Table 2 List of amendments to the protocol
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 |