Acute Renal FailurePhase 2ASK-ITNCT00711789
Angiotensin in Septic Kidney Injury Trial
A Phase 2 study testing Angiotensin II in people with Acute Renal Failure and Sepsis, run by Austin Health at 2 sites in Australia.
Trial summary
The purpose of this study is to determine the effect of a systemic infusion of angiotensin II on haemodynamics and urine output in critically ill patients with severe sepsis/septic shock and acute renal failure. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Acute Renal Failure, Sepsis, Septic Shock
- What is being tested?
- Angiotensin II
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 12 participants
- Where
- 2 sitesAustralia
- Study dates
- Feb 2010to Feb 2013
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- age ≥ 18 years
- within the first 24 hours of ICU admission
- an expected duration of ICU admission of at least 72 hours
- informed consent by patient or by proxy (i.e. next of kin)
- diagnosis of severe sepsis/septic shock
- diagnosis of kidney dysfunction (minimum RIFLE criteria - 'R'); and
- presence of a central venous catheter.
Who cannot join
- inability to provide or obtain consent;
- patient is moribund with expected death within 24 hours;
- known chronic kidney disease (CKD) or end-stage renal disease (ESRD) receiving chronic RRT;
- confirmed or suspected acute glomerulonephritis, acute interstitial nephritis, renal vasculitis or post-renal aetiology for kidney dysfunction;
- patient is already receiving (or is about to start) CRRT for acute renal failure at the time of enrolment;
- known or documented allergy to angiotensin II;
- MAP consistently > 100 mmHg with no pressor support and no easily treatable cause (eg. pain); and
- enrolling physician's belief that the study drug could not be administered for the expected study duration.
Trial locations and contacts
2 sites in 1 country.
Australia2 sites, 2 recruiting
- Recruiting
Northern Hospital
Epping, Victoria, 3074
Michael C Reade, MBBS DPhil, +61394964838, michael.reade@austin.org.au
Graeme Duke, MD FJFICM, +613 8405 8000, graeme.duke@nh.org.au
- Recruiting
The Western Hospital
Footscray, Victoria, 3011
Forbes McGain, MBBS FJFICM, +613 8345 6639, forbes.mcgain@wh.org.au
Craig French, MBBS FJFICM, +613 8345 6639, craig.french@wh.org.au
About this study
Official title: A Pilot Crossover Randomised Controlled Trial of Angiotensin II in Critically Ill Patients With Severe Sepsis and Acute Renal Failure
The purpose of this study is to determine the effect of a systemic infusion of angiotensin II on haemodynamics and urine output in critically ill patients with severe sepsis/septic shock and acute renal failure.
It will also help determine the feasibility of conducting a definitive and adequately powered randomised controlled trial of angiotensin II in such patients that would assess mortality and need for renal replacement therapy as endpoints.
Read the detailed description
Sepsis is the most common cause of ARF in the ICU. In last 50 years there have been no significant advances in our understanding of the pathogenesis, prevention or treatment of septic ARF, except for the use of renal replacement therapy (RRT) once it is established.
It has been assumed that hypotension induced by severe sepsis results in organ hypoperfusion and subsequent kidney ischaemia. This ischaemia has been believed to be one of the main factors, if not the principal factor, contributing to development of ARF in severe sepsis. Surprisingly, there is little evidence to support this assumption. Rather, emerging evidence seriously questions this traditional ischaemic-acute tubular necrosis (ATN) paradigm of septic ARF. Patients with severe sepsis have been found to have increased, rather than decreased, renal blood flow, and post mortem examination of kidneys from patients who have died with septic acute renal failure rarely show the appearance of ATN. An animal model of septic ARF found that renal blood flow was increased, while glomerular filtration rate was decreased.
These facts lead us to hypothesise that profound efferent arteriolar vasodilatation may be the cause of the observed decrease in GFR in septic ARF. The only logical explanation for the observation that RBF increases while GFR falls is that both efferent and afferent arterioles dilate, but that efferent vasodilation is greater. A selective efferent arteriolar vasoconstrictor would be expected to restore GFR. Angiotensin II is the most selective known efferent vasoconstrictor.
We hypothesise that early therapeutic intervention with angiotensin II in critically ill patients with severe sepsis/septic shock and kidney dysfunction may improve kidney function such that the need for renal replacement therapy is avoided. This would represent a significant improvement in the care of critically ill patients with severe sepsis/septic shock and ARF, a condition for which no interventions short of RRT have been shown to improve outcome. Novel and successful therapeutic interventions in this patient population would have widespread clinical implications, including improved survival and less need for long-term dialysis, with consequent resource savings.
- Conditions
- Acute Renal Failure, Sepsis, Septic Shock
- Being tested
- Angiotensin II, Saline placebo
- Keywords
- Acute renal failure, Septic shock, angiotensin II, neutrophil gelatinase associated lipocalin (NGAL), cystatin C
- Medical subject headings
- Acute Kidney Injury, Sepsis, Shock, Septic
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Angiotensin IIDrug
Angiotensin II will be given by continuous infusion for 24 hours starting at a dose of 5ng/kg/min and then titrated to a maximum dose of 15 ng/kg/min according to a blood pressure based protocol
Saline placeboDrug
Saline placebo will be given by continuous infusion according to a blood-pressure base protocol. This protocol will also incorporate noradrenaline for blood pressure control (as is true in the active drug arm), such that blood pressure targets will be rapidly achieved in both arms of the study; the only difference being that in the active drug arm, at least part of the pressor effect will be provided by angiotensin II.
| Study group | Role | What they receive |
|---|---|---|
| Angiotensin II | Active comparator | Not described Receives: Drug: Angiotensin II |
| Placebo | Placebo comparator | Not described Receives: Drug: Saline placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Urine output
Measured: During the 24 hours of infusion of study drug
Arterial blood pressure
Measured: During the 24 hour infusion of study drug
Secondary outcomes (9)
Serum creatinine
Measured: At the end of the 24 hour infusion of study drug
Serum urea
Measured: At the end of the 24 hour infusion of study drug
Serum Cystatin C
Measured: At the end of the 24 hour infusion of study drug
Serum neutrophil gelatinase associated lipocalin (NGAL)
Measured: At the end of the 24 hour infusion of study drug
Urinary cystatin C
Measured: At the end of the 24 hour infusion of study drug
Urinary NGAL
Measured: At the end of the 24 hour infusion of study drug
Urinary IL-18
Measured: At the end of the 24 hour infusion of study drug
Need for renal replacement therapy
Measured: During ICU admisison
Mortality
Measured: ICU and 28 days
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted9 Jul 2008 (estimated)
- Study startFeb 2010
- Primary completionFeb 2013 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Acute Renal FailureStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 12 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Austin Health
- Sponsor type
- Other government
- Collaborators
- Northern Health and Social Care Trust, Western Hospital, Australia
- Investigators
- Michael C Reade, MBBS DPhil, Principal investigator, Northern Hospital, Epping, Victoria, AustraliaForbes McGain, MBBS FJFICM, Principal investigator, Western Hospital, Footscray, Victoria. Australia
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00711789
- Sponsor's protocol ID
- TNH 23/08
- Acronym
- ASK-IT
- Status last verified
- Jan 2009
- First submitted
- 7 Jul 2008
- Last updated
- 23 Jun 2011
- Results posted
- No
- Data monitoring committee
- No
Study at a glance
From the registry record, last updated by the sponsor on 23 Jun 2011. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Pilot Crossover Randomised Controlled Trial of Angiotensin II in Critically Ill Patients With Severe Sepsis and Acute Renal Failure
- ClinicalTrials.gov ID
- NCT00711789
- Acronym / sponsor ID
- ASK-IT / TNH 23/08
- Conditions
- Acute Renal Failure, Sepsis, Septic Shock
- Keywords
- Acute renal failure, Septic shock, angiotensin II, neutrophil gelatinase associated lipocalin (NGAL), cystatin C
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 12 participants (estimated)
- Lead sponsor
- Austin HealthOther government
- Collaborators
- Northern Health and Social Care Trust, Western Hospital, Australia
- Study start
- Feb 2010
- Primary completion
- Feb 2013 (estimated)
- First posted
- 9 Jul 2008 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The purpose of this study is to determine the effect of a systemic infusion of angiotensin II on haemodynamics and urine output in critically ill patients with severe sepsis/septic shock and acute renal failure.
It will also help determine the feasibility of conducting a definitive and adequately powered randomised controlled trial of angiotensin II in such patients that would assess mortality and need for renal replacement therapy as endpoints.
Detailed description
Sepsis is the most common cause of ARF in the ICU. In last 50 years there have been no significant advances in our understanding of the pathogenesis, prevention or treatment of septic ARF, except for the use of renal replacement therapy (RRT) once it is established.
It has been assumed that hypotension induced by severe sepsis results in organ hypoperfusion and subsequent kidney ischaemia. This ischaemia has been believed to be one of the main factors, if not the principal factor, contributing to development of ARF in severe sepsis. Surprisingly, there is little evidence to support this assumption. Rather, emerging evidence seriously questions this traditional ischaemic-acute tubular necrosis (ATN) paradigm of septic ARF. Patients with severe sepsis have been found to have increased, rather than decreased, renal blood flow, and post mortem examination of kidneys from patients who have died with septic acute renal failure rarely show the appearance of ATN. An animal model of septic ARF found that renal blood flow was increased, while glomerular filtration rate was decreased.
These facts lead us to hypothesise that profound efferent arteriolar vasodilatation may be the cause of the observed decrease in GFR in septic ARF. The only logical explanation for the observation that RBF increases while GFR falls is that both efferent and afferent arterioles dilate, but that efferent vasodilation is greater. A selective efferent arteriolar vasoconstrictor would be expected to restore GFR. Angiotensin II is the most selective known efferent vasoconstrictor.
We hypothesise that early therapeutic intervention with angiotensin II in critically ill patients with severe sepsis/septic shock and kidney dysfunction may improve kidney function such that the need for renal replacement therapy is avoided. This would represent a significant improvement in the care of critically ill patients with severe sepsis/septic shock and ARF, a condition for which no interventions short of RRT have been shown to improve outcome. Novel and successful therapeutic interventions in this patient population would have widespread clinical implications, including improved survival and less need for long-term dialysis, with consequent resource savings.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Angiotensin II | Active comparator | Drug: Angiotensin II |
| Placebo | Placebo comparator | Drug: Saline placebo |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (7 listed)
- age ≥ 18 years
- within the first 24 hours of ICU admission
- an expected duration of ICU admission of at least 72 hours
- informed consent by patient or by proxy (i.e. next of kin)
- diagnosis of severe sepsis/septic shock
Key exclusion criteria (8 listed)
- inability to provide or obtain consent;
- patient is moribund with expected death within 24 hours;
- known chronic kidney disease (CKD) or end-stage renal disease (ESRD) receiving chronic RRT;
- confirmed or suspected acute glomerulonephritis, acute interstitial nephritis, renal vasculitis or post-renal aetiology for kidney dysfunction;
- patient is already receiving (or is about to start) CRRT for acute renal failure at the time of enrolment;
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Angiotensin IIAngiotensin II will be given by continuous infusion for 24 hours starting at a dose of 5ng/kg/min and then titrated to a maximum dose of 15 ng/kg/min according to a blood pressure based protocol | Drug | Angiotensin II |
| Saline placeboSaline placebo will be given by continuous infusion according to a blood-pressure base protocol. This protocol will also incorporate noradrenaline for blood pressure control (as is true in the active drug arm), such that blood pressure targets will be rapidly achieved in both arms of the study; the only difference being that in the active drug arm, at least part of the pressor effect will be provided by angiotensin II. | Drug | Placebo |
Primary outcome
Urine output
Time frame: During the 24 hours of infusion of study drug
Arterial blood pressure
Time frame: During the 24 hour infusion of study drug
9 secondary outcomes
Serum creatinine
Time frame: At the end of the 24 hour infusion of study drug
Serum urea
Time frame: At the end of the 24 hour infusion of study drug
Serum Cystatin C
Time frame: At the end of the 24 hour infusion of study drug
Serum neutrophil gelatinase associated lipocalin (NGAL)
Time frame: At the end of the 24 hour infusion of study drug
Urinary cystatin C
Time frame: At the end of the 24 hour infusion of study drug
Urinary NGAL
Time frame: At the end of the 24 hour infusion of study drug
Urinary IL-18
Time frame: At the end of the 24 hour infusion of study drug
Need for renal replacement therapy
Time frame: During ICU admisison
Mortality
Time frame: ICU and 28 days
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 23 Jun 2011.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Michael C Reade, MBBS DPhil principal investigator
Northern Hospital, Epping, Victoria, Australia
Forbes McGain, MBBS FJFICM principal investigator
Western Hospital, Footscray, Victoria. Australia
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Angiotensin II in people with Acute Renal Failure and Sepsis, run by Austin Health at 2 sites in Australia.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 7 inclusion and 8 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 23 Jun 2011. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in Australia. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Michael C Reade, MBBS DPhil (+61394964838, michael.reade@austin.org.au), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Urine output (time frame: During the 24 hours of infusion of study drug). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 23 Jun 2011.