Current Clinical Trials in AKI – What Questions Are They Addressing?

1. 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

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) Faubel et al CJASN 2012

8. Current Pediatric Clinical Trials

9. Current Pediatric Clinical Trials

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 UNETHICALto 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. Children Adults

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

17. 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

18. 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)

19. 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)

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. n=10 Nguyen et al CCM 2008

22. Valentine et al CCM 2012

23. 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: • ↑ NGAL will predict >10% fluid overload (FO) • ↑ NGAL will predict, in children with 10-20% FO, no improvement or worsening AKI in 24-48 hr → Decision support to start RRT • ↓ 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. The STARRT-AKIStudy: STandard versus Accelerated Initiation of Renal Replacement Therapy in Acute Kidney Injury ClinicalTrials.gov Identifier: NCT01557361

27. 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! • Acknowledgements • Stuart Goldstein Questions? bagshaw@ualberta.ca