Study protocol for a multicentre randomised controlled trial: Safety, Tolerability, efficacy and quality of life Of a human recombinant alkaline Phosphatase in patients with sepsis-associated Acute Kidney Injury (STOP-AKI).
BACKGROUND
Acute kidney injury (AKI) occurs in 55-60% of critically ill patients, and sepsis is the most common underlying cause. No pharmacological treatment options are licensed to treat sepsis-associated AKI (SA-AKI); only supportive renal replacement therapy (RRT) is available. One of the limited number of candidate compounds in clinical development to treat SA-AKI is alkaline phosphatase (AP). The renal protective effect of purified bovine intestinal AP has been demonstrated in critically ill sepsis patients. To build on these observations, a human recombinant AP (recAP) was developed, of which safety and efficacy in patients with SA-AKI will be investigated in this trial.


METHODS
This is a randomised, double-blind, placebo-controlled, 4-arm, proof-of-concept, dose-finding adaptive phase IIa/IIb study, conducted in critically ill patients with SA-AKI. A minimum of 290 patients will be enrolled at ∼50 sites in the European Union and North America. The study involves 2 parts. Patients enrolled during Part 1 will be randomly assigned to receive either placebo (n=30) or 1 of 3 different doses of recAP (n=30 per group) once daily for 3 days (0.4, 0.8 or 1.6 mg/kg). In Part 2, patients will be randomly assigned to receive the most efficacious dose of recAP (n=85), selected during an interim analysis, or placebo (n=85). Treatment must be administered within 24 hours after SA-AKI is first diagnosed and within 96 hours from first diagnosis of sepsis. The primary end point is the area under the time-corrected endogenous creatinine clearance curve from days 1 to 7. The key secondary end point is RRT incidence during days 1-28.


BACKGROUND
This study is approved by the relevant institutional review boards/independent ethics committees and is conducted in accordance with the ethical principles of the Declaration of Helsinki, guidelines of Good Clinical Practice, Code of Federal Regulations and all other applicable regulations. Results of this study will reveal the efficacy of recAP for the improvement of renal function in critically ill patients with SA-AKI and will be published in a peer-reviewed scientific journal.


BACKGROUND
NCT02182440; Pre-results.
Department of Intensive Care Medicine, Radboud university medical center, Nijmegen, The Netherlands Department of Pharmacology and Toxicology, Radboud university medical center, Nijmegen, The Netherlands.
Esther
E
Peters
Division of Nephrology, Department of Medicine, University of California, San Diego, California, USA.
Ravindra L
RL
Mehta
School of Medicine, University College Dublin, Health Sciences Centre, Belfield, Dublin, Ireland.
Patrick T
PT
Murray
PPD, Bellshill, North Lanarkshire, UK.
Jürgen
J
Hummel
Division of Intensive Care and Emergency Medicine, Department of Internal Medicine, Medical University Innsbruck, Innsbruck, Austria.
Michael
M
Joannidis
Department of Critical Care Medicine, Center for Critical Care Nephrology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
John A
JA
Kellum
AM-Pharma, Bunnik, The Netherlands.
Jacques
J
Arend
Department of Intensive Care Medicine, Radboud university medical center, Nijmegen, The Netherlands.
Peter
P
Pickkers
acute kidney injury; alkaline phosphatase; randomized controlled trial; sepsis; therapy
BMJ. 2013 Jan 08;346:e7586
23303884
Intensive Care Med. 2015 Aug;41(8):1411-23
26162677
Lancet. 2000 Dec 23-30;356(9248):2139-43
11191541
Crit Care. 2012 Jan 23;16(1):R14
22269279
Acta Anaesthesiol Scand. 2008 Oct;52(9):1259-64
18823466
N Engl J Med. 2008 Jul 3;359(1):7-20
18492867
Nephrol Dial Transplant. 2012 Mar;27(3):967-73
21891773
Crit Care Res Pract. 2013;2013:479730
23573420
Shock. 2002 Dec;18(6):561-6
12462566
Clin Pharm. 1987 May;6(5):393-8
3665390
Nature. 2002 Dec 19-26;420(6917):885-91
12490963
PLoS One. 2014 Feb 24;9(2):e89374
24586729
Am J Physiol Renal Physiol. 2009 Oct;297(4):F866-74
19625374
Lancet. 2013 Jul 13;382(9887):170-9
23727171
Purinergic Signal. 2006 Jun;2(2):335-41
18404473
Br J Pharmacol. 2015 Oct;172(20):4932-45
26222228
J Biol Chem. 2003 Apr 11;278(15):13468-79
12560324
Chest. 1992 Jun;101(6):1644-55
1303622
Clin Biochem. 2002 Sep;35(6):455-61
12413606
Biometrics. 1994 Dec;50(4):1029-41
7786985
N Engl J Med. 2003 Apr 17;348(16):1546-54
12700374
Clin Pharmacokinet. 2016 Oct;55(10):1227-37
27147514
Crit Care Med. 2009 Feb;37(2):417-23, e1
19114895
JAMA. 2016 Feb 23;315(8):801-10
26903338
Am J Kidney Dis. 2014 Jun;63(6):1038-48
24462020
Lancet. 2012 Aug 25;380(9843):756-66
22617274
Crit Care. 2012 Jun 19;16(3):R107
22713519
Crit Care Med. 2013 Feb;41(2):580-637
23353941
Eur J Clin Pharmacol. 2009 Apr;65(4):393-402
19048243