Protocol Number: CRO1888 VANISH Vasopressin vs Noradrenaline as Initial therapy in Septic Shock PROTOCOL NUMBER: CRO1888 EudraCT NUMBER: 2011-005363-24 SPONSOR: Imperial College London FUNDER: National Institute for Health Research DEVELOPMENT PHASE: PHASE IV STUDY COORDINATION CENTRE: Imperial Clinical Trials Unit PROTOCOL Version & Date: Version 2.1, 02.08.2013 Property of: Dr Anthony Gordon May not be used, divulged or published without the consent of: Dr Anthony Gordon Confidential Final Version2.1, 02.08.2013 Page 1 of 31 Downloaded From: https://jamanetwork.com/ on 09/29/2021 Protocol Number: CRO1888 Study Management Group Chief Investigator: Dr Anthony Gordon Co-investigators: Dr Stephen Brett Prof Gavin Perkins Prof Deborah Ashby Statistician: Dr Alexina Mason Trial Management: Ms Neeraja Thirunavukkarasu Study Coordination Centre For general queries, supply of trial documentation, and collection of data, please contact: Study Coordinator: Ms Neeraja Thirunavukkarasu Address: ICU – 11N, Charing Cross Hospital, Fulham Palace Road London W6 8RF E-mail: [email protected] Clinical Queries Clinical queries should be directed to Ms Neeraja Thirunavukkarasu who will direct the query to the appropriate person Sponsor Imperial College London is the main research Sponsor for this study. For further information regarding the sponsorship conditions, please contact the Head of Regulatory Compliance at: Joint Research Compliance Office 510, Lab block, 5th Floor Charing Cross Hospital Fulham Palace Road London W6 8RF Tel: 0203 311 0213 Fax: 0203 311 0203 Funder National Institute for Health Research – Research for Patient Benefit and Clinician Scientist award schemes This protocol describes the VANISH study and provides information about procedures for entering participants. The protocol should not be used as a guide for the treatment of other participants; every care was taken in its drafting, but corrections or amendments may be necessary. These will be circulated to investigators in the study, but centres entering participants for the first time are advised to contact the trials centre to confirm they have the most recent version. Problems relating to this trial should be referred, in the first instance, to the study coordination centre. This trial will adhere to the principles outlined in the Medicines for Human Use (Clinical Trials) Regulations 2004 (SI 2004/1031), amended regulations (SI 2006/1928) and the International Conference on Harmonisation Good Clinical Practice (ICH GCP) guidelines. It will be conducted in compliance with the protocol, the Data Protection Act and other regulatory requirements as appropriate. Confidential Final Version2.1, 02.08.2013 Page 2 of 31 Downloaded From: https://jamanetwork.com/ on 09/29/2021 Protocol Number: CRO1888 Table of Contents 1 STUDY SUMMARY 6 2 INTRODUCTION 8 2.1 BACKGROUND 8 2.2 RATIONALE FOR CURRENT STUDY 12 3 STUDY OBJECTIVES 12 3.1 PRIMARY OBJECTIVES 12 3.2 SECONDARY OBJECTIVES 13 4 STUDY DESCRIPTION 13 4.1 DESIGN 13 4.2 TREATMENT REGIMEN 13 5 TRIAL METHODS 13 5.1 SUBJECT SELECTION 13 5.1.1 Pre-randomisation evaluations 13 5.1.2 Inclusion Criteria 13 5.1.3 Exclusion Criteria 14 5.2 PROCEDURES AND MEASUREMENTS 14 5.2.1 Screening 14 5.2.2 Informed Consent 14 5.2.3 Randomisation 15 5.2.4 Treatments 16 5.2.5 Follow-Up 18 5.2.6 Lab evaluations 19 5.3 END POINT MANAGEMENT 19 5.3.1 Primary Outcome 19 5.3.2 Secondary Outcome 19 6 PHARMACOVIGILANCE 19 6.1 DEFINITIONS 19 6.2 CAUSALITY 20 6.3 REPORTING PROCEDURES 21 6.4 DATA MONITORING & ETHICAL COMMITTEE 22 7 EARLY DISCONTINUATION OF THE STUDY OR INDIVIDUAL SUBJECTS 23 7.1 EARLY DISCONTINUATION OF THE STUDY 23 7.2 EARLY DISCONTINUATION OF THE SUBJECTS 23 7.3 LOSS TO FOLLOW-UP 23 8 STATISTICS AND DATA ANALYSIS 23 8.1 OUTCOME MEASURES 23 8.2 POWER CALCULATIONS 23 9 TREATMENT 24 9.1 INVESTIGATIONAL MEDICINAL PRODUCT DETAILS 24 9.2 LABELLING, STORAGE AND DISPENSING 24 9.3 ACCOUNTABILITY 24 9.4 UNBLINDING 25 10 REGULATORY, ETHICAL AND LEGAL ISSUES 25 Confidential Final Version2.1, 02.08.2013 Page 3 of 31 Downloaded From: https://jamanetwork.com/ on 09/29/2021 Protocol Number: CRO1888 10.1 DECLARATION OF HELSINKI 25 10.2 GOOD CLINICAL PRACTICE 25 10.3 INDEPENDENT ETHICS COMMITTEE APPROVAL 25 10.3.1 Initial Approval 25 10.3.2 Approval of Amendments 25 10.3.3 Annual Progress Reports and End of Trial Notification 25 10.4 REGULATORY AUTHORITY APPROVAL 25 10.5 TRIAL REGISTRATION 25 10.6 INSURANCE & INDEMNITY 26 10.7 SUBJECT CONFIDENTIALITY 26 10.8 DATA PROTECTION 26 10.9 END OF TRIAL 26 10.10 STUDY DOCUMENTATION AND DATA STORAGE 26 11 ADMINSTRATIVE MATTERS 26 11.1 SOURCE DATA 26 11.2 ELECTRONIC DATA CAPTURE 27 11.3 TRIAL MANAGEMENT 27 11.3.1 Trial Steering Committee 27 11.3.2 Trial Management Group 27 11.3.3 Monitoring 27 11.4 QUALITY CONTROL AND QUALITY ASSURANCE 28 11.5 AUDITS AND INSPECTIONS 28 11.6 PUBLICATION POLICY 28 12 REFERENCES 29 Confidential Final Version2.1, 02.08.2013 Page 4 of 31 Downloaded From: https://jamanetwork.com/ on 09/29/2021 Protocol Number: CRO1888 GLOSSARY OF ABBREVIATIONS ACTH Adrenocorticotrophin Hormone AE Adverse Event AKIN Acute Kidney Injury Network AR Adverse Reaction BMJ British Medical Journal BP Blood Pressure CI Confidence Intervals CRF Case Report Form CTU Clinical Trials Unit DMEC Data Monitoring and Ethics Committee eCRF Electronic Case Record Form EDC Electronic Data Capture GCP Good Clinical Practice GMP Good Manufacturing Practice ICU Intensive Care Unit IMP Investigational Medicinal Product ISF Investigator Site File IV Intravenous MHRA Medicines and Healthcare products Regulatory Agency mRNA Messenger Ribonucleic Acid OR Odds Ratio PerLR Personal Legal Representative PIS Patient Information Sheet ProLR Professional Legal Representative REC Research Ethics Committee RNA Ribonucleic Acid RRT Renal Replacement Therapy SAE Serious Adverse Event ScvO2 Central Venous Oxygen Saturation SIRS Systemic Inflammatory Response Syndrome SmPC Summary of Product Characteristics SOFA Serial Organ Failure Assessment SOP Standard Operating Procedure SUSAR Suspected Unexpected Serious Adverse Reaction TSC Trial Steering Committee TMF Trial Master File TMG Trial Management Group VACS Vasopressin and Corticosteroids in Septic Shock Trial VASST Vasopressin and Septic Shock Trial KEYWORDS Septic shock, vasopressin, noradrenaline, hydrocortisone, blood pressure, acute kidney injury, organ failure Confidential Final Version2.1, 02.08.2013 Page 5 of 31 Downloaded From: https://jamanetwork.com/ on 09/29/2021 Protocol Number: CRO1888 1 STUDY SUMMARY TITLE Vasopressin vs Noradrenaline as Initial therapy in Septic Shock DESIGN Double-blind factorial (2x2) randomised controlled trial AIMS 1. Does vasopressin reduce renal dysfunction compared to noradrenaline when used as the initial vasopressor in the management of adult patients who have septic shock? 2. Is there an interaction between vasopressin and corticosteroids when used in the management of septic shock? POPULATION Adult patients who have septic shock managed in ICU. 412 patients will be recruited for this trial. ELIGIBILITY Adult patient who has sepsis and requires vasopressors to maintain blood pressure despite adequate fluid resuscitation TREATMENT 1. Vasopressin vs. Noradrenaline as initial vasopressor therapy and then 2. Intravenous hydrocortisone vs. “placebo” DURATION Vasopressin vs. Noradrenaline until hypotension has resolved (Maximum 28days) Hydrocortisone vs. “placebo” for 11 days PRIMARY OUTCOME Renal failure free days during the 28 days after randomisation SECONDARY OUTCOMES • Rates and duration of renal replacement therapy • Length of renal failure in survivors and non-survivors • 28-day, ICU and hospital mortality rates. • Organ failure free days in the first 28 days, assessed using the serial organ failure assessment (SOFA) score • Organ support data assessed using the standard NHS Healthcare Resource Groups • Blood, plasma and urinary biomarkers of renal function and inflammation (including genetic polymorphisms). Confidential Final Version2.1, 02.08.2013 Page 6 of 31 Downloaded From: https://jamanetwork.com/ on 09/29/2021 Protocol Number: CRO1888 SCHEMATIC TRIAL PLAN Confidential Final Version2.1, 02.08.2013 Page 7 of 31 Downloaded From: https://jamanetwork.com/ on 09/29/2021 Protocol Number: CRO1888 2 INTRODUCTION 2.1 BACKGROUND Severe sepsis is an increasingly common problem worldwide and is an important cause of mortality (10th most common cause of death in US). In the UK the incidence of severe sepsis has increased 68% over a nine year period, such that in 2004 there were 31,000 patients who had severe sepsis admitted to intensive care units in England, Wales and Northern Ireland.1 A substantial number of patients will also develop severe sepsis after admission to intensive care,2 so the total number of severe sepsis cases may be in excess of 45,000 per annum. As the population ages and receive more complex medical treatments, this will continue to rise. Mortality from sepsis is 35-50%, proportional to illness severity and the number of organs failing. Patients who have sepsis consume a disproportionate amount of resources compared to other critically ill patients. The estimated annual hospital costs for treating these patients in the UK is about £700 million.3 Septic shock, the most severe form of sepsis, is defined as hypotension in response to overwhelming infection.4 As well as appropriate antibiotic treatment one of the main treatments is cardiovascular resuscitation using intravenous fluids and catecholamines. Although usually effective at