Condition category
Signs and Symptoms
Date applied
20/09/2012
Date assigned
20/09/2012
Last edited
14/07/2015
Prospective/Retrospective
Prospectively registered
Overall trial status
Completed
Recruitment status
No longer recruiting

Plain English Summary

Background and study aims
Overwhelming infection (severe sepsis) can lead to a drop in blood pressure. This results in poor blood flow to the kidney and other vital organs. Severe infections are becoming an increasing healthcare problem. It is the 10th most common cause of death in America and it is estimated that the UK spends more than £1 billion each year treating severe infections in patients in intensive care units (ICU).
As well as antibiotics and intravenous fluids, adrenaline-type drugs are routinely used to increase blood pressure. Although usually effective at restoring blood pressure these drugs have important side effects.
Vasopressin and steroids are both naturally produced hormones that are released during times of severe illness. However, when blood pressure drops due to infection, these compensatory mechanisms often fail. Studies have shown that administering both of these drugs can help restore blood pressure and reduce the use of other adrenaline-type drugs. Recent studies found that vasopressin may be most effective if used earlier and for less severe drops in blood pressure and may have a specific role in preventing kidney failure. It may also be more effective if administered with steroids. We plan to undertake a trial to investigate if vasopressin can reduce kidney failure and the need for dialysis in patients with severe infections. We also plan to investigate if steroids cross-react with vasopressin.

Who can participate?
This study aims to recruit 412 adult patients with septic shock, being treated in 19 intensive care units (ICU) in the UK.

What does the study involve?
All patients who are clinically judged to have septic shock will be screened against the inclusion and exclusion criteria to see if they are eligible for the study. The patients will be randomised to receive either Vasopressin or Noradrenaline (Study Drug 1) by continuous infusion to stabilise their blood pressure. If the maximum limit of Study Drug 1 is reached then Study Drug 2 (hydrocortisone or placebo) will be administered. Routinely collected clinical data will be recorded on a daily basis during this time. Additional blood and urine samples will also be collected from a subset of patients on days 1, 3, 5 and 7 of the trial. Patients will be followed up at 28 days after inclusion and / or hospital discharge.

What are the possible benefits and risks of participating?
It is possible that one of the combinations of these drugs is better that then the other combinations. At the moment we do not know which combination is best. This study might help improve the treatment of people with septic shock in the future. As all the study drugs are already routinely used in the management of septic shock there is minimal extra risk from participation in this study. The doctors and nurses will watch careful for any possible side-effects and will treat them as necessary and even stop the drugs if needed. Only very small quantities of extra blood samples will be collected, usually from existing lines, but it might be necessary to collect a sample from a new needle which might result in some minor discomfort during collection and possibly a small bruise.

Where is the study run from?
The VANISH trial will run from Charing Cross Hospital, part of Imperial College London.

When is study starting and how long is it expected to run for?
It is anticipated that recruitment will start in November 2012. Participants will be recruited into the study over a period of 30 months.

Who is funding the study?
Funding has been provided by NIHR (National Institute for Health Research) - Research for Patient Benefit and Clinical Scientist award schemes.

Who is the main contact?
Mrs Neeraja Thirunavukkarasu
vanish@imperial.ac.uk

Trial website

Contact information

Type

Scientific

Primary contact

Mrs Neeraja Thirunavukkarasu

ORCID ID

Contact details

ICU Charing Cross Hospital
Fulham Palace Road
London
W6 8RF
United Kingdom
-
vanish@imperial.ac.uk

Additional identifiers

EudraCT number

2011-005363-24

ClinicalTrials.gov number

Protocol/serial number

12985

Study information

Scientific title

VAsopressin vs Noradrenaline as Initial therapy in Septic sHock: a double-blind factorial (2x2) randomised controlled trial

Acronym

VANISH

Study hypothesis

Septic shock is a condition where blood pressure reduces in response to overwhelming infections. This results in poor blood flow to the kidney and other vital organs. It is a life-threatening condition and requires emergency treatment in an intensive care unit.

Severe infections are becoming an increasing healthcare problem. It is the 10th most common cause of death in America and it is estimated that the UK spends about £700 million/year treating severe infections in patients in intensive care units.

As well as antibiotics and intravenous fluids, adrenaline-type drugs are used to increase blood pressure. Although usually effective at restoring blood pressure, these drugs have important side effects.

Vasopressin and steroids are both naturally produced hormones that are released during times of stress. However, when blood pressure drops due to infection, these compensatory mechanisms often fail. Studies have shown that administering both of these drugs can help restore blood pressure and reduce the use of other adrenaline-type drugs.

Recent studies found that vasopressin may be more effective if used earlier and for less severe drops in blood pressure.

In this study, we plan to investigate if vasopressin is more effective in reducing kidney dysfunction compared to noradrenaline when used as initial therapy in septic shock in adult patients. Also, we aim to study if there is any interaction between vasopressin and steroids in the management of septic shock.

More details can be found at http://public.ukcrn.org.uk/search/StudyDetail.aspx?StudyID=12985

Ethics approval

South Central - Oxford A REC, First MREC approval date 30/01/2012, ref: 12/SC/0014

Study design

Double-blind factorial (2x2) randomised controlled trial

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Hospitals

Trial type

Treatment

Patient information sheet

Not available in web format, please use the contact details below to request a patient information sheet

Condition

Topic: Infection, Generic Health Relevance and Cross Cutting Themes; Subtopic: Infection (all Subtopics), Generic Health Relevance (all Subtopics); Disease: Infectious diseases and microbiology , Critical Care

Intervention

1. Vasopressin vs. Noradrenaline as initial vasopressor therapy and then
2. Intravenous hydrocortisone vs. placebo

Hydrocortisone, 50mg 6 hourly
Noradrenaline, Upto 12mcg/minute
Vasopressin, Upto 0.06 U/minute

Intervention type

Drug

Phase

Not Applicable

Drug names

Vasopressin, noradrenaline

Primary outcome measures

Renal failure free days at day 28 post randomisation

Secondary outcome measures

1. Rates and duration of renal replacement therapy
2. Length of renal failure in survivors and non-survivors
3. 28-day, ICU and hospital mortality rates
4. Organ failure free days in the first 28 days, assessed using the serial organ failure assessment (SOFA) score
5. Organ support data assessed using the standard NHS Healthcare Resource Groups
6. Blood, plasma and urinary biomarkers of renal function and inflammation (including genetic polymorphisms)

Overall trial start date

01/10/2012

Overall trial end date

28/02/2015

Reason abandoned

Eligibility

Participant inclusion criteria

The target population is adult patients who require vasopressors for the management of sepsis despite fluid resuscitation.
All patients who are clinically judged to have septic shock will be screened against the specific inclusion and exclusion criteria and these criteria will be recorded in the eCRF.

Inclusion criteria will use the internationally-established consensus definitions of sepsis. In brief:
1. Fulfil 2/4 of the criteria of the systemic inflammatory response syndrome (SIRS) due to known or suspected infection vwithin the previous 24 hours. The SIRS criteria are:
1.1. Fever (>38 C) or hypothermia (< 36 C)
1.2. Tachycardia (heart rate > 90 beats per minute)
1.3. Tachypnoea (respiratory rate > 20 breaths per minute or PaCO2 < 4.3 kPa) or need for mechanical ventilation
1.4. Abnormal leukocyte count (> 12,000 cells/mm3, < 4000 cells/mm3, or > 10% immature [band] forms)
2. Hypotension despite adequate intravenous fluid resuscitation
3. Male & Female, lower age limit 16 years

Participant type

Patient

Age group

Adult

Gender

Both

Target number of participants

Planned Sample Size: 412; UK Sample Size: 412

Participant exclusion criteria

1. Patient has received a continuous infusion of vasopressors previously during this ICU admission. Vasopressors include noradrenaline, adrenaline, vasopressin, dopamine, metaraminol, phenylephrine, and (intermittent) terlipressin
2. Regular systemic corticosteroid therapy within the previous three months (this does not include inhaled steroid therapy)
3. Known adrenal dysfunction / insufficiency
4. End-stage renal failure (i.e. requiring long term dialysis)
5. Physician and team are not committed to full active care
6. Patient is known to be pregnant
7. Patient has known acute mesenteric ischaemia
8. Patient is known to have Raynaud's phenomenon, systemic sclerosis or other vasospastic diseases
9. Patient has been enrolled in another clinical trial of an investigational medicinal product within 30 days or is enrolled in another investigational study that might interact with the study drugs
10. Patient has a history of anaphylaxis to any study drug

Recruitment start date

01/11/2012

Recruitment end date

28/02/2015

Locations

Countries of recruitment

United Kingdom

Trial participating centre

ICU Charing Cross Hospital
London
W6 8RF
United Kingdom

Sponsor information

Organisation

Imperial College London (UK)

Sponsor details

South Kensington Campus (main campus)
London
SW7 2AZ
United Kingdom

Sponsor type

University/education

Website

Funders

Funder type

Government

Funder name

National Institute for Health Research (UK) - Research for Patient Benefit and Clinician Scientist award schemes

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Results and Publications

Publication and dissemination plan

Not provided at time of registration

Intention to publish date

Participant level data

Not provided at time of registration

Results - basic reporting

Publication summary

2014 protocol in: http://www.ncbi.nlm.nih.gov/pubmed/24993769

Publication citations

  1. Protocol

    Gordon AC, Mason AJ, Perkins GD, Ashby D, Brett SJ, Protocol for a randomised controlled trial of VAsopressin versus Noradrenaline as Initial therapy in Septic sHock (VANISH)., BMJ Open, 2014, 4, 7, e005866, doi: 10.1136/bmjopen-2014-005866.

Additional files

Editorial Notes