h) 
s u c h  a s  St e v e n s -J o h n s o n  S y n dr o m e  a n d  er yt h e m a  m ultif or m e.   
It  i s   al s o  r ar e   b ut   s eri o u s  if   y o u   e x p eri e n c e   a n y   n e ur o p s y c hi atri c   e v e nt s  ( e. g.,  
h all u ci n ati o n s,  d eliri u m,  or  a b n or m al  b e h a vi or).  
T h er e i s  al s o  a ri s k  of  d e at h fr o m i nfl u e n z a  
C o nfi d e nti alit y  
S u bj e ct   c o nfi d e nti alit y   will   b e   h el d   stri ctl y  i n  tr u st   b y  t h e   st u d y   d o ct or   a n d   st aff.   T hi s  
c o nfi d e nti alit y  will  b e  e xt e n d e d t o  c o v er t e sti n g  of  bi ol o gi c al  s p e ci m e n s i n  a d diti o n t o t h e 
cli ni c al i nf or m ati o n r el ati n g t o  s u bj e ct s.  
5.   
Ar e t h er e ri s k s r el at e d t o  pr e g n a n c y ?  
Pr e g n a nt  w o m e n  c a n n ot t a k e  p art i n t hi s  st u d y. If  y o u  ar e  a  w o m a n  c a p a bl e  of  h a vi n g 
c hil dr e n,  y o u  m u st  h a v e  a  pr e g n a n c y t e st.  T h e  r e s ult s  of t h at t e st  m u st  b e  n e g ati v e f or 
y o u t o  c o nti n u e i n t h e  st u d y. If  y o u  b e c o m e  pr e g n a nt ( or  s u s p e ct  pr e g n a n c y)  b ef or e t h e 
st u d y i s  c o m pl et e d,  y o u  m u st i nf or m t h e  st u d y  d o ct or.  
6.   
Ar e t h er e  b e n efit s t o  b ei n g i n t h e  st u d y ?  
T h er e  m a y  or  m a y  n ot  b e  a  dir e ct  b e n efit t o  y o u fr o m  b ei n g i n t h e  st u d y. If  y o u t a k e  p art 
i n t hi s  st u d y,  y o u  m a y al s o  h el p  ot h er s i n t h e f ut ur e.  
7.   
W h at  ar e  y o ur  o pti o n s if  y o u  d o  n ot  w a nt t o  b e i n t h e  st u d y ?  
If  y o u  d e ci d e  n ot t o j oi n t hi s  st u d y,  ot h er  o pti o n s  ar e  a v ail a bl e.  Y o u  d o  n ot  h a ve t o j oi n 
t hi s  st u d y t o  g et tr e at m e nt.  Os elt a mi vir i s  a v ail a bl e f or  u s e  o ut si d e  of  t hi s r e s e ar c h  st u d y.  
Y o u  d o  n ot  h a v e t o j oi n t hi s  st u d y. If  y o u  d o  n ot j oi n,  y o ur  c ar e  at J o h ns  H o p ki ns will  n ot 
b e  aff e ct e d.  
 
8.   
Will it  c o st  y o u  a n yt hi n g t o  b e i n t hi s  st u d y ?   
Y o u  will r e c ei v e  a  s e p ar at e I n s ur a n c e  a n d  R e s e ar c h  P arti ci p a nt  Fi n a n ci al  R e s p o n si bilit y 
I nf or m ati o n  S h e et ( S h e et).  
T hi s  S h e et  will  gi v e  y o u t h e f oll o wi n g i nf or m ati o n:  


D o  n ot  us e t his f or m f or  c o ns e nti n g r es e ar c h  
p arti ci p a nts  u nl ess t h e J o h ns  H o p ki ns  M e di ci n e  
L o g o  a p p e ar s  h er e.  
D at e:  S e pt e m b er  2 6,  2 0 1 6  
Pri n ci p al I n v esti g at or:  A n dr e a  D u g as,  M D,  P h D  
A p pli c ati o n  N o.:  I R B 0 0 0 8 0 4 0 5 
 
9  
P a g e  9  of  1 4  
C o m bi n e d I nf or m e d  C o ns e nt/ A ut h ori z ati o n  S e pt e m b er  2 6,  2 0 1 6  
•   T h e  pr o c e d ur e s, t e st s,  dr u g s  or  d e vi c e s t h at  ar e  p art  of t hi s r e s e ar c h  a n d t h at  will 
b e  p ai d f or  b y t h e  st u d y ( n o  c o st t o  y o u).   
 
•   T h e   pr o c e d ur e s,  t e st s,   dr u g s   or   d e vi c e s  t h at   will   b e   bill e d  t o   y o u   a n d/ or   y o ur  
h e alt h i n s ur er. If  y o u  h a v e  h e alt h i n s ur a n c e,  y o u  will  b e r e s p o n si bl e f or  a n y  c o -
p a y s  or  d e d u cti bl e s  n ot  c o v er e d  b y  y o ur i n s ur a n c e.   
 
9.   
Will  y o u  b e  p ai d if  y o u j oi n t hi s  st u d y ?  
Y o u  will  b e  p ai d  u p t o $ 2 7 5  if  y o u j oi n t hi s  st u d y: 
•   $ 1 0 0  at t h e  c o m pl eti o n  of  all  e nr oll m e nt  a cti viti e s . 
•   $ 7 5  if  y o u  c o m pl et e  at l e a st 8  of t h e  1 4  d ail y  di ari e s . 
•   $ 1 0 0  at t h e  c o m pl eti o n  of t h e  4 -w e e k f oll o w -u p . 
Y o u  m a y  b e r e q uir e d t o  pr o vi d e  y o ur  s o ci al  s e c urit y  n u m b er t o  b e  p ai d f or t a ki n g  p art i n 
t hi s   st u d y.   F e d er al t a x l a w r e q uir e s t h at  y o u  r e p ort  y o ur  r e s e ar c h  p a y m e nt s  w h e n   y o u 
fil e  y o ur t a x e s. If  y o ur t ot al  p a y m e nt s fr o m J o h ns  H o p ki ns e x c e e d $ 6 0 0  p er  y e ar, Jo h ns 
H o p ki ns  will r e p ort t h e s e  p a y m e nt s t o t h e I nt er n al  R e v e n u e  S er vi c e  a n d  y o u  will r e c ei v e 
a  1 0 9 9 -MI S C f or m fr o m  u s.  
1 0.   
C a n  y o u l e a v e t h e  st u d y  e arl y ?  
•  
Y o u  c a n  a gr e e t o  b e i n t h e  st u d y  n o w  a n d  c h a n g e  y o ur  mi n d l at er.  
•  
If  y o u  wi s h t o  st o p,  pl e a s e t ell  u s ri g ht a w a y.  
•  
L e a vi n g t hi s  st u d y  e arl y  will  n ot  st o p  y o u fr o m  g etti n g r e g ul ar  m e di c al  c ar e.   
If  y o u l e a v e t h e  st u d y  e arl y, J o h ns  H o p ki ns m a y  u s e  or  gi v e  o ut  y o ur  h e alt h i nf or m ati o n 
t h at it  h a s  alr e a d y  c oll e ct e d if t h e i nf or m ati o n i s  n e e d e d f or t hi s  st u d y  or  a n y f oll o w-u p 
a cti viti e s .  
1 1.   
W h y  mi g ht  w e t a k e  y o u  o ut  of t h e  st u d y  e arl y ?   
Y o u  m a y  b e t a k e n  o ut  of t h e  st u d y if:  
•  
St a yi n g i n t h e  st u d y  w o ul d  b e  h ar mf ul.  
•  
Y o u  n e e d tr e at m e nt  n ot  all o w e d i n t h e  st u d y.  
•  
Y o u f ail t o  f oll o w i n str u cti o n s. 
•  
T h e  st u d y i s  c a n c ell e d.  
•  
T h er e  m a y  b e  ot h er r e a s o n s t o t a k e  y o u  o ut  of t h e  st u d y t h at  w e  d o  n ot  k n o w  at 
t hi s ti m e.  


D o  n ot  us e t his f or m f or  c o ns e nti n g r es e ar c h  
p arti ci p a nts  u nl ess t h e J o h ns  H o p ki ns  M e di ci n e  
L o g o  a p p e ar s  h er e.  
D at e:  S e pt e m b er  2 6,  2 0 1 6  
Pri n ci p al I n v esti g at or:  A n dr e a  D u g as,  M D,  P h D  
A p pli c ati o n  N o.:  I R B 0 0 0 8 0 4 0 5 
 
1 0  
P a g e  1 0  of  1 4  
C o m bi n e d I nf or m e d  C o ns e nt/ A ut h ori z ati o n  S e pt e m b er  2 6,  2 0 1 6  
If  y o u  ar e t a k e n  o ut  of t h e  st u d y  e arl y, J o h ns  H o p ki ns m a y  u s e  or  gi v e  o ut  y o ur  h e alt h 
i nf or m ati o n t h at it  h a s alr e a d y  c oll e ct e d  if t h e i nf or m ati o n i s  n e e d e d f or t hi s  st u d y  or  a n y 
f oll o w-u p  a cti viti e s . 
1 2.   
H o w  will  y o ur  pri v a c y  b e  pr ot e ct e d ?   
W e  h a v e  r ul e s t o  pr ot e ct i nf or m ati o n  a b o ut  y o u.  F e d er al  a n d  st at e l a w s  an d t h e f e d er al 
m e di c al   Pri v a c y   R ul e   al s o   pr ot e ct   y o ur   pri v a c y.   B y   si g ni n g  t hi s  f or m   y o u   pr o vi d e   y o ur  
p er mi s si o n ,  c all e d   y o ur  “ a ut h ori z ati o n,”  f or  t h e   u s e   a n d   di s cl o s ur e   of  i nf or m ati o n  
pr ot e ct e d  b y t h e  Pri v a c y  R ul e.  
T h e r e s e ar c h t e a m  w or ki n g  o n t h e  st u d y  will  c oll e ct i nf or m ati o n  a b o ut  y o u.  T hi s i n cl u d e s 
t hi n g s l e ar n e d fr o m t h e  pr o c e d ur e s  d e s cri b e d i n t hi s  c o n s e nt f or m.  T h e y  m a y  al s o  c oll e ct 
ot h er i nf or m ati o n i n cl u di n g  y o ur  n a m e,  a d dr e s s,  d at e  of  birt h,  a n d i nf or m ati o n fr o m  y o ur 
m e di c al  r e c or d s  ( w hi c h   m a y  i n cl u d e  i nf or m ati o n   a b o ut   HI V   st at u s ,  dr u g,   al c o h ol   or  
s e x u all y  tr a n s mitt e d   di s e a s e  ( S T D)   tr e at m e nt,   g e n eti c  t e st  r e s ult s,   or   m e nt al   h e alt h  
tr e at m e nt). 
T h e r e s e ar c h t e a m  will  k n o w  y o ur i d e ntit y  a n d t h at  y o u  ar e i n t h e r e s e ar c h  st u d y.  O t h er 
p e o pl e   at  J o h ns   H o p ki ns,  p arti c ul arl y   y o ur   d o ct or s,   m a y  al s o  s e e   or   gi v e   o ut   y o ur  
i nf or m ati o n. W e  m a k e t hi s i nf or m ati o n  a v ail a bl e t o  y o ur  d o ct or s f or  y o ur  s a f et y.   
P e o pl e   o ut si d e   of  J o h ns  H o p ki ns  m a y   n e e d  t o   s e e   or  r e c ei v e   y o ur  i nf or m ati o n  f or  t hi s 
st u d y.   E x a m pl e s  i n cl u d e   g o v er n m e nt   a g e n ci e s   ( s u c h   a s  t h e   F o o d   a n d   Dr u g  
A d mi ni str ati o n),  s af et y  m o nit or s,  ot h er  sit e s  i n t h e  st u d y  a n d  c o m p a ni e s t h at  s p o n s or t h e 
st u d y.   
If  y o u  ar e i n  a  c a n c er  st u d y t h at r e c ei v e s f e d er al f u n di n g, t h e  N ati o n al  C a n c er I n stit ut e 
( N CI)  n o w r e q uir e s t h at  w e r e p ort i d e ntifi a bl e i nf or m ati o n ( s u c h  a s,  zi p  c o d e)  a b o ut  y o ur 
p arti ci p ati o n.  Y o u  m a y  c o nt a ct t h e  N CI if  y o u  h a v e  q u e sti o n s  a b o ut  h o w t hi s i nf or m ati o n 
i s  u s e d.  
W e  c a n n ot  d o t hi s  st u d y  wit h o ut  y o ur  a ut h ori z ati o n  t o  u s e  a n d  gi v e  o ut  y o ur i nf or m ati o n. 
Y o u  d o  n ot  h a v e t o  gi v e  u s t hi s  a ut h ori z ati o n . If  y o u  d o  n ot, t h e n  y o u  m a y  n ot j oi n t hi s 
st u d y.  
W e   will   u s e   a n d   di s cl o s e   y o ur  i nf or m ati o n   o nl y   a s   d e s cri b e d  i n  t hi s  f or m   a n d  i n   o ur  
N oti c e   of   Pri v a c y   Pr a cti c e s;   h o w e v er,   p e o pl e   o ut si d e  J o h ns   H o p ki ns  w h o  r e c ei v e   y o ur  
i nf or m ati o n m a y  n ot  b e  c o v er e d  b y t hi s  pr o mi s e  or  b y t h e f e d er al  Pri v a c y  R ul e .  W e tr y t o 
m a k e  s ur e t h at  e v er y o n e  w h o  n e e d s t o  s e e  y o ur i nf or m ati o n  k e e p s it  c o nfi d e nti al  –  b ut 
w e  c a n n ot  g u ar a nt e e t h at  y o ur i nf or m ati o n  will  n ot  b e r e -di s cl o s e d . 
T h e  u s e  a n d  di s cl o s ur e  of  y o ur i nf or m ati o n  h a s  n o ti m e li mit.  Y o u  m a y r e v o k e ( c a n c el ) 
y o ur   p er mi s si o n  t o   u s e   a n d   di s cl o s e   y o ur  i nf or m ati o n   at   a n y  ti m e   b y   n otif yi n g  t h e  
Pri n ci p al  I n v e sti g at or   of  t hi s   st u d y   b y   p h o n e   or  i n   writi n g.  If   y o u   c o nt a ct  t h e   Pri n ci p al  
I n v e sti g at or  b y  p h o n e, y o u  m u st f oll o w -u p  wit h  a  writt e n r e q u e st t h at i n cl u d e s t h e  st u d y 


D o  n ot  us e t his f or m f or  c o ns e nti n g r es e ar c h  
p arti ci p a nts  u nl ess t h e J o h ns  H o p ki ns  M e di ci n e  
L o g o  a p p e ar s  h er e.  
D at e:  S e pt e m b er  2 6,  2 0 1 6  
Pri n ci p al I n v esti g at or:  A n dr e a  D u g as,  M D,  P h D  
A p pli c ati o n  N o.:  I R B 0 0 0 8 0 4 0 5 
 
1 1  
P a g e  1 1  of  1 4  
C o m bi n e d I nf or m e d  C o ns e nt/ A ut h ori z ati o n  S e pt e m b er  2 6,  2 0 1 6  
n u m b er  a n d  y o ur  c o nt a ct i nf or m ati o n.  T h e  Pri n ci p al I n v e sti g at or’ s  n a m e,  a d dr e s s,  p h o n e 
a n d f a x i nf or m ati o n  ar e  o n  p a g e  o n e  of t hi s  c o n s e nt f or m.   
If  y o u  d o c a n c el  y o ur  a ut h ori z ati o n  t o  u s e  a n d  di s cl o s e  y o ur i nf or m ati o n,  y o ur  p art i n t hi s 
st u d y   will   e n d   a n d   n o  f urt h er  i nf or m ati o n   a b o ut   y o u   will   b e   c oll e ct e d.   Y o ur   r e v o c ati o n 
(c a n c ell ati o n )  w o ul d  n ot  aff e ct i nf or m ati o n  alr e a d y  c oll e ct e d i n t h e  st u d y ,  or i nf or m ati o n 
w e  di s cl o s e d  b ef or e  y o u  wr ot e t o t h e  P ri n ci p al I n v e sti g at or t o c a n c el  y o ur  a ut h ori z ati o n . 
1 3.   
W h at tr e at m e nt  c o st s  will  b e  p ai d if  y o u  ar e i nj ur e d i n t hi s  st u d y ?   
J o h ns  H o p ki ns a n d t h e f e d er al  g o v er n m e nt  d o  n ot  h a v e  a  pr o gr a m t o  p a y  y o u if  y o u  ar e 
h urt  or  h a v e  ot h er  b a d r e s ult s fr o m  b ei n g i n t h e  st u d y.  H o w e v er,  m e di c al  c ar e  at J o h ns 
H o p ki ns  i s  o p e n t o  y o u  a s it i s t o  all  si c k  or i nj ur e d  p e o pl e. 
T h e  c o st s f or  a n y tr e at m e nt  or  h o s pit al  c ar e  y o u r e c ei v e  a s t h e r e s ult  of  a  st u d y -r el at e d 
i nj ur y t h at  ar e  n ot  c o v er e d  b y  a  h e alt h i n s ur er  will  b e  bill e d t o  y o u. 
B y  si g ni n g t hi s f or m  y o u  will  n ot  gi v e  u p  a n y ri g ht s  y o u  h a v e t o  s e e k  c o m p e n s ati o n f or 
i nj ur y.  
1 4.   
W h at  ot h er t hi n g s  s h o ul d  y o u  k n o w  a b o ut t hi s r e s e ar c h  st u d y ?  
a.   W h at i s t h e I n stit uti o n al  R e vi e w  B o ar d (I R B)  a n d  h o w  d o e s it  pr ot e ct  y o u ?   
T h e J o h ns  H o p ki ns M e di ci n e I R B i s  m a d e  u p  of:  
•  
D o ct or s ; 
•  
N ur s e s ; 
•  
Et hi ci st s ; 
•  
N o n - s ci e nti st s; a n d  
•  
P e o pl e  fr o m t h e l o c al  c o m m u nit y  
 
T h e  I R B  r e vi e w s   h u m a n  r e s e ar c h   st u di e s.  It   pr ot e ct s  t h e  ri g ht s   a n d   w elf ar e   of  t h e  
p e o pl e t a ki n g  p art i n t h o s e  st u di e s.  Y o u  m a y  c o nt a ct t h e I R B if  y o u  h a v e  q u e sti o n s 
a b o ut  y o ur ri g ht s  a s  a  p arti ci p a nt  or if  y o u t hi n k  y o u  h a v e  n ot  b e e n tr e at e d f airl y.  T h e 
I R B   offi c e   n u m b er  i s  4 1 0 -9 5 5 -3 0 0 8.   Y o u   m a y   al s o   c all  t hi s   n u m b er  f or   ot h er  
q u e sti o n s,  c o n c er n s  or  c o m pl ai nt s  a b o ut t h e r e s e ar c h.  
W h e n t h e J o h ns  H o p ki ns S c h o ol  of  M e di ci n e I R Br e vi e w s  a  st u d y  at  a n ot h er  sit e, t h at 
sit e  (i n stit uti o n)  i s   s ol el y  r e s p o n si bl e  f or  t h e   s af e   c o n d u ct   of  t h e   st u d y   a n d  f or  
f oll o wi n g t h e  pr ot o c ol  a p pr o v e d  b y t h e J o h ns  H o p ki ns I R B.  
 


D o  n ot  us e t his f or m f or  c o ns e nti n g r es e ar c h  
p arti ci p a nts  u nl ess t h e J o h ns  H o p ki ns  M e di ci n e  
L o g o  a p p e ar s  h er e.  
D at e:  S e pt e m b er  2 6,  2 0 1 6  
Pri n ci p al I n v esti g at or:  A n dr e a  D u g as,  M D,  P h D  
A p pli c ati o n  N o.:  I R B 0 0 0 8 0 4 0 5 
 
1 2  
P a g e  1 2  of  1 4  
C o m bi n e d I nf or m e d  C o ns e nt/ A ut h ori z ati o n  S e pt e m b er  2 6,  2 0 1 6  
b.   W h at  d o  y o u  d o if  y o u  h a v e  q u e sti o n s  a b o ut t h e  st u d y ?   
C all  t h e   pri n ci p al  i n v e sti g at or,  Dr.  A n dr e a  D u g as   at 4 1 0 -7 3 5 -6 4 0 0   If   y o u   wi s h,   y o u  
m a y   c o nt a ct  t h e   pri n ci p al  i n v e sti g at or   b y  l ett er   or   b y  f a x.   T h e   a d dr e s s   a n d  f a x  
n u m b er   ar e   o n   p a g e   o n e   of  t hi s   c o n s e nt  f or m.  If   y o u   c a n n ot  r e a c h  t h e   pri n ci p al  
i n v e sti g at or  or  wi s h t o t al k t o  s o m e o n e  el s e,  c all t h e I R B  offi c e  at 4 1 0 -9 5 5 -3 0 0 8.  
c.   W h at  s h o ul d  y o u  d o if  y o u  ar e i nj ur e d  or ill  a s  a r e s ult  of  b ei n g i n t hi s  st u d y ?   
If   y o u  t hi n k   y o u   ar e  i nj ur e d   or  ill   b e c a u s e   of  t hi s   st u d y,   c all  Dr.  D u g as  at  4 1 0 -7 3 5 -
6 4 0 0  d uri n g r e g ul ar  offi c e  h o ur s.   
If  y o u  h a v e  a n  ur g e nt  m e di c al  pr o bl e m r el at e d t o  y o ur t a ki n g  p art i n t hi s  st u d y,  c all 
Dr.  A n dr e a  D u g as  at 4 1 0 -7 3 5 -6 4 0 0  d u ri n g r e g ul ar  offi c e  h o ur s.  Or  a n y ti m e  of  d a y, 
pl e a s e   c all  J o h ns   H o p ki ns  H o s pit al   at  4 1 0 -9 5 5 -5 0 0 0   a n d   a s k  t h e m  t o   p a g e  Dr. 
A n d r e a  D u g as t o  y o ur  p h o n e  n u m b er.  
d.   W h at  h a p p e n s t o  D at a  a n d  Bi o s p e ci m e n s  t h at  ar e  c oll e ct e d i n t h e  st u d y ?  
J o h ns  H o p ki ns a n d  o ur r e s e ar c h  p art n er s  w or k t o  u n d er st a n d  a n d  c ur e  di s e a s e s.  T h e 
bi o s p e ci m e n s  a n d/ or  d at a  y o u  pr o vi d e  ar e i m p ort a nt t o t hi s  eff ort.  
 
If  y o u j oi n t hi s  st u d y,  y o u  s h o ul d  u n d er st a n d t h at  y o u will  n ot  o w n  y o ur  bi o s p e ci m e n s 
or  d at a,  a n d  s h o ul d r e s e ar c h er s  u s e t h e m t o  cr e at e  a  n e w  pr o d u ct  or i d e a,  y o u  will 
n ot  b e n efit fi n a n ci all y.   
 
Wit h   a p pr o pri at e   pr ot e cti o n s  f or   pri v a c y,  J o h ns    H o p ki ns  m a y   s h ar e   y o ur  
bi o s p e ci m e n s  a n d i nf or m ati o n  wit h  o ur r e s e ar c h  s p o n s or s  a n d  p art n er s.  Y o ur  n a m e 
or  a n y  ot h er i d e ntif yi n g i nf or m ati o n  will  n ot  b e i n cl u d e d.  
1 5.   
W h at  d o e s  y o ur  si g n at ur e  o n t hi s  c o n s e nt f or m  m e a n ?   
  
Y o ur  si g n at ur e  o n t hi s f or m  m e a n s t h at:  
•  
Y o u  u n d er st a n d t h e i nf or m ati o n  gi v e n t o  y o u i n t hi s f or m .  
•  
Y o u  a c c e pt t h e  pr o vi si o n s i n t h e f or m . 
•  
Y o u  a gr e e t o j oi n t h e  st u d y .  
•  
Y o u   will   n ot   gi v e   u p   a n y  l e g al  ri g ht s   b y   si g ni n g  t hi s   c o n s e nt  f or m.   
 
 
 
 


D o  n ot  us e t his f or m f or  c o ns e nti n g r es e ar c h  
p arti ci p a nts  u nl ess t h e J o h ns  H o p ki ns  M e di ci n e  
L o g o  a p p e ar s  h er e.  
D at e:  S e pt e m b er  2 6,  2 0 1 6  
Pri n ci p al I n v esti g at or:  A n dr e a  D u g as,  M D,  P h D  
A p pli c ati o n  N o.:  I R B 0 0 0 8 0 4 0 5 
 
1 3  
P a g e  1 3  of  1 4  
C o m bi n e d I nf or m e d  C o ns e nt/ A ut h ori z ati o n  S e pt e m b er  2 6,  2 0 1 6  
W E  WI L L  GI V E  Y O U  A  C O P Y  O F  T HI S  SI G N E D  A N D  D A T E D  C O N S E N T  F O R M  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
Si g n at ur e  of  P arti ci p a nt                                 ( Pri nt  N a m e)                                            D at e/ Ti m e   
 
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
Si g n at ur e  of  P er s o n  O bt ai ni n g  C o n s e nt        ( Pri nt  N a m e)                                            D at e/ Ti m e  
 
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
Si g n at ur e  of  Wit n e s s t o  C o n s e nt                     ( Pri nt  N a m e)                                      D at e/ Ti m e   
Pr o c e d ur e s  ( o pti o n al  u nl e s s I R B  
or  s p o n s or  r e q uir e d) 
 
N O T E : A  C O P Y  O F  T H E  SI G N E D,  D A T E D  C O N S E N T  F O R M  M U S T  B E  K E P T  B Y  T H E  P RI N CI P A L I N V E S TI G A T O R;  A  C O P Y  M U S T  B E  GI V E N  T O  T H E 
P A R TI CI P A N T; I F  Y O U  A R E  U SI N G  E PI C  F O R  T HI S  S T U D Y  A  C O P Y  M U S T  B E  F A X E D  T O  4 1 0 -3 6 7 -7 3 8 2; I F  Y O U  A R E  N O T  U SI N G  E PI C  A  C O P Y 
M U S T  B E  P L A C E D I N  T H E  P A R TI CI P A N T’ S  M E DI C A L  R E C O R D ( U N L E S S  N O  M E DI C A L  R E C O R D  E XI S T S  O R  WI L L  B E  C R E A T E D).   
 
O N L Y  C O N S E N T  F O R M S  T H A T I N C L U D E  T H E J O H N S  H O P KI N S  M E DI CI N E  L O G O  C A N  B E  U S E D  T O  O B T AI N  T H E  C O N S E N T  O F  R E S E A R C H 
P A R TI CI P A N T S.  
 
 
 


D o  n ot  us e t his f or m f or  c o ns e nti n g r es e ar c h  
p arti ci p a nts  u nl ess t h e J o h ns  H o p ki ns  M e di ci n e  
L o g o  a p p e ar s  h er e.  
D at e:  S e pt e m b er  2 6,  2 0 1 6  
Pri n ci p al I n v esti g at or:  A n dr e a  D u g as,  M D,  P h D  
A p pli c ati o n  N o.:  I R B 0 0 0 8 0 4 0 5 
 
1 4  
P a g e  1 4  of  1 4  
C o m bi n e d I nf or m e d  C o ns e nt/ A ut h ori z ati o n  S e pt e m b er  2 6,  2 0 1 6  
D O C U M E N T A TI O N  O F  I N V E S TI G A T O R C O N S E N T  
 
M y  si g n at ur e  b el o w i n di c at es t h at I  h a v e  dis c u ss e d t h e ri s ks,  b e n efit s,  a n d  alt er n ati v es, 
a n s w er e d  a n y  q u esti o n s,  a n d  b eli e v e t h e  p arti ci p a nt is  a bl e t o  m a k e  a n i nf or m e d  c h oi c e t o 
j oi n t h e st u d y. 
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
Si g n at ur e  of  I n v e sti g at or                        ( Pri nt  N a m e)                                                     D at e/ Ti m e 
 
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
Si g n at ur e  of  P arti ci p a nt                          ( Pri nt  N a m e)                                                     D at e/ Ti m e   
 
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
Si g n at ur e  of  Wit n e s s t o  C o n s e nt                     ( Pri nt  N a m e)                                            D at e/ Ti m e   
Pr o c e d ur e s  ( o pti o n al  u nl e s s I R B  
or  s p o n s or  r e q uir e d) 
 
 
 
 
 
N O T E : A  C O P Y  O F  T H E  SI G N E D,  D A T E D  C O N S E N T  F O R M  M U S T  B E  K E P T  B Y  T H E  P RI N CI P A L I N V E S TI G A T O R;  A  C O P Y  M U S T  B E  GI V E N  T O  T H E 
P A R TI CI P A N T; I F  Y O U  A R E  U SI N G  E PI C  F O R  T HI S  S T U D Y  A  C O P Y  M U S T  B E  F A X E D  T O  4 1 0 -3 6 7 -7 3 8 2; I F  Y O U  A R E  N O T  U SI N G  E PI C  A  C O P Y 
M U S T  B E  P L A C E D I N  T H E  P A R TI CI P A N T’ S  M E DI C A L  R E C O R D ( U N L E S S  N O  M E DI C A L  R E C O R D  E XI S T S  O R  WI L L  B E  C R E A T E D).   
 
 
O N L Y  C O N S E N T  F O R M S  T H A T I N C L U D E  T H E J O H N S  H O P KI N S  M E DI CI N E  L O G O  C A N  B E  U S E D  T O  O B T AI N  T H E  C O N S E N T  O F  R E S E A R C H 
P A R TI CI P A N T S.  
 


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Table of Contents 
 
 
1. 
PROJECT OVERVIEW ...................................................................... 4 
1.1 
Project Design .......................................................................... 4 
1.2 
Objectives ................................................................................ 4 
1.2.1 
Efficacy ...................................................................... 4 
1.2.2 
Safety ......................................................................... 4 
1.2.3 
Pharmacokinetics ....................................................... 5 
1.3 
Treatments................................................................................ 5 
1.3.1  
Treatment Assignment ............................................... 5 
1.3.2  
Selection and Timing of Doses .................................. 5 
1.4 
Procedures ................................................................................ 5 
1.4.1 
Subject Identification ................................................. 5 
1.4.2 
Randomization ........................................................... 6 
1.4.3 
Blinding/Unblinding .................................................. 6 
1.4.4 
Replacement .............................................................. 6 
1.4.5  
Data Monitoring ........................................................ 6 
2. 
STATISTICAL ANALYSIS CONSIDERATIONS ............................ 7 
2.1 
Sample Size and Power ............................................................ 7 
2.2 
Analysis Population ................................................................. 7 
2.3 
Data Handling .......................................................................... 7 
2.3.1 
Outcome Measures and Predictors ............................ 7 
2.3.2 
Measurement Times .................................................. 9 
2.3.3 
Missing Data .............................................................. 9 
2.4  
Statistical Methods ................................................................... 9 
2.4.1 
General Overview and Plan of Analysis ................... 9 
2.4.2 
Hypothesis Testing .................................................... 9 
2.4.3 
Descriptive Statistics of All Study Variables ............ 9 
2.4.4 
Modeling .................................................................. 10 
2.4.5 
Multiple Comparisons ............................................. 10 
2.4.6 
Project Center Effects .............................................. 10 
3. 
STATISTICAL ANALYSIS ............................................................. 11 
3.1 
Analysis of Subject Characteristics ....................................... 11 
3.2 
Analysis of Primary Objectives ............................................. 11 
3.3 
Analysis of Secondary Objectives ......................................... 11 
3.4 
Analysis of Efficacy and Safety ............................................. 12 
3.4.1 
Efficacy .................................................................... 12 
3.4.2 
Safety ....................................................................... 12 
4. 
PROPOSED SUMMARY TABLES, GRAPHS AND 
LISTINGS .......................................................................................... 13 
4.1 
Mock Tables........................................................................... 13 
Table 1. Subject Demographics ............................................. 13 
Table 2. Subject Symptom Onset and Baseline NEWS 
Score ........................................................................ 15 
Table 3. Summary of Subject Status ...................................... 16 
Table 4. Summary of FLU-PRO Symptoms .......................... 17 


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Table 5. Clinical Outcomes .................................................... 18 
Table 6. Influenza-Related Complications ............................ 20 
Table 7. Characteristics of Subjects Initially Admitted 
to the Hospital from the ED ..................................... 21 
Table 8. Patient Screening and Testing for Influenza ............ 22 
Table 9. Summary of Adverse Events by System Organ 
Class and Preferred Term, with number (%) of 
subjects reporting at least one adverse event ........... 23 
Table 10. Summary of Adverse Events by Relationship 
to Study Drug and Severity ..................................... 23 
Table 11. Frequency of Protocol-Specific Adverse 
Event ........................................................................ 24 
4.2 
Mock Graphs .......................................................................... 25 
Figure 1. Study Patient Screening and Enrollment ................ 25 
Figure 2. FLU-PRO Symptom Severity Score for 
Enrolled Patients, by Domain of Symptoms, 
up to 14 Days from Enrollment ............................... 26 
Figure 3. Karnofsky Performance Scale, Mean and 95% 
Confidence Band of Daily Scores ........................... 26 
Figure 4. Severity of Disease for Hospitalized Patients, 
up to 14 Days from Enrollment ............................... 26 
Figure 5. Ordinal Scale for Hospitalized Patients, up to 
14 Days from Enrollment ........................................ 26 
4.3 
Mock Listings ........................................................................ 27 
Listing 1. Patient Level Adverse Events ................................ 27 
Listing 2. Serious Adverse Events ......................................... 28 
Listing 3. Deaths .................................................................... 28 
 
 
 
 


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1. 
PROJECT OVERVIEW 
 
1.1 
Project Design 
This pilot study is an open-label randomized controlled clinical trial. It is designed to 
demonstrate the feasibility of utilizing emergency departments (ED) as a primary site for subject 
enrollment in clinical trials evaluating influenza therapeutics, providing pilot data for future 
clinical trial design and planning. Adults presenting to the ED with laboratory-confirmed 
influenza who meet Centers for Disease Control and Prevention (CDC) criteria for antiviral 
treatment will be enrolled. Subjects will be randomized to either oral (oseltamivir) or intravenous 
(IV) (peramivir) antiviral treatment. 
 
1.2 
Objectives 
1.2.1 Efficacy 
1.2.1.1 Primary Objective 
To prospectively enroll high-risk subjects with laboratory-confirmed influenza into a 
randomized, open-label study of oral versus IV influenza therapeutic to include symptom 
evaluation and outcome assessments. 
 
1.2.1.2 Secondary Objectives 
Secondary Objective 1: To identify influenza-positive patients utilizing a previously 
established triage-based assessment and rapid testing algorithm for suspected influenza 
infection. 
 
Secondary Objective 2: To retrospectively evaluate all potentially eligible patients for 
potential enrollment biases. 
 
Secondary Objective 3: To create a repository of residual nasopharyngeal (NP) samples 
collected from ED patients with suspected influenza illness. 
 
 
1.2.2 Safety 
The safety will be assessed by evaluating the clinical significance of laboratory abnormalities 
and adverse events (AEs) and all serious adverse events (SAEs). The overall occurrences of 
AEs and SAEs will be reported by System Organ Class (SOC) and Preferred Term (PT). The 
AEs and SAEs will also be evaluated and reported by the relationship to study drug, severity 
and the outcome. All the results will be summarized by study arm and/or by clinical site as 
appropriate.  
 


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1.2.3 Pharmacokinetics 
The pharmacokinetics of influenza antivirals will not be studied.                                                  
1.3 
Treatments  
All eligible subjects will be randomized to receive one of two treatment groups. They will receive 
either oral or IV antiviral treatment.  
 
1.3.1  Treatment Assignment 
Randomization will be carried out using a computerized randomization system in the ratio of 
1:1. It will be performed by research staff after informed consent, laboratory results and 
verification of all eligibility criteria have been performed. 
 
Subjects randomized to the oral treatment arm will receive oral oseltamivir. Subjects 
randomized to the IV treatment group will receive IV peramivir. 
 
1.3.2  Selection and Timing of Doses 
Influenza antivirals will be dosed based on creatinine clearance (CrCl) results, as described 
below. CrCl will be calculated using the Cockcroft Gault equation (see Manual of Operating 
Procedures (MOP)). 
 
Treatment 
CrCl Result 
Dosage 
Frequency/Duration 
Oral 
Oseltamivir 
>60 mL/min 
75 mg 
Twice daily (every 12 hours) for 5 days 
>30 – 60 mL/min 
30 mg 
Twice daily (every 12 hours) for 5 days 
>10 – 30 mL/min 
30 mg 
Once daily (every 24 hours) for 5 days 
IV 
Peramivir 
≥50 mL/min 
600 mg 
One time 
30 – 49 mL/min 
200 mg 
One time 
10 – 29 mL/min 
100 mg 
One time 
 
 
1.4 
Procedures 
1.4.1 Subject Identification 
 
Research staff will review ED adult patient charts to identify patients with a positive 
laboratory-confirmed influenza test during their current ED visit. If a patient appears to be 
eligible, research staff will approach the patient, verify that the patient meets eligibility criteria, 
and determine if he/she would like to participate in the study. 
 
 
 


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To be considered eligible for enrollment, a patient must meet the inclusion criteria and must 
not meet any of the exclusion criteria listed in the protocol at the time of screening. Screening 
and enrollment occur at the same visit. Screened patients who are eligible and provide written 
consent to participate in the study, will be randomized to a treatment arm and considered as 
enrolled in the study.  
 
For secondary objective 2, research staff will identify subjects by retrospectively screening all 
ED records of patients who presented between November and April of the current influenza 
season to determine eligibility. (See Protocol). 
 
For all eligible patients, research staff will review the ED and hospital records to 
retrospectively complete a set of structured clinical data forms to collect the following: basic 
demographic data; symptoms related to the Clinical Decision Guideline (CDG); criteria for 
CDC antiviral treatment; initial presentation and clinical course at the ED, including antiviral 
treatment, antibiotic treatment, Xpert Flu test or other influenza test information; and hospital 
course if subsequently admitted. 
 
1.4.2 Randomization 
Subjects will be randomized to receive one of two treatment groups using a computerized 
randomization system in the ratio of 1:1. Randomization will be performed at study level and 
not stratified by site. 
 
1.4.3 Blinding/Unblinding 
This is an open-label study, and the administration of treatments will not be blinded.   
 
1.4.4 Replacement 
No additional subjects will be recruited to replace any subjects who are lost to follow up or 
cannot be evaluated. 
 
1.4.5  Data Monitoring 
Data and safety will be monitored by the Safety Monitoring Committee (SMC), consisting of 
the IND sponsor, JHH Co-PIs, JHU Research Program Manager, Biomedical Advanced 
Research and Development Authority (BARDA) Medical Officer, Independent Safety Monitor 
(ISM), and study biostatistician (See Data and Safety Monitoring Plan (DSMP)). 
  
 
 


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2. 
STATISTICAL ANALYSIS CONSIDERATIONS 
2.1 
Sample Size and Power 
The proposed sample size is at least 50 subjects per site, per influenza season. This sample size 
was determined, in collaboration with the Office of the Assistant Secretary for Preparedness and 
Response (ASPR)/BARDA, to be adequate for this pilot effort which is being conducted 
specifically to examine the feasibility of achieving higher recruitment rates than has historically 
been achieved in other clinical venues, and the ability to reliably collect useful therapeutic endpoint 
data from an ED enrollment site. Estimates are based on data from the JHH ED 2014-2015 
influenza season using the CDG testing algorithm, where 1604 patients were tested for influenza 
between November 2014 and April 2015, and 311 influenza-positive patients were identified. Of 
those 311 patients, approximately 75% met CDC criteria for influenza treatment (i.e., potential 
enrollment in the study) and 40% were admitted to the hospital. As 2014-2015 was a robust 
influenza season, it is estimated that a routine influenza season would have approximately 25% 
fewer influenza-positive patients. Based on similar previous ED based therapeutic clinical trials 
conducted at the JHH ED, it is anticipated that 56% of eligible patients will agree to participate in 
the study. Therefore, assuming a routine influenza season, there will be an estimated 174 eligible 
patients, of whom 97 will be enrolled (58 discharged, 39 admitted). Based on these estimates, at 
least 50 (conservatively) and up to 225 subjects could be enrolled and followed for 28 days. 
 
2.2 
Analysis Population 
The analysis population includes adults presenting to the ED with laboratory-confirmed influenza 
who meet CDC criteria for antiviral treatment. Detailed inclusion/ exclusion criteria are listed in 
the Protocol. 
 
2.3 
Data Handling 
2.3.1 Outcome Measures and Predictors 
 
Outcomes: 
 
a. For the Primary Objective:  
 
- 
The number of subjects successfully enrolled 
- 
The proportion of subjects who received treatment with IV study drug in the ED 
- 
The proportion of subjects who received (first dose) oral study drug in the ED 
- 
The proportion of subjects who complete follow-up.  
In addition, the following clinical measures will be evaluated for planning future clinical trial 
endpoints: 
 
• For all study subjects: 


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- Reported symptoms (including FLU-PRO Symptom Questionnaire) 
- Daily functional assessment 
- Patient Global Impression of Change (PGIC) on Day 7 and Day 28 
- Patient Global Impression of Severity (PGIS) at enrollment, and on Day 7 and Day 28 
- Number of subsequent medical visits or hospitalizations within 28 days of enrollment 
- Influenza-related complications including pneumonia, myocardial infarction, and 
stroke. 
 
• For subjects initially admitted to the hospital from the ED: 
- 
Severity of disease based on Intensive Care Unit (ICU) admission, mechanical 
ventilation, or oxygen supplementation  
- 
Ordinal scale up to 14 days: 
§ Death 
§ Receiving mechanical ventilation or extracorporeal membrane oxygenation 
(ECMO) 
§ In ICU (without mechanical ventilation or ECMO) 
§ Non-ICU hospitalization, requiring supplemental oxygen 
§ Non-ICU hospitalization, not requiring supplemental oxygen 
§ Not hospitalized, but unable to resume normal activities  
§ Not hospitalized with full resumption of normal activities. 
 
b. For the Secondary Objective 1:  
 
- 
The proportion of ED patients who were screened for influenza 
- 
The proportion of screened patients who met testing criteria 
- 
The proportion of patients who met testing criteria who were tested for influenza 
- 
The proportion of patients tested for influenza who were positive for influenza. 
 
c. For the Secondary Objective 2:  
 
- 
The proportion of eligible patients who were enrolled 
- 
Comparison of demographic characteristics between those who were enrolled in the study 
versus those who were identified to be potentially eligible through the retrospective chart 
review. 
§ Age 
§ Sex 
§ Race 
§ Ethnicity 
 
d. For the Secondary Objective 3:  
 
- 
The creation of a robust repository using all remnant samples of patients tested using the 
triage-based assessment and testing algorithm from November through April 2015 - 2017. 
Note that this is not a quantitative outcome. 
 
Potential predictors (independent variables) of interest: 


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• 
Enrollment: 
We will compare demographic characteristics between those who were 
enrolled and randomized in the study versus those who were eligible but not enrolled 
(declined, screen failure etc.). 
• 
Influenza Type: We will compare study outcomes between subjects with Influenza A and 
B. 
• 
Other clinical characteristics: We will compare study outcomes by various subject 
demographic, historical (i.e. past medical history and co-morbidities), and clinical 
characteristics.  
• 
Study site: 
There are 2 sites in the study. Study outcomes will be presented in total 
and by site. We will also compare subject characteristics by site for Secondary Objective 
2. 
2.3.2 Measurement Times 
Subjects will be followed for 4 weeks.  
2.3.3 Missing Data 
 
We will first assess the extent and pattern of missing data for all outcomes. If data are missing 
for only a small proportion, or if the missing is likely to be at random, data analysis will be 
conducted using available observations.  
 
If a substantial proportion of subjects have missing information, we will further explore the 
pattern of missing data, and assess whether missingness or loss to follow up is associated with 
subjects’ characteristics, disease severity or any other factors. 
 
2.4  
Statistical Methods 
2.4.1 General Overview and Plan of Analysis 
  
The analysis will be performed on data collected from both study sites, JHH and MMC.  
 
2.4.2 Hypothesis Testing 
 
There is no hypothesis testing for the study. 
  
2.4.3 Descriptive Statistics of All Study Variables 
 
Descriptive statistics including mean, median, standard deviation, range for continuous 
outcomes and frequency/proportion for categorical outcomes will be used to characterize study 
outcomes. 
 


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In addition, we will compare demographic characteristics between those who were enrolled 
and randomized in the study versus those who were eligible but not enrolled (declined, screen 
failure, etc.).  
 
2.4.4 Modeling 
 
No statistical modeling will be performed for the study. 
 
2.4.5 Multiple Comparisons 
 
No adjustment for multiple comparisons will be applied. 
 
2.4.6 Project Center Effects 
 
There are two clinical sites in the study. We recommend exploring randomization balance by 
site. It may also be of interest to compare subject characteristics and the primary outcomes by 
site.  
 
 
 


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3. 
STATISTICAL ANALYSIS 
3.1 
Analysis of Subject Characteristics 
Subject characteristics will be presented (see Tables 1 and 2). These characteristics will be 
summarized separately by study arm as well as combined. 
 
3.2 
Analysis of Primary Objectives 
Primary Objective: 
To prospectively enroll high-risk subjects with laboratory-confirmed 
influenza into a randomized, open-label study of oral versus IV influenza therapeutic to include 
symptom evaluation and outcome assessments. 
 
Analysis: 
Number of patients screened, enrolled and randomized will be plotted in Figure 1. 
Descriptive statistics including mean, median, standard deviation, range for continuous outcomes 
and frequency/proportion for categorical outcomes will be used to characterize study outcomes.  
 
All results will be summarized separately by study arm as well as combined. Results will be 
summarized in Tables 3-7. Ordinal scale up to 14 days for subjects who initially admitted to the 
hospital from the emergency department, as well as Karnofsky Performance Scale will also be 
plotted (Figures 2 and 3). 
 
3.3 
Analysis of Secondary Objectives 
Secondary Objective 1: To identify influenza-positive patients utilizing a previously established 
triage-based assessment and rapid testing algorithm for suspected influenza infection. 
 
Analysis: Frequencies and proportions will be presented in Table 8. 
 
Secondary Objective 2: To retrospectively evaluate all potentially eligible patients for potential 
enrollment biases.  
 
Analysis: The analysis will involve a retrospective chart review and comparisons of subject 
characteristics. It is not part of Westat’s scope of work, and is therefore not included in this SAP.  
 
Secondary Objective 3: To create a repository of residual nasopharyngeal (NP) samples collected 
from ED patients with suspected influenza illness. 
 
Analysis: There is no quantitative data collection for this objective. No statistical analysis will 
be performed. 
 


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3.4 
Analysis of Efficacy and Safety  
3.4.1 Efficacy 
As this is an exploratory study, data analysis will be principally descriptive. Potential clinical 
endpoints will be described using descriptive statistics for the purposes of future trial 
planning, and no statistical comparisons between the oral and IV antiviral arms will be made. 
 
3.4.2 Safety 
Safety will be assessed by evaluating the clinical significance of laboratory abnormalities and 
AEs and all serious adverse events SAEs. The overall occurrences of AEs and SAEs will be 
reported by SOC and PT. The AEs and SAEs will also be evaluated and reported by the 
relationship to study drug, severity and the outcome. All the results will be summarized by 
study arm and/or by clinical site as appropriate. Results will be presented in Tables 9 - 11 and 
Listings 1 – 3.  
 
 
 
 


4. 
PROPOSED SUMMARY TABLES, GRAPHS AND LISTINGS 
4.1 
Mock Tables 
Table 1. Subject Demographics 
Characteristics 
Site 1 
Site 2 
Total  
 
Arm 1 
(n= ) 
Arm 2 
(n= ) 
Total 
(n= ) 
Arm 1 
(n= ) 
Arm 2 
(n= ) 
Total 
(n= ) 
Arm 1 
(n= ) 
Arm 2 
(n= ) 
Total 
(n= ) 
Age 
 
 
 
 
 
 
 
 
        n 
 
 
 
 
 
 
 
 
 
 
Mean (SD), Min--Max 
 
 
 
 
 
 
 
 
Sex, n (%) 
 
 
 
 
 
 
 
 
 
Female 
 
 
 
 
 
 
 
 
Male 
 
 
 
 
 
 
 
Ethnicity, n (%) 
 
 
 
 
 
 
 
 
Hispanic or Latino 
 
 
 
 
 
 
 
 
Non-Hispanic or Non-Latino 
 
 
 
 
 
 
 
 
Unknown 
 
 
 
 
 
 
 
Race, n (%) 
 
 
 
 
 
 
 
 
American Indian or Alaskan Native 
 
 
 
 
 
 
 
 
Asian 
 
 
 
 
 
 
 
 
Black or African American 
 
 
 
 
 
 
 
 
Native Hawaiian/Other Pacific Islander 
 
 
 
 
 
 
 
 
White 
 
 
 
 
 
 
 
 
Other 
 
 
 
 
 
 
 
CDC Criteria for Antiviral Treatment, n (%) 
 
 
 
 
 
 
 
 
 
 
Hospital Admission 
 
 
 
 
 
 
 
 
 
 
Complications/Pneumonia 
 
 
 
 
 
 
 
 
 


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Characteristics 
Site 1 
Site 2 
Total  
 
Arm 1 
(n= ) 
Arm 2 
(n= ) 
Total 
(n= ) 
Arm 1 
(n= ) 
Arm 2 
(n= ) 
Total 
(n= ) 
Arm 1 
(n= ) 
Arm 2 
(n= ) 
Total 
(n= ) 
 
Age 65 or Greater 
 
 
 
 
 
 
 
 
 
 
Chronic Pulmonary 
 
 
 
 
 
 
 
 
 
 
Chronic Cardiovascular 
 
 
 
 
 
 
 
 
 
 
Chronic Renal 
 
 
 
 
 
 
 
 
 
 
Chronic Hepatic 
 
 
 
 
 
 
 
 
 
 
Chronic Hematologic 
 
 
 
 
 
 
 
 
 
 
Chronic Metabolic 
 
 
 
 
 
 
 
 
 
 
Chronic Neurologic 
 
 
 
 
 
 
 
 
 
 
Immunosuppression 
 
 
 
 
 
 
 
 
 
 
Pregnancy or Less than Two Weeks Postpartum 
 
 
 
 
 
 
 
 
 
 
Morbid Obesity 
 
 
 
 
 
 
 
 
 
 
Resides in Nursing Home 
 
 
 
 
 
 
 
 
 
 
Native American 
 
 
 
 
 
 
 
 
 
 
Study Arm:  
 
Arm 1 = Oral antiviral treatment (Oseltamivir) 
 
Arm 2 = IV antiviral treatment (Peramivir) 
 
 
 
 


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Table 2. Subject Symptom Onset and Baseline NEWS Score 
 
N (%) 
Site 1 
Site 2 
Total 
Influenza Type 
Arm 1 
(n= ) 
Arm 2 
(n= ) 
Total 
(n= ) 
Arm 1 
(n= ) 
Arm 2 
(n= ) 
Total 
(n= ) 
Arm 1 
(n= ) 
Arm 2 
(n= ) 
Total 
(n= ) 
A 
(n= ) 
B 
(n= ) 
Time of Symptom Onset 
at Enrollment 
 
 
 
 
 
 
 
 
 
 
 
 
Within 2 Days 
 
 
 
 
 
 
 
 
 
 
 
3 Days 
 
 
 
 
 
 
 
 
 
 
 
4 Days 
 
 
 
 
 
 
 
 
 
 
NEWS Score 
 
 
 
 
 
 
 
 
 
 
 
Median (Min—Max) 
 
 
 
 
 
 
 
 
 
 
 
 
0 
 
 
 
 
 
 
 
 
 
 
 
 
1-3 
 
 
 
 
 
 
 
 
 
 
 
 
4-6 
 
 
 
 
 
 
 
 
 
 
 
 
>6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 3. Summary of Subject Status 
 
 
N (%) 
Site 1 
Site 2 
Total 
Influenza Type 
Arm 1 
(n= ) 
Arm 2 
(n= ) 
Total 
(n= ) 
Arm 1 
(n= ) 
Arm 2 
(n= ) 
Total 
(n= ) 
Arm 1 
(n= ) 
Arm 2 
(n= ) 
Total 
(n= ) 
A 
(n= ) 
B 
(n= ) 
Subjects Enrolled 
 
 
 
 
 
 
 
 
 
 
Subjects Completed 
Treatment (%) in the ED 
 
 
 
 
 
 
 
 
 
 
 
Subjects Completed 
Follow up 
 
 
 
 
 
 
 
 
 
 
 
Number of Doses (Median,  
Min—Max)
 
- 
- 
 
- 
- 
 
- 
- 
- 
- 
NEWS Score 
 
 
 
 
 
 
 
 
 
 
Percent Daily Dairies 
Completed
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 4. Summary of FLU-PRO Symptoms  
 
 
Symptom Severity 
Score by Domain 
of Symptoms 
 Mean (Standard Deviation), Min-Max 
Site 1 
Site 2  
Total 
Influenza Type 
Arm 1 
(n= ) 
Arm 2 
(n= ) 
Total 
(n= ) 
Arm 1 
(n= ) 
Arm 2 
(n= ) 
Total 
(n= ) 
Arm 1 
(n= ) 
Arm 2 
(n= ) 
Total 
(n= ) 
A 
(n= ) 
B 
(n= ) 
Nose 
 
 
 
 
 
 
 
 
 
 
Throat 
 
 
 
 
 
 
 
 
 
 
Eyes 
 
 
 
 
 
 
 
 
 
 
Chest/ Respiratory 
 
 
 
 
 
 
 
 
 
 
Gastrointestinal 
 
 
 
 
 
 
 
 
 
 
Body/ Systemic 
 
 
 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
 
# Days Missed 
Questionnaire 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 5. Clinical Outcomes 
 
Outcomes 
Site 1 
Site 2 
Total 
Influenza 
Type 
Arm 1 
(n= ) 
Arm 2 
(n= ) 
Total 
(n= ) 
Arm 1 
(n= ) 
Arm 2 
(n= ) 
Total 
(n= ) 
Arm 1 
(n= ) 
Arm 2 
(n= ) 
Total 
(n= ) 
A 
(n= )
B 
(n= ) 
Pneumonia  
 
 
 
 
 
 
 
 
 
 
 
Inpatient, n (%) 
 
 
 
 
 
 
 
 
 
 
 
Outpatient, n (%) 
 
 
 
 
 
 
 
 
 
 
 
Pneumonia Severity Index 
 
(Median, Min—Max) 
 
 
 
 
 
 
 
 
 
 
 
Hospitalization, n (%) 
 
 
 
 
 
 
 
 
 
 
 
LOS 
 
(Mean, St. Dev., Min—Max) 
 
 
 
 
 
 
 
 
 
 
 
 
Hospitalization with 
Pneumonia,   
n (%)   
 
LOS 
 
(Mean, St. Dev.,  Min—Max) 
 
 
 
 
 
 
 
 
 
 
 
Karnofsky Performance Scale 
 
 
 
 
 
 
 
 
 
 
 
 
Mean, St. Dev. 
 
 
 
 
 
 
 
 
 
 
 
 
Median, Min—Max 
 
 
 
 
 
 
 
 
 
 
 
Patient Global Impression of Change 
 
(Median, Min—Max)  
 
 
 
 
 
 
 
 
 
 
 
 
Day 7 
 
 
 
 
 
 
 
 
 
 
 
 
Day 28 
 
 
 
 
 
 
 
 
 
 
 
Patient Global Impression of 
Severity  
(Median, Min—Max) 
 
 
 
 
 
 
 
 
 
 
 
 
Enrollment 
 
 
 
 
 
 
 
 
 
 
 
 
Day 7 
 
 
 
 
 
 
 
 
 
 
 
 
Day 28 
 
 
 
 
 
 
 
 
 
 
 


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Outcomes 
Site 1 
Site 2 
Total 
Influenza 
Type 
Arm 1 
(n= ) 
Arm 2 
(n= ) 
Total 
(n= ) 
Arm 1 
(n= ) 
Arm 2 
(n= ) 
Total 
(n= ) 
Arm 1 
(n= ) 
Arm 2 
(n= ) 
Total 
(n= ) 
A 
(n= )
B 
(n= ) 
Number of Subsequent Medical 
Visits or Hospitalizations  
 
(Median, Min—Max) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 6. Influenza-Related Complications 
 
Influenza-Related Complications               
# Subjects (%) 
Site 1 
Site 2 
Total 
Influenza 
Type 
Arm 1 
(n= ) 
Arm 2 
(n= ) 
Total 
(n= ) 
Arm 1 
(n= ) 
Arm 2 
(n= ) 
Total 
(n= ) 
Arm 1 
(n= ) 
Arm 2 
(n= ) 
Total 
(n= ) 
A 
(n= )
B 
(n= )
Pneumonia 
  
  
 
 
 
 
 
 
 
 
 
Myocardial Infarction 
  
  
 
 
 
 
 
 
 
 
 
Stroke 
  
  
 
 
 
 
 
 
 
 
 
Severity of Disease 
 
 
 
 
 
 
 
 
 
 
 
 
Intensive Care Unit (ICU) Admission 
 
 
 
 
 
 
 
 
 
 
 
 
Mechanical Ventilation 
 
 
 
 
 
 
 
 
 
 
 
 
Oxygen Supplementation 
 
 
 
 
 
 
 
 
 
 
 
Ordinal Scale (up to 14 Days) 
 
 
 
 
 
 
 
 
 
 
 
 
Death 
 
 
 
 
 
 
 
 
 
 
 
 
Mechanical Ventilation or 
 
Extracorporeal Membrane 
 
Oxygenation (ECMO) 
 
 
 
 
 
 
 
 
 
 
 
 
ICU without Mechanical 
 
Ventilation or ECMO 
 
 
 
 
 
 
 
 
 
 
 
 
Non-ICU Hospitalization, Requiring 
 
Supplemental Oxygen 
 
 
 
 
 
 
 
 
 
 
 
 
Non-ICU Hospitalization, Not 
 
Requiring Supplemental Oxygen 
 
 
 
 
 
 
 
 
 
 
 
 
Not Hospitalized, but Unable to 
 
Resume Normal Activities 
 
 
 
 
 
 
 
 
 
 
 
 
Not Hospitalized, with Full 
 
Resumption of Normal Activities 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 7. Characteristics of Subjects Initially Admitted to the Hospital from the ED 
 
 
Characteristics 
# Subjects (%) 
Site 1
Site 2
Total
Influenza Type
Arm 1 
(n= ) 
Arm 2 
(n= ) 
Total 
(n= ) 
Arm 1 
(n= )
Arm 2 
(n= )
Total 
(n= )
Arm 1 
(n= )
Arm 2 
(n= )
Total 
(n= )
A 
(n= )
B 
(n= )
Severity of Disease 
 
 
 
 
 
 
 
 
 
 
 
Intensive Care Unit (ICU) 
Admission 
 
 
 
 
 
 
 
 
 
 
 
Mechanical Ventilation 
 
 
 
 
 
 
 
 
 
 
 
Oxygen Supplementation 
 
 
 
 
 
 
 
 
 
 
 
Ordinal Scale (up to 14 Days) 
 
 
 
 
 
 
 
 
 
 
 
Death 
 
 
 
 
 
 
 
 
 
 
 
Mechanical Ventilation or 
 
Extracorporeal Membrane 
 
Oxygenation (ECMO) 
 
 
 
 
 
 
 
 
 
 
 
 
ICU without Mechanical 
 
Ventilation or ECMO 
 
 
 
 
 
 
 
 
 
 
 
 
Non-ICU Hospitalization, 
Requiring Supplemental Oxygen 
 
 
 
 
 
 
 
 
 
 
 
 
Non-ICU Hospitalization, 
Not Requiring Supplemental 
Oxygen 
 
 
 
 
 
 
 
 
 
 
 
 
Not Hospitalized, but 
Unable to Resume Normal 
Activities 
 
 
 
 
 
 
 
 
 
 
 
 
Not Hospitalized, with Full 
Resumption of Normal Activities 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 8. Patient Screening and Testing for Influenza 
 
 
Site 1 
Site 2 
Total 
N 
% 
N 
% 
N 
% 
Patients through ED 
 
 
 
 
Of Patients through ED, N(%) Screened with 
CDG 
 
 
 
 
Of Patients Screened with CDG, N(%) Who 
Met Testing Criteria (score ≥3) 
 
 
 
 
Of Patients Who Met Testing Criteria, N(%) 
Who Had Tests Ordered 
 
 
 
 
 
 
Of Patients Who Met Testing Criteria, N(%) 
Who Had Tests Collected and Resulted 
 
 
 
 
 
 
Of Those Tested, N(%) Positive for Influenza 
 
 
 
 
 
 
Of Those Tested Positive, N(%) Enrolled and 
Randomized 
 
 
 
 
 
 
 
 
 
 


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Table 9. Summary of Adverse Events by System Organ Class and Preferred Term, with number (%) of subjects reporting at least one 
adverse event 
 
SYSTEM 
ORGAN CLASS 
Study Arm 1 
Study Arm 2 
Total 
Grade of AE 
Grade of AE 
Grade of AE 
     Preferred Term 
1 
2 
3 
4 
5 
Total
1 
2 
3 
4 
5 
Total
1 
2 
3 
4 
5 
Total
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 10. Summary of Adverse Events by Relationship to Study Drug and Severity 
 
Adverse Events 
Study Arm 1 
Study Arm 2 
Total  
# Events 
% 
# Events 
% 
# Events 
% 
Total Number of Adverse Events 
 
- 
 
- 
 
- 
Relatedness to Study 
  
  
 
 
 
 
 
Not related 
  
  
 
 
 
 
 
Related 
  
  
 
 
 
 
Severity of AE 
  
  
 
 
 
 
 
Mild 
  
  
 
 
 
 
 
Moderate 
  
  
 
 
 
 
 
Severe 
  
  
 
 
 
 
 
Potentially Life Threatening or 
 
Disabling 
 
 
 
 
 
 
 
Death 
 
 
 
 
 
 
 
 
 
 
 


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Table 11. Frequency of Protocol-Specific Adverse Event 
 
Symptoms 
AE Code 
(MedDRA, CTCAE) 
N (%) 
Allergy/Hypersensitivity Reaction 
 
  
Rash or Skin Reaction 
 
  
Altered Mental Status 
 
  
--- 
 
  
 
 
  
 
 
 
 


4.2 
Mock Graphs 
Figure 1. Study Patient Screening and Enrollment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EXCLUDED: 
•
Did not meet enrollment criteria (N =) 
EXCLUDED: 
•
Declined (N =)  
•
Did not like the idea of participating in 
research (N =) 
•
Felt too sick to be in a study (N =) 
 
 
Consented 
N = 
Approached 
N =  
Enrolled & Randomized 
N =  
EXCLUDED: 
•
Screen Failures (N =)  
•
Did not want to wait for required labs 
(N =) 
•
HIV exclusion criteria (N = ) 
•
Liver function exclusion criteria (N=) 
Met Enrollment Criteria 
N =  
Influenza Positive Patients 
N =  
Treated and Analyzed 
N =  
EXCLUDED: 
•
Dropped out (N =)  
Not Approached: 
• 
Research staff missed patient (N =) 
• 
Patient left department prior to Flu Pos 
result (N=) 
• 
Patient ineligible (N=) 
• 
Age <18 years  (N=) 
 


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Figure 2. FLU-PRO Symptom Severity Score for Enrolled Patients, by Domain of Symptoms, up 
to 14 Days from Enrollment  
 
Figure 3. Karnofsky Performance Scale, Mean and 95% Confidence Band of Daily Scores 
 
 
Figure 4. Severity of Disease for Hospitalized Patients, up to 14 Days from Enrollment 
 
Figure 5. Ordinal Scale for Hospitalized Patients, up to 14 Days from Enrollment 
 
 
 


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4.3 
Mock Listings 
Listing 1. Patient Level Adverse Events 
 
Patient 
Identifier 
Site 
Study 
Arm 
Start 
Date 
Resolutio
n Date 
AE Code 
(MedDRA
, CTCAE) 
Severity 
SAE? 
(Y/N) 
Related-
ness 
Hospitali-
zation 
Type 
Outcome 
Comments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severity of AE: 
 
Relatedness to Study Drug: 
1 = Mild 
 
0 = Not related 
2 = Moderate 
 
1 = Related 
3 = Severe 
 
 
4 = Potentially Life threatening or disabling  
5 = Death 
 
 
Outcome: 
 
Hospitalization: 
1 = Ongoing 
 
0 = None 
2 = Resolved without sequelae 
 
1 = ICU 
3 = Resolved with sequelae 
 
2 = Step down unit 
4 = Death** 
 
3 = Other 
5 = Worsened 
6 = Chronic 
7 = Lost to follow-up 
 
 
 
  
**Provide further details regarding all reported serious AEs and deaths in the SAE and Subject Deaths tables listed at the end of this 
section. 
 
 
 


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Listing 2. Serious Adverse Events 
 
Patient 
Identifier
 
Site
 
Study 
Arm 
SAE 
Onset 
Date 
Outcome 
Date 
Outcome
SAE 
Classification
 
Severity 
Related to 
Study Drug 
Description of Actions 
and Outcomes (e.g. 
hospitalization, 
withdrawn from study) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severity of SAE: 
 
 
Relatedness to Intervention: 
1 = Mild 
 
 
0 = Not related 
2 = Moderate 
 
 
1 = Related 
3 = Severe 
 
 
4 = Life threatening or disabling 
 
5 = Death 
 
 
SAE Classification: 
 
 
 
 
Outcome: 
1 = Death 
 
 
1 = Ongoing 
2 = Life threatening 
 
 
2 = Resolved without sequelae 
3 = Inpatient hospitalization 
 
 
3 = Resolved with sequelae 
or prolonged hospitalization 
 
 
4 = Death** 
4 = Persistent/significant disability/incapacity 
5 = Worsened 
5 = Resulted in congenital anomaly/birth defect 
6 = Chronic 
6 = Important medical event 
 
 
7 = Lost to follow-up 
 
Listing 3. Deaths 
Patient 
Identifier 
 
Site 
Study 
Arm 
Age 
Date 
Enrolled 
Treatme
nt Date 
Cause of 
Death 
Date of 
Death 
Comments 
 
 
 
 
 
 
 


Seasons 3 & 4 Protocol 
 
Version: 2.0 
Influenza Therapeutic Pilot 
 
9/26/2016 
2 
 
Table of Contents 
Sponsor and Principal Investigator Signatures ...................................................................................... 5 
List of Abbreviations................................................................................................................................... 6 
Protocol Summary ...................................................................................................................................... 8 
Schematic of Study Design ..................................................................................................................... 10 
1. 
Background ....................................................................................................................................... 11 
1.1. 
Scientific Rationale ................................................................................................................... 11 
1.2. 
Potential Risks and Benefits ................................................................................................... 11 
1.2.1. 
Potential Risks ...................................................................................................................... 12 
1.2.2. 
Potential Benefits.................................................................................................................. 14 
2. 
Objectives .......................................................................................................................................... 14 
2.1. 
Study Objectives ....................................................................................................................... 14 
2.2. 
Study Outcome Measures ...................................................................................................... 15 
3. 
Systematic Influenza Testing in the Emergency Department ................................................... 16 
3.1. 
Clinical Decision Guideline/Electronic Decision Support System Implementation ........ 16 
3.1.1. 
Clinical Decision Guideline ................................................................................................. 16 
3.1.2. 
Electronic Decision Support System ................................................................................. 17 
3.1.3. 
Run-In Period ........................................................................................................................ 18 
3.2. 
Biological Specimens ............................................................................................................... 18 
3.2.1. 
Safety Precautions ............................................................................................................... 18 
3.2.2. 
Sample Collection ................................................................................................................ 18 
3.2.3. 
Sample Processing and Labeling ...................................................................................... 18 
3.2.4. 
Clinical Use of Waste Specimens ...................................................................................... 19 
4. 
Screening, Enrollment, and Follow-Up of Study Subjects ......................................................... 19 
4.1. 
Retrospective Chart Review ................................................................................................... 19 
4.1.1. 
Screening ............................................................................................................................... 19 
4.1.2. 
Eligibility Criteria ................................................................................................................... 19 
4.1.3. 
Informed Consent ................................................................................................................. 20 
4.1.4. 
Data Collection ..................................................................................................................... 20 
4.2. 
Methods: Randomized Controlled Trial of Influenza Antivirals ......................................... 20 
4.2.1. 
Eligibility Criteria ................................................................................................................... 20 
4.2.2. 
Screening ............................................................................................................................... 22 


Seasons 3 & 4 Protocol 
 
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Influenza Therapeutic Pilot 
 
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4.2.3. 
Informed Consent ................................................................................................................. 23 
5. 
Study Visit Evaluations: Randomized Controlled Trial of Influenza Antivirals ........................ 23 
5.1. 
Screening/Enrollment .............................................................................................................. 23 
5.1.1. 
Chart Review ......................................................................................................................... 24 
5.1.2. 
Clinical Evaluations .............................................................................................................. 24 
5.1.3. 
Treatment Assignment Procedures ................................................................................... 25 
5.1.4. 
Treatment Administration .................................................................................................... 25 
5.1.5. 
Enrollment Completion ........................................................................................................ 26 
5.2. 
Follow-Up................................................................................................................................... 26 
5.2.1. 
Daily Diary ............................................................................................................................. 26 
5.2.2. 
Day 3 and Day 7 Subject “Check-In” ................................................................................. 27 
5.2.3. 
Day 28 Subject Follow-Up .................................................................................................. 27 
5.2.4. 
Medical Record Review ....................................................................................................... 27 
6. 
Study Drug Management ................................................................................................................ 28 
6.1. 
Study Drug Supply ................................................................................................................... 28 
6.2. 
Study Drug Formulation and Storage.................................................................................... 28 
6.3. 
Study Drug Dispensing and Administration .......................................................................... 29 
6.4. 
Study Drug Labeling ................................................................................................................ 29 
6.5. 
Study Drug Accountability ....................................................................................................... 29 
6.6. 
Monitoring Subject Compliance to Study Drug .................................................................... 29 
7. 
Adverse Event Management .......................................................................................................... 29 
7.1. 
General Management of Adverse Events ............................................................................ 30 
7.2. 
Protocol-Specific Adverse Event Management ................................................................... 30 
7.2.1. 
Allergy/Hypersensitivity Reaction to Study Drug ............................................................. 30 
7.2.2. 
Rash or Skin Reaction ......................................................................................................... 31 
7.2.3. 
Altered Mental Status .......................................................................................................... 31 
8. 
Safety Reporting ............................................................................................................................... 31 
8.1. 
Documenting, Recording, and Reporting Adverse Events ................................................ 31 
8.1.1. 
Adverse Event ....................................................................................................................... 31 
8.1.2. 
Serious Adverse Event ........................................................................................................ 32 
9. 
Statistical Considerations ................................................................................................................ 33 
9.1. 
Study Objectives ....................................................................................................................... 33 


Seasons 3 & 4 Protocol 
 
Version: 2.0 
Influenza Therapeutic Pilot 
 
9/26/2016 
4 
 
9.2. 
Sample Size Considerations .................................................................................................. 34 
9.3. 
Final Analysis Plan ................................................................................................................... 34 
10. 
Clinical Management Issues ....................................................................................................... 34 
10.1. 
Early Discontinuation of Study Treatment ........................................................................ 34 
10.2. 
Study Withdrawal.................................................................................................................. 35 
11. 
Protection of Human Subjects & Other Ethical Considerations ............................................ 35 
11.1. 
Ethical Conduct of the Study .............................................................................................. 35 
11.2. 
Institutional Review Board .................................................................................................. 35 
11.3. 
Informed Consent of Study Subjects ................................................................................. 35 
11.4. 
Confidentiality of Study Subjects ....................................................................................... 35 
12. 
Data Management ........................................................................................................................ 36 
12.1. 
Data Management Responsibilities ................................................................................... 36 
12.2. 
Data Capture Methods ........................................................................................................ 37 
12.3. 
Data Submission .................................................................................................................. 37 
12.4. 
Quality Control ...................................................................................................................... 37 
12.5. 
Protocol Deviations .............................................................................................................. 38 
12.6. 
Source Documents and Access to Source Data/Documents ........................................ 39 
12.7. 
Clinical Site Monitoring ........................................................................................................ 39 
Appendix 1: Schedule of Evaluations.................................................................................................... 40 
Appendix 2: Shipping of Nasopharyngeal Specimens for Storage................................................... 42 
Appendix 2a: Notice of Shipment .......................................................................................................... 43 
 
 
 


Seasons 3 & 4 Protocol 
 
Version: 2.0 
Influenza Therapeutic Pilot 
 
9/26/2016 
5 
 
Sponsor and Principal Investigator Signatures 
 
 
Sponsor Signature: 
 
 
 
 
 
 
Johns Hopkins University Representative 
 
 
 
 
 
 
Date 
Principal Investigator Statement and Signature: 
 
I have read and understand this protocol, agree to participate as a Principal Investigator, will 
ensure the protocol is followed as outlined, and will comply with applicable regulations and with 
Good Clinical Practice. 
 
 
 
 
 
 
Principal Investigator 
 
 
 
 
 
 
Date 
 
 
 
 
 
 
 


Seasons 3 & 4 Protocol 
 
Version: 2.0 
Influenza Therapeutic Pilot 
 
9/26/2016 
6 
 
 
List of Abbreviations 
 
AE 
Adverse Event/Adverse Experience 
AIDS 
Acquired Immunodeficiency Syndrome 
ASPR 
Assistant Secretary for Preparedness and Response 
BARDA 
Biomedical Advanced Research and Development Authority 
BMI 
Body Mass Index 
CBC 
Complete Blood Count 
CDC 
Centers for Disease Control and Prevention 
CDG 
Clinical Decision Guideline 
CFR 
Code of Federal Regulations 
Co-PI 
Co-Principal Investigator 
CQI 
Continuous Quality Improvement 
CrCl 
Creatinine Clearance 
CRF 
Case Report Form 
DAIDS 
Division of AIDS 
ECMO 
Extracorporeal Membrane Oxygenation 
ED 
Emergency Department 
EDSS 
Electronic Decision Support System 
EMR 
Electronic Medical Record 
FDA 
US Food and Drug Administration 
G6PD 
Glucose-6-Phosphate Dehydrogenase 
GCP 
Good Clinical Practice 
HAART 
Highly Active Antiretroviral Therapy 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human Immunodeficiency Virus 
IATA 
International Air Transport Association 
ICF 
Informed Consent Form 
ICU 
Intensive Care Unit 
ID 
Identification 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 
IT 
Information Technology 
IV 
Intravenous 
JHH 
Johns Hopkins Hospital 
LAIV 
Live Attenuated Influenza Vaccine 
MMC 
Maricopa Medical Center 
MOP 
Manual of Operating Procedures 
NP 
Nasopharyngeal 
OC 
Oracle Clinical 


Seasons 3 & 4 Protocol 
 
Version: 2.0 
Influenza Therapeutic Pilot 
 
9/26/2016 
7 
 
OHRP 
Office For Human Research Protections 
PGIC 
Patient Global Impression of Change 
PGIS 
Patient Global Impression of Severity 
PHI 
Protected Health Information 
PI 
Principal Investigator 
QA 
Quality Assurance 
RCT 
Randomized Controlled Trial 
RDC 
Remote Data Capture 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SMC 
Safety Monitoring Committee 
SOP 
Standard Operating Procedure 
TAT 
Turnaround Time 
US 
United States 
 
 
 
 
 


Seasons 3 & 4 Protocol 
 
Version: 2.0 
Influenza Therapeutic Pilot 
 
9/26/2016 
8 
 
Protocol Summary 
 
Title: 
A Pilot Randomized Controlled Trial for Feasibility of Enrolling 
Subjects for Influenza Therapeutic Trials and Administering 
Influenza Antivirals in the Emergency Department to High Risk 
Subjects 
Population: 
Adults presenting to the emergency department (ED) with 
laboratory-confirmed influenza who meet Centers for Disease 
Control and Prevention (CDC) criteria for antiviral treatment 
Informed Consent: 
Written informed consent 
Number of Sites: 
2 – large, urban, academically-affiliated, US EDs  
Study Duration: 
September 2015 – September 2018 
Subject Participation 
Duration: 
4 weeks 
Description of Agent 
or Intervention: 
Subjects will be randomized to either oral (oseltamivir) or 
intravenous (IV) (peramivir) antiviral treatment. 
Objectives: 
 
This pilot study is designed to demonstrate the feasibility of utilizing 
EDs as a primary site for subject enrollment in clinical trials 
evaluating influenza therapeutics, providing pilot data for future 
clinical trial design and planning.  
Primary Objective: To prospectively enroll high-risk subjects with 
laboratory-confirmed influenza into a randomized, open-label study 
of oral versus IV influenza therapeutic to include symptom 
evaluation and outcome assessments. 
Secondary Objective 1: To identify influenza-positive patients 
utilizing a previously established triage-based assessment and rapid 
testing algorithm for suspected influenza infection.  
Secondary Objective 2: To retrospectively evaluate all potentially 
eligible patients for potential enrollment biases. 
Secondary Objective 3: To create a repository of residual 
nasopharyngeal (NP) samples collected from ED patients with 
suspected influenza illness. 
Description of Study 
Design: 
This is an open-label randomized controlled clinical trial in which 
subjects with influenza are randomized to either oral (oseltamivir) or 
IV (peramivir) antiviral treatment.  


Seasons 3 & 4 Protocol 
 
Version: 2.0 
Influenza Therapeutic Pilot 
 
9/26/2016 
9 
 
Estimated 
Time 
to 
Complete 
Enrollment: 
Subject enrollment will occur over two influenza seasons (November 
2015 – April 2017) or longer, at the co-principal investigators’ (Co-
PIs’) discretion, based on influenza prevalence. 
 
 
 
 


Seasons 3 & 4 Protocol 
 
Version: 2.0 
Influenza Therapeutic Pilot 
 
9/26/2016 
10 
 
Schematic of Study Design 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
YES 
Eligibility Criteria (must meet all): 
 
18 years of age and older 
 
Positive influenza test 
 
Meets CDC criteria for antiviral treatment 
 
Symptomatic ≤4 days (96 hours) prior to antiviral treatment 
 
Able to provide informed consent and comply with follow-up  
 
Does not meet any exclusion criteria (see section 4.2.1) 
Enrollment and Randomization 
(regardless of severity or disposition 
decision) 
 
Baseline laboratory tests and 
chest x-ray 
 
Structured questionnaire 
(demographics, history of 
present illness, past medical 
history)  
Daily Diary (14 days) 
NO 
Ineligible 
PERAMIVIR (IV) 
OSELTAMIVIR (oral) 
Follow-Up (28 days) 
 
Symptoms 
 
Medication adherence (if applicable)  
 
Functional assessment 
 
Symptoms 
 
Other medical visits  
 
Functional assessment 
 
Chart review (Day 7 and Day 28)  


Seasons 3 & 4 Protocol 
 
Version: 2.0 
Influenza Therapeutic Pilot 
 
9/26/2016 
11 
 
1. Background 
1.1. 
Scientific Rationale 
Although new influenza therapeutics are needed to mediate population level morbidity and 
mortality associated with both seasonal and pandemic influenza, clinical trials evaluating 
emerging therapeutics have been challenging. One well-recognized challenge with prior large 
trials is that they historically have recruited otherwise healthy subjects at clinical sites with 
relatively low rates of recruitment, resulting in the need to engage up to hundreds of recruitment 
sites, and a relative lack of patients with more severe and/or complicated illness. This has 
introduced management challenges with trial implementation and evaluation, including high 
associated costs for subject recruitment and retention. 
As the first line of care for many patients with influenza, and over 130 million visits/year, US 
emergency departments (EDs) represent an as yet untapped clinical venue for recruiting 
individuals with influenza into clinical trials. Notably, EDs also have the advantage of caring for 
patients early in their clinical course, and frequently serve as the initial site of care for those with 
complicated and/or severe influenza. Taken together, this creates opportunities which could be 
leveraged for design and implementation of more streamlined influenza therapeutic clinical trial 
design. We propose a pilot study to demonstrate the feasibility of utilizing EDs as primary sites 
for subject enrollment in clinical trials evaluating influenza therapeutics, providing data to inform 
future clinical trial design and planning. 
1.2. 
Potential Risks and Benefits 
The risks and benefits for subjects enrolled in this trial are appropriately balanced. All of the 
study interventions are consistent with recommended clinical practice. The triage algorithm for 
influenza testing is a standard operating procedure (SOP) in the ED from November through 
April. The drugs under study (i.e., oseltamivir and peramivir) have both been approved by the 
US Food and Drug Administration (FDA) for the treatment of acute uncomplicated influenza in 
patients 18 years and older who have been symptomatic for no more than two days. 
Additionally, the Centers for Disease Control and Prevention (CDC), Infectious Diseases 
Society of America, and the World Health Organization recommend antiviral treatment with a 
neuraminidase inhibitor as soon as possible for all persons with suspected or confirmed 
influenza who are at higher risk for influenza complications, or who have severe or complicated 
illness. These recommendations come from multiple observational studies showing reduction in 
morbidity and mortality. The strongest evidence remains in hospitalized patients, where both 
early initiation of antiviral treatment (less than two days from illness onset) and treatment up to 
five days after symptom onset were associated with reduced mortality, with greater benefit 
associated with earlier initiation of treatment. All subjects in this study will be adults at higher 
risk for influenza, who are recommended to receive antiviral treatment in accordance with CDC 
recommendations. Many of these subjects may require hospitalization for disease severity 
and/or 
underlying 
conditions. 
[http://www.cdc.gov/flu/professionals/antivirals/antiviral-use-
influenza.htm]  


Seasons 3 & 4 Protocol 
 
Version: 2.0 
Influenza Therapeutic Pilot 
 
9/26/2016 
12 
 
1.2.1. 
Potential Risks 
The risks to subjects enrolled in the study will be comparable to those encountered by similar 
patients receiving standard care. These risks include minor risks associated with study 
participation and adverse events (AEs), including reactions to the study drugs (see below). 
Subjects will be carefully screened to ensure that they meet all study inclusion criteria and do 
not have any exclusion criteria that would put them at unnecessary risk from study participation. 
Subjects will be contacted for follow-up at Day 28, and will have access 24 hours a day, 7 days 
a week, to on-call research staff, investigators, and emergency care if questions should arise.  
Minor risks associated with study participation include added time associated with completing 
study questionnaires, pain or discomfort during a blood draw, or unanticipated disclosure of a 
subject’s underlying medical conditions. To minimize these risks and discomforts, trained 
personnel who have completed all Health Insurance Portability and Accountability Act (HIPAA) 
training and procedures associated with enrollment of human subjects and study related 
procedures, will approach, consent, enroll patients, and collect data. Further, trained personnel 
will only approach patients and conduct study related activities during patients’ ED wait times, 
decreasing risk of potential increased ED care time associated with study related procedures. 
Baseline laboratory tests and a chest x-ray are non-invasive and standard treatment in the ED, 
and therefore, pose no additional study-associated risk. To minimize any potential discomfort, 
trained personnel will collect all specimens. 
Subjects will be carefully screened for possible AEs after receiving study drug, and will be 
provided with information to contact the study team for any possible AE that occurs throughout 
the trial. Subjects with findings suggestive of possible AEs will have the appropriate 
investigations performed. Serious adverse events (SAEs) will be defined a priori, and reported 
to the independent safety monitor (ISM) and the Institutional Review Board (IRB) as described 
in section 8; subjects will be advised and provided with referral sites to seek medical treatment.  
The study will be conducted in accordance with Good Clinical Practice (GCP), and full 
compliance with 21 Code of Federal Regulations (CFR) Parts 11, 50, 54, 56, and 312; 45 CFR 
Part 46 (Protection of Human Subjects); and the HIPAA Privacy Rule. Procedures for managing 
protected health information (PHI) will be included in the written informed consent form (ICF). 
Numerous safeguards will be put in place to ensure the confidentiality and integrity of all data, 
addressing both the human and physical elements of protecting subject confidentiality. These 
include data management staff training in protection of human subjects and the ethical conduct 
of human research, systematic backup for the centralized database, use of encrypted data on 
durable media, and utilization of encryption and role-based access mechanisms for remote 
access in compliance with industry best practices and consistent with security and privacy 
requirements of the IRB. Any paper documentation containing PHI, such as informed consent 
documents, will be stored securely by research staff. See section 11.4 for further information on 
maintaining confidentiality to reduce PHI disclosure risks.  
Depending on the randomization, a subject may receive oseltamivir or peramivir. According to 
the current package insert, the following warnings and precautions, drug interactions, and AEs 
are reported with these study drugs: 


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Oseltamivir (Tamiflu) 
Warnings and Precautions: 
Serious skin/hypersensitivity reactions such as Stevens-Johnson Syndrome, toxic 
epidermal necrolysis and erythema multiforme: Discontinue TAMIFLU and initiate 
appropriate treatment if allergic-like reactions occur or are suspected. 
Neuropsychiatric events: Patients with influenza, including those receiving TAMIFLU, 
particularly pediatric patients, may be at an increased risk of confusion or abnormal 
behavior early in their illness. Monitor for signs of abnormal behavior. 
Drug Interactions: 
Live attenuated influenza vaccine (LAIV), intranasal:  
Do not administer until 48 hours following cessation of TAMIFLU.  
Do not administer TAMIFLU until two weeks following administration of the LAIV, 
unless medically indicated. 
Adverse Reactions: 
Most common adverse reactions (>1% and more common than with placebo): 
Treatment studies – Nausea, vomiting, bronchitis, insomnia, vertigo. 
Prophylaxis studies – Nausea, vomiting, diarrhea, abdominal pain. 
Peramivir (Rapivab) 
Warnings and Precautions: 
Serious skin/hypersensitivity reactions such as Stevens-Johnson Syndrome and 
erythema multiforme have occurred with RAPIVAB. 
Neuropsychiatric events: Patients with influenza may be at an increased risk of 
hallucinations, delirium, and abnormal behavior early in their illness. Monitor for signs of 
abnormal behavior. 
Drug Interactions: 
LAIV, intranasal: Avoid use of LAIV within 2 weeks before or 48 hours after 
administration of RAPIVAB, unless medically indicated. 
Adverse Reactions: 
Most common adverse reaction (incidence >2%) is diarrhea. 
This study is only enrolling subjects with confirmed influenza who are recommended to receive 
antiviral treatment according to current CDC guidelines, and treating them with appropriate 


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antiviral drugs which have been FDA approved to treat patients with influenza. The most 
commonly used antiviral treatment for influenza is oseltamivir, which is recommended by the 
CDC antiviral treatment guidelines. Oseltamivir has a low side effect profile, and has been 
shown to reduce the duration of symptoms in randomized control trials with outpatients and is 
approved by the FDA for treatment of uncomplicated influenza within 48 hours of symptom 
onset. Observational studies have shown that oseltamivir reduces mortality, hospital length of 
stay, and influenza-related complications in various high-risk groups. Peramivir, which is in the 
same neuraminidase inhibitor class as oseltamivir but is delivered in an intravenous (IV) 
formulation, has likewise been approved by the FDA for treatment of uncomplicated influenza 
within 48 hours of symptom onset. Peramivir also has a low side effect profile. There are 
insufficient studies to date, regarding the use of peramivir for hospitalized patients with 
influenza. 
1.2.2. 
Potential Benefits 
All of the study interventions are standard of care for patients with influenza, and both of the 
drugs under study are currently FDA approved and used for the treatment of acute 
uncomplicated influenza.  
Subjects will receive study drugs free of charge. Additionally, subjects will have more intensive 
follow-up than would be routinely provided for ED patients in these facilities, and therefore, any 
potential complications or treatment failure will be addressed more promptly than standard of 
care might otherwise allow. Further, an independent, on-call infectious diseases specialist will 
be made available as part of the study procedures to provide real time consultation to clinicians 
caring for subjects participating in the study, which may provide additional benefit to subjects 
participating in the study. Finally, participation in this study will help inform future studies of 
influenza treatment, which could help in developing improved treatment for future patients with 
influenza.  
 
2. Objectives 
2.1. 
Study Objectives 
Primary Objective: To prospectively enroll high-risk subjects with laboratory-confirmed influenza 
into a randomized, open-label study of oral versus IV influenza therapeutic to include symptom 
evaluation and outcome assessments. 
Secondary Objective 1: To identify influenza-positive patients utilizing a previously established 
triage-based assessment and rapid testing algorithm for suspected influenza infection.  
Secondary Objective 2: To retrospectively evaluate all potentially eligible patients for potential 
enrollment biases. 
Secondary Objective 3: To create a repository of residual nasopharyngeal (NP) samples 
collected from ED patients with suspected influenza illness.  


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2.2. 
Study Outcome Measures 
Primary Objective: To prospectively enroll high-risk subjects with laboratory-confirmed influenza 
into a randomized, open-label study of oral versus IV influenza therapeutic to include symptom 
evaluation and outcome assessments. 
Outcomes: The number of subjects successfully enrolled; the proportion of subjects who 
complete treatment with IV or oral study drug in the ED; the proportion of subjects who 
complete follow-up.  
In addition, the following clinical measures will be evaluated for planning future clinical trial 
endpoints: 
 
For all subjects: 
o Reported symptoms (including FLU-PRO Symptom Questionnaire); 
o Daily functional assessment; 
o Patient Global Impression of Change (PGIC) on Day 7 and Day 28; 
o Patient Global Impression of Severity (PGIS) at enrollment, and on Day 7 and Day 
28; 
o Number of subsequent medical visits or hospitalizations within 28 days of enrollment; 
and 
o Influenza-related complications including pneumonia, myocardial infarction, and 
stroke. 
 
For subjects initially admitted to the hospital from the ED: 
o Severity of disease based on Intensive Care Unit (ICU) admission, mechanical 
ventilation, or oxygen supplementation; and  
o Ordinal scale up to 14 days: 
 
Death; 
 
Receiving mechanical ventilation or extracorporeal membrane oxygenation 
(ECMO); 
 
In ICU (without mechanical ventilation or ECMO); 
 
Non-ICU hospitalization, requiring supplemental oxygen; 
 
Non-ICU hospitalization, not requiring supplemental oxygen; 
 
Not hospitalized, but unable to resume normal activities; and  
 
Not hospitalized with full resumption of normal activities. 


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Secondary Objective 1: To identify influenza-positive patients utilizing a previously established 
triage-based assessment and rapid testing algorithm for suspected influenza infection.  
Outcomes: The proportion of ED patients who were screened for influenza; the proportion of 
screened patients who met testing criteria; the proportion of patients who met testing criteria 
who were tested for influenza; the proportion of patients tested for influenza who were 
positive for influenza. 
Secondary Objective 2: To retrospectively evaluate all potentially eligible patients for potential 
enrollment biases.  
Outcome: The proportion of eligible patients who were enrolled; comparison of demographic 
characteristics between those who were prospectively enrolled versus not enrolled. 
Secondary Objective 3: To create a repository of residual NP samples collected from ED 
patients with suspected influenza illness.  
Outcome: The creation of a robust repository using all remnant samples of patients tested 
using the triage-based assessment and testing algorithm from November 2015 through April 
2017.  
 
3. Systematic Influenza Testing in the Emergency Department 
3.1. 
Clinical Decision Guideline/Electronic Decision Support System 
Implementation 
Prior to the initiation of the study, a previously derived Clinical Decision Guideline (CDG) for 
ordering influenza testing was fully integrated into the site’s electronic medical record (EMR) 
utilizing an Electronic Decision Support System (EDSS). This EDSS has now been integrated 
into the EMR at the Johns Hopkins Hospital (JHH) and at the Maricopa Medical Center (MMC) 
to inform clinician practice. This systematic influenza screening and testing program is part of 
the standard ED practice for recognition and management of patients with suspected influenza. 
3.1.1. 
Clinical Decision Guideline 
The previously derived and validated CDG will guide influenza testing in ED patients as follows: 
A patient will be indicated for influenza testing with Xpert Flu if he/she has a symptom score 
of 3 or greater. The symptom score is based on the following:  
 
Within the past 7 days, new or worsening cough (2 points) 
 
Within the past 7 days, new headache (1 point) 
 
Within the past 7 days, new subjective fever (1 point) 
 
Documented temperature at triage of 38C (100.4F) or greater (1 point) 


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3.1.2. 
Electronic Decision Support System 
Working collaboratively with a locally determined team (e.g., physicians, nursing, and 
information technology (IT) staff), the clinical pathway using an EDSS with the CDG has been 
integrated into the clinical flow and EMR to prompt influenza testing at initial triage. The overall 
flow of the EDSS is depicted in Figure 1. The EDSS will begin functioning in October of each 
influenza season. 
 
 
 
Figure 1: EDSS flow for influenza testing 
 
The EDSS will evaluate if the patient should receive influenza testing by screening for the 
criteria of the CDG. To determine if the patient is indicated for Xpert Flu testing, a triage nurse 
will be prompted (at triage) to complete the brief series of questions outlined above. If the 
testing is not indicated by the CDG (i.e., a score of less than 3), then there is no further action 
related to this EDSS. If the patient is indicated for influenza testing according to the CDG (i.e., a 
score of 3 or greater), then the EDSS will automatically generate a prompt stating that the Xpert 
Flu test is indicated for this patient. If the triage nurse orders the Xpert Flu test, an NP swab will 
be performed, and the specimen will be sent to the laboratory for processing. Alternatively, if the 
influenza test is not ordered, the triage nurse will be prompted to enter one of the following 
reasons for not testing: “Patient refused”; “Patient diagnosed with influenza within previous 48 
hours”; or “Other, (insert text).”  
For any patient receiving an Xpert Flu test through the EDSS, the result of the test will be 
recorded in the EMR when complete. Turnaround time (TAT) from placing the order to result 
received in the EMR will be tracked and it is anticipated that the laboratory will achieve TATs of 
less than 120 minutes (based on historical experience). However, while this is the expectation, if 
it is not met it does not constitute a protocol violation, as the influenza testing is part of routine 
care. 
Providers may choose to treat or not treat patients as is clinically indicated.  


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3.1.3. 
Run-In Period 
Beginning in October and running through April 30 of each influenza season or later, at the co-
principal investigators’ (Co-PIs’) discretion, based on influenza prevalence, all ED patients who 
are assessed at triage will be evaluated by the CDG and EDSS to determine if they meet the 
testing criteria of the CDG. To evaluate whether or not the CDG and EDSS are being properly 
implemented, there will be a run-in period during October of each influenza season. The 
purpose of this run-in period is to identify and correct any potential problems with 
implementation of the CDG and EDSS. Principal investigators (PIs) and research staff will 
closely monitor the implementation of the CDG and EDSS through a standardized monitoring 
and continuous quality improvement (CQI) process. 
During the run-in period, research staff will monitor implementation of the CDG and EDSS to 
ensure that registered ED patients are screened, and if they meet testing criteria, ensure that 
the order is placed and the test occurs. Research staff may be on site to act as a resource or to 
troubleshoot if any problems arise.  
Ongoing monitoring will occur throughout the study period (November 1 – April 30 of each 
influenza season, or later, at the Co-PIs’ discretion, based on influenza prevalence). 
Additionally, the Biomedical Advanced Research and Development Authority (BARDA) 
personnel will periodically conduct an independent audit to provide relevant feedback which will 
be informative for guiding future clinical trials. 
3.2. 
Biological Specimens 
3.2.1. 
Safety Precautions 
All safety guidelines of the local safety committee and/or institutional policies for handling 
biological specimens must be followed. Universal precautions guidelines are to be observed. 
3.2.2. 
Sample Collection 
From each patient who is indicated for Xpert Flu testing by the CDG through the EDSS, an NP 
sample will be collected by clinical staff according to standard of care practice, using a flocked 
swab and universal viral transport media, as is standard clinical practice. All staff collecting NP 
swabs must undergo appropriate training as required by the medical institution. Once collected, 
specimens will be transported to the hospital clinical virology laboratory and expeditiously 
processed according to institutional laboratory protocols.  
3.2.3. 
Sample Processing and Labeling 
Between November 1 and April 30 of each influenza season, following sample collection, one 
aliquot will be removed for immediate rapid testing using Xpert Flu. A sterile pipette, will be used 
to aliquot the remaining specimen into approximately five 0.5 mL aliquots. Each aliquot will be 
placed in a separate microtube and labeled with a Waste Specimen identification number and 
date of collection. These aliquots will be immediately stored in a -80⁰C freezer until shipment (a 
log sheet will be maintained on the freezer or in another specified area in the laboratory to 


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indicate waste sample number, collection date/time, storage time). Freezer boxes will be labeled 
with “BARDA ED FLU PILOT RCT,” the collection site, and the lowest waste specimen 
identification number included in that freezer box. If samples go outside of range minus -20⁰C, 
the samples will be considered compromised and the Coordinating Center must be notified 
immediately. 
3.2.4. 
Clinical Use of Waste Specimens  
Leftover samples will be batched, shipped to, and stored at the central study laboratory at JHH 
for future analysis (see Appendix 2). These de-identified samples and results will not be 
available for clinical care. 
 
4. Screening, Enrollment, and Follow-Up of Study Subjects 
This section describes the screening, enrollment and follow-up procedures for the:  
1. Retrospective Chart Review; and the 
2. Randomized Controlled Trial of Influenza Antivirals.  
During the 2015-2016 influenza season, this study was implemented only at JHH. During the 
2016-2017 influenza season, this study will operate at both JHH and MMC. 
4.1. 
Retrospective Chart Review 
In order to evaluate the full potential ED population who might have met criteria for enrollment, 
all potentially eligible patients will be evaluated via a retrospective chart review. Basic 
demographic characteristics of patients who were not approached for enrollment, and those 
who were approached but not enrolled, will be compared (in a de-identified manner) with those 
who were enrolled into the Randomized Controlled Trial of Influenza Antivirals. 
4.1.1. 
Screening 
Research staff will identify subjects by retrospectively screening all ED patient records who 
presented between November and April of each influenza season, or later, at PI discretion, 
based on influenza prevalence, for patients who meet all eligibility criteria. Basic presenting, 
demographic, and eligibility information will be recorded on the Screening and Enrollment Log 
for every patient who is screened for potential enrollment. Patients that do not meet inclusion 
criteria will be excluded from the Retrospective Chart Review; the reason for exclusion will be 
recorded. 
4.1.2. 
Eligibility Criteria 
Inclusion Criteria 
Full ED chart review will be performed on individuals who meet the following inclusion criteria at 
the time of the ED visit: 


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1) 18 years of age or older; 
2) Adult ED visit between November and April of each influenza season, or later, at the Co-
PIs’ discretion, based on influenza prevalence; and 
3) Positive influenza test associated with the ED visit 
Exclusion Criteria 
There are no exclusion criteria. 
4.1.3. 
Informed Consent 
Under a HIPAA waiver of consent, research staff will review patient charts to screen and confirm 
enrollment eligibility. This retrospective evaluation utilizes information that is already collected 
for clinical purposes and all data collected for the retrospective chart abstraction will ultimately 
be stripped of personal identifiers (see section 4.1.4).  
4.1.4. 
Data Collection  
For all eligible patients, research staff will review the ED and hospital records to retrospectively 
complete a set of structured clinical data forms to collect the following: basic demographic data; 
symptoms related to the CDG; criteria for CDC antiviral treatment; initial presentation and 
clinical course at the ED, including antiviral treatment, antibiotic treatment, Xpert Flu test or 
other influenza test information; and hospital course if subsequently admitted.  
In accordance with HIPAA regulations, no subject personal identifiers will be entered into the 
study database. Personal identifiers such as name and medical record number will be collected 
and recorded on a separate study identification (ID) sheet for purposes of completing the 
retrospective chart review. This identifying information will be linked to the remainder of the 
subject information only through the study ID number, and will ultimately be stripped of 
identifying information after all necessary data and samples are collected. Personal identifiers 
will be destroyed upon final completion and verification of the study database. 
All study documents will be kept locked in a limited access area. The study ID sheet that links 
the study ID numbers to the subject personal identifiers will be kept under double lock separate 
from all research files, accessible only to research staff. 
4.2. 
Methods: Randomized Controlled Trial of Influenza Antivirals 
4.2.1. 
Eligibility Criteria 
Inclusion Criteria 
To be considered eligible, patients must meet the criteria listed below at the time of screening: 
1) 18 years of age or older; 
2) Laboratory-confirmed positive influenza test associated with their current ED visit; 


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3) Presence of at least 1 of the following symptoms of acute respiratory illness for ≤4 days 
(96 hours):  
a. New or increased cough; 
b. New or increased shortness of breath;  
c. Change in sputum production (for adults 65 years of age or older); 
d. Sinus pain; 
e. Nasal congestion; 
f. Rhinorrhea; 
g. Sore throat;  
h. Subjective fever; or 
i. 
Documented fever of ≥38C. 
4) Meets at least one of the CDC criteria for antiviral treatment, defined as: 
a. 65 years of age or older; 
b. Pregnant* or less than two weeks postpartum; 
c. American Indian or Alaska Native; 
d. Morbid obesity (body mass index (BMI) ≥40); 
e. Current resident of nursing home or other chronic-care facility; 
f. Diagnosis 
of chronic 
pulmonary 
disease, 
cardiovascular 
disease 
(except 
hypertension alone), renal disease, hepatic disease, hematologic disease, metabolic 
disorders, neurologic and neurodevelopment conditions, or immunosuppression 
(including that caused by medications or by human immunodeficiency virus (HIV) 
infection);  
g. Admission to inpatient or an observation unit; or 
h. Clinical diagnosis of pneumonia (by the ED provider) 
*For the purpose of this study, pregnancy is an exclusion criterion. 
Exclusion Criteria 
To be considered eligible for enrollment, a patient must not meet any of the criteria listed below 
at the time of screening: 
1) Does not speak or understand English (JHH); or English or Spanish (MMC);  


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2) Unable or unwilling to provide informed consent; 
3) Previously enrolled in the study during the current influenza season; 
4) Unable to take oral medication; 
5) Unable to comply with all planned study procedures including availability for follow-up 
and willingness to complete study diary and self-assessment; 
6) Use of neuraminidase inhibitors within the past seven days; 
7) Known allergic reaction to neuraminidase inhibitors; 
8) Pregnant or breastfeeding; 
9) End-stage renal disease, defined as:  
a. Currently undergoing dialysis (either hemo or peritoneal); or  
b. Creatinine clearance (CrCl) of <10 mL/min. 
10) End-stage liver disease, as determined by the treating ED provider; 
11) Glucose-6-phosphate dehydrogenase (G6PD) deficiency by patient report; 
12) Immunodeficiency, defined as: 
a. Solid organ transplant patients receiving immunosuppression; 
b. Hematopoietic stem cell transplant patients within 12 months of transplant or with 
ongoing immunosuppression; 
c. Oncology patients who have had chemotherapy within the past 30 days; 
d. Current treatment with steroids equivalent to 10 mg of prednisone or more per day 
for greater than two weeks; 
e. Rheumatologic patients receiving immunosuppressive therapy; or 
f. HIV patients who meet one of the following criteria: 
i. 
Have a CD4 cell count of <200 cells/mm3 within the past 3 months;  
ii. 
Not actively receiving highly active antiretroviral therapy (HAART); or  
iii. 
Have an absolute lymphocyte count <1.0 x 103 cells/μL conducted at the current 
ED visit 
4.2.2. 
Screening 
Eligible subjects will be recruited by dedicated research staff 24 hours a day, 7 days a week. 
Screening and enrollment occur at the same visit.  


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Under a HIPAA waiver of consent, research staff will review current ED patient charts for adult 
ED patients who have a positive laboratory-confirmed influenza test during their current ED visit. 
If a patient appears to be eligible, the research staff will approach the patient’s ED provider to 
inform them that the patient is potentially eligible. Alternatively, providers may also refer 
potentially eligible patients to research staff. With the provider’s approval, research staff will 
approach the patient, verify that the patient meets eligibility criteria, and determine if he/she 
would like to participate in the study. 
Eligibility information will be recorded for every patient who is approached for potential study 
enrollment using a Screening and Enrollment Log. Patients who do not meet inclusion criteria or 
who meet an exclusion criterion will be deemed ineligible; the reason for their exclusion will be 
recorded. Screened patients who meet all inclusion and no exclusion criteria, i.e., who are 
eligible, will be approached for informed consent. For those patients who decline participation, 
the given reason for refusal to participate will be recorded. Screened patients who are eligible 
and provide written consent to participate in the study, will be randomized to a treatment arm 
and considered as enrolled in the study.  
4.2.3. 
Informed Consent 
Consent forms will be IRB-approved and the patient will be given sufficient time to read and 
review the document and discuss it with his/her family member, friend, or legal representative. If 
he/she requires assistance to reach his/her family member, friend, or legal representative, such 
as the use of a telephone, that will be facilitated. After this, he/she will be specifically asked if 
he/she has any questions or concerns, which will be addressed, or would like more time to 
consider his/her participation, which will also be provided. The investigator or research staff will 
explain the research study to the patient and answer any questions that may arise. The patient 
will sign the ICF prior to any procedures being done specifically for the study. The subject may 
withdraw consent at any time throughout the course of the trial. A copy of the signed informed 
consent will be given to the subject for his/her records; another copy will be included in the 
patient’s chart, and the original will be filed in a study binder. The rights and welfare of the 
subject will be protected by emphasizing to all potential study subjects that they will still be able 
to receive medical care at the facility if they decline to participate in this study. The site PI or 
designee will also sign the consent form indicating that the subject understands the risks and 
benefits of the study. 
 
5. Study Visit Evaluations: Randomized Controlled Trial of Influenza 
Antivirals 
5.1. 
Screening/Enrollment 
Following written informed consent, the research staff will complete an eligibility checklist and 
assign a study ID number. The following information and evaluations will be performed:  


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5.1.1. 
Chart Review 
Research staff will gather the following information: 
 
Basic laboratory studies: 
o Complete blood count (CBC); 
o Complete or basic metabolic panel; and  
o Serum (or urine) beta-hcg (for women of childbearing potential*). 
 
Calculate CrCl using the Cockcroft Gault equation (see Manual of Operating Procedures 
(MOP)); and  
 
Baseline chest x-ray. 
*For the purposes of this study, women will be considered of non-childbearing potential if they 
are greater than age 54 and have had no menses in the previous 12 months or if they are 
surgically sterile (e.g., hysterectomy with or without oophorectomy; fallopian tube ligation; 
endometrial ablation). 
In the majority of cases the above mentioned tests will be obtained for clinical purposes (at the 
time of enrollment or within the previous 24 hours). In cases where any of those tests have not 
been obtained, research staff will complete those tests as part of study procedures; results of 
these laboratory and/or imaging results will be given to the treating ED provider to include in 
his/her medical assessment of the patient. Patients with a CrCl <10 mL/min (or on 
hemodialysis), a positive beta-hcg, or those who did not have the appropriate laboratory studies 
performed, will be ineligible for enrollment and will not be randomized to receive antiviral 
treatment through this study.  
5.1.2. 
Clinical Evaluations 
Demographics and clinical data (medical and health history) will be collected using brief 
structured data forms and will include: 
 
Basic demographic data; 
 
Vaccination history; 
 
Co-morbid illness; 
 
History of present illness; 
 
Baseline PGIS; and the 
 
First day of the validated Daily FLU-PRO Symptom Questionnaire (F10) and the 
Functional Assessment (F12) form.  


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5.1.3. Treatment Assignment Procedures 
All eligible subjects will be randomized to receive one of two treatment groups using a 
computerized randomization system in the ratio of 1:1. Subjects will be randomized to receive 
either oral or IV antiviral treatment. Randomization will be performed by research staff after 
informed consent, laboratory results, and verification of all eligibility criteria have been 
performed (see MOP). 
5.1.4. Treatment Administration 
Subjects will begin their treatment regimen in the ED as described below: 
Oseltamivir 
Subjects randomized to the oral treatment arm will receive oral oseltamivir. Oseltamivir will 
be dosed based on CrCl results, as described below.  
 
CrCl Result 
 
Dosage of Oral 
Oseltamivir 
Frequency/Duration 
>60 mL/min 
75 mg 
Twice daily (every 12 hours) for 5 days 
>30 – 60 mL/min 
30 mg 
Twice daily (every 12 hours) for 5 days 
>10 – 30 mL/min 
30 mg 
Once daily (every 24 hours) for 5 days 
 
The first dose will be administered in the ED following randomization. The remaining doses 
will be taken on the subsequent four days, whether they are inpatient or outpatient, based 
on the screening CrCl results. If a dose is missed, subjects will be instructed to take the 
missed dose as soon as they remember, unless it is two hours or less before the next 
scheduled dose; in this case, subjects will be instructed to discard the missed dose, and 
continue to take the next dose at the usual time. Subjects will be instructed not to take two 
doses at a time to make up for a missed dose. 
Peramivir 
Subjects randomized to the IV treatment group will receive IV peramivir. Peramivir will be 
dosed based on CrCl results, as described below.  
CrCl Result 
 
Dosage of IV 
Peramivir 
Frequency/Duration 
≥50 mL/min 
600 mg 
One time 
30 – 49 mL/min 
200 mg 
One time 
10 – 29 mL/min 
100 mg 
One time 
 
 


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Subjects in the IV treatment arm will receive a single dose of IV peramivir in the ED following 
randomization. If the subject does not have an IV line, one will be placed by the clinical staff. If 
the clinical team’s plan is for the subject to be discharged home from the ED, he/she will receive 
no further study drug. If the clinical team’s plan is for the subject to be admitted to the hospital, 
the subject’s influenza treatment after leaving the ED will be up to the discretion of the inpatient 
treating provider. The inpatient treating provider will be informed of the subject’s participation in 
the study and will be provided with the option to continue the use of IV peramivir at the same 
dose (based on CrCl result) for each subsequent day for up to four days. Treatment will stop 
upon discharge from the hospital. Should a subject remain in the hospital after five days of 
treatment, and the subject is symptomatically better, treatment will stop. If the subject remains 
hospitalized after five days of treatment and has not improved, the treating provider will have the 
option to continue the use of IV peramivir daily for another five-day course.  
Study treatment, either oral or IV, may be stopped at the discretion of the treating provider 
should the provider believe that it is in the subject’s best medical interest.  
Treating providers of subjects who are admitted to the hospital will be provided with 24 hours a 
day/7 days per week access to an infectious diseases specialist, who will be available to consult 
on the use of peramivir and oseltamivir in admitted subjects. 
5.1.5. Enrollment Completion 
At the completion of all enrollment processes, subjects will be reminded that they need to 
complete a daily diary (to assess daily symptom severity, safety data, study drug adherence, as 
applicable, and provide a functional assessment) for 14 days between 3:00 PM – 11:59 PM 
local time. Subjects will be encouraged to complete the daily diary at the same time each day. 
Subjects will be reminded that research staff will be contacting them regarding daily diary 
entries and self-assessments, and at Days 3, 7, and 28 to collect follow-up information.  
Subjects will also be asked to sign an authorization for release of health information which will 
allow research staff to obtain information on the subject’s visits to other hospitals, should there 
be any subsequent medical encounters in the following 28 days. 
Subjects who are discharged from the ED will be instructed to follow the ED standard discharge 
procedures.  
5.2. 
Follow-Up 
After enrollment (Day 1), subjects will be expected to complete a daily diary each day for 14 
days, and complete “check-ins” on Days 3 and 7, and a follow-up assessment on Day 28. 
Research staff will also review the subject’s medical records on Day 7 and Day 28. 
5.2.1. 
Daily Diary 
Beginning with the day of enrollment, for 14 consecutive days, subjects will be asked to 
complete a daily diary. The daily diary is expected to take approximately 10 minutes per day to 
complete, and will consist of the following 3 sections: 1) FLU-PRO Symptom Questionnaire 


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(“Symptom Diary”); 2) medication adherence, side effect profile (including skin reactions and 
rash, neuropsychiatric events, nausea, vomiting, and diarrhea), and hospitalization history; and 
3) a functional assessment.  
Research staff will provide subjects with access to the web-based daily diary. The diary may be 
completed either by the subject via a secure web-based system that can be accessed from a 
personal web-enabled device, such as a laptop, personal computer, or tablet; or by personal 
contact (in-person or telephone) with trained research staff who will ask the questions and 
complete the web-based survey on behalf of the subject. If the subject is in the hospital, 
research staff will visit the subject daily to complete the diary.  
Each day following enrollment, the research staff will review the subject’s previous day’s diary to 
verify whether or not the diary entry was completed. Missed diary entries cannot be made up. If 
a diary entry is missed, the research staff will call to remind the subject to complete the next 
diary entry as well as all remaining entries. Research staff may also offer to continue to contact 
the subject daily to assist the subject in completing the daily diary. If at any point the subject 
reports a skin reaction, rash, confusion, or hallucinations, research staff will immediately call to 
instruct the subject to return to the ED for evaluation (see section 7.2). 
5.2.2. 
Day 3 and Day 7 Subject “Check-In” 
Research staff will call all subjects on Days 3 and 7 to assess tolerability of the study drug, any 
potential AEs, and hospitalization history. Additionally, on Day 7, subjects will be asked to 
complete the PGIC and PGIS. If the subject is in the hospital on Days 3 and/or 7, research staff 
will visit the subject in person to complete the “check-in,” and collect an NP swab to assess the 
duration and magnitude of virus shedding. If research staff are unable to reach subjects on 
Days 3 and 7, those “check-in” visits will be considered missed visits. Research staff must 
document each attempt made to reach the subject in the research record.   
5.2.3. 
Day 28 Subject Follow-Up 
Twenty-eight days from the date of enrollment, research staff will call the subject by telephone 
to complete the Follow-Up Assessment (F13) form, PGIC, and PGIS. Contact will be attempted 
on four consecutive days (unless requested otherwise by the subject) with at least one of the 
calls occurring during non-working hours (i.e., evenings or weekends). Subjects may be 
categorized as “unavailable for follow-up” if: 1) there is a minimum of four failed contact 
attempts; 2) the provided contact numbers are non-functional; or 3) the subject requests no 
further contact from the study. 
If the subject remains in the hospital, he/she will undergo an in-person interview to complete the 
required evaluations. 
5.2.4. 
Medical Record Review 
Research staff will review subjects’ medical records on Day 7 and Day 28. The following records 
will be reviewed: 


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 
Day 7: Medical records from the subject’s enrollment ED visit. 
 
Day 28: Medical records from subsequent ED visits, outpatient visits, and 
hospitalizations that occurred since the ED enrollment visit through Day 28. If the subject 
reports visits to other medical facilities at the “check-in” visits, the Day 28 follow-up visit, 
or at any other time, those records will be obtained and included in the medical record 
review. 
6. Study Drug Management 
6.1. 
Study Drug Supply 
Two types of study drug will be used in the Randomized Controlled Trial of Influenza Antivirals. 
Subjects will be randomized to one of the following treatments: 
 
Oseltamivir (oral); or 
 
Peramivir (IV). 
JHH and MMC will purchase oseltamivir. 
BioCryst Pharmaceuticals, Inc. will provide peramivir to JHH for this study. JHH will distribute 
peramivir to MMC with permission from BioCryst Pharmaceuticals, Inc. 
6.2. 
Study Drug Formulation and Storage 
Oseltamivir (Tamiflu) 
For this study oseltamivir capsules of 30 mg and 75 mg doses will be used. 
 
30 mg capsules (30 mg free base equivalent of the phosphate salt): light yellow hard 
gelatin capsules. “ROCHE” is printed in blue ink on the light yellow body and “30 mg” is 
printed in blue ink on the light yellow cap. 
 
75 mg capsules (75 mg free base equivalent of the phosphate salt): grey/light yellow 
hard gelatin capsules. “ROCHE” is printed in blue ink on the grey body and “75 mg” is 
printed in blue ink on the light yellow cap. 
Oseltamivir capsules should be stored at 25C (77F); excursions permitted to 15 to 30C (59 
to 86F). 
Peramivir (Rapivab) 
Peramivir injection is a clear, colorless sterile, isotonic solution. Each single-use vial contains 
200 mg per 20 mL (10 mg/mL) of peramivir in a clear glass vial. Peramivir injection is supplied in 
cartons containing three single-use vials.  
Vials of peramivir injection should be stored in original cartons at 20° to 25°C (68° to 
77°F). Excursions are permitted to 15° to 30°C (59° to 86°F).  


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6.3. 
Study Drug Dispensing and Administration 
Oseltamivir will be prescribed and dispensed based on the subject’s CrCl result obtained at 
screening. The first dose of oseltamivir will be administered in the ED. The remaining doses will 
be dispensed and given to the subject before being discharged from the ED (see section 5.1.4). 
Peramivir will be prescribed and dispensed based on the subject’s CrCl result obtained at 
screening. Peramivir is prescribed as a onetime dose to be administered in the ED. If the 
subject is admitted to the hospital from the ED, the inpatient treating provider may choose to 
continue administering IV peramivir (see section 5.1.4). Refer to the peramivir package insert for 
instructions on preparing peramivir for IV infusion.  
6.4. 
Study Drug Labeling 
The Pharmacist of Record (PoR) is responsible for ensuring that each container of study drug, 
dispensed to subjects, is labeled in accordance with federal, local, and institutional labeling 
requirements. The label must bear the statement, "Caution: New Drug--Limited by Federal (or 
United States) law to investigational use" per 21 CFR 312.6 (a). 
6.5. 
Study Drug Accountability 
The PoR at each site is responsible for ordering, receiving, storing, and dispensing study drug 
and will be required to maintain study drug accountability records. Study drug supply must be 
stored separately from other clinical drug supplies and/or hospital stock. At study end all unused 
and expired oseltamivir will be destroyed according to institutional policies; peramivir will be 
returned to JHH. Subjects will not return unused study drug (see the MOP). 
6.6. 
Monitoring Subject Compliance to Study Drug 
To assess subject adherence to oseltamivir, research staff will review the subject’s daily diary 
each day. Subjects will report whether or not study drug for the previous day was taken. This 
information will be abstracted and entered on the Medication Form (F24). 
 
7. Adverse Event Management 
The 21 CFR 312.32 (a) defines an AE (also referred to as an adverse experience) as any 
unfavorable and unintended sign (e.g., an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a drug, and does not imply any judgment about causality. 
An AE can arise with any use of the drug (e.g., off-label use, use in combination with another 
drug) and with any route of administration, formulation, or dose, including an overdose. The 
occurrence of an AE may come to the attention of research staff during or after the study 
procedures and interviews. 


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7.1. 
General Management of Adverse Events 
Acute management of any AE will be according to best clinical practices and the judgment of 
the site investigator. The relationship between the AE and the study intervention will be 
presumed related, unless a clearly recognized alternate etiology is identified. Alternative 
explanations for clinical or laboratory abnormalities must be sought prior to study drug 
discontinuation. 
The following requirements for managing AEs during study participation should be followed, 
unless otherwise specified in section 7.2: 
 
Grades 1-4 AEs (not related to study drug): 
Subjects may continue taking study drug per the discretion of the site investigator. The 
site investigator will monitor all AEs unrelated to study drug according to best clinical 
practices. Report the event as an AE, following instructions in section 8.1.1. 
 
 
Grades 1 and 2 AEs (related to study drug): 
Subjects may continue taking study drug without alteration of the dosage or frequency, 
with the exceptions noted in section 7.2. The site investigator will monitor subjects 
according to best clinical practices. If the site investigator deems that the AE warrants 
study drug discontinuation, this should be communicated to the protocol team, prior to 
discontinuing the subject from study drug. Report the event as an AE, following 
instructions in section 8.1.1. 
 
 
Grades 3 and 4 AEs (related to study drug): 
The site investigator will determine whether or not subjects may continue taking study 
drug based on his/her clinical judgment. The site investigator will closely monitor 
subjects according to best clinical practices until the AE resolves or stabilizes. If the site 
investigator deems that the AE warrants temporary or permanent study drug 
discontinuation, this should be communicated to the protocol team as soon as possible 
and preferably, prior to discontinuing the subject from study drug. Report the event as an 
AE, following instructions in section 8.1.1; and as an SAE if criteria are met, following 
instructions in section 8.1.2. 
7.2. 
Protocol-Specific Adverse Event Management 
7.2.1. 
Allergy/Hypersensitivity Reaction to Study Drug 
If an allergic reaction occurs, instruct the subject to hold the next study drug dose and go to the 
ED immediately. 
 
Grades 1 and 2: Discontinue study drug immediately. The site investigator will closely 
monitor the subject according to best clinical practices until the AE resolves or stabilizes. 
Report the event as an AE, following instructions in section 8.1.1. 
 


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 
Grades 3 and 4: Discontinue study drug immediately. The site investigator will closely 
monitor the subject according to best clinical practices until the AE resolves or stabilizes. 
Report the event as an AE and SAE, following instructions in sections 8.1.1 and 8.1.2. 
7.2.2. 
Rash or Skin Reaction 
If a rash or skin reaction occurs, instruct the subject to hold the next study drug dose and go to 
the ED immediately. Any rash or skin reaction that is assessed to be possibly, probably, or 
definitely related to study drug will be considered an allergy/hypersensitivity reaction to study 
drug.  
 
Grades 1 - 4 (not related): Subjects may continue taking study drug per the discretion of 
the site investigator. The site investigator will monitor all AEs unrelated to study drug 
according to best clinical practices. Report the event as an AE, following instructions in 
section 8.1.1. 
 
 
Grades 1 and 2 (related): Refer to section 7.2.1 for AE management instructions.  
 
 
Grades 3 and 4 (related): Refer to section 7.2.1 for AE management instructions. 
7.2.3. 
Altered Mental Status 
If a change in behavior occurs, such as confusion or hallucinations, instruct the subject to hold 
the next study drug dose and go to the ED immediately. Refer to section 7.1 for AE 
management instructions. 
  
8. Safety Reporting 
8.1. 
Documenting, Recording, and Reporting Adverse Events 
At each follow-up contact with the subject (i.e., phone call follow-up for outpatient and in-person 
follow-up for inpatients), information regarding AEs and unanticipated problems will be elicited 
by appropriate questioning and will be documented and reported as outlined below.   
8.1.1. 
Adverse Event 
All AEs including local and systemic reactions not meeting the criteria for an SAE will be 
captured on the Adverse Events (F20) form. All AEs occurring while on study will be 
documented appropriately regardless of relationship.  
Any medical condition that was present at the time that the subject was screened/enrolled will 
be considered a baseline event. It will not be considered an AE. However, if the event worsens 
at any time after study drug administration through completion of the study period (Day 28), the 
event will be reported as an AE. 
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Severity of all AEs will be assessed by a site investigator using the Division of AIDS (DAIDS) 
Table for Grading the Severity of Adult and Pediatric Adverse Events (Version 2.0, November 
2014). The grading scale is as follows: 
Mild (Grade 1): Mild symptoms causing no or minimal interference with usual social and 
functional activities with intervention not indicated 
Moderate (Grade 2): Moderate symptoms causing greater than minimal interference with 
usual social and functional activities with intervention indicated 
Severe (Grade 3): Severe symptoms causing inability to perform usual social and 
functional activities with intervention or hospitalization indicated 
Potentially Life-Threatening (Grade 4): Potentially life-threatening symptoms causing 
inability to perform basic self-care functions with intervention indicated to prevent 
permanent impairment, persistent disability, or death 
Death (Grade 5): Events resulting in death 
Relationship to study drug or causality (likelihood that the event is related to the study drug) will 
be assessed for all AEs by the site investigator and the ISM. For the purposes of investigational 
new drug (IND) safety reporting, ‘reasonable possibility’ of relationship means there is evidence 
to suggest a causal relationship between the study drug and the AE. Such evidence includes 
temporal relationship between study drug administration and event, a known or suspected 
response pattern based on similar agents, and the likelihood (or lack thereof) of an alternative 
etiology. If a site investigator assesses an AE to be definitely, probably, or possibly related to 
study drug, the AE will be reported as related. If an AE can be clearly explained by another 
cause not related to the study drug, then the AE will be reported as not related and an 
alternative etiology will be documented.  
Note: Causality assessment is based on available information at the time of the assessment of 
the event. The investigator and/or the ISM may revise the causality assessment as additional 
information becomes available. 
8.1.2. 
Serious Adverse Event 
An SAE is an AE that results in one or more of the following outcomes (International Conference 
on Harmonization (ICH) E6): 
 
Death during the period of protocol-defined surveillance. 
 
Events that are life-threatening (i.e., an immediate threat to life). 
 
Events requiring hospitalization or prolongation of hospitalization. 
 
Events resulting in a persistent or significant incapacity or substantial disruption of the 
ability to conduct normal life functions. 
 
Congenital abnormalities/birth defects. 
 
Other important medical events that may jeopardize the subject and may require 
intervention to prevent one of the outcomes listed above. 


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All SAEs will be recorded on the SAE Report Form (F21), signed by the PI, and followed until 
satisfactory resolution, or until the event is deemed chronic or the subject is stable.  
Many of the subjects enrolled in this study will have significant influenza-related illness, and it is 
expected that approximately 40% of enrolled subjects will be hospitalized during their enrollment 
ED visit due to severe influenza at baseline. If the subject is hospitalized due to their baseline 
illness, the event will not be reported as an SAE. However if the subject’s condition worsens 
after study drug administration and requires prolongation of the hospitalization, the event will be 
reported as an SAE. Subsequent events that result in hospitalization after the initial ED 
enrollment visit will be reported as SAEs (see MOP).  
Site PIs will report all deaths and immediately life-threatening events to the IRB within 24 hours 
of awareness. All remaining SAEs will be reported to the IRB within 7 days of awareness, or per 
institutional policy.  
An ISM will be appointed to provide an independent safety review for SAEs immediately after 
they occur. The ISM will be a clinician with relevant expertise who is not otherwise associated 
with the study.  
A Safety Monitoring Committee (SMC), consisting of the IND sponsor, JHH Co-PIs, Johns 
Hopkins University Research Program Manager, BARDA Medical Officer, the ISM, and the 
study biostatistician will review and monitor the safety and compliance data as well as the 
overall study progress on a regular basis. 
Site PIs will report all SAEs to Westat Regulatory Affairs via fax within one business day of the 
site’s awareness of the event. Westat Regulatory Affairs will notify the ISM and copy the SMC 
within one business day of the SAE Report Form (F21) receipt. The ISM will assess the 
relationship of the SAE to the study drug and the expectedness of the event to determine the 
reporting status to the FDA. The ISM will return his assessment to Westat and the SMC within 
24 hours. Westat will report the SAE to the FDA per the ISM’s recommendation. SAEs will also 
be reported to BARDA and BioCryst Pharmaceuticals, Inc. (if the subject is in the peramivir arm) 
within the same timeframe as required by the FDA. 
 
9. Statistical Considerations 
9.1. 
Study Objectives 
Primary Objective: To prospectively enroll high-risk subjects with laboratory-confirmed influenza 
into a randomized, open-label study of oral versus IV influenza therapeutic to include symptom 
evaluation and outcome assessments. 
Secondary Objective 1: To identify influenza-positive patients utilizing a previously established 
triage-based assessment and rapid testing algorithm for suspected influenza infection. 
Secondary Objective 2: To retrospectively evaluate all potentially eligible patients for potential 
enrollment biases. 


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Secondary Objective 3: To create a repository of residual NP samples collected from ED 
patients with suspected influenza illness. 
9.2. 
Sample Size Considerations 
The proposed sample size is at least 50 subjects per site, per influenza season. This sample 
size was determined, in collaboration with ASPR/BARDA, to be adequate for this pilot effort 
which is being conducted specifically to examine the feasibility of achieving higher recruitment 
rates than has historically been achieved in other clinical venues, and the ability to reliably 
collect useful therapeutic endpoint data from an ED enrollment site. Estimates are based on 
data from the JHH ED 2014-2015 influenza season using the aforementioned testing algorithm, 
where 1604 patients were tested for influenza between November 2014 and April 2015, and 311 
influenza-positive patients were identified. Of those 311 patients, approximately 75% met CDC 
criteria for influenza treatment (i.e., potential enrollment in the study) and 40% were admitted to 
the hospital. As 2014-2015 was a robust influenza season, it is estimated that a routine 
influenza season would have approximately 25% fewer influenza-positive patients. Based on 
similar previous ED based therapeutic clinical trials conducted at the JHH ED, it is anticipated 
that 56% of eligible patients will agree to participate in the study. Therefore, assuming a routine 
influenza season, there will be an estimated 174 eligible patients, of whom 97 will be enrolled 
(58 discharged, 39 admitted). Based on these estimates, at least 50 (conservatively) and up to 
225 subjects could be enrolled and followed for 28 days. 
9.3. 
Final Analysis Plan 
As this is an exploratory study, data analysis will be principally descriptive. Rates of discreet 
events, as well as mean values for numerical data will be calculated. Statistical comparisons 
between groups (e.g., Secondary Objective 2) will be completed using t-test or chi squared as 
appropriate. This study is designed to be pilot in nature, and the anticipated sample size (225 
subjects) is not sufficient for comparison of outcomes between the two treatment groups. 
Hence, potential clinical endpoints will be described using descriptive statistics for the purposes 
of future trial planning, and no statistical comparisons between the oral and PO antiviral arms 
will be made. 
 
10. 
Clinical Management Issues 
The following clinical management guidelines apply to both treatment groups. 
10.1. 
Early Discontinuation of Study Treatment 
Subjects will be discontinued from study drug for any of the following reasons: 
 
Completion of protocol-defined study drug administration period; 
 
Any allergic reaction to study drug; 
 
Site investigator or treating provider clinical decision to discontinue study drug; or 


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 
Request by subject.  
CRFs will be used to capture both the intended total dosage of study treatment as well as the 
dosage actually received. Reasons for early termination of study treatment will be recorded. 
10.2. 
Study Withdrawal 
A subject may be withdrawn from the study for the following reasons: 
 
Development of relevant exclusion criteria; 
 
Subject withdraws consent to participate in the study; or 
 
The study is discontinued. 
All subjects should otherwise be followed according to the protocol. Subjects may withdraw from 
the study at any time at their request. Even if a subject does not receive all or any of the 
assigned study treatment, or some required data or specimens cannot be collected, every effort 
should be made to follow subjects for clinical outcomes until the end of the 28-day study period. 
 
11. 
Protection of Human Subjects & Other Ethical Considerations 
11.1. 
Ethical Conduct of the Study 
The study will be conducted according to the Declaration of Helsinki in its current version 
(2013); the requirements of 21 CFR Parts 11, 50, 54, 56, and 312; ICH GCP Guidelines; Human 
Subjects Protection and Data Protection Acts; the US Office for Human Research Protections 
(OHRP); and to the local law and regulations, whichever affords greater protection of human 
subjects. 
11.2. 
Institutional Review Board 
Prior to the initiation of the study, the protocol, ICF, and any subject information materials will be 
submitted to and approved by the JHH and MMC IRBs. Any future amendments to the study 
protocol, consent materials, and subject information materials will be approved before they are 
placed into use.  
11.3. 
Informed Consent of Study Subjects 
Informed consent must be obtained as described previously for enrollment into the Randomized 
Controlled Trial of Influenza Antivirals.  
11.4. 
Confidentiality of Study Subjects 
In accordance with HIPAA regulations, no subject personal identifiers will be entered into the 
study database. Personal identifiers such as name, contact phone number, and medical record 
number will be collected and recorded on a separate study ID sheet. This identifying information 


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will be linked to the remainder of the subject information only through the study ID number, and 
will ultimately be stripped after all necessary data is collected. The study database, which will be 
accessible to research staff and PIs as well as key study personnel at Westat, will only contain 
study ID numbers and will not contain any personal identifiers. Personal identifiers will be 
destroyed upon final completion and verification of the study database. 
Subject confidentiality will be held strictly in trust by the investigators and research staff. This 
confidentiality will be extended to cover testing of biological specimens and genetic tests in 
addition to the clinical information relating to subjects. The clinical study sites will permit access 
to all documents and records that may require inspection by the sponsor or its authorized 
representatives, IRB, or regulatory agency representatives, including but not limited to, medical 
records (e.g., office, clinic or hospital) and pharmacy records for the subjects in this study. 
Data obtained in this study will be maintained in a 21 CFR Part 11-compliant, secure encrypted 
remote data capture (RDC) system. Access to the RDC system is limited to approved 
individuals; the PIs and Westat will set the level of access for individuals to the database. 
Information that can be used to identify specific subjects will not be entered in RDC and will only 
be available to the PIs, other research staff directly involved in the study and that interact with 
the subjects, and site monitors. 
 
12. 
Data Management 
12.1. 
Data Management Responsibilities 
The site investigators are responsible for ensuring the accuracy, completeness, legibility, and 
timeliness of the data reported. All CRFs and/or source documents should be completed in a 
neat, legible manner to ensure accurate interpretation of data. Blue or black ink is required to 
ensure clarity of reproduced copies. When making changes or corrections, cross out the original 
entry with a single line, and initial and date the change.  
Research staff will complete a web-based training for entering study data into the Oracle Clinical 
(OC)-RDC database. Westat will provide training on CRF completion before the start of the 
study. Ongoing in-service trainings may be conducted periodically throughout the study, as 
necessary. Verification of training will be documented and maintained in each site’s study 
regulatory binder. Data collection is the responsibility of the research staff at the sites under the 
supervision of the site investigators. During the study, the site investigators must maintain 
complete and accurate documentation for the study. Data analysis will be the responsibility of 
the Johns Hopkins University Protocol Co-PIs, under the direction of the protocol biostatistician. 
Each subject will be assigned a unique study ID number for use on CRFs and in the database. 
Names or any other personal identifiers will not be entered on any CRF or the study database. 
Forms that contain the subjects’ name, date of birth, or contact information will be kept on-site 
and filed in a secured cabinet. A study ID sheet, the key linking each subject to his/her unique 
study ID number, will be created and kept secured by the site investigators under double lock 
separate from all research files, accessible only to research staff. 


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All CRFs must be reviewed by the research staff for accuracy, clarity, and completion, and by 
the data entry staff for completion. Study related laboratory reports will be reviewed and signed 
by a site investigator. AEs must be assessed for severity and relationship to study drug, and 
reviewed by the site investigators or designee. Data reported on the CRF that are derived from 
source documents or chart review should be consistent with the source documents or the 
discrepancies should be explained in the subject’s research record. The subject will not be 
contacted for CRF data validation. 
12.2. 
Data Capture Methods 
Data will be captured using paper CRFs in blue or black ink with all text printed neatly and 
legibly (i.e., do not use cursive writing except when writing a signature), and with all fields 
completed except when left blank as specified by a skip pattern. Once completed, CRFs will be 
promptly entered into a 21 CFR Part 11-compliant, secure, password-protected electronic 
database by trained research staff. Data capture will be ongoing throughout the period of the 
study. 
Daily diary data will be entered into a 21 CFR Part 11 compliant database that will be developed 
by Westat. Subjects may access the web-based daily diary system with a user ID and password 
from any personal computer, laptop, or tablet; or they may complete the daily diary as an 
interview (phone or in-person) with a research staff member, who will enter the data into the 
database for the subject (see MOP). 
12.3. 
Data Submission 
Sites must follow the guidelines for CRF completion and data entry that are specified in the 
MOP. Once the study database is developed and validated, the RDC screens will be available 
for data entry to research staff who have completed protocol training as well as OC-RDC 
training. Research staff at each site will be responsible for ensuring that CRF data are entered 
into RDC, as specified in the MOP.  
12.4. 
Quality Control 
Source data is all information in original records and certified copies of original records of 
clinical findings, observations, or other activities in a clinical study necessary for the 
reconstruction and evaluation of the study. All CRFs must have corresponding source 
documentation on file at the clinical sites to substantiate all submitted data, unless the CRF 
serves as the source document. For this study, many of the CRFs will be used as source 
documentation. However, it should be noted that additional source documents may be required, 
such as laboratory reports, hospital records, and clinical memoranda, to describe or clarify data 
reported on the CRFs.  
The CRFs that will serve as source documents are listed in the MOP. 
Data Accuracy Check: Data edits through range checks and field inconsistencies will be built 
into the RDC database to enable real time correction of key entries and CRF completion errors. 
In addition, all data that is entered into OC-RDC will be checked against the CRF shortly after 


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data entry by a different research staff member. For a randomly selected 10% of the subjects, 
all data forms and data entry will be checked by a different research staff member to ensure 
appropriate data collection. Any corrections will be noted, initialed, and resolved by consensus 
between the two research staff. Corrected data will be entered into OC-RDC as appropriate. 
Research staff will generate a report of the data accuracy check. 
If it is determined that the original data recorded on a CRF is incorrect, both the hard copy CRF 
and the electronic database must be updated to reflect the change. The procedure for 
performing data updates is as follows:  
 
Using blue or black ink, strike a single horizontal line through the incorrect data value on 
the CRF, taking care not to obliterate the original entry. Do not erase or use white out;  
 
Record the correct data value adjacent to the original value;  
 
Record your initials and the current date next to the updated information;  
 
Make the necessary modifications in OC-RDC. 
Data Completion Check: All data entered into OC-RDC will be evaluated monthly by Westat 
data management staff for CRF completion. If at the time of the data completion check there are 
CRFs that have not been entered in OC-RDC, Westat will send site research staff a missing 
forms report by email. Site Research staff will have 10 business days from receipt of a missing 
forms report to enter the data in OC-RDC or respond to the sender with a dispute such as a 
subject’s missed visit or early termination or request an extension during times of high 
enrollment. These timelines for review and resolution of missing data may be shortened if 
necessary prior to an interim analysis and at the end of the study in an effort to receive the 
necessary data prior to the analysis. . 
12.5. 
Protocol Deviations 
A protocol deviation is any non-compliance with the study protocol, GCP, or protocol-specific 
MOP requirements. The noncompliance may be either on the part of the subject, the site 
investigator, or other study personnel. As a result of deviations, corrective actions are to be 
developed by the site and implemented promptly. 
These practices are consistent with ICH E6: 
4.5 
Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3 
5.1 
Quality Assurance and Quality Control, section 5.1.1 
5.20 
Noncompliance, sections 5.20.1, and 5.20.2 
All protocol deviations, as defined above, must be addressed on the Protocol Deviation (F22) 
form. A completed copy of the Protocol Deviation form must be maintained in the regulatory file 
as well as in the subject's chart.  


Seasons 3 & 4 Protocol 
 
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It is the responsibility of the site PIs and other study personnel to use continuous vigilance to 
identify and report protocol deviations. The site PIs and other study personnel are responsible 
for knowing and adhering to their IRB requirements. Only protocol deviations that are related to 
subject safety and/or eligibility will be reported to the local IRB per its guidelines. 
12.6. 
Source Documents and Access to Source Data/Documents 
ASPR/BARDA will assist the Co-PIs in creating source documents for the study prior to subject 
enrollment, including source documents to record information on screening (i.e., meeting 
inclusion and exclusion criteria), enrollment (demographics, patient history, pre-existing 
conditions, etc.), laboratory and medical record data, AEs, and all information entered on the 
CRFs.  
The study sites will maintain appropriate medical and research records for this trial, in 
compliance with ICH E6 and regulatory and institutional requirements for the protection of the 
confidentiality of subjects. Each site will permit authorized representatives of BARDA, its 
designees, site monitors, and appropriate regulatory agencies to examine (and when required 
by applicable law, to copy) clinical records for the purposes of quality assurance (QA) reviews, 
audits, and evaluation of the study safety and progress. These representatives will be permitted 
access to all source data, which include, but are not limited to, hospital records, clinical and 
office charts, laboratory notes, memoranda, evaluation checklists, pharmacy dispensing 
records, recorded data from automated instruments, copies or transcriptions certified after 
verification as being accurate and complete, microfiches, photographic negatives, microfilm or 
magnetic media, x-rays, and subject files and records kept at the pharmacy, at the laboratories, 
and at medico-technical departments involved in the clinical trial. 
12.7. 
Clinical Site Monitoring 
Site monitors will visit sites to review selected portions of the individual subject records, 
including consent forms, CRFs, and supporting source documentation to ensure protection of 
study subjects, compliance with the protocol, and accuracy and completeness of records. 
Regulatory files, as required, will also be inspected to ensure that regulatory requirements are 
being followed. 
Site monitors will also visit sites’ investigational pharmacies to review the overall study product 
management system, including receipt, storage, disposition and accountability of study agents. 
Regulatory files kept within the pharmacy will also be inspected to ensure that regulatory 
requirements are being followed. 


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Appendix 1: Schedule of Evaluations 
Evaluation/Test 
Screening 
Enrollment 
Day 3 
Day 7 
Day 14 
Day 28 
Obtain informed consent 
x 
 
 
 
 
 
Demographics 
x 
 
 
 
 
 
Medical History 
x 
 
 
 
 
 
Medical Assessment 
x 
 
 
 
 
 
CBCa 
x 
 
 
 
 
 
Complete or Basic Metabolic Panela, b 
x 
 
 
 
 
 
Beta-hcg (serum or urine) for women of child-
bearing potentiala, c 
x 
 
 
 
 
 
Chest X-Raya 
 
x 
 
 
 
 
NP swab for storage 
 
x 
 
 
 
 
NP Swab: duration and magnitude of virus 
sheddingf 
 
 
x 
x 
 
 
Study Drug Administrationd 
 
x 
 
 
 
 
Subject Check-Ine 
 
 
x 
x 
 
 
Medical Chart Review 
 
 
 
x 
 
x 
Follow-Up Assessment 
 
 
 
 
 
x 
PGIS 
 
x 
 
x 
 
x 
PGIC 
 
 
 
x 
 
x 
Daily Diaryg (FLU-PRO Symptom 
Questionnaire (F10) and Functional 
Assessment (F12) form 
 
x 
 
 
 
 
Obtain authorization for release of health 
information 
 
x 
 
 
 
 
a 
If conducted as part of clinical care at enrollment or within the previous 24 hours, data may be extracted from 
the medical record. 
b 
Calculate CrCl using the Cockcroft Gault equation to determine eligibility. 
c 
Women will be considered of non-childbearing potential if they are greater than age 54 and have had no 
menses in the previous 12 months, or if they are surgically sterile (e.g., hysterectomy with or without 
oophorectomy; fallopian tube ligation; endometrial ablation). 
d 
First dose of oral oseltamivir will be administered in the ED; the one time dose of IV peramivir will be 
administered in the ED. 
e 
Conduct “check-ins” via phone. If the subject is in the hospital, complete the “check-in,” in person in the 
hospital. 


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f 
Collect NP swabs if the subject is hospitalized for the “check-in” visits. 
g 
The Daily Diary FLU-PRO Symptom Questionnaire (F10) and Functional Assessment (F12) form will be 
completed in the ED. The subject will complete the daily diary for 14 days via the internet or by personal 
contact with trained research staff. Research staff will review subjects’ daily diaries each day.   
 
 


 
42 
 
Appendix 2: Shipping of Nasopharyngeal Specimens for Storage 
 
Shipping Instructions 
Frozen aliquots will be batch shipped monthly to the central study laboratory at Johns Hopkins 
University Division of Virology and stored for future analysis. These de-identified samples and 
results will not be available for clinical care. 
All shipments will be made in accordance with institutional environmental safety regulations 
regarding shipment of hazardous materials. Frozen samples will be shipped by properly trained 
staff in an insulated container with dry ice and next day delivery to ensure samples remain 
frozen in accordance with International Air Transport Association (IATA) regulations. The 
laboratory is not open on the weekends or holidays; shipments must be received Monday – 
Friday only (excluding holidays).  
 
 
Shipping address and contact info: 
 
ATTN: Michael Forman  
 
Johns Hopkins Hospital 
 
600 North Wolfe St 
 
Pathology B136 
 
Baltimore, MD 21287 
 
Phone: (410) 955-2642 
 
Fax: (410) 614-8087 
 
Email: mformaa@jhmi.edu 
 
When shipping the specimens, create a “notice of shipment” (Appendix 2a: Notice of Shipment) 
that includes the sender’s name, phone and fax numbers, the study IDs, the shipping 
information and fax it to the above fax number, ATTN: Michael Forman. Upon receipt of the 
specimens, someone at the receiving laboratory will sign and fax back the notice, indicating 
receipt of shipment and specimens. 
 
 


 
43 
 
Appendix 2a: Notice of Shipment 
 
NOTICE OF SHIPMENT 
BARDA: Influenza Therapeutic Trial Study 
 
Shipping address and contact info:  
ATTN: Michael Forman  
 
Johns Hopkins Hospital 
 
600 North Wolfe St 
 
Pathology B136 
 
Baltimore, MD 21287 
 
Phone: 410-955-2642 
 
Fax: 410-614-8087  
 
Email: mformaa@jhmi.edu 
 
Part I: To be completed by Sender at time of shipment:  
Senders Name: 
 
 
Senders Phone Number: 
 
 
Senders Fax Number: 
 
Study IDs of included 
specimens: 
 
Shipping Information: 
 
Part II: To be completed by Michael Forman’s Research Staff upon receipt of shipment and faxed 
back to Sender: 
Name:  
 
 
Signature: