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A Phase 3 Study of LJPC-501 in Patients With Catecholamine-Resistant Hypotension (ATHOS-3)

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ClinicalTrials.gov Identifier: NCT02338843
Recruitment Status : Completed
First Posted : January 14, 2015
Results First Posted : January 17, 2018
Last Update Posted : March 27, 2018
Sponsor:
Information provided by (Responsible Party):
La Jolla Pharmaceutical Company

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Conditions Catecholamine-resistant Hypotension (CRH)
Distributive Shock
High Output Shock
Sepsis
Interventions Drug: LJPC-501
Drug: Placebo
Enrollment 344
Recruitment Details  
Pre-assignment Details  
Arm/Group Title LJPC-501 (Angiotensin II) Placebo (0.9% Sodium Chloride Solution)
Hide Arm/Group Description Treatment arm Injection for Intravenous Infusion Placebo arm Volume matched saline administered via intravenous infusion
Period Title: Overall Study
Started [1] 163 158
Completed 119 100
Not Completed 44 58
Reason Not Completed
Adverse Event             2             1
Death             40             53
Physician Decision             1             0
Withdrawal by Subject             0             2
Subject Recovered             0             2
Discontinued prior to randomizat             1             0
[1]
Discrepancy between enrollment and started numbers due to 23 pts who enrolled but were not treated.
Arm/Group Title LJPC-501 (Angiotensin II) Placebo (0.9% Sodium Chloride Solution) Total
Hide Arm/Group Description

Treatment arm

LJPC-501: Treatment arm

Placebo arm

Placebo: PBO

Total of all reporting groups
Overall Number of Baseline Participants 163 158 321
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Median (Inter-Quartile Range)
Unit of measure:  Years
Number Analyzed 163 participants 158 participants 321 participants
63
(52 to 75)
65
(53 to 75)
64
(52 to 75)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 163 participants 158 participants 321 participants
Female
71
  43.6%
55
  34.8%
126
  39.3%
Male
92
  56.4%
103
  65.2%
195
  60.7%
Region of Enrollment  
Measure Type: Count of Participants
Unit of measure:  Participants
New Zealand Number Analyzed 163 participants 158 participants 321 participants
4
   2.5%
5
   3.2%
9
   2.8%
Canada Number Analyzed 163 participants 158 participants 321 participants
26
  16.0%
10
   6.3%
36
  11.2%
Belgium Number Analyzed 163 participants 158 participants 321 participants
0
   0.0%
1
   0.6%
1
   0.3%
United States Number Analyzed 163 participants 158 participants 321 participants
90
  55.2%
110
  69.6%
200
  62.3%
Finland Number Analyzed 163 participants 158 participants 321 participants
5
   3.1%
2
   1.3%
7
   2.2%
United Kingdom Number Analyzed 163 participants 158 participants 321 participants
9
   5.5%
9
   5.7%
18
   5.6%
Australia Number Analyzed 163 participants 158 participants 321 participants
24
  14.7%
19
  12.0%
43
  13.4%
France Number Analyzed 163 participants 158 participants 321 participants
5
   3.1%
1
   0.6%
6
   1.9%
Germany Number Analyzed 163 participants 158 participants 321 participants
0
   0.0%
1
   0.6%
1
   0.3%
Body Mass Index (BMI)   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
BMI ≥ 30 Number Analyzed 161 participants 155 participants 316 participants
69
  42.9%
71
  45.8%
140
  44.3%
BMI < 30 Number Analyzed 161 participants 155 participants 316 participants
92
  57.1%
84
  54.2%
176
  55.7%
[1]
Measure Analysis Population Description: BMI could not be calculated for two patients in the treatment group and three patients in the placebo group.
Mean Arterial Pressure (MAP)  
Median (Inter-Quartile Range)
Unit of measure:  mmHg
Number Analyzed 163 participants 158 participants 321 participants
66.3
(63.7 to 69.0)
66.3
(63.0 to 68.3)
66.3
(63.7 to 68.7)
APACHE II Score   [1] 
Median (Inter-Quartile Range)
Unit of measure:  Points
Number Analyzed 163 participants 158 participants 321 participants
27
(22 to 33)
29
(22 to 34)
28
(22 to 33)
[1]
Measure Description: The Acute Physiology and Chronic Health Evaluation (APACHE II) is a severity score and mortality estimation tool developed from a large sample of ICU patients in the United States. The APACHE II score is made of 12 physiological variables and 2 disease-related variables. The APACHE II score ranges from 0 to 71 points, with higher scores correlating to worse outcomes.
Vasopressor Dose  
Median (Inter-Quartile Range)
Unit of measure:  Mcg/kg/min
Number Analyzed 163 participants 158 participants 321 participants
0.33
(0.23 to 0.56)
0.34
(0.23 to 0.56)
0.34
(0.23 to 0.56)
Cause of Shock  
Measure Type: Count of Participants
Unit of measure:  Participants
Sepsis Number Analyzed 163 participants 158 participants 321 participants
127
  77.9%
132
  83.5%
259
  80.7%
Other, potentially sepsis Number Analyzed 163 participants 158 participants 321 participants
20
  12.3%
11
   7.0%
31
   9.7%
Pancreatitis Number Analyzed 163 participants 158 participants 321 participants
0
   0.0%
2
   1.3%
2
   0.6%
Vasoplegia Number Analyzed 163 participants 158 participants 321 participants
10
   6.1%
9
   5.7%
19
   5.9%
Other Number Analyzed 163 participants 158 participants 321 participants
6
   3.7%
4
   2.5%
10
   3.1%
1.Primary Outcome
Title An Increased MAP, Defined as Achievement of a Day 1 MAP at 3 Hours Following the Initiation of Study Drug, of ≥ 75 mmHg OR a 10 mmHg Increase in Baseline MAP
Hide Description Response with respect to mean arterial pressure (MAP) at hour 3 after the start of infusion was defined as an increase from baseline of at least 10 mm Hg or an increase to at least 75 mm Hg, without an increase in the dose of background vasopressors.
Time Frame Hour 3
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title LJPC-501 (Angiotensin II) Placebo (0.9% Sodium Chloride Solution)
Hide Arm/Group Description:

Treatment arm

LJPC-501: Treatment arm

Placebo arm

Placebo: PBO

Overall Number of Participants Analyzed 163 158
Measure Type: Count of Participants
Unit of Measure: Participants
114
  69.9%
37
  23.4%
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection LJPC-501 (Angiotensin II), Placebo (0.9% Sodium Chloride Solution)
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Regression, Logistic
Comments Stratified logistic regression model. Adjusted by baseline MAP and APACHE II, vasopressin use and average NED 6 hours prior to randomization.
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 7.95
Confidence Interval (2-Sided) 95%
4.76 to 13.3
Estimation Comments [Not Specified]
Time Frame Adverse events were collected from study drug initiation through Day 28.
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title LJPC-501 (Angiotensin II) Placebo (0.9% Sodium Chloride Solution)
Hide Arm/Group Description

Treatment arm

LJPC-501: Treatment arm

Placebo arm

Placebo: PBO

All-Cause Mortality
LJPC-501 (Angiotensin II) Placebo (0.9% Sodium Chloride Solution)
Affected / at Risk (%) Affected / at Risk (%)
Total   75/163 (46.01%)      85/158 (53.80%)    
Hide Serious Adverse Events
LJPC-501 (Angiotensin II) Placebo (0.9% Sodium Chloride Solution)
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   99/163 (60.74%)      106/158 (67.09%)    
Blood and lymphatic system disorders     
Anaemia  1/163 (0.61%)  1 1/158 (0.63%)  1
Coagulopathy  0/163 (0.00%)  0 1/158 (0.63%)  1
Thrombocytopenia  1/163 (0.61%)  1 1/158 (0.63%)  1
Cardiac disorders     
Acute myocardial infarction  2/163 (1.23%)  2 2/158 (1.27%)  2
Aortic valve incompetence  0/163 (0.00%)  0 1/158 (0.63%)  1
Arrhythmia  1/163 (0.61%)  1 0/158 (0.00%)  0
Atrial fibrillation  5/163 (3.07%)  5 5/158 (3.16%)  5
Atrioventricular block  1/163 (0.61%)  1 0/158 (0.00%)  0
Bradycardia  1/163 (0.61%)  1 2/158 (1.27%)  2
Cardiac arrest  7/163 (4.29%)  10 9/158 (5.70%)  10
Cardiac failure  0/163 (0.00%)  0 1/158 (0.63%)  1
Cardiac failure congestive  0/163 (0.00%)  0 1/158 (0.63%)  1
Cardio-respiratory arrest  3/163 (1.84%)  3 5/158 (3.16%)  5
Cardiogenic shock  2/163 (1.23%)  2 4/158 (2.53%)  4
Cardiopulmonary failure  1/163 (0.61%)  1 0/158 (0.00%)  0
Myocardial infarction  0/163 (0.00%)  0 1/158 (0.63%)  1
Pulseless electrical activity  0/163 (0.00%)  0 1/158 (0.63%)  1
Right ventricular dysfunction  1/163 (0.61%)  1 0/158 (0.00%)  0
Supraventricular tachycardia  1/163 (0.61%)  1 4/158 (2.53%)  4
Tachycardia  2/163 (1.23%)  2 0/158 (0.00%)  0
Ventricular fibrillation  2/163 (1.23%)  2 0/158 (0.00%)  0
Ventricular tachycardia  5/163 (3.07%)  5 3/158 (1.90%)  3
Gastrointestinal disorders     
Dysphagia  0/163 (0.00%)  0 1/158 (0.63%)  1
Gastrointestinal haemorrhage  0/163 (0.00%)  0 1/158 (0.63%)  1
Gastrointestinal mucosal exfoliation  1/163 (0.61%)  1 0/158 (0.00%)  0
Haematemesis  1/163 (0.61%)  1 0/158 (0.00%)  0
Intestinal ischaemia  1/163 (0.61%)  1 3/158 (1.90%)  3
Intestinal perforation  0/163 (0.00%)  0 1/158 (0.63%)  1
Pancreatitis  0/163 (0.00%)  0 1/158 (0.63%)  1
Pancreatitis necrotising  0/163 (0.00%)  0 1/158 (0.63%)  1
General disorders     
Device dislocation  1/163 (0.61%)  1 0/158 (0.00%)  0
Hypothermia  0/163 (0.00%)  0 1/158 (0.63%)  1
Medical device complication  0/163 (0.00%)  0 1/158 (0.63%)  1
Multi-organ failure  25/163 (15.34%)  25 23/158 (14.56%)  23
Pyrexia  1/163 (0.61%)  1 0/158 (0.00%)  0
Hepatobiliary disorders     
Acute hepatic failure  0/163 (0.00%)  0 1/158 (0.63%)  1
Cholecystitis  0/163 (0.00%)  0 1/158 (0.63%)  1
Hepatic failure  1/163 (0.61%)  1 1/158 (0.63%)  1
Hepatic function abnormal  1/163 (0.61%)  1 0/158 (0.00%)  0
Hepatic vascular thrombosis  1/163 (0.61%)  1 0/158 (0.00%)  0
Hyperbilirubinaemia  0/163 (0.00%)  0 1/158 (0.63%)  1
Ischaemic hepatitis  0/163 (0.00%)  0 1/158 (0.63%)  1
Liver disorder  1/163 (0.61%)  1 0/158 (0.00%)  0
Infections and infestations     
Abdominal abscess  1/163 (0.61%)  1 0/158 (0.00%)  0
Abdominal infection  1/163 (0.61%)  1 0/158 (0.00%)  0
Bacteraemia  0/163 (0.00%)  0 1/158 (0.63%)  1
Cardiac valve vegetation  0/163 (0.00%)  0 1/158 (0.63%)  1
Clostridium difficile colitis  0/163 (0.00%)  0 1/158 (0.63%)  1
Clostridium difficile sepsis  0/163 (0.00%)  0 1/158 (0.63%)  1
Enterobacter bacteraemia  1/163 (0.61%)  1 0/158 (0.00%)  0
Liver abscess  1/163 (0.61%)  1 0/158 (0.00%)  0
Necrotising fasciitis  1/163 (0.61%)  1 0/158 (0.00%)  0
Peritonitis  0/163 (0.00%)  0 1/158 (0.63%)  1
Pneumonia  2/163 (1.23%)  2 3/158 (1.90%)  3
Postoperative wound infection  0/163 (0.00%)  0 1/158 (0.63%)  1
Pulmonary sepsis  1/163 (0.61%)  1 0/158 (0.00%)  0
Sepsis  3/163 (1.84%)  3 2/158 (1.27%)  2
Septic shock  18/163 (11.04%)  18 10/158 (6.33%)  10
Tracheobronchitis  1/163 (0.61%)  1 0/158 (0.00%)  0
Injury, poisoning and procedural complications     
Gastrointestinal anastomotic leak  1/163 (0.61%)  1 0/158 (0.00%)  0
Gastrostomy tube site complication  1/163 (0.61%)  1 0/158 (0.00%)  0
Post procedural haemorrhage  0/163 (0.00%)  0 1/158 (0.63%)  1
Pulmonary contusion  0/163 (0.00%)  0 1/158 (0.63%)  1
Investigations     
Alanine aminotransferase increased  1/163 (0.61%)  1 0/158 (0.00%)  0
Blood lactic acid increased  1/163 (0.61%)  1 0/158 (0.00%)  0
Electrocardiogram QT prolonged  0/163 (0.00%)  0 1/158 (0.63%)  1
Electrocardiogram ST segment elevation  1/163 (0.61%)  1 0/158 (0.00%)  0
Liver function test abnormal  1/163 (0.61%)  1 0/158 (0.00%)  0
Staphylococcus test positive  1/163 (0.61%)  2 0/158 (0.00%)  0
Metabolism and nutrition disorders     
Failure to thrive  2/163 (1.23%)  2 1/158 (0.63%)  1
Hyperkalaemia  0/163 (0.00%)  0 1/158 (0.63%)  1
Metabolic acidosis  1/163 (0.61%)  1 0/158 (0.00%)  0
Musculoskeletal and connective tissue disorders     
Muscle necrosis  1/163 (0.61%)  1 0/158 (0.00%)  0
Rhabdomyolysis  1/163 (0.61%)  1 0/158 (0.00%)  0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Hepatic cancer  1/163 (0.61%)  1 0/158 (0.00%)  0
Lung adenocarcinoma stage IV  0/163 (0.00%)  0 1/158 (0.63%)  1
Lymphoma  0/163 (0.00%)  0 1/158 (0.63%)  1
Pancreatic carcinoma metastatic  1/163 (0.61%)  1 0/158 (0.00%)  0
Plasma cell leukaemia  0/163 (0.00%)  0 1/158 (0.63%)  1
Prostate cancer  0/163 (0.00%)  0 1/158 (0.63%)  1
Small cell carcinoma  0/163 (0.00%)  0 1/158 (0.63%)  1
Nervous system disorders     
Brain hypoxia  1/163 (0.61%)  1 0/158 (0.00%)  0
Brain injury  1/163 (0.61%)  1 2/158 (1.27%)  2
Brain oedema  0/163 (0.00%)  0 2/158 (1.27%)  2
Cerebral haemorrhage  0/163 (0.00%)  0 1/158 (0.63%)  1
Cerebral infarction  1/163 (0.61%)  1 0/158 (0.00%)  0
Cerebral ischaemia  0/163 (0.00%)  0 1/158 (0.63%)  1
Depressed level of conciousness  1/163 (0.61%)  1 0/158 (0.00%)  0
Encephalopathy  0/163 (0.00%)  0 1/158 (0.63%)  1
Haemorrhage intracranial  0/163 (0.00%)  0 1/158 (0.63%)  1
Hemiparesis  1/163 (0.61%)  1 0/158 (0.00%)  0
Hypoxic-ischaemic encephalopathy  1/163 (0.61%)  1 0/158 (0.00%)  0
Ischaemic stroke  1/163 (0.61%)  1 0/158 (0.00%)  0
Metabolic encephalopathy  0/163 (0.00%)  0 1/158 (0.63%)  1
Subarachnoid haemorrhage  0/163 (0.00%)  0 1/158 (0.63%)  1
Toxic leukoencephalopathy  1/163 (0.61%)  1 0/158 (0.00%)  0
Psychiatric disorders     
Mental status change  1/163 (0.61%)  1 0/158 (0.00%)  0
Renal and urinary disorders     
Chronic kidney disease  0/163 (0.00%)  0 1/158 (0.63%)  1
Renal failure  1/163 (0.61%)  1 1/158 (0.63%)  1
Renal impairment  1/163 (0.61%)  1 0/158 (0.00%)  0
Renal tubular necrosis  0/163 (0.00%)  0 1/158 (0.63%)  1
Respiratory, thoracic and mediastinal disorders     
Acute pulmonary oedema  1/163 (0.61%)  1 0/158 (0.00%)  0
Acute respiratory distress syndrome  0/163 (0.00%)  0 2/158 (1.27%)  2
Acute respiratory failure  3/163 (1.84%)  3 5/158 (3.16%)  5
Aspiration  1/163 (0.61%)  1 0/158 (0.00%)  0
Bronchomalacia  1/163 (0.61%)  1 0/158 (0.00%)  0
Bronchopleural fistula  0/163 (0.00%)  0 1/158 (0.63%)  1
Hypoxia  1/163 (0.61%)  1 0/158 (0.00%)  0
Interstitial lung disease  0/163 (0.00%)  0 1/158 (0.63%)  1
Pharyngeal haemorrhage  1/163 (0.61%)  1 0/158 (0.00%)  0
Pleural effusion  1/163 (0.61%)  1 1/158 (0.63%)  1
Pneumonia aspiration  1/163 (0.61%)  1 1/158 (0.63%)  1
Pneumothorax  1/163 (0.61%)  1 3/158 (1.90%)  3
Pulmonary oedema  1/163 (0.61%)  1 0/158 (0.00%)  0
Respiratory arrest  1/163 (0.61%)  1 0/158 (0.00%)  0
Respiratory distress  0/163 (0.00%)  0 2/158 (1.27%)  2
Respiratory failure  8/163 (4.91%)  8 11/158 (6.96%)  11
Skin and subcutaneous tissue disorders     
Skin discolouration  1/163 (0.61%)  1 0/158 (0.00%)  0
Skin necrosis  1/163 (0.61%)  1 0/158 (0.00%)  0
Vascular disorders     
Aortic dissection  0/163 (0.00%)  0 1/158 (0.63%)  1
Circulatory collapse  0/163 (0.00%)  0 1/158 (0.63%)  1
Deep vein thrombosis  3/163 (1.84%)  3 0/158 (0.00%)  0
Distributive shock  1/163 (0.61%)  1 4/158 (2.53%)  4
Hypotension  5/163 (3.07%)  5 3/158 (1.90%)  3
Peripheral ischaemia  5/163 (3.07%)  5 3/158 (1.90%)  3
Shock  3/163 (1.84%)  3 3/158 (1.90%)  3
Shock haemorrhagic  1/163 (0.61%)  1 0/158 (0.00%)  0
Vasospasm  1/163 (0.61%)  1 0/158 (0.00%)  0
1
Term from vocabulary, MedDRA (18.0)
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
LJPC-501 (Angiotensin II) Placebo (0.9% Sodium Chloride Solution)
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   110/163 (67.48%)      108/158 (68.35%)    
Blood and lymphatic system disorders     
Anaemia  11/163 (6.75%)  11 9/158 (5.70%)  9
Thrombocytopenia  15/163 (9.20%)  15 10/158 (6.33%)  10
Cardiac disorders     
Atrial fibrillation  17/163 (10.43%)  18 16/158 (10.13%)  18
Bradycardia  6/163 (3.68%)  6 9/158 (5.70%)  9
Metabolism and nutrition disorders     
Hypokalaemia  13/163 (7.98%)  14 10/158 (6.33%)  10
Hypophosphataemia  6/163 (3.68%)  6 11/158 (6.96%)  11
Psychiatric disorders     
Agitation  6/163 (3.68%)  6 8/158 (5.06%)  8
Delirium  9/163 (5.52%)  9 1/158 (0.63%)  1
Renal and urinary disorders     
Acute kidney injury  8/163 (4.91%)  8 10/158 (6.33%)  11
Respiratory, thoracic and mediastinal disorders     
Pleural effusion  8/163 (4.91%)  8 8/158 (5.06%)  8
Vascular disorders     
Hypertension  9/163 (5.52%)  11 9/158 (5.70%)  9
Hypotension  13/163 (7.98%)  16 7/158 (4.43%)  7
1
Term from vocabulary, MedDRA (18.0)
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS 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.
All investigators were restricted from publishing individual papers until the study-wide publication was published. After this time, investigator restrictions varied by institution.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: George Tidmarsh, MD, PhD
Organization: La Jolla Pharmaceutical Company
Phone: 858-207-4264
EMail: gtidmarsh@ljpc.com
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Layout table for additonal information
Responsible Party: La Jolla Pharmaceutical Company
ClinicalTrials.gov Identifier: NCT02338843    
Other Study ID Numbers: LJ501-CRH01
First Submitted: January 1, 2015
First Posted: January 14, 2015
Results First Submitted: November 28, 2017
Results First Posted: January 17, 2018
Last Update Posted: March 27, 2018