Clinical trial NCT02498444
Conditions: Single Ventricle
Keywords: Fontan Treprostinil Remodulin Single ventricle
Sponsor: Stanford University
Start date: 2015-09-01; Completion date: 2020-12-01
Enrollment: 34 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to test the efficacy of treprostinil (TRE) in the perioperative non-fenestrated, extracardiac Fontan patients in order to reduce duration of chest tube drainage (in days).

The Fontan operation is performed for patients with single ventricle physiology as the final palliation to create a series circulation, with passive systemic venous return to the pulmonary arteries and the single ventricle solely providing systemic output.

Patients undergoing extracardiac Fontan tend to have elevation of Fontan pressures immediately following the operation with inflammation from surgery requiring additional fluid administration to maintain blood pressure. Increased Fontan pressures and fluid overload lead to prolonged chest tube drainage.

The hypothesis is that treprostinil, a prostacyclin drug that dilates the pulmonary arteries, will improve immediate postoperative Fontan pressures. Treprostinil is not FDA approved for this use. Anecdotally and in a small case series, prostacyclin therapy has been shown to assist in transitioning patients off nitric oxide. The investigators believe that this improvement in hemodynamics will decrease duration of chest tube drainage resulting in a shorter length of hospital stay.

Detailed description:
In order to understand the effect of treprostinil on Fontan patients, this study has two parts:

1. reactivity testing with inhaled treprostinil in the cardiac catheterization lab for pre-Fontan patients undergoing routine catheterization in anticipation of the Fontan operation;
2. perioperative use of subcutaneous treprostinil starting immediately pre-op until postoperative day #7 to improve immediate postoperative hemodynamics and ultimately reduce overall length of hospital stay.

The investigators hope to learn how pulmonary vasodilator therapy affects and/or improves post- operative hemodynamics following the Fontan operation. This knowledge would be very important in the care of single ventricle patients following the Fontan operation if there is improvement of immediate outcomes and reduction of hospital length of stay. On a broader scale, if the use of treprostinil in perioperative Fontan patients can achieve the same results other centers achieve with the use of a fenestration this may have wide scale implications in the nationwide treatment of Fontan patients.

Arms: arm 1: The subcutaneous continuous treprostinil infusion will start at a dose of 2 ng/kg/min. The dose will be increased over the first 24 hours to goal 10 ng/kg/min through day five. On postoperative day six, the dose will be decreased by 2 ng/kg/min every 8 hours with plans for discontinuation on postoperative day seven. arm 2: Saline administration via subcutaneous infusion
Interventions: intervention 1: Treprostinil
Intervention descriptions: intervention 1: Administration of drug (treprostinil) vs placebo (saline) in the post-operative period

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
Perioperative Treprostinil in Pediatric Patients Undergoing the Fontan 
Operation 
Study Protocol and Statistical Analysis Plan 
NCT02498444 
March 1, 2015 


	  
	  
	  
	  
Perioperative	  Treprostinil	  	  
in	  Pediatric	  Patients	  Undergoing	  the	  Fontan	  Operation	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
Principal	  Investigators:	  Jeffrey	  A.	  Feinstein	  MD,	  MPH;	  Stephanie	  L.	  Siehr	  MD	  
	  
Study	  Site:	  Lucile	  Packard	  Children’s	  Hospital	  at	  Stanford	  University	  
	  
Primary	  Contact	  Information:	  	  
	  
Jeffrey	  Feinstein	  
Pediatric	  Cardiology	  	  
The	  Heart	  Center	  
750	  Welch	  Road	  –	  Suite	  305	  
Palo	  Alto	  	  CA	  94304	  
Email:	  Jeff.	  Feinstein@stanford.edu	  
Phone:	  650.725.2297	  
Fax:	  650.725.8343	  
	  
Protocol	  version:	  2.1	  
	  
Date:	  1	  March	  2015	  
	  
IRB	  Approval	  Date:	  Pending	  FDA	  Review	  
	  


2	  
[PERIOPERATIVE	  TREPROSTINIL	  IN	  FONTANS]	  
	  
	  
	  
Background	  Information	  
	  
The	  Fontan	  operation	  is	  performed	  in	  patients	  with	  single	  ventricle	  physiology	  
as	  the	  final	  step	  to	  create	  a	  circulation	  in	  series.	  First	  performed	  in	  1971	  (Fontan	  et	  
al,	  Thorax	  1971)	  for	  patients	  with	  tricuspid	  atresia,	  it	  has	  since	  has	  been	  modified	  
to	  serve	  as	  the	  completion	  phase	  for	  all	  patients	  with	  single	  ventricle	  physiology.	  	  
Currently,	   approximately	   1000	   Fontan	   operations	   are	   performed	   per	   year	   in	   the	  
United	  States	  (Jacobs	  et	  al,	  World	  J	  Pediatr	  Congenit	  Heart	  Surg	  2013).	  
	  
The	   Fontan	   operation	   results	   in	   passive	   systemic	   venous	   return	   to	   the	  
pulmonary	  arteries,	  and	  as	  such,	  a	  low	  pulmonary	  vascular	  resistance	  is	  critical	  to	  
post-­‐operative	   recovery	   and	   favorable	   long-­‐term	   outcomes.	   	   It	   has	   been	   well	  
described	  that	  a	  transient	  increase	  in	  pulmonary	  vascular	  resistance	  occurs	  in	  the	  
immediate	   post-­‐operative	   period	   as	   a	   result	   of	   the	   inflammatory	   response	   to	  
surgery	   with	   or	   without	   cardiopulmonary	   bypass,	   manifest	   clinically	   as	   a	   higher	  
Fontan	  pressure	  and	  higher	  transpulmonary	  gradient	  (the	  difference	  between	  the	  
Fontan	  pressure	  and	  atrial	  pressure).	  	  It	  is	  likely	  due	  to	  endothelial	  dysfunction	  in	  
the	   pulmonary	   arteries	   with	   a	   decrease	   in	   vasodilator	   and	   increase	   in	  
vasoconstrictor	  mediators.	  
	  
Inhaled	  nitric	  oxide	  as	  a	  pulmonary	  vasodilator	  has	  been	  shown	  to	  improve	  flow	  
through	  the	  Fontan	  circuit	  (Goldman	  et	  al,	  Circulation	  1996)	  and,	  in	  a	  small	  case	  
series	   (Miyaji	   et	   al,	   JTCVS	   2003),	   epoprostenol	   has	   been	   shown	   to	   assist	   in	  
transitioning	   single	   ventricle	   patients	   off	   nitric	   oxide.	  A	   recent	   prospective,	   non-­‐
randomized	  trial	  of	  sildenafil	  immediately	  post	  Fontan	  did	  not	  show	  a	  difference	  in	  
outcomes	  (Mendoza	  et	  al,	  Cardiol	  Young	  2014).	  


3	  
	  
	  
	  
3	  
	  
	  
At	  many	  centers,	  a	  fenestration	  is	  created	  at	  the	  time	  of	  the	  Fontan	  operation	  to	  
allow	   a	   'pop-­‐off'	   of	   systemic	   venous	   blood	   to	   the	   pulmonary	   venous	   atrium	   to	  
maintain	   low	   Fontan	   pressures	   and	   cardiac	   output.	   	   While	   this	   comes	   at	   the	  
expense	  of	  hypoxemia,	  in	  the	  immediate	  post-­‐operative	  period	  where	  a	  transient	  
increase	   in	   pulmonary	   vascular	   resistance	   is	   seen,	   it	   yields	   a	   shorter	   duration	   of	  
chest	  tube	  drainage,	  length	  of	  stay,	  and	  smoother	  post-­‐operative	  course.	  At	  Lucile	  
Packard	   Children’s	   Hospital	   (LPCH),	   our	   surgeons	   perform	   the	   Fontan	   operation	  
without	  cardiopulmonary	  bypass	  and	  without	  a	  fenestration,	  citing	  the	  hypoxemia,	  
risk	   of	   thromboembolism	   and	   need	   for	   an	   additional,	   subsequent,	   procedure	   to	  
close	  the	  fenestration	  as	  their	  rationale	  for	  this	  approach.	  
	  
Patients	   undergoing	   a	   Fontan	   procedure	   at	   LPCH	   have	   a	   median	   length	   of	  
hospital	  stay	  of	  ~16	  days	  (McCammond	  et	  al,	  Pediatr	  Cardiol	  2012).	  Nationally,	  the	  
median	  length	  of	  stay	  in	  the	  largest	  series	  is	  closer	  to	  8	  days	  (Rogers	  et	  al,	  JACC	  
2012).	  	  We	  believe	  that	  the	  transient	  elevation	  in	  pulmonary	  vascular	  resistance	  
resulting	   from	   the	   surgical	   insult,	   greater	   amount	   of	   dissection	   required	   (our	  
procedures	  are	  done	  without	  cardiopulmonary	  bypass),	  and	  lack	  of	  a	  fenestration	  
lead	   to	   longer	   duration	   of	   chest	   tube	   drainage	   and	   length	   of	   stay	   seen	   in	   our	  
patients.	   The	   use	   of	   a	   fenestration	   in	   other	   institutions	   allows	   maintenance	   of	  
cardiac	   output	   during	   this	   period	   of	   limited	   pulmonary	   blood	   flow	   and	   reduces	  
Fontan	  pressures	  to	  limit	  pleural	  drainage,	  but	  does	  not	  reduce	  pulmonary	  vascular	  
resistance.	  
	  


4	  
[PERIOPERATIVE	  TREPROSTINIL	  IN	  FONTANS]	  
	  
	  
	  
Objectives/Purpose	  
	  
We	   hypothesize	   that	   perioperative	   use	   of	   subcutaneous	   treprostinil	   will	  
minimize	   the	   surgically-­‐induced	   elevation	   in	   pulmonary	   vascular	   resistance,	  
improve	  postoperative	  hemodynamics,	  decrease	  the	  need	  for	  post-­‐operative	  fluid	  
resuscitation,	   and	   ultimately	   result	   in	   decreased	   duration	   of	   chest	   tube	   drainage	  
and	  shorter	  hospital	  length	  of	  stay.	  	  
	  
In	   addition,	   we	   believe	   those	   shown	   to	   be	   particularly	   responsive	   to	   the	  
postoperative	   treprostinil	   may	   be	   identifiable	   pre-­‐operatively	   using	   vasodilator	  
testing	  during	  their	  routine	  pre-­‐operative	  cardiac	  catheterization.	  
	  
Study	  Design	  
	  
Randomized,	  blinded,	  placebo	  controlled	  study	  in	  which	  patients	  undergoing	  the	  
Fontan	  operation	  at	  LPCH	  who	  are	  enrolled	  in	  the	  study	  will	  receive	  treprostinil	  (or	  
saline)	  in	  the	  perioperative	  period.	  	  Subcutaneous	  treprostinil	  is	  normally	  diluted	  in	  
normal	   saline.	   The	   placebo	   group	   will	   receive	   saline	   alone.	   Patients	   will	   be	  
randomized	  1:1	  (treprostinil	  :	  placebo).	  
	  
Selection	  and	  Exclusion	  of	  Subjects	  
	  
All	  pediatric	  patients	  will	  be	  considered	  eligible	  if	  they	  are	  undergoing	  a	  primary	  
Fontan	  operation	  and/or	  pre-­‐Fontan	  cardiac	  catheterization	  at	  LPCH.	  
	  
	  
	  


5	  
	  
	  
	  
5	  
Exclusion	  criteria:	  
1. Platelet	  count	  <	  50K	  	  
2. Dermatologic	   condition	   that	   renders	   the	   patient	   unable	   to	   tolerate	   a	  
subcutaneous	   infusion	   (can	   still	   take	   part	   in	   inhaled	   vasodilator	   testing	  
during	  cardiac	  catheterization)	  
3. Currently	  receiving	  any	  vasodilator	  therapy	  	  specifically	  for	  the	  purpose	  of	  
pulmonary	  vasodilation	  (e.g.	  Phosphodiesterase	  Type	  5	  inhibitor,	  Endothelin	  
receptor	  antagonist,	  Prostacyclin)	  
	  
Treatment	  of	  Subjects	  
The	  study	  will	  be	  comprised	  of	  2	  parts:	  	  
	  
1. Acute,	  vasodilator	  testing	  with	  inhaled	  treprostinil	  (in	  the	  catheterization	  lab)	  at	  
the	  time	  of	  pre-­‐operative	  Fontan	  catheterization	  	  
The	   protocol	   for	   administration	   of	   inhaled	   treprostinil	   has	   been	  
previously	   published	   (Takatsuki	   et	   al,	   Pediatrc	   Cardiol	   2013)	   and	  
involves	  3-­‐6	  breaths	  (18-­‐36	  µg)	  initially,	  repeated	  5	  minutes	  later	  if	  
no	  effect	  with	  9	  breaths	  (54	  µg)	  total.	  Repeat	  hemodynamics	  will	  be	  
performed	   after	   drug	   administration	   to	   measure	   Fontan/pulmonary	  
artery	   pressure,	   pulmonary	   vascular	   resistance	   and	   cardiac	   index.	  
	  
2. Perioperative	  infusion	  of	  subcutaneous	  treprostinil	  surgical	  Day	  0	  to	  Day	  7.	  
Based	  on	  our	  experience	  with	  treprostinil	  in	  patients	  with	  pulmonary	  


6	  
[PERIOPERATIVE	  TREPROSTINIL	  IN	  FONTANS]	  
	  
	  
arterial	   hypertension	   (Siehr	   et	   al,	   JHLT	   2013)	   and	   single	   ventricle	  
physiology,	   we	   propose	   the	   following	   protocol	   for	   subcutaneous	  
treprostinil	  administration	  in	  the	  perioperative	  period:	  
The	  subcutaneous	  catheter	  will	  be	  placed	  in	  the	  operating	  room	  (to	  
minimize	  discomfort)	  and	  the	  initial	  infusion	  (either	  2	  ng/kg/min	  or	  
saline-­‐only	   placebo)	   will	   be	   started	   after	   anesthetic	   induction.	  
Treprostinil	   will	   be	   increased	   by	   2	   ng/kg/min	   every	   3	   hours	   to	   a	  
target	   dose	   of	   10	   ng/kg/min	   within	   24	   hours.	   	   We	   anticipate	   the	  
patient	   will	   be	   on	   4ng/kg/min	   at	   the	   completion	   of	   the	   Fontan	  
procedure	  when	  transferred	  to	  the	  cardiac	  intensive	  care	  unit.	  	  The	  
dose	  will	  remain	  at	  10	  ng/kg/min	  through	  day	  five,	  though	  may	  be	  
decreased	  
if	  
significant	  
hypotension	  
occurs.	  
Beginning	  
on	  
postoperative	   day	   six,	   the	   dose	   will	   be	   decreased	   by	   2	   ng/kg/min	  
every	   8	   hours	   with	   plans	   for	   treprostinil	   to	   be	   discontinued	   by	  
postoperative	  day	  seven.	  
	  
Assessment	  of	  Efficacy	  
	  
The	   primary	   outcome	   is	   chest	   tube	   duration	   (days).	   	   Chest	   tube	   removal	   (the	  
usual	   determinant	   of	   length	   of	   stay)	   is	   performed,	   per	   protocol,	   when	   the	   total	  
output	  is	  less	  than	  2	  ml/kg/24	  hours.	  Secondary	  outcomes	  include	  hospital	  length	  of	  
stay	  (days),	  total	  volume	  of	  chest	  tube	  output,	  time	  to	  extubation,	  amount	  of	  fluid	  
intake	  per	  24	  hours,	  blood	  product	  administration	  per	  24	  hours,	  urine	  output	  per	  24	  
hours,	  markers	  of	  cardiac	  output	  (lactate,	  mixed	  venous	  saturation,	  chemistry	  panel	  


7	  
	  
	  
	  
7	  
looking	   at	   end	   organ	   function	   such	   as	   BUN,	   creatinine,	   liver	   function	   tests),	   in	  
hospital	  mortality	  and	  12	  month	  mortality.	  	  Hemodynamics	  will	  include	  Fontan	  and	  
atrial	  pressures	  while	  indwelling	  catheters	  are	  present,	  systolic	  blood	  pressure	  and	  
heart	   rate	   over	   the	   first	   96	   hours	   post-­‐operative.	   All	   data	   collected	   are	   part	   of	  
standard	  care	  for	  this	  population	  in	  our	  institution.	  
	  
Cardiac	   catheterization	   derived	   pre-­‐operative	   hemodynamics,	  and	   response	   to	  
inhaled	  
treprostinil	  
will	  
be	  
recorded	  
and	  
compared	  
to	  
post-­‐operative	  
hemodynamics	   and	   post-­‐operative	   course	   to	   determine	   whether	   post-­‐operative	  
response	  to	  subcutaneous	  treprostinil	  correlates	  with	  pre-­‐operative	  testing	  and	  to	  
determine	   whether	   pre-­‐operative	   hemodynamics	   and	   response	   to	   treprostinil	  
“testing”	   in	   the	   catheterization	   lab	   can	   predict	   which	   patients	   received	   	   the	   most	  
benefit	  from	  treprostinil.	  	  
	  
Assessment	  of	  Safety/Adverse	  Events	  and	  report	  
	  
A	   research	   coordinator	   will	   track	   adverse	   events,	   which	   will	   be	   immediately	  
reported	   to	   Drs.	   Siehr	   and	   Feinstein.	   The	   research	   staff,	   led	   by	   Dr.	   Siehr,	   will	   be	  
responsible	  for	  reporting	  these	  events	  to	  the	  IRB.	  	  A	  DSMB	  will	  meet	  after	  the	  initial	  
six	  patients	  are	  enrolled	  and	  quarterly	  thereafter.	  
	  
An	   adverse	   event	   is	   any	   untoward	   medical	   experience	   occurring	   to	   a	   subject	  
during	   a	   clinical	   trial	   whether	   or	   not	   it	   is	   related	   to	   the	   study	   drug.	  	   An	   adverse	  
event	   may	   include	   an	   intercurrent	   illness,	   injury,	   or	   any	   other	   concomitant	  
impairment	   of	   the	   subject’s	   health,	   as	   well	   as	   abnormal	   laboratory	   findings	   if	  
deemed	  to	  have	  clinical	  significance.	  	  Adverse	  events	  may	  also	  include	  worsening	  of	  


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an	  existing	  symptom	  or	  condition	  or	  post-­‐treatment	  events	  that	  occur	  as	  a	  result	  of	  
protocol-­‐mandated	  procedures.	  
	  
A	   serious	   adverse	   event	   (SAE)	   is	   an	   adverse	   event	   occurring	   at	   any	   dose	   that	  
results	  in	  any	  of	  the	  following	  outcomes:	  
• Death	  
• A	  life-­‐threatening	  adverse	  event	  
• Inpatient	  hospitalization	  or	  prolongation	  of	  existing	  hospitalization	  
• A	  persistent	  or	  significant	  disability/incapacity	  
• A	  congenital	  anomaly/birth	  defect	  
	  
In	   addition,	   important	   medical	   events	   that	   may	   not	   result	   in	   death,	   be	   life-­‐
threatening,	  or	  require	  hospitalization	  may	  be	  considered	  serious	  when,	  based	  upon	  
appropriate	   medical	   judgment,	   they	   may	   jeopardize	   the	   subject	   and	   require	  
medical/surgical	   intervention	   to	   prevent	   one	   of	   the	   outcomes	   listed	   above.	  	   Life-­‐
threatening	  means	  that	  the	  subject	  was,	  in	  the	  view	  of	  the	  investigator,	  at	  immediate	  
risk	  of	  death	  from	  the	  event	  as	  it	  occurred.	  	  It	  does	  not	  mean	  that	  the	  event,	  had	  it	  
occurred	  in	  a	  more	  severe	  form,	  might	  have	  caused	  death.	  
	  
An	  adverse	  event	  or	  SAE	  occurring	  during	  the	  study	  must	  be	  documented	  in	  the	  
subject’s	  source	  documents	  and	  on	  the	  appropriate	  CRF	  page.	  	  Information	  relating	  
to	   the	   adverse	   event	   such	   as	   onset	   and	   cessation	   date	   and	   times,	   intensity,	  
seriousness,	  relationship	  to	  study	  drug,	  and	  outcome	  is	  also	  to	  be	  documented	  in	  the	  
CRF.	  	  Where	  possible,	  adverse	  events	  should	  be	  recorded	  using	  standard	  medical	  
terminology.	  	  If	  several	  signs	  or	  symptoms	  are	  clearly	  related	  to	  a	  medically	  defined	  


9	  
	  
	  
	  
9	  
diagnosis	  or	  syndrome,	  the	  diagnosis	  or	  syndrome	  should	  be	  recorded	  on	  the	  CRF	  
page,	  not	  the	  individual	  signs	  and	  symptoms.	  
	  
All	   adverse	   events	   should	   be	   followed	   until	   either	   resolution	   (or	   return	   to	  
normal	  or	  baseline	  values),	  until	  they	  are	  judged	  by	  the	  investigator	  to	  no	  longer	  be	  
clinically	  significant,	  or	  for	  at	  least	  4	  weeks	  if	  the	  adverse	  event	  extends	  beyond	  the	  
final	   visit.	  	   All	   SAEs	   that	   occur	   during	   the	   study	   will	   be	   followed	   until	   resolution,	  
death,	  or	  the	  subject	  is	  lost	  to	  follow-­‐up	  even	  if	  they	  are	  ongoing	  more	  than	  4	  weeks	  
after	  completion	  of	  the	  final	  visit.	  	  Supplemental	  measurements	  and/or	  evaluations	  
may	   be	   necessary	   to	   investigate	   fully	   the	   nature	   and/or	   causality	   of	   an	   adverse	  
event	  or	  SAE.	  	  This	  may	  include	  additional	  laboratory	  tests,	  diagnostic	  procedures,	  
or	  consultation	  with	  other	  healthcare	  professionals.	  	  CRF	  pages	  should	  be	  updated	  
with	  any	  new	  or	  additional	  information	  as	  appropriate.	  
	  
The	  investigators	  shall	  report	  all	  serious	  adverse	  events	  in	  English	  to	  UT	  GDS	  by	  
fax	   (+	   1	   919-­‐313-­‐1297/	   +44	   (0)	   1932	   573888)	   (US/ex-­‐US)	   or	   e-­‐mail	  
(drugsafety@unither.com)	  using	  a	  MedWatch	  3500A	  Form/CIOMS	  I	  Form	  (US/ex-­‐
US).	  Cases	  requiring	  expedited	  reporting	  to	  the	  regulatory	  authority	  should	  be	  sent	  
to	  UT	  GDS	  on	  or	  before	  the	  date	  Investigator	  send	  the	  report	  to	  the	  authority	  and	  
should	  be	  the	  exact	  document	  Investigator	  is	  submitting	  to	  the	  regulatory	  authority.	  	  
All	   other	   serious	   cases	   should	   be	   submitted	   within	   10	   days	   of	   Investigator	   initial	  
awareness.	  For	  purposes	  of	  reportability,	  UT	  GDS	  Day	  0	  will	  be	  the	  date	  when	  we	  
receive	  the	  case	  report	  from	  Investigator.	  


10	  
[PERIOPERATIVE	  TREPROSTINIL	  IN	  FONTANS]	  
	  
	  
	  
The	   investigators	   further	   agrees	   to	   make	   available	   promptly	   to	   UT	   GDS	   such	  
records	  (e.g.,	  source	  documents)	  as	  may	  be	  necessary	  and	  pertinent	  for	  UT	  GDS	  to	  
further	  investigate	  a	  case	  report.	  	  	  
	  
Should	   the	   Investigator	   receive	   follow-­‐up	   information	   for	   any	   serious	   adverse	  
event	  reports,	  Investigator	  shall	  be	  responsible	  for	  reporting	  all	  follow	  up	  to	  UT	  GDS	  
by	   fax	   (+	   1	   919-­‐313-­‐1297/	   +44	   (0)	   1932	   573888)	   (US/ex-­‐US)	   or	   e-­‐mail	  
(drugsafety@unither.com)	  
using	  
a	  
MedWatch	  
3500A	  
Form/CIOMS	  
I	  
Form/MedWatch	   3500A	   Form	   (US/ex-­‐US),	   based	   upon	   the	   timelines	   above,	   and	  
should	   be	   the	   exact	   document	   the	   Investigator	   is	   submitting	   to	   the	   regulatory	  
authority;	  
	  
In	   accordance	   with	   FDA,	   European,	   and	   national	   regulations,	   the	   sponsor	   will	  
notify	   the	   FDA,	   other	   competent	   authorities,	   and	   all	   participating	   investigators	   of	  
any	  adverse	  event	  that	  is	  considered	  to	  be	  possibly	  attributable	  to	  study	  drug	  and	  is	  
both	  serious	  and	  unexpected.	  	  The	  investigator	  must	  report	  these	  adverse	  events	  to	  
their	  IRB	  or	  EC	  in	  accordance	  with	  applicable	  national	  regulations	  and	  guidelines	  set	  
forth	  by	  the	  IRB	  or	  EC.	  
	  
Study	  Discontinuation	  
	  
The	   study	   will	   end	   when	   42	   patients	   (21	   each	   in	   the	   treprostinil	   and	   placebo	  
group)	  have	  been	  enrolled.	  All	  patients	  will	  be	  under	  the	  direct	  care	  of	  physicians	  in	  
the	   Division	   of	   Pediatric	   Cardiology	   throughout	   the	   treatment	   portion	   of	   the	  
protocol	   	   (in	   the	   cardiac	   catheterization	   lab,	   the	   cardiac	   intensive	   care	   unit,	   and	  


11	  
	  
	  
	  
11  
acute	  care	  floor).	  Phone	  follow	  up	  with	  their	  primary	  cardiologist	  and	  family	  will	  be	  
collected	  12	  months	  post-­‐operatively.	  
	  
Statistics,	  including	  power	  calculations	  and	  details	  of	  data	  analysis	  plan	  
	  
Chest	   tube	   duration	   (days)	   was	   analyzed	   on	   the	   natural	   logarithm	   scale.	  	   The	  
geometric	   mean	   of	   chest	   tube	   days	   in	   the	   historical	   cohort	   of	   138	   patients	  
(unselected,	   date	   of	   operation	   2004-­‐2012)	   was	   11.8	   days	   and	   the	   standard	  
deviation	   (log	   scale)	   was	   0.52.	  	   With	   42	   subjects	   randomized	   1:1	   we	   have	   80%	  
power	  to	  detect	  a	  33%	  reduction	  in	  CT	  days.	  	  These	  calculations	  are	  based	  on	  the	  
use	  of	  a	  two-­‐sample	  t-­‐test	  with	  sample	  sizes	  42	  and	  138	  and	  a	  one-­‐sided	  significance	  
level	  of	  5%.	  
	  
Data	  handling	  and	  record	  keeping	  
	  
All	  data	  will	  be	  kept	  in	  RedCap	  in	  a	  dedicated,	  HIPAA	  compliant,	  database.	  The	  
patient	  will	  be	  coded	  by	  as	  001	  -­‐	  042	  based	  on	  date	  of	  enrollment.	  Only	  the	  research	  
staff	  will	  have	  access	  to	  the	  database	  and	  all	  exported	  data	  for	  analysis	  will	  be	  free	  
of	  identifying	  information.	  Data	  will	  be	  entered	  on	  a	  Stanford	  secured,	  encrypted,	  
password	  protected	  computer.	  
	  
	  


12	  
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References	  
Fontan	   F,	   Baudet	   E:	   Surgical	   repair	   of	   tricuspid	   atresia,	   Thorax.	   1971	  
May;26(3):240-­‐8.	  
Jacobs	   JP,	   Maruszewski	   B:	   Functionally	   univentricular	   heart	   and	   the	   Fontan	  
operation:	  lessons	  learned	  about	  patterns	  of	  practice	  and	  outcomes	  from	  the	  
congenital	   heart	   surgery	   databases	   of	   the	   European	   association	   for	   cardio-­‐
thoracic	  surgery	  and	  the	  society	  of	  thoracic	  surgeons.	  World	  J	  Pediatr	  Congenit	  
Heart	  Surg.	  2013	  Oct;4(4):349-­‐55.	  	  
Goldman	  AP,	  Delius	  RE,	  Deanfield	  JE,	  Miller	  OI,	  de	  Leval	  MR,	  Sigston	  PE,	  Macrae	  DJ:	  
Pharmacological	   control	   of	   pulmonary	   blood	   flow	   with	   inhaled	   nitric	   oxide	  
after	   the	   fenestrated	   Fontan	   operation.	   Circulation.	   1996	   Nov	   1;94(9	  
Suppl):II44-­‐8.	  
Miyaji	   K,	   Nagata	   N,	   Miyamoto	   T,	   Kitahori	   K.Combined	   therapy	   with	   inhaled	   nitric	  
oxide	   and	   intravenous	   epoprostenol	   (prostacyclin)	   for	   critical	   pulmonary	  
perfusion	   after	   the	   Fontan	   procedure.	   J	   Thorac	   Cardiovasc	   Surg.	   2003	  
Feb;125(2):437-­‐9.	  
Mendoza	   A,	   Albert	   L,	   Belda	   S,	   Casanueva	   L,	   Herrera	   D,	   Granados	   MA,	   Velasco	   JM,	  
García	   E,	   Aguilar	   JM,	   Comas	   JV.	   Pulmonary	   vasodilator	   therapy	   and	   early	  
postoperative	  outcome	  after	  modified	  Fontan	  operation.	  Cardiol	  Young.	  2014	  
Sep	  16:1-­‐5.	  [Epub	  ahead	  of	  print]	  
	  


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13  
McCammond	  AN,	  Kuo	  K,	  Parikh	  VN,	  Abdullah	  K,	  Balise	  R,	  Hanley	  FL,	  Roth	  SJ.	  Early	  
outcomes	  
after	  
extracardiac	  
conduit	  
Fontan	  
operation	  
without	  
cardiopulmonary	  bypass.	  Pediatr	  Cardiol.	  2012	  Oct;33(7):1078-­‐85.	  	  
Takatsuki	  S,	  Parker	  DK,	  Doran	  AK,	  Friesen	  RH,	  Ivy	  DD.	  Acute	  pulmonary	  vasodilator	  
testing	   with	   inhaled	   treprostinil	   in	   children	   with	   pulmonary	   arterial	  
hypertension.	  Pediatr	  Cardiol.	  2013	  Apr;34(4):1006-­‐12.	  	  
Siehr	  SL,	  Ivy	  DD,	  Miller-­‐Reed	  K,	  Ogawa	  M,	  Rosenthal	  DN,	  Feinstein	  JA.	  Children	  with	  
pulmonary	   arterial	   hypertension	   and	   prostanoid	   therapy:	   long-­‐term	  
hemodynamics.	  J	  Heart	  Lung	  Transplant.	  2013	  May;32(5):546-­‐52.