STOP-AKI: A Safety, Tolerability, Efficacy and QoL Study of Human recAP in the Treatment of Patients With SA-AKI

• Sponsor: AM-Pharma (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02182440
• Collaborator: PPD (Industry)
• Enrollment: 301
• Locations: 58
• Arms: 4
• Actual Duration (Months): 33.3
• Patients Per Site: 5.2
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The purpose of this study is to determine whether recombinant Alkaline Phosphatase (recAP) is effective and save, and to determine the most effective dose, in the treatment of patients with acute kidney injury caused by sepsis.

Condition or Disease	Intervention/Treatment	Phase
Acute Kidney Injury	Biological: recAP; Other: Placebo	Phase 2

Detailed Description

Design:

Adaptive trial with two stages and interim analysis

• Stage 1: four arms; three dose groups and placebo. n=30/arm. (n=120)

• Interim analysis based on 120 subjects, with continued recruitment, adding 11 subjects to Stage 1 safety population (n=131): to evaluate safety and select dose for stage 2

• Stage 2: one dose group and placebo. N=85/arm. (n=170) Total n in the study: 301.

Primary objectives

• To investigate the effect of recAP on renal function (measured creatinine clearance D1-D7 period, incidence and duration of renal replacement therapy (RRT) over 28 days, eGFR at D60 and D90) and related clinical parameters (ICU stay, Hospital stay, Mechanical ventilation over 28 days, SOFA and SAPS2 scores 28 days) in patients with SA-AKI.

• To determine effective therapeutic dose(s) of recAP.

Secondary objectives

• To investigate the safety and tolerability of recAP in patients with SA AKI. (assessed by independent Data Monitoring Board, adverse events over 90 days study period, laboratory values, ECG, physical examniations, vital signs, Anti Drug Antibodies)

• To investigate the pharmacokinetic profile (PK) of recAP in a subset of patients (part 1, n=120) with SA AKI. (Population PK; AUC D1-7, Cmax, Cmin, Tmax, terminal T1/2)

• To investigate the immunogenic potential of recAP in patients with SA AKI. (anti-drug antibodies at D14, D28, D60 and D90)

• To investigate the effect on quality of life (using the EuroQol, EQ-5D) following study inclusion, at ICU discharge, and Day 90.

Other objectives

• To evaluate whether specific patient groups can be identified that benefit most from recAP treatment or patient groups that are non-responders

Study Design

• Study Type: Interventional
• Actual Enrollment: 301 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A DB Four-Arm, Parallel Group, Proof of Concept, Dose-Finding Adaptive Phase 2a/2b RCT to Investigate the Safety, Tolerability and Efficacy and Effect on QoL of Human Recombinant Alkaline Phosphatase in Patients With Sepsis-Associated AKI
• Actual Study Start Date: Dec 18, 2014
• Actual Primary Completion Date: May 25, 2017
• Actual Study Completion Date: Sep 27, 2017

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo 1 hour IV infusion once daily for 3 days	Other: Placebo; 1 hour IV infusion once daily for 3 days
Experimental: 0.4 mg/kg (250 U/kg) recAP 1 hour IV infusion once daily for 3 days	Biological: recAP; One hour infusions once daily for three days; Other Names: Recombinant Alkaline Phosphatase
Experimental: 0.8 mg/kg (500 U/kg) recAP 1 hour IV infusion once daily for 3 days	Biological: recAP; One hour infusions once daily for three days; Other Names: Recombinant Alkaline Phosphatase
Experimental: 1.6 mg/kg (1000 U/kg) recAP 1 hour IV infusion once daily for 3 days	Biological: recAP; One hour infusions once daily for three days; Other Names: Recombinant Alkaline Phosphatase

Outcome Measures

Primary Outcome Measures

1. Area Under the Time Corrected Endogenous Creatinine Clearance From Day 1 to Day 7 (AUC1-7) [7 days]

   Primary endpoint is calculated as the average of the standardized endogenous creatinine clearance values over the first seven days between the placebo and 1.6 mg/kg recAP arm. Standardized endogenous creatinine clearance is assessed on each days from D1 to Day 7 during a 6 +/- 1 hour period and calculated in mL/min as the mean creatinine clearance over the period. The study started with 4 treatment arms of which 0.4 mg/kg recAP and the 0.8 mg/kg recAP were dropped after the interim analysis. The number of the patients in the dropped arm are respectively 30 and 32. Therefore the statistical analysis has been performed only on the placebo and 1.6 mg/kg group.

Secondary Outcome Measures

1. Number of Participants Who Had Renal Replacement Therapy (RRT) During the Period Day 1 to Day 28, Inclusive [28 days]

   During the study the days on Renal Replacement Therapy (RRT) was recorded for each patients. During the first 7 days of the study (D1 to D7 included), patients were only allowed to receive continuous RRT, thereafter patients were also allowed to receive intermittent RRT. Standardization of RRT was attempted by providing guidelines to start and stop RRT (see protocol). Statistical analysis was only performed on the placebo and 1.6 mg/kg recAP arm due to the small number of patients treated with the doses of 0.4 mg/kg and 0.8 mg/kg recAP. Those two doses were dropped in part 2 of the study.

Other Outcome Measures

1. All-cause Mortality at Day 28 [Day 28]

   Number of patients in the ITT set, who died in the period between day 1 to day 28. Statistical analysis was only performed on the placebo and 1.6 mg/kg recAP arm due to the small number of patients treated with the doses of 0.4 mg/kg and 0.8 mg/kg recAP. Those two doses were dropped in part 2 of the study.

2. All-cause Mortality at Day 90 [Day 90]

   Number of patients in the ITT set, who died in the period between Day 1 and Day 90 Statistical analysis was only performed on the placebo and 1.6 mg/kg recAP arm due to the small number of patients treated with the doses of 0.4 mg/kg and 0.8 mg/kg recAP. Those two doses were dropped in part 2 of the study.

3. Number of Participants Meeting at Least One MAKE 60 Criteria [Day 60]

   Make 60 is composed of patients that meet at least one of the following criteria at day 60: had eGFR < 60 mL/min (calculated by using the CKD-EPI formula) or became dialysis dependent up to Day 60 or died prior to Day 60 Statistical analysis was only performed on the placebo and 1.6 mg/kg recAP arm due to the small number of patients treated with the doses of 0.4 mg/kg and 0.8 mg/kg recAP. Those two doses were dropped in part 2 of the study.

4. Number of Patients Who Meet at Least One of the MAKE 90 Criteria [Day 90]

   Make 90 includes patients who meet at least one of the following parameters at Day 90: had eGFR <60 ml/min at Day 90, estimated by the CKD-EPI formula based on a serum creatinine or was dialysis dependent up to Day 90 or was hospitalized for a new episode of acute kidney injury prior to Day 90 or died, prior to Day 90 Statistical analysis was only performed on the placebo and 1.6 mg/kg recAP arm due to the small number of patients treated with the doses of 0.4 mg/kg and 0.8 mg/kg recAP. Those two doses were dropped in part 2 of the study.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 85 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Signed Informed Consent Form (patient, legal representative or independent investigator)

2. Age 18 to 85 years, inclusive

3. Is admitted to the ICU or Intermediate Care Unit

4. Has diagnosis of sepsis (< 96 hrs prior to first study drug), according to criteria defined by the American College of Chest Physicians/Society of Critical Care Medicine:

5. Has a proven or strongly suspected bacterial infection.

6. Has at least 2 of 4 SIRS criteria 72 hrs < screening and 96 hrs < first study drug

7. First diagnosis of AKI: AKI Stage 1 or greater, according to the AKIN criteria (time-window adjusted):

8. Increase in serum creatinine > 26.2 µmol/L (0.30 mg/dL) in 48 hrs prior to screening, or

9. Increase in serum creatinine to > 150% (> 1.5-fold) from reference creatinine value in 48 hrs prior to screening

10. Urinary output < 0.5 mL/kg/h for > 6 hours following adequate fluid resuscitation

11. Continuing AKI needs to be confirmed by a confirmative fluid corrected serum creatinine measure, or

12. When the AKI diagnosis was made according to the AKIN urine output criteria (urinary output < 0.5 mL/kg/h for > 6 hours), the oliguria or anuria should still meet the AKIN urine output criteria prior to randomization.

Exclusion Criteria:

1. Woman of childbearing potential with a positive pregnancy test, pregnant, or breastfeeding.

2. Weighs more than 115 kg (253 lb).

3. Has life support limitations.

4. Is known to be human immunodeficiency virus positive.

5. Has urosepsis.

6. Is already on dialysis (RRT) or anticipated to receive RRT within 24 hours after study drug dosing due to the underlying disease.

7. Is receiving immunosuppressant treatment or is on chronic high doses of steroids equivalent to prednisone/prednisolone 0.5 mg/kg/day, including solid organ transplant patients. Patients with septic shock treated with hydrocortisone (e.g., 3 × 100 mg) can be included.

8. Is expected to have rapidly fatal outcome (within 24 hours).

9. Has known, confirmed fungal sepsis.

10. Has advanced chronic liver disease, confirmed by a Child-Pugh score of 10 to 15.

11. Has acute pancreatitis with no established source of infection.

12. Has participated in another investigational study within 30 days prior to enrollment.

13. Is not expected to survive for 28 days due to medical conditions other than SA AKI, including cancer, end-stage cardiac disease, cardiac arrest requiring cardiopulmonary resuscitation or with pulseless electrical activity or asystole within the past 30 days, end stage lung disease, and end stage liver disease.

14. Has known prior history of Chronic Kidney Disease with a documented estimated Glomerular Filtration Rate (eGFR) < 60 mL/min by Modification of Diet in Renal Disease MDRD or CKD-EPI formula, known GFR < 60 mL/min, or a known history of persistent creatinine level > 150 µmol/L (1.70 mg/dL) for reasons other than the current sepsis condition.

15. Has diagnosis of malaria or other parasite infections.

16. Has burns on > 20% of body surface.

17. Has had AKI diagnosis according to inclusion criteria > 24 hours prior to study drug administration.

18. Is anticipated to be treated with non-continuous RRT from Day 1 to Day 7.

19. During Day 1 to Day 7 continuous RRT is anticipated to be started or stopped not according to per protocol criteria.

20. The AKI is most likely attributable to other causes than sepsis, such as nephrotoxic drugs and renal perfusion-related.

21. Improvement in serum creatinine of at least 0.30 mg/dL or (26.2 µmol/L) prior to administration of the study drug.

22. Patients who use nephrotoxic medication and who fulfill the SA-AKI inclusion criteria at screening are not eligible if the use of this nephrotoxic medication is to continue when alternative, medically appropriate, non-nephrotoxic medication is available.

23. Has a history of known IV drug abuse.

24. Is an employee or family member of the investigator or study site personnel.

25. Has active hematological malignancy.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama at Birmingham	Birmingham	Alabama	United States	35294
2	Tampa General Hospital, Division Emergency Medicine	Tampa	Florida	United States	33606
3	Eastern Idaho Medical Consultants LLC	Idaho Falls	Idaho	United States	83404
4	University of Cincinnati Medical Center	Cincinnati	Ohio	United States	45267
5	UPMC	Pittsburgh	Pennsylvania	United States	15261
6	University of Texas Houston Medical School	Houston	Texas	United States	77030
7	Medizinische Universität Innsbruck	Innsbruck	Tirol	Austria	6020
8	Universitätsklinik für Allgemeine und Chirurgische Intensivmedizin	Innsbruck	Tirol	Austria	6020
9	Hôpital Erasme	Brussels	Brussel	Belgium	B-1070
10	CHU UCL Mont Godinne	Yvoir	Namur	Belgium	B-5530
11	University Hospital Ghent	Gent	Oost Vlaanderen	Belgium	9000
12	University Hospital Antwerpen	Antwerpen		Belgium	B-2650
13	Cliniques Universitaires Saint Luc-UCL	Brussels		Belgium	1200
14	CHU Brugmann	Brussels		Belgium	B-1020
15	UZ Brussel	Brussels		Belgium	B-1090
16	Fakultni nemocnice u sv. Anny v Brne	Brno	Jihomoravský Kraj	Czechia	656 91
17	Oblastni nemocnice Kolin, a.s.	Kolin		Czechia	280 02
18	Fakultni nemocnice Plzen	Pilsen		Czechia	30460
19	Helsingin Yliopistollinen Keskussairaala	Helsinki		Finland	FI-00290
20	Kuopion Yliopistollinen Sairaala	Kuopio		Finland	70210
21	Tampereen yliopistollinen sairaala	Tampere		Finland	33520
22	Hôpital Universitaire Dupuytren	Limoges	Haute-Vienne	France	87042
23	Hôpital Charles Nicolle	Rouen	Seine-Maritime	France	76031
24	Centre Hospitalier Departemental de Vendee	La Roche sur Yon	Vendée	France	85925
25	CHU Angers	Angers		France	49933
26	Centre Hospitalier Victor Dupouy - hopital	Argenteuil		France
27	CHRU Nantes - Hospital	Nantes		France
28	Hôpital Lariboisière	Paris		France	75010
29	Hôpitaux Universitaires de Strasbourg	Strasbourg		France	67090
30	University Hospital Frankfurt, Anaesthesia, Intensive Care Medicine & Pain Therapy	Frankfurt am Main,	Hessen	Germany	60590
31	Universitätsmedizin Greifswald Klinik für Anästhesiologie, IntensivmedizinNotfallmedizin und Schmerzmedizin	Greifswald	Mecklenburg-Vorpommern	Germany	17475
32	Medizinische Hochschule Hannover Hospital - Zentrum Innere Medizin - Klinik fuer Pneumologie	Hannover	Niedersachsen	Germany	30625
33	Universitätsklinikum Schleswig-Holstein - Klinik für Anästhesiologie und Operative Intensivmedizin	Kiel	Schleswig-Holstein	Germany	24105
34	Helios Klinikum Erfurt -Klinik fur Anaesthesie, Intensivmedizin und Schmerztherapie	Erfurt	Thüringen	Germany	99089
35	Universitatsklinikum Jena - Klinik für Anästhesiologie und Intensivmedzin	Jena	Thüringen	Germany	07747
36	Universitätsklinikum Hamburg Eppendorf Department Intensive Care Medicine	Hamburg		Germany	20246
37	St. Vincent's University Hospital	Dublin		Ireland
38	Medical Center Leeuwarden	Leeuwarden	Friesland	Netherlands	8934 AD
39	Radboud University Nijmegen	Nijmegen	Gelderland	Netherlands	6525 GA
40	Canisius Wilhelmina Ziekenhuis	Nijmegen	Gelderland	Netherlands	6532 SZ
41	Jeroen Bosch Ziekenhuis	's Hertogenbosch	Noord-Brabant	Netherlands	5223 GZ
42	VU Medisch Centrum	Amsterdam	Noord-Holland	Netherlands	1081 HV
43	Medisch Spectrum Twente	Enschede	Overijssel	Netherlands	7513 ER
44	Erasmus Medisch Centrum	Rotterdam	Zuid-Holland	Netherlands	3015 CE
45	Ikazia Ziekenhuis	Rotterdam	Zuid-Holland	Netherlands	3083 AN
46	Gelre Ziekenhuizen - Hospital	Apeldoorn,		Netherlands	7334 DZ
47	Hospital Universitario Germans Trias i Pujol Medicina Intensiva Hospital General,	Badalona	Barcelona	Spain	08916
48	Hospital de La Santa Creu i Sant Pau	Barcelona	Cataluna	Spain	08025
49	Corporacio Sanitaria Parc Tauli	Sabadell	Cataluna	Spain	08208
50	Hospital Mutua de Terrassa	Terrassa	Cataluña	Spain	08221
51	Hospital Universitario Vall d'Hebron	Barcelona		Spain	08035
52	Hospital Universitario 12 de Octubre, Unidad de Cuidados Intensivos Hospital General	Madrid		Spain	28041
53	Hospital Universitari de Tarragona Joan XXIII	Tarragona		Spain	43007
54	Royal Surrey County Hospital - Intensive Care Unit	Guildford	Surrey	United Kingdom	GU2 7XX
55	Royal Infirmary of Edinburgh	Edinburgh		United Kingdom	EH16 4SB
56	Royal London Hospital	London		United Kingdom	E1 1BB
57	University College London	London		United Kingdom	NW1 2BU
58	St James University Hospital	London		United Kingdom

Sponsors and Collaborators

• AM-Pharma
• PPD

Investigators

• Study Director: Jacques Arend, MD DiMD, AM Pharma BV
• Study Chair: Peter Pickkers, Prof MD. PhD, Department Intensive Care, Radboud University Medical Center

Study Documents (Full-Text)

• Study Protocol - Feb 3, 2016
• Statistical Analysis Plan - Sep 27, 2017

More Information

Publications

None provided.

• Responsible Party: AM-Pharma
• ClinicalTrials.gov Identifier: NCT02182440
• Other Study ID Numbers: AP-recAP-AKI-02-01; 2014-000761-40
• First Posted: Jul 8, 2014
• Last Update Posted: Mar 23, 2020
• Last Verified: Mar 1, 2020

• Individual Participant Data (IPD) Sharing Statement: Undecided
• Plan to Share IPD: Undecided
• Keywords provided by AM-Pharma: SA-AKI; Sepsis; AKI; Recombinant Alkaline Phosphatase; recAP
• Additional relevant MeSH terms: Acute Kidney Injury

Study Results

Participant Flow

Recruitment Details	Patients suffering sepsis associated acute kidney injury and admitted to the ICU were recruited from December 2014 to May 2017 in 10 European countries and the USA.53 Sites recruited patients. Sepsis diagnosis was established following the Sepsis-2 criteria and AKI diagnosis was established following the AKIN criteria.
Pre-assignment Detail	Patients should show a continuation of AKI measured by a confirmatory serum creatinine value, which did not decrease > or = 0.3 mg/dL compared to the diagnostic serum creatinine value or by a continuation of urine output of < 0.5 mg/kg/h for more than 6 hours.

Arm/Group Title	Placebo	0.4 mg/kg (250 U/kg) recAP	0.8 mg/kg (500 U/kg) recAP	1.6 mg/kg (1000 U/kg) recAP
Arm/Group Description	One hour IV infusion of Placebo once daily for three consecutive days	One hour IV infusion of 0.4 mg/kg recAP once daily for three consecutive days	One hour IV infusions of 0.8 mg/kg recAP once daily for three consecutive days	One hour IV infusions of 1.6 mg/kg recAP once daily for three consecutive days
Period Title: Overall Study
STARTED	116	39	35	111
ITTcombined	116	31	32	111
ITTinterim	30	31	32	29
Safety Population	112	38	35	109
COMPLETED	71	25	24	81
NOT COMPLETED	45	14	11	30

Baseline Characteristics

Arm/Group Title	Placebo	0.4 mg/kg (250 U/kg) recAP	0.8 mg/kg (500 U/kg) recAP	1.6 mg/kg (1000 U/kg) recAP	Total
Arm/Group Description	One hour IV infusion of placebo once daily for 3 consecutive days	One hour IV infusions of 0.4 mg/kg recAP once daily for three consecutive days	One hour IV infusions of 0.8 mg/kg recAP once daily for three consecutive days	One hour IV infusions of 1.6 mg/kg recAP once daily for three consecutive days	Total of all reporting groups
Overall Participants	116	31	32	111	290
Age (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	68.0	67.0	66.5	65.0	67.0
Sex: Female, Male (Count of Participants)
Female	32 27.6%	8 25.8%	16 50%	29 26.1%	85 29.3%
Male	84 72.4%	23 74.2%	16 50%	82 73.9%	205 70.7%
Race/Ethnicity, Customized (Count of Participants)
White	95 81.9%	25 80.6%	27 84.4%	95 85.6%	242 83.4%
Black	4 3.4%	0 0%	0 0%	1 0.9%	5 1.7%
Asian	1 0.9%	2 6.5%	0 0%	1 0.9%	4 1.4%
Other	0 0%	0 0%	1 3.1%	0 0%	1 0.3%
Not collected	16 13.8%	4 12.9%	4 12.5%	14 12.6%	38 13.1%
Region of Enrollment (participants) [Number]
Austria	11 9.5%	2 6.5%	2 6.3%	11 9.9%	26 9%
Netherlands	28 24.1%	8 25.8%	7 21.9%	28 25.2%	71 24.5%
Belgium	12 10.3%	5 16.1%	5 15.6%	13 11.7%	35 12.1%
United States	14 12.1%	1 3.2%	1 3.1%	11 9.9%	27 9.3%
Czechia	3 2.6%	2 6.5%	3 9.4%	5 4.5%	13 4.5%
Ireland	1 0.9%	0 0%	0 0%	0 0%	1 0.3%
Finland	6 5.2%	1 3.2%	3 9.4%	6 5.4%	16 5.5%
United Kingdom	12 10.3%	5 16.1%	3 9.4%	11 9.9%	31 10.7%
France	16 13.8%	4 12.9%	4 12.5%	14 12.6%	38 13.1%
Spain	9 7.8%	3 9.7%	4 12.5%	7 6.3%	23 7.9%
Germany	4 3.4%	0 0%	0 0%	5 4.5%	9 3.1%
BMI (kg/m2) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [kg/m2]	26.3	25.8	27.4	26.8	26.6
APACHE II (units on a scale) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [units on a scale]	26.0	30.0	26.0	25.0	26.0
SOFA score (units on a scale) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [units on a scale]	10.0	10.0	9.0	10.0	10.0
Mechanical ventilation (Count of Participants)
Count of Participants [Participants]	68 58.6%	23 74.2%	20 62.5%	70 63.1%	181 62.4%
Vasopressor/ionotropic therapy (Count of Participants)
Count of Participants [Participants]	103 88.8%	28 90.3%	30 93.8%	102 91.9%	263 90.7%
Heart rate (beats/min) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [beats/min]	98.0	93.0	90.0	95.0	95.5
Bloodpressure (mmHg) [Median (Inter-Quartile Range) ]
Systolic bloodpressure	112.0	108.0	118.5	107.0	110
Diastolic bloodpressure	56.5	54.0	58.0	55.0	56.0
Body temperature (Count of Participants)
<36oC	11 9.5%	4 12.9%	5 15.6%	11 9.9%	31 10.7%
>= 36oC and =< 38oC	76 65.5%	20 64.5%	22 68.8%	79 71.2%	197 67.9%
>38oC	27 23.3%	7 22.6%	5 15.6%	18 16.2%	57 19.7%
eGFR (mL/min) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [mL/min]	37.5	27.2	25.6	29.7	31.8
Endogenous Creatinine clearance (mL/min) [Median (Inter-Quartile Range) ]
Baseline	31.8	14.4	26.0	24.1	27.9
Day 1	35.9	28.3	25.2	26.0	29.4
AKI stage (Count of Participants)
AKI Stage 1	91 78.4%	22 71%	23 71.9%	81 73%	217 74.8%
AKI Stage 2	16 13.8%	5 16.1%	5 15.6%	17 15.3%	43 14.8%
AKI Stage 3	5 4.3%	4 12.9%	4 12.5%	11 9.9%	24 8.3%
Urine output (mL/h) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [mL/h]	60.0	50.0	27.4	39.1	46.3
Serum Creatinine (mg/dL) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [mg/dL]	1.8	2.3	1.9	2.0	1.9

Outcome Measures

1. Primary Outcome

Title	Area Under the Time Corrected Endogenous Creatinine Clearance From Day 1 to Day 7 (AUC1-7)
Description	Primary endpoint is calculated as the average of the standardized endogenous creatinine clearance values over the first seven days between the placebo and 1.6 mg/kg recAP arm. Standardized endogenous creatinine clearance is assessed on each days from D1 to Day 7 during a 6 +/- 1 hour period and calculated in mL/min as the mean creatinine clearance over the period. The study started with 4 treatment arms of which 0.4 mg/kg recAP and the 0.8 mg/kg recAP were dropped after the interim analysis. The number of the patients in the dropped arm are respectively 30 and 32. Therefore the statistical analysis has been performed only on the placebo and 1.6 mg/kg group.
Time Frame	7 days

Outcome Measure Data

Analysis Population Description

ITT combined includes all patients randomized in part 1 and part 2 of the study, excluding patients recruited whilst the interim analysis is performed to treatment arms not selected for Part 2. Some values were discarded by the adjudication committee.

Arm/Group Title	Placebo	0.4 mg/kg (250 U/kg) recAP	0.8 mg/kg (500 U/kg) recAP	1.6 mg/kg (1000 U/kg) recAP
Arm/Group Description	One hour IV infusion of Placebo once daily for three consecutive days	One hour IV infusions of 0.4 mg/kg recAP once daily for three consecutive days	One hour IV infusions of 0.8 mg/kg recAP once daily for three consecutive days	One hour IV infusions of 1.6 mg/kg recAP once daily for three consecutive days
Measure Participants	106	30	32	108
Part 1	41.35	43.30	64.25	61.10
Part 2	44.51	51.76
Part 1 + Part 2	45.6	46.95	63.54	55.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, 1.6 mg/kg (1000 U/kg) recAP
	Comments	Analysis for Part 1
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.949
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Difference in LS means
	Estimated Value	-16.53
	Confidence Interval	(2-Sided) 95%; -62.57 to 29.50
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 19.243
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, 1.6 mg/kg (1000 U/kg) recAP
	Comments	Analysis for Part 2
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.691
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Difference in LS means
	Estimated Value	-4.65
	Confidence Interval	(2-Sided) 95%; -23.09 to 13.80
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 9.305
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, 1.6 mg/kg (1000 U/kg) recAP
	Comments	Combination of analysis results from Part 1 (see statistical Analysis 1) and Part 2 (see Statistical analysis 2)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.896
	Comments
	Method	Inverse normal method
	Comments
Method of Estimation	Estimation Parameter	Combined p-value
	Estimated Value	0.896
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments	The p-values from Part 1 (see Statistical Analysis 1) and Part 2 (see Statistical Analysis 2) were combined to an overall p-value using the inverse normal method.

2. Secondary Outcome

Title	Number of Participants Who Had Renal Replacement Therapy (RRT) During the Period Day 1 to Day 28, Inclusive
Description	During the study the days on Renal Replacement Therapy (RRT) was recorded for each patients. During the first 7 days of the study (D1 to D7 included), patients were only allowed to receive continuous RRT, thereafter patients were also allowed to receive intermittent RRT. Standardization of RRT was attempted by providing guidelines to start and stop RRT (see protocol). Statistical analysis was only performed on the placebo and 1.6 mg/kg recAP arm due to the small number of patients treated with the doses of 0.4 mg/kg and 0.8 mg/kg recAP. Those two doses were dropped in part 2 of the study.
Time Frame	28 days

Outcome Measure Data

Analysis Population Description

ITT combined

Arm/Group Title	Placebo	0.4 mg/kg (250 U/kg) recAP	0.8 mg/kg (500U/kg) recAP	1.6 mg/kg (1000 U/kg) recAP
Arm/Group Description	One hour IV infusion of Placebo once daily for three consecutive days	One hour IV infusions of 0.4 mg/kg recAP once daily for three consecutive days	One hour IV infusions of 0.8 mg/kg recAP once daily for three consecutive days	One hour IV infusions of 1.6 mg/kg recAP once daily for three consecutive days
Measure Participants	116	31	32	111
Count of Participants [Participants]	34 29.3%	11 35.5%	7 21.9%	40 36%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, 1.6 mg/kg (1000 U/kg) recAP
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.28
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.4
	Confidence Interval	(2-Sided) 95%; 0.8 to 2.4
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Other Pre-specified Outcome

Title	All-cause Mortality at Day 28
Description	Number of patients in the ITT set, who died in the period between day 1 to day 28. Statistical analysis was only performed on the placebo and 1.6 mg/kg recAP arm due to the small number of patients treated with the doses of 0.4 mg/kg and 0.8 mg/kg recAP. Those two doses were dropped in part 2 of the study.
Time Frame	Day 28

Outcome Measure Data

Analysis Population Description

ITT set

Arm/Group Title	Placebo	0.4 mg/kg (250 U/kg) recAP	0.8 mg/kg (500 U/kg) recAP	1.6 mg/kg (1000 U/kg) recAP
Arm/Group Description	One hour IV infusion of placebo once daily for three consecutive days	One hour IV infusions of 0.4 mg/kg recAP once daily for three consecutive days	One hour IV infusions of 0.8 mg/kg recAP once daily for three consecutive days	One hour IV infusions of 1.6 mg/kg recAP once daily for three consecutive days
Measure Participants	116	31	32	111
Count of Participants [Participants]	31 26.7%	8 25.8%	4 12.5%	16 14.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, 1.6 mg/kg (1000 U/kg) recAP
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.02
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.12
	Confidence Interval	(2-Sided) 95%; 0.02 to 0.23
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Other Pre-specified Outcome

Title	All-cause Mortality at Day 90
Description	Number of patients in the ITT set, who died in the period between Day 1 and Day 90 Statistical analysis was only performed on the placebo and 1.6 mg/kg recAP arm due to the small number of patients treated with the doses of 0.4 mg/kg and 0.8 mg/kg recAP. Those two doses were dropped in part 2 of the study.
Time Frame	Day 90

Outcome Measure Data

Analysis Population Description

ITT

Arm/Group Title	Placebo	0.4 mg/kg (250 U/kg) recAP	0.8 mg/kg (500 U/kg) recAP	1.6 mg/kg (1000 U/kg) recAP
Arm/Group Description	One hour IV infusion of Placebo once daily for three consecutive days	One hour IV infusions of 0.4 mg/kg recAP once daily for three consecutive days	One hour IV infusions of 0.8 mg/kg recAP once daily for three consecutive days	One hour IV infusions of 1.6 mg/kg recAP once daily for three consecutive days
Measure Participants	116	31	32	111
Count of Participants [Participants]	34 29.3%	9 29%	6 18.8%	19 17.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, 1.6 mg/kg (1000 U/kg) recAP
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.03
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.12
	Confidence Interval	(2-Sided) 95%; 0.01 to 0.23
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Other Pre-specified Outcome

Title	Number of Participants Meeting at Least One MAKE 60 Criteria
Description	Make 60 is composed of patients that meet at least one of the following criteria at day 60: had eGFR < 60 mL/min (calculated by using the CKD-EPI formula) or became dialysis dependent up to Day 60 or died prior to Day 60 Statistical analysis was only performed on the placebo and 1.6 mg/kg recAP arm due to the small number of patients treated with the doses of 0.4 mg/kg and 0.8 mg/kg recAP. Those two doses were dropped in part 2 of the study.
Time Frame	Day 60

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	0.4 mg/kg (250 U/kg) recAP	0.8 mg/kg (500 U/kg) recAP	1.6 mg/kg (1000 U/kg) recAP
Arm/Group Description	One hour IV infusion of Placebo once daily for three consecutive days	One hour IV infusions of 0.4 mg/kg recAP once daily for three consecutive days	One hour IV infusions of 0.8 mg/kg recAP once daily for three consecutive days	One hour IV infusions of 1.6 mg/kg recAP once daily for three consecutive days
Measure Participants	116	31	32	111
Count of Participants [Participants]	46 39.7%	13 41.9%	11 34.4%	30 27%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, 1.6 mg/kg (1000 U/kg) recAP
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.045
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.77
	Confidence Interval	(2-Sided) 95%; 1.0 to 3.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Other Pre-specified Outcome

Title	Number of Patients Who Meet at Least One of the MAKE 90 Criteria
Description	Make 90 includes patients who meet at least one of the following parameters at Day 90: had eGFR <60 ml/min at Day 90, estimated by the CKD-EPI formula based on a serum creatinine or was dialysis dependent up to Day 90 or was hospitalized for a new episode of acute kidney injury prior to Day 90 or died, prior to Day 90 Statistical analysis was only performed on the placebo and 1.6 mg/kg recAP arm due to the small number of patients treated with the doses of 0.4 mg/kg and 0.8 mg/kg recAP. Those two doses were dropped in part 2 of the study.
Time Frame	Day 90

Outcome Measure Data

Analysis Population Description

ITT

Arm/Group Title	Placebo	0.4 mg/kg (250 U/kg) recAP	0.8 mg/kg (500U/kg) recAP	1.6 mg/kg (1000 U/kg) recAP
Arm/Group Description	One hour IV infusion of Placebo once daily for three consecutive days	One hour IV infusions of 0.4 mg/kg recAP once daily for three consecutive days	One hour IV infusions of 0.8 mg/kg recAP once daily for three consecutive days	One hour IV infusions of 1.6 mg/kg recAP once daily for three consecutive days
Measure Participants	116	31	32	111
Count of Participants [Participants]	46 39.7%	13 41.9%	10 31.3%	29 26.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, 1.6 mg/kg (1000 U/kg) recAP
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.03
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.85
	Confidence Interval	(2-Sided) 95%; 1.06 to 3.26
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	Adverse events were collected from the time the patient signed the informed consent form until Day 28
Arm/Group Title	Placebo		0.4 mg/kg (250 U/kg) recAP		0.8 mg/kg (500 U/kg) recAP		1.6 mg/kg (1000 U/kg) recAP
Arm/Group Description	One hour IV infusion of Placebo once daily for three consecutive days		One hour IV infusion of 0.4 mg/kg recAP once daily for three consecutive days		One hour IV infusions of 0.8 mg/kg recAP once daily for three consecutive days		One hour IV infusions of 1.6 mg/kg recAP once daily for three consecutive days
All Cause Mortality
	Placebo		0.4 mg/kg (250 U/kg) recAP		0.8 mg/kg (500 U/kg) recAP		1.6 mg/kg (1000 U/kg) recAP
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	33/112 (29.5%)		10/38 (26.3%)		6/35 (17.1%)		19/109 (17.4%)
Serious Adverse Events
	Placebo		0.4 mg/kg (250 U/kg) recAP		0.8 mg/kg (500 U/kg) recAP		1.6 mg/kg (1000 U/kg) recAP
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	56/112 (50%)		18/38 (47.4%)		11/35 (31.4%)		47/109 (43.1%)
Blood and lymphatic system disorders
Anaemia	2/112 (1.8%)		0/38 (0%)		0/35 (0%)		0/109 (0%)
Disseminated intravascular coagulation	0/112 (0%)		1/38 (2.6%)		0/35 (0%)		0/109 (0%)
Thrombocytopenia	0/112 (0%)		1/38 (2.6%)		0/35 (0%)		2/109 (1.8%)
Cardiac disorders
Acute myocardial infarction	1/112 (0.9%)		0/38 (0%)		0/35 (0%)		0/109 (0%)
Arterial fibrillation	1/112 (0.9%)		0/38 (0%)		0/35 (0%)		0/109 (0%)
Cardiac arrest	4/112 (3.6%)		0/38 (0%)		1/35 (2.9%)		4/109 (3.7%)
Cardiac failure	2/112 (1.8%)		0/38 (0%)		0/35 (0%)		0/109 (0%)
Cardiac failure acute	1/112 (0.9%)		0/38 (0%)		0/35 (0%)		0/109 (0%)
Cardio-respiratory arrest	0/112 (0%)		0/38 (0%)		1/35 (2.9%)		0/109 (0%)
Cardiogenic shock	2/112 (1.8%)		0/38 (0%)		0/35 (0%)		1/109 (0.9%)
Cardiovascular insufficiency	0/112 (0%)		0/38 (0%)		0/35 (0%)		1/109 (0.9%)
Myocardiac infarction	1/112 (0.9%)		0/38 (0%)		0/35 (0%)		2/109 (1.8%)
Supraventricular tachycardia	0/112 (0%)		0/38 (0%)		0/35 (0%)		1/109 (0.9%)
Ventricular fibrillation	0/112 (0%)		0/38 (0%)		1/35 (2.9%)		0/109 (0%)
Ventricular tachycardia	1/112 (0.9%)		0/38 (0%)		0/35 (0%)		0/109 (0%)
Ear and labyrinth disorders
Deafness unilateral	0/112 (0%)		0/38 (0%)		0/35 (0%)		1/109 (0.9%)
Gastrointestinal disorders
Acute abdomen	0/112 (0%)		0/38 (0%)		0/35 (0%)		1/109 (0.9%)
Ascites	0/112 (0%)		0/38 (0%)		0/35 (0%)		1/109 (0.9%)
Colonic pseudo-obstruction	1/112 (0.9%)		0/38 (0%)		0/35 (0%)		0/109 (0%)
Duodenal perforation	0/112 (0%)		0/38 (0%)		0/35 (0%)		1/109 (0.9%)
Gastric fistula	0/112 (0%)		0/38 (0%)		1/35 (2.9%)		0/109 (0%)
Gastric ulcer haemorrhage	2/112 (1.8%)		0/38 (0%)		0/35 (0%)		1/109 (0.9%)
Gastrointestinal haemorrage	0/112 (0%)		1/38 (2.6%)		0/35 (0%)		1/109 (0.9%)
Ileus	0/112 (0%)		0/38 (0%)		0/35 (0%)		1/109 (0.9%)
Incarcerated inguinal hernia	0/112 (0%)		0/38 (0%)		0/35 (0%)		1/109 (0.9%)
Intestinal infarction	0/112 (0%)		0/38 (0%)		0/35 (0%)		1/109 (0.9%)
Intestinal ischaemia	2/112 (1.8%)		0/38 (0%)		1/35 (2.9%)		1/109 (0.9%)
Intestinal obstruction	0/112 (0%)		1/38 (2.6%)		0/35 (0%)		0/109 (0%)
Intestinal perforation	0/112 (0%)		0/38 (0%)		0/35 (0%)		2/109 (1.8%)
Intral abdominal haemorrhage	0/112 (0%)		0/38 (0%)		1/35 (2.9%)		0/109 (0%)
Ischemia enteritis	0/112 (0%)		0/38 (0%)		0/35 (0%)		1/109 (0.9%)
Large intestinal haemorrhage	0/112 (0%)		1/38 (2.6%)		0/35 (0%)		0/109 (0%)
Large intestine perforation	0/112 (0%)		0/38 (0%)		0/35 (0%)		1/109 (0.9%)
Mesenteric vein thrombosis	0/112 (0%)		0/38 (0%)		0/35 (0%)		1/109 (0.9%)
Rectal Haemorrhage	0/112 (0%)		1/38 (2.6%)		0/35 (0%)		0/109 (0%)
Upper gastrointestinal haemorrhage	1/112 (0.9%)		0/38 (0%)		0/35 (0%)		0/109 (0%)
General disorders
Astenia	1/112 (0.9%)		0/38 (0%)		0/35 (0%)		0/109 (0%)
General physical health deterioration	1/112 (0.9%)		0/38 (0%)		0/35 (0%)		0/109 (0%)
Multiple organ dysfunction syndrome	7/112 (6.3%)		2/38 (5.3%)		0/35 (0%)		5/109 (4.6%)
Hepatobiliary disorders
Cholestasis	1/112 (0.9%)		0/38 (0%)		0/35 (0%)		0/109 (0%)
Gallbladder perforation	1/112 (0.9%)		0/38 (0%)		0/35 (0%)		0/109 (0%)
Hepatic failure	1/112 (0.9%)		0/38 (0%)		0/35 (0%)		0/109 (0%)
Hepatic haematoma	1/112 (0.9%)		0/38 (0%)		0/35 (0%)		0/109 (0%)
Hepatorenal syndrome	0/112 (0%)		1/38 (2.6%)		0/35 (0%)		0/109 (0%)
Infections and infestations
Abdominal abscess	1/112 (0.9%)		0/38 (0%)		0/35 (0%)		1/109 (0.9%)
Abdominal sepsis	1/112 (0.9%)		0/38 (0%)		0/35 (0%)		0/109 (0%)
Abscess intestinal	0/112 (0%)		0/38 (0%)		0/35 (0%)		1/109 (0.9%)
Bronchopulmonary aspergillosis	0/112 (0%)		1/38 (2.6%)		0/35 (0%)		0/109 (0%)
Candida infection	0/112 (0%)		0/38 (0%)		0/35 (0%)		1/109 (0.9%)
Cholecystitis infective	1/112 (0.9%)		0/38 (0%)		0/35 (0%)		0/109 (0%)
Clostridium Difficile infection	1/112 (0.9%)		0/38 (0%)		0/35 (0%)		0/109 (0%)
Gastroenteritis	1/112 (0.9%)		0/38 (0%)		0/35 (0%)		0/109 (0%)
Iatrogenic infection	0/112 (0%)		1/38 (2.6%)		0/35 (0%)		0/109 (0%)
Infectious pleural effusion	0/112 (0%)		0/38 (0%)		0/35 (0%)		1/109 (0.9%)
Lower respiratory tract infection	0/112 (0%)		1/38 (2.6%)		0/35 (0%)		0/109 (0%)
Lung abscess	0/112 (0%)		0/38 (0%)		0/35 (0%)		2/109 (1.8%)
Necrotising fasciitis	0/112 (0%)		1/38 (2.6%)		0/35 (0%)		1/109 (0.9%)
Necrotising soft tissue infection	0/112 (0%)		0/38 (0%)		0/35 (0%)		1/109 (0.9%)
Peritoneal abscess	0/112 (0%)		0/38 (0%)		0/35 (0%)		1/109 (0.9%)
Peritonitis	1/112 (0.9%)		0/38 (0%)		1/35 (2.9%)		1/109 (0.9%)
Pharyngeal abscess	0/112 (0%)		0/38 (0%)		0/35 (0%)		1/109 (0.9%)
Pneumonia	3/112 (2.7%)		0/38 (0%)		2/35 (5.7%)		4/109 (3.7%)
Pneumonia herpes viral	0/112 (0%)		1/38 (2.6%)		0/35 (0%)		0/109 (0%)
Postoperative wound infection	0/112 (0%)		0/38 (0%)		0/35 (0%)		1/109 (0.9%)
Septic shock	11/112 (9.8%)		2/38 (5.3%)		4/35 (11.4%)		3/109 (2.8%)
Soft tissue infection	0/112 (0%)		0/38 (0%)		0/35 (0%)		1/109 (0.9%)
Injury, poisoning and procedural complications
Abdominal wound dehiscence	1/112 (0.9%)		1/38 (2.6%)		0/35 (0%)		0/109 (0%)
Anastomic leak	0/112 (0%)		1/38 (2.6%)		0/35 (0%)		0/109 (0%)
Intestinal anastomosis complication	1/112 (0.9%)		0/38 (0%)		0/35 (0%)		0/109 (0%)
Post procedural haemorrhage	0/112 (0%)		1/38 (2.6%)		1/35 (2.9%)		0/109 (0%)
Procedural complication	1/112 (0.9%)		0/38 (0%)		0/35 (0%)		0/109 (0%)
Wound necrosis	0/112 (0%)		0/38 (0%)		1/35 (2.9%)		0/109 (0%)
Investigations
Electrocardiogram QT prolonged	1/112 (0.9%)		0/38 (0%)		0/35 (0%)		0/109 (0%)
General physical condition abnormal	0/112 (0%)		0/38 (0%)		0/35 (0%)		1/109 (0.9%)
Metabolism and nutrition disorders
Caxhexia	1/112 (0.9%)		0/38 (0%)		0/35 (0%)		0/109 (0%)
Musculoskeletal and connective tissue disorders
Connective tissue disorders fasciitis	1/112 (0.9%)		0/38 (0%)		0/35 (0%)		0/109 (0%)
Nervous system disorders
Cerebral haemorrhage	0/112 (0%)		1/38 (2.6%)		0/35 (0%)		0/109 (0%)
Cerebrovascular accident	0/112 (0%)		0/38 (0%)		1/35 (2.9%)		0/109 (0%)
Depressed level of consciousness	0/112 (0%)		1/38 (2.6%)		0/35 (0%)		0/109 (0%)
Haemorrhage intracranial	1/112 (0.9%)		0/38 (0%)		0/35 (0%)		0/109 (0%)
Ischaemic stroke	0/112 (0%)		1/38 (2.6%)		0/35 (0%)		1/109 (0.9%)
Metabolic encepalopathy	0/112 (0%)		0/38 (0%)		0/35 (0%)		1/109 (0.9%)
Neuromyopathy	0/112 (0%)		1/38 (2.6%)		0/35 (0%)		0/109 (0%)
Sedation	0/112 (0%)		0/38 (0%)		0/35 (0%)		1/109 (0.9%)
Subarachnoid haemorrhage	0/112 (0%)		0/38 (0%)		0/35 (0%)		1/109 (0.9%)
Psychiatric disorders
Confusional state	0/112 (0%)		0/38 (0%)		0/35 (0%)		1/109 (0.9%)
Renal and urinary disorders
Acute kidney injury	1/112 (0.9%)		1/38 (2.6%)		0/35 (0%)		1/109 (0.9%)
Renal failure	1/112 (0.9%)		0/38 (0%)		0/35 (0%)		0/109 (0%)
Respiratory, thoracic and mediastinal disorders
Acute lung injury	0/112 (0%)		0/38 (0%)		0/35 (0%)		1/109 (0.9%)
Acute pulmonary oedema	0/112 (0%)		0/38 (0%)		1/35 (2.9%)		0/109 (0%)
Acute respiratory distress syndrome	1/112 (0.9%)		0/38 (0%)		0/35 (0%)		0/109 (0%)
Acute respiratory failure	0/112 (0%)		0/38 (0%)		0/35 (0%)		1/109 (0.9%)
Chronic obstructive pulmonary disease	0/112 (0%)		0/38 (0%)		1/35 (2.9%)		0/109 (0%)
Epistaxis	1/112 (0.9%)		0/38 (0%)		0/35 (0%)		0/109 (0%)
Hypoxia	1/112 (0.9%)		2/38 (5.3%)		0/35 (0%)		0/109 (0%)
Pulmonary congestion	0/112 (0%)		0/38 (0%)		0/35 (0%)		1/109 (0.9%)
Pulmonary embolism	1/112 (0.9%)		0/38 (0%)		0/35 (0%)		1/109 (0.9%)
Pulmonary haemorrhage	0/112 (0%)		1/38 (2.6%)		0/35 (0%)		0/109 (0%)
Pulmonary oedema	2/112 (1.8%)		0/38 (0%)		0/35 (0%)		0/109 (0%)
Respiratory arrest	0/112 (0%)		0/38 (0%)		0/35 (0%)		1/109 (0.9%)
Respiratory distress	0/112 (0%)		0/38 (0%)		0/35 (0%)		1/109 (0.9%)
Respiratory failure	10/112 (8.9%)		4/38 (10.5%)		1/35 (2.9%)		4/109 (3.7%)
Skin and subcutaneous tissue disorders
Skin necrosis	0/112 (0%)		0/38 (0%)		0/35 (0%)		1/109 (0.9%)
Vascular disorders
Arterial haemorrhage	1/112 (0.9%)		0/38 (0%)		0/35 (0%)		1/109 (0.9%)
Arterial insufficiency	1/112 (0.9%)		0/38 (0%)		0/35 (0%)		0/109 (0%)
Capillary disorder	1/112 (0.9%)		0/38 (0%)		0/35 (0%)		0/109 (0%)
Circulatory collapse	0/112 (0%)		1/38 (2.6%)		0/35 (0%)		0/109 (0%)
Peripheral artery thrombosis	0/112 (0%)		1/38 (2.6%)		0/35 (0%)		0/109 (0%)
Peripheral ischemia	1/112 (0.9%)		0/38 (0%)		0/35 (0%)		2/109 (1.8%)
Shock	2/112 (1.8%)		0/38 (0%)		0/35 (0%)		1/109 (0.9%)
Shock haemorrhage	1/112 (0.9%)		0/38 (0%)		0/35 (0%)		1/109 (0.9%)
Other (Not Including Serious) Adverse Events
	Placebo		0.4 mg/kg (250 U/kg) recAP		0.8 mg/kg (500 U/kg) recAP		1.6 mg/kg (1000 U/kg) recAP
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	111/112 (99.1%)		35/38 (92.1%)		31/35 (88.6%)		103/109 (94.5%)
Blood and lymphatic system disorders
Thrombocytosis	1/112 (0.9%)		0/38 (0%)		3/35 (8.6%)		3/109 (2.8%)
Cardiac disorders
Arterial flutter	1/112 (0.9%)		2/38 (5.3%)		2/35 (5.7%)		3/109 (2.8%)
Bradycardia	3/112 (2.7%)		2/38 (5.3%)		0/35 (0%)		1/109 (0.9%)
Sinus tachycardia	5/112 (4.5%)		1/38 (2.6%)		0/35 (0%)		7/109 (6.4%)
Gastrointestinal disorders
Abdominal Pain	9/112 (8%)		0/38 (0%)		3/35 (8.6%)		3/109 (2.8%)
Constipation	13/112 (11.6%)		1/38 (2.6%)		3/35 (8.6%)		12/109 (11%)
Diarrhoea	12/112 (10.7%)		2/38 (5.3%)		3/35 (8.6%)		16/109 (14.7%)
Ileus apralytic	0/112 (0%)		0/38 (0%)		0/35 (0%)		7/109 (6.4%)
Impaired gastric emptying	8/112 (7.1%)		1/38 (2.6%)		2/35 (5.7%)		8/109 (7.3%)
Nausea	14/112 (12.5%)		4/38 (10.5%)		3/35 (8.6%)		13/109 (11.9%)
Vomiting	5/112 (4.5%)		3/38 (7.9%)		1/35 (2.9%)		6/109 (5.5%)
Abdominal distension	4/112 (3.6%)		2/38 (5.3%)		2/35 (5.7%)		4/109 (3.7%)
General disorders
Generalised oedemia	5/112 (4.5%)		3/38 (7.9%)		2/35 (5.7%)		9/109 (8.3%)
Multiple organ dysfunction syndrome	7/112 (6.3%)		2/38 (5.3%)		0/35 (0%)		5/109 (4.6%)
Oedema peripheral	17/112 (15.2%)		4/38 (10.5%)		5/35 (14.3%)		21/109 (19.3%)
Pain	5/112 (4.5%)		0/38 (0%)		2/35 (5.7%)		1/109 (0.9%)
Pyrexia	7/112 (6.3%)		2/38 (5.3%)		3/35 (8.6%)		10/109 (9.2%)
Infections and infestations
Cellulitis	1/112 (0.9%)		2/38 (5.3%)		0/35 (0%)		0/109 (0%)
Fungal infection	3/112 (2.7%)		2/38 (5.3%)		0/35 (0%)		1/109 (0.9%)
Herpes simplex	1/112 (0.9%)		3/38 (7.9%)		0/35 (0%)		1/109 (0.9%)
Oral herpes	1/112 (0.9%)		1/38 (2.6%)		2/35 (5.7%)		3/109 (2.8%)
Injury, poisoning and procedural complications
Wound dehiscence	0/112 (0%)		0/38 (0%)		2/35 (5.7%)		3/109 (2.8%)
Investigations
Blood phosphorus decreased	2/112 (1.8%)		2/38 (5.3%)		1/35 (2.9%)		3/109 (2.8%)
Breath sound abnormal	0/112 (0%)		1/38 (2.6%)		2/35 (5.7%)		1/109 (0.9%)
Cardiac murmur	1/112 (0.9%)		0/38 (0%)		2/35 (5.7%)		0/109 (0%)
Haemoglobin decreased	9/112 (8%)		2/38 (5.3%)		1/35 (2.9%)		8/109 (7.3%)
Blood potassium decreased	2/112 (1.8%)		0/38 (0%)		2/35 (5.7%)		2/109 (1.8%)
Metabolism and nutrition disorders
Hyperglycemia	3/112 (2.7%)		2/38 (5.3%)		1/35 (2.9%)		7/109 (6.4%)
Hyperkalaemia	5/112 (4.5%)		2/38 (5.3%)		0/35 (0%)		6/109 (5.5%)
Hypernatraemia	10/112 (8.9%)		0/38 (0%)		1/35 (2.9%)		6/109 (5.5%)
Hypoglycaemia	1/112 (0.9%)		3/38 (7.9%)		3/35 (8.6%)		9/109 (8.3%)
Hypokalaemia	17/112 (15.2%)		5/38 (13.2%)		3/35 (8.6%)		14/109 (12.8%)
Hypomagnesaemia	4/112 (3.6%)		2/38 (5.3%)		0/35 (0%)		2/109 (1.8%)
Hypophosphataemia	4/112 (3.6%)		2/38 (5.3%)		1/35 (2.9%)		6/109 (5.5%)
Metabolic acidosis	3/112 (2.7%)		0/38 (0%)		2/35 (5.7%)		3/109 (2.8%)
Metabolic alkalosis	3/112 (2.7%)		0/38 (0%)		2/35 (5.7%)		3/109 (2.8%)
Nervous system disorders
Intensive care unit acquired weakness	4/112 (3.6%)		1/38 (2.6%)		2/35 (5.7%)		5/109 (4.6%)
Psychiatric disorders
Agitation	6/112 (5.4%)		2/38 (5.3%)		2/35 (5.7%)		13/109 (11.9%)
Anxiety	3/112 (2.7%)		3/38 (7.9%)		2/35 (5.7%)		3/109 (2.8%)
Delirium	20/112 (17.9%)		5/38 (13.2%)		5/35 (14.3%)		14/109 (12.8%)
Insomnia	10/112 (8.9%)		2/38 (5.3%)		2/35 (5.7%)		13/109 (11.9%)
Disorientation	0/112 (0%)		3/38 (7.9%)		1/35 (2.9%)		2/109 (1.8%)
Respiratory, thoracic and mediastinal disorders
Atelectasis	5/112 (4.5%)		1/38 (2.6%)		1/35 (2.9%)		6/109 (5.5%)
Dyspnoea	8/112 (7.1%)		0/38 (0%)		1/35 (2.9%)		1/109 (0.9%)
Hypoxia	1/112 (0.9%)		3/38 (7.9%)		1/35 (2.9%)		1/109 (0.9%)
Lung infiltration	0/112 (0%)		0/38 (0%)		2/35 (5.7%)		0/109 (0%)
Pleural effusion	11/112 (9.8%)		3/38 (7.9%)		4/35 (11.4%)		14/109 (12.8%)
Tachypnoea	0/112 (0%)		2/38 (5.3%)		0/35 (0%)		0/109 (0%)
Wheezing	0/112 (0%)		0/38 (0%)		2/35 (5.7%)		0/109 (0%)
Skin and subcutaneous tissue disorders
Decubitus ulcer	2/112 (1.8%)		1/38 (2.6%)		1/35 (2.9%)		9/109 (8.3%)
Erythema	3/112 (2.7%)		2/38 (5.3%)		2/35 (5.7%)		1/109 (0.9%)
Skin discolouration	0/112 (0%)		2/38 (5.3%)		0/35 (0%)		0/109 (0%)
Vascular disorders
Hypertension	10/112 (8.9%)		2/38 (5.3%)		6/35 (17.1%)		14/109 (12.8%)
Hypotension	10/112 (8.9%)		5/38 (13.2%)		2/35 (5.7%)		6/109 (5.5%)
Phlebitis	2/112 (1.8%)		1/38 (2.6%)		2/35 (5.7%)		2/109 (1.8%)
Haematoma	5/112 (4.5%)		1/38 (2.6%)		2/35 (5.7%)		2/109 (1.8%)

Limitations/Caveats

[Not Specified]

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.