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Table 2 List of amendments to the protocol

From: Design and conduct of the activated protein C and corticosteroids for human septic shock (APROCCHSS) trial

Amendments number Changes in protocol CPP approval date ANSM approval date Official version of trial protocol
1 Changes in following exclusion criteria:
 “surgical procedure in the past 7 days” was changed for “surgical procedure within 72 h, or any surgery associated with high risk of bleeding, or a planned surgery within 24 h”
 “chronic liver disease” was clarified as “chronic liver disease with Child score C”
 “severe thrombopenia” was clarified” as severe thrombopenia (<30,000/mm3, before transfusion)
Minor wording modifications in title, study acronym, randomization paragraph
Recruitment of 4 additional centers
14/02/2008 27/03/2008 Protocol V2 dated 28/01/2008
2 Recruitment of 1 additional center
Withdrawal of 1 center
12/06/2008 Not applicable Protocol V2 dated 28/01/2008 unchanged
3 Recruitment of 9 additional centers 03/07/2008 Not applicable Protocol V2 dated 28/01/2008 unchanged
4 Recruitment of 1 additional center 13/11/2008 Not applicable Protocol V2 dated 28/01/2008 unchanged
5 The time window for the use of a prepared (i.e., ready for infusion) infusion bag of Xigris and of its placebo was increased from 14 h to 24 h 12/02/2009 26/12/2008 Protocol V3 dated 11/12/2008
6 Recruitment of 1 additional center
Change in contact details of 3 centers
15/01/2009 Not applicable Protocol V3 dated 11/12/2008 unchanged
7 Recruitment of 1 additional center 9/04/2009 Not applicable Protocol V3 dated 11/12/2008 unchanged
8 Recruitment of 2 additional centers 18/06/2009 Not applicable Protocol V3 dated 11/12/2008 unchanged
9 The exclusion criteria: surgical procedure within 72 h, or any surgery associated with high risk of bleeding, or a planned surgery within 24 h “was changed for” surgical procedure within 12 h, or any surgery associated with high risk of bleeding 17/09/2009 25/08/2009 Protocol V3.0 dated 20/07/2009
10 Recruitment of 1 additional center 12/11/2009 Not applicable Protocol V3.0 dated 20/07/2009 unchanged
11 Recruitment of 1 additional center 10/12/2009 Not applicable Protocol V3.0 dated 20/07/2009 unchanged
12 Recruitment of 1 additional center 11/03/2010 Not applicable Protocol V3.0 dated 20/07/2009 unchanged
13 Inclusion criteria: admitted to the ICU for <7 days was removed.
New exclusion criteria: patients who had a previous episode of sepsis during the same hospital stay
Prolongation of the recruitment period
Recruitment of 3 additional centers
Withdrawal of 11 inactive centers
10/06/2010 11/06/2010 Protocol V4 dated 10/05/2010
14 Withdrawal of 4 inactive centers 09/09/2010 Not applicable Protocol V4 dated 10/05/2010 unchanged
15 Recruitment of 1 additional center 23/11/2010 Not applicable Protocol V4 dated 10/05/2010 unchanged
16 Recruitment of 1 additional center
Implementation of biobanking: serum, plasma, DNA
Change in informed consent sheet
23/11/2010 09/11/2010 Protocol V6 dated 03/11/2010
Informed consent sheet V1.1 dated 26/10/2010
17 Recruitment of 1 additional center 13/10/2010 Not applicable Protocol V6 dated 03/11/2010 unchanged
18 Recruitment of 7 additional centers 13/01/2011 Not applicable Protocol V6 dated 03/11/2010 unchanged
19 Recruitment of 1 additional center 7/04/2011 Not applicable Protocol V6 dated 03/11/2010 unchanged
20 Recruitment of 1 additional center 12/05/2011 Not applicable Protocol V6 dated 03/11/2010 unchanged
20 BIS Following the withdrawal of DAA from the market:
 Study design was modified from a 2 × 2 factorial to a two-parallel groups’ trial
 Withdrawal of following exclusion criteria:
  (1) any surgery in the past 12 h, or any surgery associated with high risk of bleeding;
  (2) chronic liver disease with a Child score C;
  (3) recent trauma;
  (4) any intracranial mass, or stroke or head injury in the past 3 months;
  (5) severe thrombocytopenia (<30,000/mm3, before platelet transfusion);
  (6) formal indication for anticoagulation, or any other condition associated with increased risk of bleeding, as appreciated by the patient’s physician
Change in informed consent form
10/02/2012 18/04/2012 Protocol V7 du 30/11/2011
Informed consent sheet V3.0 dated 05/01/2012
21 Prolongation of recruitment period 05/07/2012 Not applicable Protocol V8 dated 27/06/2012
Informed consent form V3.1 dated 21/09/2012
22 Recruitment of 2 additional centers 13/09/2012 Not applicable Protocol V9 dated 27/08/2012
23 Recruitment of 2 additional centers Withdrawal of 4 centers 13/12/2012 Not applicable Protocol V10 dated 04/12/2012
24 Recruitment of 2 additional centers
Removal of exclusion criteria related to XIGRIS
Withdrawal of 5 centers
21/03/2013 22/03/2013 Protocol V11.0 dated 20/02/2013
Protocol V11.1 dated 18/03/2013
25 Minor edits to the informed consent form upon CPP request 24/04/2014 Not applicable Protocol V12 du 15/10/2013
Informed consent form V3.2 dated 21 01 2014
26 Suspension of inclusions upon DSMB request
Changes in DSMB members
18/09/2014 29/08/2014 Protocol V13 dated 24/07/2014
27 Request to restart inclusion following:
(1) demonstration of the quality of study active drugs and placebos
(2) advice from DSMB
13/11/2014 07/10/2014 Protocol V13 dated 24/07/2014, unchanged
28 Prolongation of trial duration 11/06/2015 Not applicable Protocol V14.0 dated 12/05/2015
  1. CPP comité de protection des personnes, ANSM Agence nationale de sécurité des médicaments et produits de santé
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