1. Sean M Bagshaw, MD, MSc Division of Critical Care Medicine Faculty of Medicine and Dentistry, University of Alberta 1 st International Symposium on AKI in Children Cincinnati, Ohio September 28, 2012 Current Clinical Trials in AKI – What Questions Are They Addressing?

2. Disclosure Summary Sean M Bagshaw, MD, MSc –Consultancy: Gambro Inc. –Speaking: Gambro Inc., Alere Inc.

3. Learning Objectives Review Current Clinical Trials in AKI –Adult –Pediatric Discuss Barriers to Trials in Children Future Directions

4. 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, %) Prevention trials75687 Contrast Media28 0 Cardiac Surgery30237 Specific Settings17 0 Management trials43421 General Settings23 0 Specific Settings20191 Faubel et al CJASN 2012

5. Interventions for Prevent CI-AKI Population/SettingsOutcomes Hydration NAC NaHCO3 α-tocopherol (vit E) Darbepoetin Erythropoetin Deferiprone Glutathione Nicorandil Oxygen (100%) Pentoxifylline Sarpogrelate Statin LVEDP-based RenalGuard All CKD DM ACS/STEMI Cardiac catheterization Primary PCI 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

6. Interventions for Prevent CSA-AKIOutcomes 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 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)

7. SettingInterventionOutcomes ACSSevofluraneInfarct size + AKI CirrhosisAlbuminRenal function at 3 months Critical IllnessErythropoetin NAC + deferoxamine Tight glycemic control Urine NGAL at 96 hr Protein metabolism + AKI AKI RAS – StentingDistal embolic protectionCrCl + CysC at 1, 3 month RhabdomyolysisNAC, HVHF, botheGFR, RIFLE max, mortality SepsisNaHCO3, 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 SyndromeRasburicaseUric acid + AKI

8. Current Pediatric Clinical Trials ClinicalTrials.govPopulationPhaseNInterventionOutcomeStatus NCT01245595 Cardiac Surgery II160AminophyllinepRIFLE (5 days)R NCT01336959 Cardiac Surgery II140BCT197AKI (2 days)R NCT01316497 Cardiac Surgery II105RIPCpRIFLE (4 days)C NCT01260259 Cardiac Surgery II100RIPCAKI (3 days)R NCT00982527 Cardiac Surgery II80FenoldopamUrine biomarkersC NCT01228305 Cardiac Surgery II30Acetaminophen Oxidative stress/AKI (2 nd ) R NCT01398709 Cardiac Surgery III100Rewarm rateMortality/AKI (2 nd )NR NCT01398722 Cardiac Surgery III800ITTMortality/AKI (2 nd )NR

9. Current Pediatric Clinical Trials ClinicalTrials.govPopulationPhaseNInterventionOutcomeStatus NCT01641289MalariaII50AcetaminophenAKIR NCT01416298Critically IllII100 NGAL-based fluid management Predictive value NGALR

10. 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

11. 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

12. 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

13. 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) Are the results of ADULT trials concordant with PEDIATRIC trials? Ioannidis et al J Pediatr 2010

14. Outcome (%)TGCCONp Received Insulin912<0.01 Hypoglycemia199<0.01 Infection551.0 Hospital Mortality221.0 Hospital Stay (d)870.20 Readmit (30 d)970.29 ChildrenAdults

16. Adult/Pediatric Collaboration Critical Illness – Focused Interventions: –Resuscitation in Sepsis –Corticosteroids in Sepsis –Extracorporeal support –Traumatic brain injury

17. Chua et al J Crit Care 2012 Population: Adults patients admitted to ICU with DKA (n=23) Design: Retrospective cohort study Exposure: Resuscitation with PL vs. NS in first 12 hr

18. 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

19. (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)

20. 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

21. Nguyen et al CCM 2008 n=10

22. Valentine et al CCM 2012

24. NGAL-Directed RRT Initiation Use of Neutrophil Gelatinase- Associated 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

25. 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

26. STARRT-AKI The STARRT-AKI Study: STandard versus Accelerated Initiation of Renal Replacement Therapy in Acute Kidney Injury ClinicalTrials.gov Identifier: NCT01557361

27. SPARK The SPARK Study: A randomized controlled trial of furoSemide in critically ill Patients with eARly acute Kidney injury ClinicalTrials.gov Identifier: NCT00978354

28. Thank You For Your Attention! Questions? bagshaw@ualberta.ca Acknowledgements Stuart Goldstein