A Study of THR-184 in Patients at Risk of Developing Cardiac Surgery Associated-Acute Kidney Injury (CSA-AKI)

• Sponsor: Thrasos Innovation, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01830920
• Collaborator: (none)
• Enrollment: 452
• Locations: 41
• Arms: 5
• Duration (Months): 28
• Patients Per Site: 11
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

The purpose of this study is to determine whether THR-184 when administered around the time of cardiac surgery that requires cardiopulmonary bypass can prevent or ameliorate the development of acute kidney injury.

Condition or Disease	Intervention/Treatment	Phase
Acute Kidney Injury	Drug: THR-184; Drug: Placebo	Phase 2

Detailed Description

The study has been designed to include patients scheduled for cardiac surgery who are considered at increased risk for developing CSA-AKI. The eligibility criteria are intended to enrich the study population with such patients.

Stage 1 consisted of 140 patients randomized in a 1:1:1:1 ratio (approximately 35 patients per treatment arm) to Placebo or to one of three (3) THR-184 dose arms:

• initial pre-surgery low dose of THR-184 by three (3) post-surgery doses at the low dose, or

• initial pre-surgery middle dose of THR-184 followed by three (3) post-surgery doses at the low dose, or

• initial pre-surgery high dose of THR-184 followed by three (3) post-surgery doses at the low dose

An interim analysis (IA) was performed by the Independent Statistical Center (ISC) and presented to the Independent Data Monitoring Committee (IDMC). The IDMC indicated no safety concerns and recommended that the study continue with the placebo arm and the initial pre-surgery high dose arm. Additionally, another dosing arm will be added, which will increase the dose post-surgery.

Stage 2 will consist of approximately 270 patients randomized in a 1:1:2 ratio to Placebo or to a dose selected from one of the two (2) THR-184 dose arms:

• initial pre-surgery high dose of THR-184, followed by (3) post-surgery doses at the original low dose;

• initial pre-surgery high dose of THR-184, followed by (3) post-surgery doses at ~80% of the pre-surgery dose

Study treatment (THR-184 or placebo) will consist of one 60-minute IV infusion administered prior to surgery, followed by a 60-minute IV infusion administered, beginning in the early post-operative period, and followed by two (2) additional 60-minute IV infusions administered, on consecutive days post-cardiac surgery.

The primary endpoint for the evaluation of efficacy in patients receiving THR-184, as compared to patients receiving Placebo, will be the proportion of patients developing CSA-AKI as measured by the Kidney Disease Improving Global Outcomes (KDIGO) criteria, as follows:

• Increase in Serum creatinine (SCr) by ≥0.3 mg/dl (>26.5 µmol/l) within 48 hours post-surgery; or

• Increase in SCr to ≥1.5 times a baseline which has been measured in the previous 7 days; or

• Urine volume <0.5 ml/kg/h for 6 hours post-operatively

If at least one of these measures is present by the 7 day assessment, a patient will be considered to have developed CSA-AKI.

Study Design

• Study Type: Interventional
• Actual Enrollment: 452 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Multi-Center, Parallel-Group, Randomized, Double Blind, Adaptive Study Investigating the Safety and Efficacy of THR-184 in Patients at Increased Risk of Developing Cardiac Surgery Associated-Acute Kidney Injury (CSA-AKI)
• Study Start Date: May 1, 2013
• Actual Primary Completion Date: Sep 1, 2015
• Actual Study Completion Date: Sep 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo An identical appearing placebo will be administered.	Drug: Placebo; A normal saline solution identical in appearance to the active drug solution; Other Names: Saline solution
Experimental: THR-184 Dose 1 THR-184 initial pre-surgery low dose followed by (3) post surgery doses at the low dose.	Drug: THR-184; THR-184 is a synthetic oligopeptide administered intravenously.; Other Names: Synthetic oligopeptide
Experimental: THR-184 Dose 2 THR-184 initial pre-surgery mid-dose followed by (3) post surgery doses at the low dose.	Drug: THR-184; THR-184 is a synthetic oligopeptide administered intravenously.; Other Names: Synthetic oligopeptide
Experimental: THR-184 Dose 3 THR-184 initial pre-surgery high dose followed by (3) post surgery doses at the low dose.	Drug: THR-184; THR-184 is a synthetic oligopeptide administered intravenously.; Other Names: Synthetic oligopeptide
Experimental: THR-184 Dose 4 THR-184 initial pre-surgery high dose followed by (3) post surgery doses ~80% of the pre-surgery dose.	Drug: THR-184; THR-184 is a synthetic oligopeptide administered intravenously.; Other Names: Synthetic oligopeptide

Outcome Measures

Primary Outcome Measures

1. Incidence of Acute Kidney Injury (AKI) [7 days]

   Acute kidney injury (AKI) is defined using the KDIGO criteria, in which AKI is defined as any of the following: Increase in SCr by ≥0.3 mg/dl (≥26.5 µmol/l) within 48 hours; or Increase in SCr to ≥1.5 times baseline, which is known or presumed to have occurred within the prior 7 days; or Urine volume <0.5 ml/kg/h for 6 hours.

Secondary Outcome Measures

1. Incidence of AKI [7 days]

   AKI is defined using the SCr-KDIGO criteria, defined as the following: Increase in SCr by ≥0.3 mg/dl (≥26.5 µmol/l) within 48 hours; or Increase in SCr to ≥1.5 times baseline, which is known or presumed to have occurred within the prior 7 days.

2. Severity of AKI [7 days]

   AKI is defined using the KDIGO criteria, in which AKI is defined as any of the following: Increase in SCr by ≥0.3 mg/dl (≥26.5 µmol/l) within 48 hours; or Increase in SCr to ≥1.5 times baseline, which is known or presumed to have occurred within the prior 7 days; or Urine volume <0.5 ml/kg/h for 6 hours. Staging of AKI is defined as the following: Stage 1: SCr 1.5 - 1.9 times baseline OR ≥0.3 mg/dL (≥26.5 µmol/L) increase, Urine output <0.5 ml/kg/hr for 6-12 hours Stage 2: SCr 2.0-2.9 times baseline, Urine output <0.5 ml/kg/h for ≥ 12 hours Stage 3: SCr 3.0 times baseline OR Increase in SCr to ≥5.0 mg/dL (≥353.6 µmol/L) OR Initiation of renal replacement therapy OR In patients <18 years, decrease in eGFR to <35 ml/min per 1.73 m^2, Urine output <0.3 ml/kg/h for ≥24 hours OR Anuria for ≥12 hours. No AKI is considered the best outcome, and Stage 3 the worst outcome.

3. Duration of AKI [7 days OR up to discharge after surgery]

   AKI is defined using the Scr-KDIGO criteria. Duration of AKI is defined as the number of days from start of AKI (SCr-KDIGO) where either SCr increase ≥ 0.3 mg/dL above pre-AKI reference point (if the value exists) or if SCr increase ≥1.5 times baseline or dialysis in the first 7 days up to discharge if prior to 7 days.

Other Outcome Measures

1. Composite of Death, Dialysis, or Sustained Impaired Renal Function [Day 30]

   Sustained impaired renal function defined as a 35% increase in SCr from baseline at Day 30.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Male or female and >18 years of age.

• Scheduled for a non-emergent coronary and/or valve surgery procedure requiring CPB, to include:

• coronary artery bypass graft (CABG) alone;

• aortic valve replacement or repair alone, with or without aortic root repair;

• mitral, tricuspid, or pulmonic valve replacement or repair alone;

• simultaneous replacement of several cardiac valves;

• CABG with aortic, mitral, tricuspid, or pulmonic valve replacement or repair;

• CABG with combined cardiac valve replacement or repair.

• Have the following risk factors for CSA-AKI:

• eGFR ≥ 20 and < 30 ml/min/1.73m2 OR

• eGFR ≥ 30 and < 60 ml/min/1.73m2 and ONE of the following additional risk factors (other than age ≥ 75 years) OR

• eGFR ≥ 60 ml/min/1.73m2 and TWO of the following additional risk factors

Additional Risk Factors:

• Age ≥ 75 years;

• Combined valve & coronary surgery;

• Previous cardiac surgery with sternotomy;

• Documented NYHA Class III or IV within 1 year prior to surgery;

• Left ventricular ejection fraction (LVEF) ≤ 35% by invasive or noninvasive diagnostic cardiac imaging - echocardiography, nuclear imaging, computed tomography, magnetic resonance imaging or angiography performed within 90 days prior to surgery. (If LVEF ≤ 35% by any invasive or noninvasive imaging procedure, patient meets the risk factor.)

• Insulin-requiring diabetes;

• Non-insulin-requiring diabetes and the presence of ≥+2 proteinuria on urinalysis (medical history or dipstick);

• Preoperative anemia (hemoglobin <11g/dl for men and women).

Exclusion Criteria:

If any of the following criteria apply prior to surgery, the patient will be excluded from the study:

• Age > 85 years;

• Weight >174 kg or 383 lbs;

• The presence of AKI (KDIGO criteria) at the time of screening ;

• Surgery to be performed without CPB;

• Surgery to be performed under conditions of circulatory arrest or hypothermia with rectal temperature < 28°Celsius (82.4° Fahrenheit);

• eGFR (MDRD) <20 ml/min/1.73m2;

• Surgery for aortic dissection;

• Surgery to correct a major congenital heart defect (e.g., Tetralogy of Fallot, transposition of the great vessels, single ventricle, Ebsteins anomaly. Bicuspid aortic valve is not to be considered a congenital heart defect.);

• Prior organ transplantation;

• Dialysis-dependence;

• Administration of iodinated contrast media within 24 hours prior to cardiac surgery;

• If received contrast media prior to 24 hours and have AKI as defined by KDIGO criteria;

• Cardiogenic shock or haemodynamic instability within the 24 hours prior to surgery, including the anesthesia induction period; as defined by a systolic BP <80 mm Hg and pulse >120 beats per minute (bpm) and requirement for inotropes or vasopressors or other mechanical devices such as intra-aortic balloon counter-pulsation (IABP);

• Requirement for any of the following within seven (7) days prior to cardiac surgery:

• defibrillator or permanent pacemaker,

• mechanical ventilation,

• intra-aortic balloon counter-pulsation (IABP),

• left ventricular assist device (LVAD),

• other forms of mechanical circulatory support (MCS);

• Cardiopulmonary resuscitation within 14 days prior to cardiac surgery;

• Known history of cancer within the past 5 years, except for carcinoma in situ of the cervix or adequately treated basal cell carcinoma of the skin;

• Known or suspected sepsis at time of screening;

• Known or suspected glomerulonephritis or interstitial nephritis at time of screening;

• Confirmed or treated endocarditis within previous 30 days prior to cardiac surgery;

• Other current active infection requiring antibiotic treatment;

• Patients with known active human immunodeficiency virus infection;

• Documented history of HIV antibodies;

• Patients with known active Hepatitis B (HBV) or Hepatitis C (HCV) infection;

• Documented history of HCV antibodies;

• Documented history of HBV antigens;

• Patients on immunosuppressant drugs or prednisone over the dose of 20 mg per day;

• Inadequate hepatic function, defined as total bilirubin or alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2 times the upper limit of normal (ULN) at time of screening or Child Pugh Class C liver disease ( see appendix 6) or higher;

• Any congenital coagulation disorder;

• Pregnancy or lactation;

• If patient has "Do Not Resuscitate" (DNR) status;

• Known hypersensitivity to the study drug or any of its excipients;

• Treatment with an investigational drug or participation in an interventional trial within 60 days prior to 1st dose of study drug;

• In the opinion of the investigator any disease processes or confounding variables that would inappropriately alter the outcome of the study;

• Inability to comply with the requirements of the study protocol.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama-Birmingham	Birmingham	Alabama	United States	35294
2	University of Southern California	Los Angeles	California	United States	90033
3	Stanford University	Stanford	California	United States	94305
4	Harbor - University of California Los Angeles Medical Center	Torrance	California	United States	90503
5	Danbury Hospital	Danbury	Connecticut	United States	06810
6	River City Clinical Research	Jacksonville	Florida	United States	32207
7	University of Chicago	Chicago	Illinois	United States	60637
8	Advocate Christ Medical Center	Oak Lawn	Illinois	United States	60453
9	Indiana Ohio Heart	Fort Wayne	Indiana	United States	46804
10	Indiana Heart-St. Vincent Medical Group	Indianapolis	Indiana	United States	46290
11	Maine Medical Center	Portland	Maine	United States	04102
12	John Hopkins University	Baltimore	Maryland	United States	21287
13	Suburban Hospital	Bethesda	Maryland	United States	20814
14	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
15	Baystate Medical Center	Springfield	Massachusetts	United States	01199
16	Cardiac and Vascular Research Center of Northern Michigan	Petoskey	Michigan	United States	49770
17	Covenant Medical Center	Saginaw	Michigan	United States	48602
18	Washington University	St. Louis	Missouri	United States	63110
19	St. Joseph's Regional Medical Center	Paterson	New Jersey	United States	07503
20	St. Peter's Hospital	Albany	New York	United States	12208
21	Columbia University	New York	New York	United States	10032
22	Duke University Medical Center	Durham	North Carolina	United States	27710
23	Durham VA Medical Center	Durham	North Carolina	United States	27710
24	Lindner Research Center-Christ Hospital	Cincinnati	Ohio	United States	45219
25	The Ohio State University Medical Center	Columbus	Ohio	United States	43210
26	Erlanger Health System	Chattanooga	Tennessee	United States	37404
27	Memorial Hospital	Chattanooga	Tennessee	United States	37404
28	Vanderbilt University Medical Center	Nashville	Tennessee	United States	37212
29	Baylor University Medical Center, Soltero Cardiovascular Research Center	Dallas	Texas	United States	75226
30	University of Texas, Houston	Houston	Texas	United States	77030
31	Cardiothoracic Surgical Associates	Richmond	Virginia	United States	23225
32	Foothills Medical Centre	Calgary	Alberta	Canada	T2N 2T9
33	St-John Regional Hospital Facility	St-John	New Brunswick	Canada	E2L4L2
34	Hamilton Health Sciences Corporation	Hamilton	Ontario	Canada	L8L 2X2
35	University of Ottawa Heart Institute	Ottawa	Ontario	Canada	K1Y 4W7
36	St. Michael's Hospital	Toronto	Ontario	Canada	M5B 1W8
37	Institut de Cardiologie de Montréal	Montréal	Quebec	Canada	H1T 1C8
38	Centre hospitalier de l'université de Montréal(CHUM)- Hôtel-Dieu	Montréal	Quebec	Canada	H2W 1T8
39	MUHC - Royal Victoria Hospital	Montréal	Quebec	Canada	H3A 1A1
40	Sacre Cœur Hospital	Montréal	Quebec	Canada	H4J 1C5
41	Institut Universitaire de Cardiologie et de Pneumologie de Québec	Québec	Quebec	Canada	G1V 4G5

Sponsors and Collaborators

• Thrasos Innovation, Inc.

Investigators

• Study Director: Andreas Orfanos, MBBCh, Thrasos Innovation, Inc.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Thrasos Innovation, Inc.
• ClinicalTrials.gov Identifier: NCT01830920
• Other Study ID Numbers: A-003; 2741202
• First Posted: Apr 12, 2013
• Last Update Posted: Apr 20, 2017
• Last Verified: Mar 1, 2017

• Keywords provided by Thrasos Innovation, Inc.: Acute Kidney Injury; AKI; Cardiac surgery
• Additional relevant MeSH terms: Acute Kidney Injury; Wounds and Injuries

Study Results

Participant Flow

Arm/Group Title	Placebo	THR-184 Dose 1	THR-184 Dose 2	THR-184 Dose 3	THR-184 Dose 4
Arm/Group Description	An identical appearing placebo will be administered. Placebo: A normal saline solution identical in appearance to the active drug solution	THR-184 initial pre-surgery low dose followed by (3) post surgery doses at the low dose. THR-184: THR-184 is a synthetic oligopeptide administered intravenously.	THR-184 initial pre-surgery mid-dose followed by (3) post surgery doses at the low dose. THR-184: THR-184 is a synthetic oligopeptide administered intravenously.	THR-184 initial pre-surgery high dose followed by (3) post surgery doses at the low dose. THR-184: THR-184 is a synthetic oligopeptide administered intravenously.	THR-184 initial pre-surgery high dose followed by (3) post surgery doses ~80% of the pre-surgery dose. THR-184: THR-184 is a synthetic oligopeptide administered intravenously.
Period Title: Overall Study
STARTED	126	46	48	125	107
Received Allocated Drug	115	45	47	119	105
COMPLETED	105	40	40	109	99
NOT COMPLETED	21	6	8	16	8

Baseline Characteristics

Arm/Group Title	Placebo	THR-184 Dose 1	THR-184 Dose 2	THR-184 Dose 3	THR-184 Dose 4	Total
Arm/Group Description	An identical appearing placebo will be administered. Placebo: A normal saline solution identical in appearance to the active drug solution	THR-184 initial pre-surgery low dose followed by (3) post surgery doses at the low dose. THR-184: THR-184 is a synthetic oligopeptide administered intravenously.	THR-184 initial pre-surgery mid-dose followed by (3) post surgery doses at the low dose. THR-184: THR-184 is a synthetic oligopeptide administered intravenously.	THR-184 initial pre-surgery high dose followed by (3) post surgery doses at the low dose. THR-184: THR-184 is a synthetic oligopeptide administered intravenously.	THR-184 initial pre-surgery high dose followed by (3) post surgery doses ~80% of the pre-surgery dose. THR-184: THR-184 is a synthetic oligopeptide administered intravenously.	Total of all reporting groups
Overall Participants	115	45	47	119	105	431
Age (years) [Mean (Inter-Quartile Range) ]
Mean (Inter-Quartile Range) [years]	71.5	68.8	72.7	72.5	70.0	71.3
Sex: Female, Male (Count of Participants)
Female	44 38.3%	18 40%	13 27.7%	39 32.8%	34 32.4%	148 34.3%
Male	71 61.7%	27 60%	34 72.3%	80 67.2%	71 67.6%	283 65.7%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 0.9%	0 0%	1 2.1%	1 0.8%	2 1.9%	5 1.2%
Asian	2 1.7%	2 4.4%	0 0%	1 0.8%	3 2.9%	8 1.9%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	5 4.3%	3 6.7%	1 2.1%	5 4.2%	3 2.9%	17 3.9%
White	105 91.3%	40 88.9%	44 93.6%	110 92.4%	95 90.5%	394 91.4%
More than one race	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	2 1.7%	0 0%	1 2.1%	2 1.7%	2 1.9%	7 1.6%
Region of Enrollment (participants) [Number]
Canada	46 40%	17 37.8%	27 57.4%	55 46.2%	55 52.4%	200 46.4%
United States	69 60%	28 62.2%	20 42.6%	64 53.8%	50 47.6%	231 53.6%

Outcome Measures

1. Primary Outcome

Title	Incidence of Acute Kidney Injury (AKI)
Description	Acute kidney injury (AKI) is defined using the KDIGO criteria, in which AKI is defined as any of the following: Increase in SCr by ≥0.3 mg/dl (≥26.5 µmol/l) within 48 hours; or Increase in SCr to ≥1.5 times baseline, which is known or presumed to have occurred within the prior 7 days; or Urine volume <0.5 ml/kg/h for 6 hours.
Time Frame	7 days

Outcome Measure Data

Analysis Population Description

Per Protocol Analysis set -

Arm/Group Title	Placebo	THR-184 Dose 1	THR-184 Dose 2	THR-184 Dose 3	THR-184 Dose 4
Arm/Group Description	An identical appearing placebo will be administered. Placebo: A normal saline solution identical in appearance to the active drug solution	THR-184 initial pre-surgery low dose followed by (3) post surgery doses at the low dose. THR-184: THR-184 is a synthetic oligopeptide administered intravenously.	THR-184 initial pre-surgery mid-dose followed by (3) post surgery doses at the low dose. THR-184: THR-184 is a synthetic oligopeptide administered intravenously.	THR-184 initial pre-surgery high dose followed by (3) post surgery doses at the low dose. THR-184: THR-184 is a synthetic oligopeptide administered intravenously.	THR-184 initial pre-surgery high dose followed by (3) post surgery doses ~80% of the pre-surgery dose. THR-184: THR-184 is a synthetic oligopeptide administered intravenously.
Measure Participants	93	24	29	91	71
Count of Participants [Participants]	73 63.5%	18 40%	22 46.8%	71 59.7%	50 47.6%

2. Secondary Outcome

Title	Incidence of AKI
Description	AKI is defined using the SCr-KDIGO criteria, defined as the following: Increase in SCr by ≥0.3 mg/dl (≥26.5 µmol/l) within 48 hours; or Increase in SCr to ≥1.5 times baseline, which is known or presumed to have occurred within the prior 7 days.
Time Frame	7 days

Outcome Measure Data

Analysis Population Description

Per Protocol Analysis set

Arm/Group Title	Placebo	THR-184 Dose 1	THR-184 Dose 2	THR-184 Dose 3	THR-184 Dose 4
Arm/Group Description	An identical appearing placebo will be administered. Placebo: A normal saline solution identical in appearance to the active drug solution	THR-184 initial pre-surgery low dose followed by (3) post surgery doses at the low dose. THR-184: THR-184 is a synthetic oligopeptide administered intravenously.	THR-184 initial pre-surgery mid-dose followed by (3) post surgery doses at the low dose. THR-184: THR-184 is a synthetic oligopeptide administered intravenously.	THR-184 initial pre-surgery high dose followed by (3) post surgery doses at the low dose. THR-184: THR-184 is a synthetic oligopeptide administered intravenously.	THR-184 initial pre-surgery high dose followed by (3) post surgery doses ~80% of the pre-surgery dose. THR-184: THR-184 is a synthetic oligopeptide administered intravenously.
Measure Participants	93	24	29	91	71
Count of Participants [Participants]	53 46.1%	13 28.9%	17 36.2%	51 42.9%	35 33.3%

3. Secondary Outcome

Title	Severity of AKI
Description	AKI is defined using the KDIGO criteria, in which AKI is defined as any of the following: Increase in SCr by ≥0.3 mg/dl (≥26.5 µmol/l) within 48 hours; or Increase in SCr to ≥1.5 times baseline, which is known or presumed to have occurred within the prior 7 days; or Urine volume <0.5 ml/kg/h for 6 hours. Staging of AKI is defined as the following: Stage 1: SCr 1.5 - 1.9 times baseline OR ≥0.3 mg/dL (≥26.5 µmol/L) increase, Urine output <0.5 ml/kg/hr for 6-12 hours Stage 2: SCr 2.0-2.9 times baseline, Urine output <0.5 ml/kg/h for ≥ 12 hours Stage 3: SCr 3.0 times baseline OR Increase in SCr to ≥5.0 mg/dL (≥353.6 µmol/L) OR Initiation of renal replacement therapy OR In patients <18 years, decrease in eGFR to <35 ml/min per 1.73 m^2, Urine output <0.3 ml/kg/h for ≥24 hours OR Anuria for ≥12 hours. No AKI is considered the best outcome, and Stage 3 the worst outcome.
Time Frame	7 days

Outcome Measure Data

Analysis Population Description

Per Protocol Analysis set

Arm/Group Title	Placebo	THR-184 Dose 1	THR-184 Dose 2	THR-184 Dose 3	THR-184 Dose 4
Arm/Group Description	An identical appearing placebo will be administered. Placebo: A normal saline solution identical in appearance to the active drug solution	THR-184 initial pre-surgery low dose followed by (3) post surgery doses at the low dose. THR-184: THR-184 is a synthetic oligopeptide administered intravenously.	THR-184 initial pre-surgery mid-dose followed by (3) post surgery doses at the low dose. THR-184: THR-184 is a synthetic oligopeptide administered intravenously.	THR-184 initial pre-surgery high dose followed by (3) post surgery doses at the low dose. THR-184: THR-184 is a synthetic oligopeptide administered intravenously.	THR-184 initial pre-surgery high dose followed by (3) post surgery doses ~80% of the pre-surgery dose. THR-184: THR-184 is a synthetic oligopeptide administered intravenously.
Measure Participants	93	24	29	91	71
No AKI	20 17.4%	6 13.3%	7 14.9%	20 16.8%	21 20%
Stage I AKI	47 40.9%	10 22.2%	12 25.5%	48 40.3%	29 27.6%
Stage II AKI	23 20%	7 15.6%	9 19.1%	22 18.5%	18 17.1%
Stage III AKI	3 2.6%	1 2.2%	1 2.1%	1 0.8%	3 2.9%

4. Secondary Outcome

Title	Duration of AKI
Description	AKI is defined using the Scr-KDIGO criteria. Duration of AKI is defined as the number of days from start of AKI (SCr-KDIGO) where either SCr increase ≥ 0.3 mg/dL above pre-AKI reference point (if the value exists) or if SCr increase ≥1.5 times baseline or dialysis in the first 7 days up to discharge if prior to 7 days.
Time Frame	7 days OR up to discharge after surgery

Outcome Measure Data

Analysis Population Description

Per Protocol Analysis set

Arm/Group Title	Placebo	THR-184 Dose 1	THR-184 Dose 2	THR-184 Dose 3	THR-184 Dose 4
Arm/Group Description	An identical appearing placebo will be administered. Placebo: A normal saline solution identical in appearance to the active drug solution	THR-184 initial pre-surgery low dose followed by (3) post surgery doses at the low dose. THR-184: THR-184 is a synthetic oligopeptide administered intravenously.	THR-184 initial pre-surgery mid-dose followed by (3) post surgery doses at the low dose. THR-184: THR-184 is a synthetic oligopeptide administered intravenously.	THR-184 initial pre-surgery high dose followed by (3) post surgery doses at the low dose. THR-184: THR-184 is a synthetic oligopeptide administered intravenously.	THR-184 initial pre-surgery high dose followed by (3) post surgery doses ~80% of the pre-surgery dose. THR-184: THR-184 is a synthetic oligopeptide administered intravenously.
Measure Participants	93	24	29	91	71
Mean (Standard Deviation) [days]	3.7 (2.44)	2.4 (1.80)	2.8 (1.92)	3.4 (2.49)	3.5 (2.47)

5. Other Pre-specified Outcome

Title	Composite of Death, Dialysis, or Sustained Impaired Renal Function
Description	Sustained impaired renal function defined as a 35% increase in SCr from baseline at Day 30.
Time Frame	Day 30

Outcome Measure Data

Analysis Population Description

Per Protocol Analysis set

Arm/Group Title	Placebo	THR-184 Dose 1	THR-184 Dose 2	THR-184 Dose 3	THR-184 Dose 4
Arm/Group Description	An identical appearing placebo will be administered. Placebo: A normal saline solution identical in appearance to the active drug solution	THR-184 initial pre-surgery low dose followed by (3) post surgery doses at the low dose. THR-184: THR-184 is a synthetic oligopeptide administered intravenously.	THR-184 initial pre-surgery mid-dose followed by (3) post surgery doses at the low dose. THR-184: THR-184 is a synthetic oligopeptide administered intravenously.	THR-184 initial pre-surgery high dose followed by (3) post surgery doses at the low dose. THR-184: THR-184 is a synthetic oligopeptide administered intravenously.	THR-184 initial pre-surgery high dose followed by (3) post surgery doses ~80% of the pre-surgery dose. THR-184: THR-184 is a synthetic oligopeptide administered intravenously.
Measure Participants	93	24	29	91	71
Subjects meeting Endpoint	11 9.6%	4 8.9%	5 10.6%	11 9.2%	12 11.4%
Subjects not meeting Endpoint	77 67%	17 37.8%	20 42.6%	73 61.3%	47 44.8%
Subjects excluded from measure	5 4.3%	3 6.7%	4 8.5%	7 5.9%	12 11.4%

6. Other Pre-specified Outcome

Title	Composite of Death, Dialysis, or Sustained Impaired Renal Function
Description	Sustained impaired renal function defined as a 35% increase in SCr from baseline at Day 30.
Time Frame	Day 30

Outcome Measure Data

Analysis Population Description

Per Protocol Analysis set

Arm/Group Title	Placebo	THR-184 Dose 1	THR-184 Dose 2	THR-184 Dose 3	THR-184 Dose 4
Arm/Group Description	An identical appearing placebo will be administered. Placebo: A normal saline solution identical in appearance to the active drug solution	THR-184 initial pre-surgery low dose followed by (3) post surgery doses at the low dose. THR-184: THR-184 is a synthetic oligopeptide administered intravenously.	THR-184 initial pre-surgery mid-dose followed by (3) post surgery doses at the low dose. THR-184: THR-184 is a synthetic oligopeptide administered intravenously.	THR-184 initial pre-surgery high dose followed by (3) post surgery doses at the low dose. THR-184: THR-184 is a synthetic oligopeptide administered intravenously.	THR-184 initial pre-surgery high dose followed by (3) post surgery doses ~80% of the pre-surgery dose. THR-184: THR-184 is a synthetic oligopeptide administered intravenously.
Measure Participants	93	24	29	91	71
Subjects meeting Endpoint	14 12.2%	5 11.1%	4 8.5%	9 7.6%	16 15.2%
Subjects not meeting Endpoint	59 51.3%	13 28.9%	15 31.9%	65 54.6%	55 52.4%
Subjects excluded from measure	20 17.4%	6 13.3%	10 21.3%	17 14.3%	0 0%

Adverse Events

Time Frame	Data were collected over approximately 90 days post-cardiac surgery, with a 14 day Screening Period prior to surgery.
Adverse Event Reporting Description	Systematic Assessment: each patient was evaluated at least once a day until day 7 post-surgery or until discharge from the hospital. Subjects returned for a follow-up visit on Day 30 and Day 90 and follow-up phone calls were conducted on Day 14 and Day 60.
Arm/Group Title	Placebo		THR-184 Dose 1		THR-184 Dose 2		THR-184 Dose 3		THR-184 Dose 4
Arm/Group Description	An identical appearing placebo will be administered. Placebo: A normal saline solution identical in appearance to the active drug solution		THR-184 initial pre-surgery low dose followed by (3) post surgery doses at the low dose. THR-184: THR-184 is a synthetic oligopeptide administered intravenously.		THR-184 initial pre-surgery mid-dose followed by (3) post surgery doses at the low dose. THR-184: THR-184 is a synthetic oligopeptide administered intravenously.		THR-184 initial pre-surgery high dose followed by (3) post surgery doses at the low dose. THR-184: THR-184 is a synthetic oligopeptide administered intravenously.		THR-184 initial pre-surgery high dose followed by (3) post surgery doses ~80% of the pre-surgery dose. THR-184: THR-184 is a synthetic oligopeptide administered intravenously.
All Cause Mortality
	Placebo		THR-184 Dose 1		THR-184 Dose 2		THR-184 Dose 3		THR-184 Dose 4
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo		THR-184 Dose 1		THR-184 Dose 2		THR-184 Dose 3		THR-184 Dose 4
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	48/115 (41.7%)		21/45 (46.7%)		28/47 (59.6%)		50/119 (42%)		43/105 (41%)
Blood and lymphatic system disorders
Anaemia	0/115 (0%)		2/45 (4.4%)		0/47 (0%)		1/119 (0.8%)		0/105 (0%)
Haemorrhagic anaemia	0/115 (0%)		0/45 (0%)		0/47 (0%)		1/119 (0.8%)		0/105 (0%)
Coagulopathy	0/115 (0%)		0/45 (0%)		1/47 (2.1%)		1/119 (0.8%)		0/105 (0%)
Heparin-induced thrombocytopenia	0/115 (0%)		1/45 (2.2%)		0/47 (0%)		0/119 (0%)		0/105 (0%)
Thrombocytopenia	1/115 (0.9%)		0/45 (0%)		0/47 (0%)		0/119 (0%)		0/105 (0%)
Cardiac disorders
Atrial fibrillation	7/115 (6.1%)		0/45 (0%)		3/47 (6.4%)		4/119 (3.4%)		3/105 (2.9%)
Atrioventricular block complete	1/115 (0.9%)		0/45 (0%)		1/47 (2.1%)		4/119 (3.4%)		1/105 (1%)
Cardiac arrest	1/115 (0.9%)		2/45 (4.4%)		2/47 (4.3%)		1/119 (0.8%)		1/105 (1%)
Ventricular fibrillation	0/115 (0%)		1/45 (2.2%)		1/47 (2.1%)		0/119 (0%)		1/105 (1%)
Arrythmia	0/115 (0%)		2/45 (4.4%)		0/47 (0%)		0/119 (0%)		0/105 (0%)
Atrioventricular block	1/115 (0.9%)		0/45 (0%)		0/47 (0%)		0/119 (0%)		1/105 (1%)
Cardio-respiratory arrest	0/115 (0%)		0/45 (0%)		1/47 (2.1%)		1/119 (0.8%)		0/105 (0%)
Sinus node dysfunction	0/115 (0%)		0/45 (0%)		1/47 (2.1%)		1/119 (0.8%)		0/105 (0%)
Torsade de pointes	1/115 (0.9%)		0/45 (0%)		0/47 (0%)		0/119 (0%)		1/105 (1%)
Ventricular tachycardia	0/115 (0%)		0/45 (0%)		0/47 (0%)		0/119 (0%)		2/105 (1.9%)
Arrhythmia supraventricular	1/115 (0.9%)		0/45 (0%)		0/47 (0%)		0/119 (0%)		0/105 (0%)
Atrial flutter	0/115 (0%)		1/45 (2.2%)		0/47 (0%)		0/119 (0%)		0/105 (0%)
Atrial tachycardia	0/115 (0%)		0/45 (0%)		0/47 (0%)		1/119 (0.8%)		0/105 (0%)
Atrioventricular block second degree	0/115 (0%)		0/45 (0%)		0/47 (0%)		1/119 (0.8%)		0/105 (0%)
Bundle branch block left	0/115 (0%)		0/45 (0%)		0/47 (0%)		0/119 (0%)		1/105 (1%)
Nodal arrhythmia	0/115 (0%)		0/45 (0%)		0/47 (0%)		1/119 (0.8%)		0/105 (0%)
Nodal rhythm	0/115 (0%)		0/45 (0%)		0/47 (0%)		1/119 (0.8%)		0/105 (0%)
Pulseless electrical activity	0/115 (0%)		0/45 (0%)		0/47 (0%)		1/119 (0.8%)		0/105 (0%)
Supraventricular tachycardia	0/115 (0%)		0/45 (0%)		0/47 (0%)		0/119 (0%)		1/105 (1%)
Tachycardia	0/115 (0%)		0/45 (0%)		0/47 (0%)		0/119 (0%)		1/105 (1%)
Cardiac failure congestive	5/115 (4.3%)		1/45 (2.2%)		2/47 (4.3%)		3/119 (2.5%)		4/105 (3.8%)
Cardiogenic shock	4/115 (3.5%)		2/45 (4.4%)		2/47 (4.3%)		2/119 (1.7%)		2/105 (1.9%)
Cardiac failure	1/115 (0.9%)		0/45 (0%)		0/47 (0%)		1/119 (0.8%)		1/105 (1%)
Low cardiac output syndrome	2/115 (1.7%)		0/45 (0%)		0/47 (0%)		0/119 (0%)		0/105 (0%)
Cardiac failure chronic	0/115 (0%)		0/45 (0%)		0/47 (0%)		1/119 (0.8%)		0/105 (0%)
Cardiorenal syndrome	0/115 (0%)		0/45 (0%)		0/47 (0%)		1/119 (0.8%)		0/105 (0%)
Pericardial effusion	2/115 (1.7%)		0/45 (0%)		0/47 (0%)		1/119 (0.8%)		2/105 (1.9%)
Cardiac tamponade	1/115 (0.9%)		1/45 (2.2%)		0/47 (0%)		0/119 (0%)		0/105 (0%)
Dressler's syndrome	1/115 (0.9%)		0/45 (0%)		0/47 (0%)		0/119 (0%)		0/105 (0%)
Pericarditis	0/115 (0%)		0/45 (0%)		0/47 (0%)		0/119 (0%)		1/105 (1%)
Acute myocardial infarction	0/115 (0%)		1/45 (2.2%)		1/47 (2.1%)		0/119 (0%)		1/105 (1%)
Myocardial infarction	1/115 (0.9%)		0/45 (0%)		0/47 (0%)		1/119 (0.8%)		1/105 (1%)
Angina pectoris	0/115 (0%)		0/45 (0%)		0/47 (0%)		2/119 (1.7%)		0/105 (0%)
Angina unstable	0/115 (0%)		0/45 (0%)		0/47 (0%)		1/119 (0.8%)		0/105 (0%)
Left ventricular dysfunction	0/115 (0%)		0/45 (0%)		1/47 (2.1%)		0/119 (0%)		1/105 (1%)
Right ventricular dysfunction	0/115 (0%)		0/45 (0%)		1/47 (2.1%)		0/119 (0%)		1/105 (1%)
Cardiomyopathy	1/115 (0.9%)		0/45 (0%)		0/47 (0%)		0/119 (0%)		0/105 (0%)
Myocardial rupture	0/115 (0%)		0/45 (0%)		0/47 (0%)		0/119 (0%)		1/105 (1%)
Systolic dysfunction	0/115 (0%)		0/45 (0%)		0/47 (0%)		0/119 (0%)		1/105 (1%)
Eye disorders
Diplopia	0/115 (0%)		0/45 (0%)		0/47 (0%)		1/119 (0.8%)		0/105 (0%)
Optic neuropathy	0/115 (0%)		0/45 (0%)		0/47 (0%)		0/119 (0%)		1/105 (1%)
Gastrointestinal disorders
Gastrointestinal haemorrhage	1/115 (0.9%)		0/45 (0%)		0/47 (0%)		0/119 (0%)		1/105 (1%)
Gastric haemorrhage	0/115 (0%)		0/45 (0%)		0/47 (0%)		1/119 (0.8%)		0/105 (0%)
Ileus	0/115 (0%)		0/45 (0%)		0/47 (0%)		0/119 (0%)		1/105 (1%)
Small intestinal obstruction	0/115 (0%)		0/45 (0%)		1/47 (2.1%)		0/119 (0%)		0/105 (0%)
Dysphagia	0/115 (0%)		0/45 (0%)		1/47 (2.1%)		0/119 (0%)		0/105 (0%)
Duodenal ulcer	0/115 (0%)		0/45 (0%)		0/47 (0%)		1/119 (0.8%)		0/105 (0%)
Intestinal ischaemia	0/115 (0%)		0/45 (0%)		0/47 (0%)		1/119 (0.8%)		0/105 (0%)
General disorders
Non-cardiac chest pain	1/115 (0.9%)		0/45 (0%)		0/47 (0%)		2/119 (1.7%)		1/105 (1%)
Multi-organ failure	0/115 (0%)		1/45 (2.2%)		0/47 (0%)		0/119 (0%)		1/105 (1%)
Asthenia	0/115 (0%)		0/45 (0%)		0/47 (0%)		1/119 (0.8%)		0/105 (0%)
Pyrexia	0/115 (0%)		0/45 (0%)		0/47 (0%)		1/119 (0.8%)		0/105 (0%)
Device malfunction	0/115 (0%)		0/45 (0%)		0/47 (0%)		1/119 (0.8%)		0/105 (0%)
Hepatobiliary disorders
Ischaemic hepatitis	1/115 (0.9%)		0/45 (0%)		0/47 (0%)		0/119 (0%)		1/105 (1%)
Hepatic congestion	0/115 (0%)		1/45 (2.2%)		0/47 (0%)		0/119 (0%)		0/105 (0%)
Hepatic failure	0/115 (0%)		0/45 (0%)		0/47 (0%)		1/119 (0.8%)		0/105 (0%)
Hypertransaminasaemia	0/115 (0%)		1/45 (2.2%)		0/47 (0%)		0/119 (0%)		0/105 (0%)
Liver injury	0/115 (0%)		0/45 (0%)		1/47 (2.1%)		0/119 (0%)		0/105 (0%)
Infections and infestations
Postoperative wound infection	1/115 (0.9%)		1/45 (2.2%)		1/47 (2.1%)		1/119 (0.8%)		4/105 (3.8%)
Pneumonia	3/115 (2.6%)		0/45 (0%)		0/47 (0%)		1/119 (0.8%)		2/105 (1.9%)
Sepsis	1/115 (0.9%)		1/45 (2.2%)		0/47 (0%)		0/119 (0%)		0/105 (0%)
Urinary tract infection	0/115 (0%)		1/45 (2.2%)		0/47 (0%)		1/119 (0.8%)		0/105 (0%)
Abscess limb	0/115 (0%)		0/45 (0%)		0/47 (0%)		1/119 (0.8%)		0/105 (0%)
Diabetic foot infection	0/115 (0%)		1/45 (2.2%)		0/47 (0%)		0/119 (0%)		0/105 (0%)
Post procedural infection	0/115 (0%)		0/45 (0%)		1/47 (2.1%)		0/119 (0%)		0/105 (0%)
Septic shock	1/115 (0.9%)		0/45 (0%)		0/47 (0%)		0/119 (0%)		0/105 (0%)
Wound abscess	1/115 (0.9%)		0/45 (0%)		0/47 (0%)		0/119 (0%)		0/105 (0%)
Cellulitis	1/115 (0.9%)		0/45 (0%)		1/47 (2.1%)		0/119 (0%)		0/105 (0%)
Clostridium difficile colitis	0/115 (0%)		0/45 (0%)		0/47 (0%)		1/119 (0.8%)		0/105 (0%)
Cystitis escherichia	0/115 (0%)		1/45 (2.2%)		0/47 (0%)		0/119 (0%)		0/105 (0%)
Endocarditis enterococcal	0/115 (0%)		0/45 (0%)		0/47 (0%)		1/119 (0.8%)		0/105 (0%)
Enterobacter infection	0/115 (0%)		0/45 (0%)		0/47 (0%)		1/119 (0.8%)		0/105 (0%)
Escherichia sepsis	0/115 (0%)		0/45 (0%)		0/47 (0%)		1/119 (0.8%)		0/105 (0%)
Pseudomonas infection	1/115 (0.9%)		0/45 (0%)		0/47 (0%)		0/119 (0%)		0/105 (0%)
Staphylococcal infection	0/115 (0%)		0/45 (0%)		0/47 (0%)		1/119 (0.8%)		0/105 (0%)
Injury, poisoning and procedural complications
Post procedural haemorrhage	3/115 (2.6%)		0/45 (0%)		3/47 (6.4%)		2/119 (1.7%)		1/105 (1%)
Cardiac valve replacement complication	0/115 (0%)		0/45 (0%)		0/47 (0%)		1/119 (0.8%)		0/105 (0%)
Coronary vascular graft occlusion	1/115 (0.9%)		0/45 (0%)		0/47 (0%)		0/119 (0%)		0/105 (0%)
Febrile nonhaemolytic transfusion reaction	0/115 (0%)		0/45 (0%)		1/47 (2.1%)		0/119 (0%)		0/105 (0%)
Incision site pain	1/115 (0.9%)		0/45 (0%)		0/47 (0%)		0/119 (0%)		0/105 (0%)
Mechanical ventilation complication	0/115 (0%)		0/45 (0%)		0/47 (0%)		1/119 (0.8%)		0/105 (0%)
Mental status changes postoperative	0/115 (0%)		0/45 (0%)		1/47 (2.1%)		0/119 (0%)		0/105 (0%)
Post procedural haematoma	1/115 (0.9%)		0/45 (0%)		0/47 (0%)		0/119 (0%)		0/105 (0%)
Post procedural myocardial infarction	0/115 (0%)		0/45 (0%)		0/47 (0%)		0/119 (0%)		1/105 (1%)
Post procedural stroke	1/115 (0.9%)		0/45 (0%)		0/47 (0%)		0/119 (0%)		0/105 (0%)
Postoperative thoracic procedure complication	0/115 (0%)		1/45 (2.2%)		0/47 (0%)		0/119 (0%)		0/105 (0%)
Procedural complication	1/115 (0.9%)		0/45 (0%)		0/47 (0%)		0/119 (0%)		0/105 (0%)
Procedural haemorrhage	0/115 (0%)		0/45 (0%)		0/47 (0%)		1/119 (0.8%)		0/105 (0%)
Seroma	0/115 (0%)		0/45 (0%)		0/47 (0%)		0/119 (0%)		1/105 (1%)
Wound dishiscence	0/115 (0%)		0/45 (0%)		1/47 (2.1%)		0/119 (0%)		0/105 (0%)
Fibula fracture	1/115 (0.9%)		0/45 (0%)		0/47 (0%)		0/119 (0%)		0/105 (0%)
Thoracic vertebral fracture	0/115 (0%)		0/45 (0%)		0/47 (0%)		1/119 (0.8%)		0/105 (0%)
Investigations
Hepatic enzyme increased	0/115 (0%)		0/45 (0%)		1/47 (2.1%)		1/119 (0.8%)		1/105 (1%)
Transaminases increased	1/115 (0.9%)		0/45 (0%)		0/47 (0%)		0/119 (0%)		0/105 (0%)
Haemoglobin decreased	1/115 (0.9%)		0/45 (0%)		0/47 (0%)		0/119 (0%)		0/105 (0%)
Oxygen saturation decreased	0/115 (0%)		0/45 (0%)		1/47 (2.1%)		0/119 (0%)		0/105 (0%)
Blood creatinine increased	0/115 (0%)		0/45 (0%)		0/47 (0%)		0/119 (0%)		1/105 (1%)
Metabolism and nutrition disorders
Dehydration	1/115 (0.9%)		0/45 (0%)		0/47 (0%)		1/119 (0.8%)		1/105 (1%)
Hyperkalaemia	1/115 (0.9%)		0/45 (0%)		0/47 (0%)		1/119 (0.8%)		0/105 (0%)
Fluid overload	0/115 (0%)		0/45 (0%)		1/47 (2.1%)		0/119 (0%)		0/105 (0%)
Hyperglycaemia	0/115 (0%)		0/45 (0%)		0/47 (0%)		1/119 (0.8%)		0/105 (0%)
Hypertriglyceridaemia	0/115 (0%)		0/45 (0%)		0/47 (0%)		0/119 (0%)		1/105 (1%)
Gout	0/115 (0%)		0/45 (0%)		0/47 (0%)		1/119 (0.8%)		0/105 (0%)
Musculoskeletal and connective tissue disorders
Chrondocalcinosis pyrophosphate	1/115 (0.9%)		0/45 (0%)		0/47 (0%)		0/119 (0%)		0/105 (0%)
Intervertebral disc degeneration	0/115 (0%)		1/45 (2.2%)		0/47 (0%)		0/119 (0%)		0/105 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Small cell carcinoma	1/115 (0.9%)		0/45 (0%)		0/47 (0%)		0/119 (0%)		0/105 (0%)
Nervous system disorders
Cerebrovascular accident	1/115 (0.9%)		1/45 (2.2%)		0/47 (0%)		2/119 (1.7%)		0/105 (0%)
Cerebral infarction	0/115 (0%)		1/45 (2.2%)		0/47 (0%)		0/119 (0%)		0/105 (0%)
Embolic stroke	0/115 (0%)		0/45 (0%)		0/47 (0%)		1/119 (0.8%)		0/105 (0%)
Subarachnoid haemorrhage	0/115 (0%)		1/45 (2.2%)		0/47 (0%)		0/119 (0%)		0/105 (0%)
Transient ischaemic attack	0/115 (0%)		0/45 (0%)		0/47 (0%)		1/119 (0.8%)		0/105 (0%)
Syncope	1/115 (0.9%)		0/45 (0%)		0/47 (0%)		1/119 (0.8%)		1/105 (1%)
Neurological symptom	1/115 (0.9%)		1/45 (2.2%)		0/47 (0%)		0/119 (0%)		0/105 (0%)
Coma	0/115 (0%)		1/45 (2.2%)		0/47 (0%)		0/119 (0%)		0/105 (0%)
Stupor	0/115 (0%)		0/45 (0%)		0/47 (0%)		1/119 (0.8%)		0/105 (0%)
Hypoxic-ischaemic encephalopathy	1/115 (0.9%)		0/45 (0%)		0/47 (0%)		0/119 (0%)		0/105 (0%)
Metabolic encephalopathy	0/115 (0%)		1/45 (2.2%)		0/47 (0%)		0/119 (0%)		0/105 (0%)
Seizure	0/115 (0%)		0/45 (0%)		0/47 (0%)		1/119 (0.8%)		1/105 (1%)
Hemiparesis	0/115 (0%)		0/45 (0%)		0/47 (0%)		1/119 (0.8%)		0/105 (0%)
Psychiatric disorders
Confusional state	1/115 (0.9%)		0/45 (0%)		0/47 (0%)		0/119 (0%)		1/105 (1%)
Delirium	0/115 (0%)		0/45 (0%)		0/47 (0%)		0/119 (0%)		1/105 (1%)
Catatonia	0/115 (0%)		0/45 (0%)		0/47 (0%)		1/119 (0.8%)		0/105 (0%)
Renal and urinary disorders
Acute kidney injury	1/115 (0.9%)		0/45 (0%)		0/47 (0%)		4/119 (3.4%)		4/105 (3.8%)
Renal failure	1/115 (0.9%)		0/45 (0%)		0/47 (0%)		0/119 (0%)		2/105 (1.9%)
Chronic kidney disease	0/115 (0%)		0/45 (0%)		0/47 (0%)		1/119 (0.8%)		0/105 (0%)
Haematuria	0/115 (0%)		0/45 (0%)		0/47 (0%)		1/119 (0.8%)		0/105 (0%)
Urinary retention	0/115 (0%)		0/45 (0%)		0/47 (0%)		0/119 (0%)		1/105 (1%)
Calculus ureteric	1/115 (0.9%)		0/45 (0%)		0/47 (0%)		0/119 (0%)		0/105 (0%)
Respiratory, thoracic and mediastinal disorders
Pleural effusion	5/115 (4.3%)		1/45 (2.2%)		5/47 (10.6%)		6/119 (5%)		3/105 (2.9%)
Pneumothorax	1/115 (0.9%)		0/45 (0%)		0/47 (0%)		0/119 (0%)		1/105 (1%)
Respiratory failure	2/115 (1.7%)		2/45 (4.4%)		1/47 (2.1%)		1/119 (0.8%)		3/105 (2.9%)
Hypoxia	1/115 (0.9%)		0/45 (0%)		2/47 (4.3%)		1/119 (0.8%)		0/105 (0%)
Dyspnoea	1/115 (0.9%)		0/45 (0%)		0/47 (0%)		2/119 (1.7%)		0/105 (0%)
Acute respiratory failure	0/115 (0%)		0/45 (0%)		1/47 (2.1%)		1/119 (0.8%)		0/105 (0%)
Haemoptysis	1/115 (0.9%)		0/45 (0%)		0/47 (0%)		0/119 (0%)		0/105 (0%)
Respiratory distress	0/115 (0%)		1/45 (2.2%)		0/47 (0%)		0/119 (0%)		0/105 (0%)
Pulmonary oedema	0/115 (0%)		0/45 (0%)		0/47 (0%)		1/119 (0.8%)		1/105 (1%)
Acute respiratory distress syndrome	0/115 (0%)		0/45 (0%)		0/47 (0%)		1/119 (0.8%)		0/105 (0%)
Lung consolidation	0/115 (0%)		1/45 (2.2%)		0/47 (0%)		0/119 (0%)		0/105 (0%)
Pneumonia aspiration	1/115 (0.9%)		0/45 (0%)		0/47 (0%)		0/119 (0%)		0/105 (0%)
Pulmonary embolism	1/115 (0.9%)		0/45 (0%)		0/47 (0%)		0/119 (0%)		2/105 (1.9%)
Pulmonary hypertension	1/115 (0.9%)		0/45 (0%)		0/47 (0%)		0/119 (0%)		0/105 (0%)
Mediastinal haemorrhage	1/115 (0.9%)		0/45 (0%)		0/47 (0%)		1/119 (0.8%)		1/105 (1%)
Chronic obstructive pulmonary disease	0/115 (0%)		0/45 (0%)		0/47 (0%)		2/119 (1.7%)		0/105 (0%)
Epistaxis	0/115 (0%)		0/45 (0%)		0/47 (0%)		0/119 (0%)		1/105 (1%)
Surgical and medical procedures
Implantable defibrillator replacement	0/115 (0%)		0/45 (0%)		1/47 (2.1%)		0/119 (0%)		0/105 (0%)
Wound drainage	0/115 (0%)		0/45 (0%)		0/47 (0%)		1/119 (0.8%)		0/105 (0%)
Vascular disorders
Hypotension	3/115 (2.6%)		1/45 (2.2%)		1/47 (2.1%)		1/119 (0.8%)		3/105 (2.9%)
Orthostatic hypotension	1/115 (0.9%)		0/45 (0%)		0/47 (0%)		0/119 (0%)		1/105 (1%)
Shock	1/115 (0.9%)		0/45 (0%)		0/47 (0%)		0/119 (0%)		1/105 (1%)
Haemodynamic instability	0/115 (0%)		0/45 (0%)		1/47 (2.1%)		0/119 (0%)		0/105 (0%)
Peripheral vascular disorder	0/115 (0%)		0/45 (0%)		0/47 (0%)		1/119 (0.8%)		0/105 (0%)
Air embolism	0/115 (0%)		0/45 (0%)		0/47 (0%)		0/119 (0%)		1/105 (1%)
Haemorrhage	0/115 (0%)		0/45 (0%)		1/47 (2.1%)		0/119 (0%)		0/105 (0%)
Hypertension	0/115 (0%)		0/45 (0%)		1/47 (2.1%)		0/119 (0%)		0/105 (0%)
Other (Not Including Serious) Adverse Events
	Placebo		THR-184 Dose 1		THR-184 Dose 2		THR-184 Dose 3		THR-184 Dose 4
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	112/115 (97.4%)		41/45 (91.1%)		46/47 (97.9%)		116/119 (97.5%)		103/105 (98.1%)
Blood and lymphatic system disorders
Anaemia	34/115 (29.6%)		18/45 (40%)		13/47 (27.7%)		31/119 (26.1%)		25/105 (23.8%)
Thrombocytopenia	13/115 (11.3%)		11/45 (24.4%)		9/47 (19.1%)		17/119 (14.3%)		11/105 (10.5%)
Leukocytosis	6/115 (5.2%)		4/45 (8.9%)		3/47 (6.4%)		8/119 (6.7%)		3/105 (2.9%)
Coagulopathy	5/115 (4.3%)		1/45 (2.2%)		3/47 (6.4%)		4/119 (3.4%)		2/105 (1.9%)
Cardiac disorders
Ventricular tachycardia	1/115 (0.9%)		0/45 (0%)		0/47 (0%)		6/119 (5%)		3/105 (2.9%)
Atrioventricular block complete	2/115 (1.7%)		0/45 (0%)		1/47 (2.1%)		8/119 (6.7%)		2/105 (1.9%)
Arrhythmia	1/115 (0.9%)		4/45 (8.9%)		0/47 (0%)		3/119 (2.5%)		3/105 (2.9%)
Ventricular fibrillation	1/115 (0.9%)		2/45 (4.4%)		3/47 (6.4%)		3/119 (2.5%)		2/105 (1.9%)
Atrioventricular block first degree	0/115 (0%)		3/45 (6.7%)		3/47 (6.4%)		1/119 (0.8%)		2/105 (1.9%)
Low cardiac output syndrome	11/115 (9.6%)		3/45 (6.7%)		3/47 (6.4%)		7/119 (5.9%)		4/105 (3.8%)
Pericardial disorders	6/115 (5.2%)		3/45 (6.7%)		0/47 (0%)		7/119 (5.9%)		3/105 (2.9%)
Gastrointestinal disorders
Nausea	24/115 (20.9%)		14/45 (31.1%)		9/47 (19.1%)		24/119 (20.2%)		25/105 (23.8%)
Vomiting	4/115 (3.5%)		6/45 (13.3%)		4/47 (8.5%)		2/119 (1.7%)		7/105 (6.7%)
Constipation	19/115 (16.5%)		10/45 (22.2%)		4/47 (8.5%)		14/119 (11.8%)		11/105 (10.5%)
Oral soft tissue conditions	0/115 (0%)		0/45 (0%)		3/47 (6.4%)		0/119 (0%)		0/105 (0%)
General disorders
Oedema peripheral	20/115 (17.4%)		7/45 (15.6%)		5/47 (10.6%)		14/119 (11.8%)		19/105 (18.1%)
Asthenia	4/115 (3.5%)		4/45 (8.9%)		1/47 (2.1%)		4/119 (3.4%)		1/105 (1%)
Secretion discharge	2/115 (1.7%)		2/45 (4.4%)		3/47 (6.4%)		0/119 (0%)		0/105 (0%)
Body temperature conditions	6/115 (5.2%)		2/45 (4.4%)		3/47 (6.4%)		3/119 (2.5%)		2/105 (1.9%)
Hepatobiliary disorders
Hepatobiliary disorders	3/115 (2.6%)		4/45 (8.9%)		1/47 (2.1%)		3/119 (2.5%)		4/105 (3.8%)
Infections and infestations
Urinary tract infection	13/115 (11.3%)		7/45 (15.6%)		3/47 (6.4%)		8/119 (6.7%)		11/105 (10.5%)
Postoperative wound infection	4/115 (3.5%)		3/45 (6.7%)		1/47 (2.1%)		4/119 (3.4%)		12/105 (11.4%)
Pneumonia	10/115 (8.7%)		1/45 (2.2%)		2/47 (4.3%)		4/119 (3.4%)		5/105 (4.8%)
Bacterial infectious disorders	8/115 (7%)		5/45 (11.1%)		3/47 (6.4%)		9/119 (7.6%)		5/105 (4.8%)
Injury, poisoning and procedural complications
Procedural pain	22/115 (19.1%)		9/45 (20%)		9/47 (19.1%)		34/119 (28.6%)		27/105 (25.7%)
Anaemia postoperative	5/115 (4.3%)		6/45 (13.3%)		1/47 (2.1%)		8/119 (6.7%)		5/105 (4.8%)
Post procedural haemorrhage	4/115 (3.5%)		1/45 (2.2%)		4/47 (8.5%)		3/119 (2.5%)		3/105 (2.9%)
Wound complication	6/115 (5.2%)		4/45 (8.9%)		3/47 (6.4%)		6/119 (5%)		7/105 (6.7%)
Investigations
Haemoglobin decreased	6/115 (5.2%)		1/45 (2.2%)		2/47 (4.3%)		4/119 (3.4%)		11/105 (10.5%)
Urine output decreased	4/115 (3.5%)		0/45 (0%)		1/47 (2.1%)		6/119 (5%)		2/105 (1.9%)
Blood creatinine increased	2/115 (1.7%)		0/45 (0%)		3/47 (6.4%)		3/119 (2.5%)		4/105 (3.8%)
Cardiac and vascular investigations (excl. enzyme tests)	8/115 (7%)		2/45 (4.4%)		2/47 (4.3%)		4/119 (3.4%)		8/105 (7.6%)
Hepatobiliary investigations	3/115 (2.6%)		5/45 (11.1%)		2/47 (4.3%)		7/119 (5.9%)		7/105 (6.7%)
Blood magnesium decreased	8/115 (7%)		2/45 (4.4%)		1/47 (2.1%)		3/119 (2.5%)		0/105 (0%)
Blood calcium decreased	2/115 (1.7%)		3/45 (6.7%)		0/47 (0%)		0/119 (0%)		0/105 (0%)
Blood lactate dehydrogenase increased	2/115 (1.7%)		3/45 (6.7%)		2/47 (4.3%)		3/119 (2.5%)		2/105 (1.9%)
Protein and chemistry analyses NEC	5/115 (4.3%)		3/45 (6.7%)		1/47 (2.1%)		5/119 (4.2%)		0/105 (0%)
Metabolic, nutritional and blood gas investigations	2/115 (1.7%)		3/45 (6.7%)		3/47 (6.4%)		2/119 (1.7%)		1/105 (1%)
Metabolism and nutrition disorders
Hypokalemia	24/115 (20.9%)		7/45 (15.6%)		7/47 (14.9%)		35/119 (29.4%)		14/105 (13.3%)
Hypocalcaemia	16/115 (13.9%)		9/45 (20%)		10/47 (21.3%)		27/119 (22.7%)		12/105 (11.4%)
Hypomagnesaemia	7/115 (6.1%)		5/45 (11.1%)		4/47 (8.5%)		6/119 (5%)		4/105 (3.8%)
Hypoalbuminaemia	12/115 (10.4%)		6/45 (13.3%)		5/47 (10.6%)		17/119 (14.3%)		10/105 (9.5%)
Acid-base disorders	3/115 (2.6%)		2/45 (4.4%)		3/47 (6.4%)		4/119 (3.4%)		1/105 (1%)
Fluid overload	16/115 (13.9%)		12/45 (26.7%)		13/47 (27.7%)		30/119 (25.2%)		18/105 (17.1%)
Hyperkalemia	8/115 (7%)		5/45 (11.1%)		5/47 (10.6%)		7/119 (5.9%)		6/105 (5.7%)
Hyperglycaemia	11/115 (9.6%)		11/45 (24.4%)		8/47 (17%)		15/119 (12.6%)		10/105 (9.5%)
Musculoskeletal and connective tissue disorders
Pain in extremity	3/115 (2.6%)		5/45 (11.1%)		1/47 (2.1%)		2/119 (1.7%)		2/105 (1.9%)
Nervous system disorders
Hypoaesthesia	3/115 (2.6%)		1/45 (2.2%)		4/47 (8.5%)		2/119 (1.7%)		1/105 (1%)
Central nervous system vascular disorders	1/115 (0.9%)		5/45 (11.1%)		0/47 (0%)		5/119 (4.2%)		1/105 (1%)
Psychiatric disorders
Delirium	9/115 (7.8%)		1/45 (2.2%)		1/47 (2.1%)		4/119 (3.4%)		7/105 (6.7%)
Confusional state	5/115 (4.3%)		3/45 (6.7%)		0/47 (0%)		3/119 (2.5%)		4/105 (3.8%)
Insomnia	4/115 (3.5%)		5/45 (11.1%)		1/47 (2.1%)		3/119 (2.5%)		12/105 (11.4%)
Agitation	1/115 (0.9%)		3/45 (6.7%)		2/47 (4.3%)		1/119 (0.8%)		3/105 (2.9%)
Renal and urinary disorders
Acute kidney injury	18/115 (15.7%)		13/45 (28.9%)		6/47 (12.8%)		23/119 (19.3%)		14/105 (13.3%)
Renal failure	4/115 (3.5%)		2/45 (4.4%)		4/47 (8.5%)		2/119 (1.7%)		5/105 (4.8%)
Urinary retention	7/115 (6.1%)		1/45 (2.2%)		0/47 (0%)		4/119 (3.4%)		2/105 (1.9%)
Reproductive system and breast disorders
Penile and scrotal disorders (excl. infections and inflammations)	1/115 (0.9%)		3/45 (6.7%)		0/47 (0%)		0/119 (0%)		2/105 (1.9%)
Respiratory, thoracic and mediastinal disorders
Respiratory failure	6/115 (5.2%)		2/45 (4.4%)		2/47 (4.3%)		4/119 (3.4%)		7/105 (6.7%)
Dyspnoea	5/115 (4.3%)		2/45 (4.4%)		0/47 (0%)		8/119 (6.7%)		5/105 (4.8%)
Cough	3/115 (2.6%)		1/45 (2.2%)		1/47 (2.1%)		6/119 (5%)		4/105 (3.8%)
Hypoxia	3/115 (2.6%)		0/45 (0%)		5/47 (10.6%)		3/119 (2.5%)		3/105 (2.9%)
Atelectasis	9/115 (7.8%)		6/45 (13.3%)		7/47 (14.9%)		10/119 (8.4%)		7/105 (6.7%)
Pulmonary oedema	3/115 (2.6%)		3/45 (6.7%)		1/47 (2.1%)		5/119 (4.2%)		4/105 (3.8%)
Pneumothorax	5/115 (4.3%)		1/45 (2.2%)		4/47 (8.5%)		7/119 (5.9%)		4/105 (3.8%)
Skin and subcutaneous tissue disorders
Decubitus ulcer	2/115 (1.7%)		0/45 (0%)		3/47 (6.4%)		1/119 (0.8%)		0/105 (0%)
Surgical and medical procedures
Surgical and medical procedures	4/115 (3.5%)		1/45 (2.2%)		4/47 (8.5%)		2/119 (1.7%)		5/105 (4.8%)
Vascular disorders
Hypotension	25/115 (21.7%)		8/45 (17.8%)		14/47 (29.8%)		21/119 (17.6%)		19/105 (18.1%)
Hypertension	5/115 (4.3%)		4/45 (8.9%)		6/47 (12.8%)		9/119 (7.6%)		5/105 (4.8%)
Vascular haemorrhagic disorders	5/115 (4.3%)		2/45 (4.4%)		3/47 (6.4%)		3/119 (2.5%)		3/105 (2.9%)

Limitations/Caveats

A limitation of this analysis was that if a subject left the hospital with AKI, the duration of AKI was automatically assigned as 7 days.

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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.