Current Clinical Trials in
AKI – What Questions
Are They Addressing?
Sean M Bagshaw, MD, MSc
Division of Critical Care Medicine
Faculty of Medicine and Dentistry, University of Alberta
1st International Symposium on AKI in Children
Cincinnati, Ohio
September 28, 2012
Disclosure Summary
• Sean M Bagshaw, MD, MSc
– Consultancy: Gambro Inc.
– Speaking: Gambro Inc., Alere Inc.
Learning Objectives
• Review Current Clinical Trials in AKI
– Adult
– Pediatric
• Discuss Barriers to Trials in Children
• Future Directions
• Search of ClinicalTrials.gov - 126 clinical trials
– Adult trials ~ 118 (93.6%)
– Pediatric trials ~ 8 (6.4%) → now 10 (updated)
No. (%)
Adult (n, %)
Pediatric (n, %)
75
68
7
Contrast Media
28
28
0
Cardiac Surgery
30
23
7
Specific Settings
17
17
0
43
42
1
General Settings
23
23
0
Specific Settings
20
19
1
Prevention trials
Management trials
Faubel et al CJASN 2012
Interventions for
Prevent CI-AKI
Hydration
NAC
NaHCO3
α-tocopherol (vit E)
Darbepoetin
Erythropoetin
Deferiprone
Glutathione
Nicorandil
Oxygen (100%)
Pentoxifylline
Sarpogrelate
Statin
LVEDP-based
RenalGuard
Population/Settings
All
CKD
DM
ACS/STEMI
Cardiac catheterization
Primary PCI
Outcomes
AKI:
Changes in RBF in 7 hr
≥25% ↑ sCr in 48 hr
≥25% ↑ sCr in 72 hr
≥0.3 mg/dL ↑sCr
≥0.5 mg/dL ↑sCr in 72 hr
≥25% or ≥0.5 mg/dL sCr in 24 hr
≥25% or ≥0.5 mg/dL sCr in 24-48 hr
AKI and RRT initiation
RRT initiation
↑sCr or RRT in 6 months
Composite:
Renal and Cardiac events at 90-days
Death, RRT, persistent decline in
kidney function at 90-days
Interventions for Prevent CSA-AKI
Drug Therapy Interventions:
Acetaminophen
Statin (atorvastatin)
Erythropoetin
NAC, NaHCO3, NAC + NaHCO3
Propofol
Rasburicase
Selenium
Fenoldopam
Minocycline
Remote Ischemic Preconditioning
Process Interventions:
Tight glycemic control
Transfusion triggers
Hypo/normothermic CPB
Preoperative RRT or intraop UF
Outcomes
Oxidative Stress (F2isoP)
Drug pharmacokinetics
Safety
SOFA score
AKI by :
RIFLE/AKIN classification
Δ sCr at 2, 3, 4, 5 days
Δ cystatin C
Δ eGFR
Biomarkers (NGAL)
ACS plus AKI
TnI release plus AKI
Composite:
ACS, stroke or AKI
Death, AKI and complications
MACE (including AKI)
Setting
Intervention
Outcomes
Sevoflurane
Infarct size + AKI
Albumin
Renal function at 3 months
Critical Illness
Erythropoetin
NAC + deferoxamine
Tight glycemic control
Urine NGAL at 96 hr
Protein metabolism + AKI
AKI
RAS – Stenting
Distal embolic protection
CrCl + CysC at 1, 3 month
Rhabdomyolysis
NAC, HVHF, both
eGFR, RIFLE max, mortality
NaHCO3, HES
Cascade HF
RIFLE, Mortality, Renal recovery,
Days without VP, AKI
Surgery (non-cardiac):
Hip repair, aortic,
general, abdominal
Hemospan vs HES
Curcumin
NAC
Hemodynamic (PiCCO)
Fluid strategies (RELIEF)
Hypotension + AKI
sCr at day 4
AKI
sCr at day 3
Mortality + AKI
Tumor Lysis Syndrome
Rasburicase
Uric acid + AKI
ACS
Cirrhosis
Sepsis
Current Pediatric Clinical Trials
ClinicalTrials.gov
Population
Phase
N
Intervention
Outcome
Status
NCT01245595
Cardiac
Surgery
II
160
Aminophylline
pRIFLE (5 days)
R
NCT01336959
Cardiac
Surgery
II
140
BCT197
AKI (2 days)
R
NCT01316497
Cardiac
Surgery
II
105
RIPC
pRIFLE (4 days)
C
NCT01260259
Cardiac
Surgery
II
100
RIPC
AKI (3 days)
R
NCT00982527
Cardiac
Surgery
II
80
Fenoldopam
Urine biomarkers
C
NCT01228305
Cardiac
Surgery
II
30
Acetaminophen
Oxidative
stress/AKI (2nd)
R
NCT01398709
Cardiac
Surgery
III
100
Rewarm rate
Mortality/AKI (2nd)
NR
NCT01398722
Cardiac
Surgery
III
800
ITT
Mortality/AKI (2nd)
NR
Current Pediatric Clinical Trials
ClinicalTrials.gov
NCT01641289
NCT01416298
Population
Phase
N
Intervention
Outcome
Status
Malaria
II
50
Acetaminophen
AKI
R
100
NGAL-based
fluid
management
Predictive value NGAL
R
Critically Ill
II
Barriers to Evidence in Kids
• Challenges with INFORMED CONSENT
– Novel methods (i.e. staged consent procedures)
– Multi-factorial assessments of competence
• Paucity of dedicated FUNDING to pediatric AKI
– Smaller “market” size – less industry interest
Faubel et al CJASN 2012
Barriers to Evidence in Kids
• Need for specialized DOSING/FORMULATIONS
• Limited “at-risk” population – trial design/logistics
– FEWER CHILDREN with disease
– FEWER OUTCOME EVENTS (RRT, death)
• Often EXCLUDED from ADULT randomized
trials
Barriers to Evidence in Kids
• CHILDREN are “under-studied”
– 8/118 (6.4%) of AKI-related trials listed on
ClinicalTrials.gov involved children
• Implications/consequences:
– Lack of data on efficacy/safety of interventions
– Off label use common (extrapolation from adults)
• Arguably UNETHICAL to exclude children in
randomized trials focused on AKI (and in general)
• MISSED OPPORTUNITY
Are the results of ADULT trials concordant with PEDIATRIC trials?
• 9 topics with statistically significant discrepancies, 4 clinically important:
–
–
–
–
Arteminisnin vs. quinine for severe malaria (↑ survival in adults, not children)
Phenobarb in cerebral malaria (↑ survival in adults, ↑ mortality in children)
Long-acting β-agonist in asthma (↓ exacerbation in adults, not children)
Corticosteroids in meningitis (↑ survival in adults, not children)
Ioannidis et al J Pediatr 2010
Outcome (%)
TGC
CON
p
Received Insulin
91
2
<0.01
Hypoglycemia
19
9
<0.01
Infection
5
5
1.0
Hospital Mortality
2
2
1.0
Hospital Stay (d)
8
7
0.20
Readmit (30 d)
9
7
0.29
Children
Adults
Adult/Pediatric Collaboration
• Critical Illness – Focused Interventions:
– Resuscitation in Sepsis
– Corticosteroids in Sepsis
– Extracorporeal support
– Traumatic brain injury
• Population: Adults patients admitted to ICU with DKA (n=23)
• Design: Retrospective cohort study
• Exposure: Resuscitation with PL vs. NS in first 12 hr
Chua et al J Crit Care 2012
Australasian Resuscitation In Sepsis Evaluation
• Design: Multi-national, multi-centre (45),
randomized, controlled trial
• Population: Adult patients with severe sepsis
presenting to the ED
• Intervention: EGDT compared to standard-of-care
• Target Recruitment: 1600 patients (800 in each arm)
Australasian Resuscitation In Sepsis Evaluation
(UK Study) – 47 sites - started Feb 2011 – recruitment
goal 1260 adult septic patients (n=515)
(US Study) – 26 sites - started Mar 2008 – recruitment
goal 1900 adult septic patients (n=1161)
Adult/Pediatric Collaboration
• AKI – Focused Interventions:
– Prevention of CSA-AKI*
•
•
•
•
•
Acetaminophen
Fenoldopam
RIPC
Tight glycemic control
Rewarming
– Prevention of CKD after AKI
– Optimal timing of RRT initiation
– Blood purification in Sepsis/MODS
* Currently duplicate trials in children + adults
n=10
Nguyen et al CCM 2008
Valentine et al CCM 2012
Valentine et al CCM 2012
NGAL-Directed RRT Initiation
Use of Neutrophil GelatinaseAssociated Lipocalin (NGAL) to
Optimize Fluid Dosing, Continuous
Renal Replacement Therapy (CRRT)
Initiation and Discontinuation in
Critically Ill Children With Acute
Kidney Injury (AKI)
ClinicalTrials.gov Identifier: NCT01416298
Available at: http://www.clinicaltrials.gov/ct2/show/NCT01416298?term=NCT01416298&rank=1
NGAL-Directed RRT Initiation
Hypotheses:
1.
↑ NGAL will predict >10% fluid overload (FO)
2.
↑ NGAL will predict, in children with 10-20%
FO, no improvement or worsening AKI in 24-48
hr → Decision support to start RRT
3.
↓ NGAL will be associated with improvement in
urine output and initial resolution of AKI in <72
hr → Decision support to stop RRT
Available at: http://www.clinicaltrials.gov/ct2/show/NCT01416298?term=NCT01416298&rank=1
The STARRT-AKI Study:
STandard versus Accelerated
Initiation of Renal
Replacement Therapy in
Acute Kidney Injury
ClinicalTrials.gov Identifier: NCT01557361
The SPARK Study:
A randomized controlled trial
of furoSemide in critically ill
Patients with eARly
acute Kidney injury
ClinicalTrials.gov Identifier: NCT00978354
Thank You For Your Attention!
Questions?
bagshaw@ualberta.ca
Acknowledgements
• Stuart Goldstein