Catecholamine-resistant Hypotension (CRH), Distributive Shock, High Output Shock, Sepsis
Conditions
Brief summary
This is a Phase 3, double-blind, randomized study of LJPC-501 (angiotensin II) in adult patients diagnosed with catecholamine-resistant hypotension (CRH) conducted in multiple centers globally.
Detailed description
Catecholamine-resistant hypotension (CRH) is an often fatal condition resulting from an underlying cause such as septic shock, inflammation due to trauma, or severe drug reactions. When these conditions occur, most patients will respond to either volume expansion or vasopressor treatment. However, some patients will require excessive doses of vasopressors and will be deemed to be resistant. Angiotensin II is a peptide hormone naturally produced by the body that regulates blood pressure via vasoconstriction and sodium reabsorption. LJPC-501 (angiotensin II) is being developed for the treatment of patients with catecholamine-resistant hypotension (CRH). This is a multi-site, randomized, double-blind, placebo-controlled study. Adult patients with CRH, who are hospitalized in an ICU setting, may be eligible to participate. Approximately 315 patients will be enrolled.
Interventions
DRUGLJPC-501
Treatment arm
DRUGPlacebo
PBO
Sponsors
La Jolla Pharmaceutical Company
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Adult patients ≥ 18 years of age with CRH, defined as those who require a total sum catecholamine dose of \> 0.2 mcg/kg/min for a minimum of 6 hours and a maximum of 48 hours, to maintain a MAP between 55-70 mmHg. 2. Patients are required to have central venous access and an arterial line present, and these are expected to remain present for at least the initial 48 hours of study. 3. Patients are required to have an indwelling urinary catheter present, and it is expected to remain present for at least the initial 48 hours of study. 4. Patients must have received at least 25 mL/kg of crystalloid or colloid equivalent over the previous 24-hour period, and be adequately volume resuscitated in the opinion of the treating investigator. 5. Patients must have clinical features of high-output shock by meeting one of the following criteria. 1. Central venous oxygen saturation (ScvO2) \> 70% (either by oximetry catheter or by central venous blood gas) and central venous pressure (CVP) \> 8 mmHg. OR 2. Cardiac Index (CI) \> 2.3 L/min/1.73 m2. Patient must meet 5a or 5b to be eligible. 6. Patient or legal surrogate is willing and able to provide written informed consent and comply with all protocol requirements.
Exclusion criteria
1. Patients who are \< 18 years of age. 2. Any patient with burns covering \> 20% of total body surface area (TBSA). 3. Patients with a Cardiovascular (CV) SOFA score ≤ 3. 4. Patients diagnosed with acute occlusive coronary syndrome requiring intervention. 5. Patients on veno-arterial (VA) ECMO. 6. Patients who have been on ECMO for less than 12 hours. 7. Patients in liver failure with a Model for End-Stage Liver Disease (MELD) score of ≥ 30. 8. Patients with a history of asthma or who are currently experiencing bronchospasm requiring the use of inhaled bronchodilators, if not mechanically ventilated. 9. Patients with acute mesenteric ischemia or a history of mesenteric ischemic. 10. Patients with a history of, presence of, or highly-suspected of having an aortic dissection or abdominal aortic aneurysm. 11. Patients requiring more than 500 mg daily of hydrocortisone or equivalent glucocorticoid medication as a standing dose. 12. Patients with Raynaud's phenomenon, systemic sclerosis or vasospastic disease. 13. Patients with an expected lifespan of \< 12 hours. 14. Patients with active bleeding AND an anticipated need (within 48 hours of initiation of the study) for transfusion of \> 4 units of packed red blood cells. 15. Patients with active bleeding AND hemoglobin \< 7g/dL or any other condition that would contraindicate serial blood sampling. 16. Patients with an absolute neutrophil count (ANC) of \< 1000 cells/mm3. 17. Patients with a known allergy to mannitol. 18. Patients who are current participating in another interventional clinical trial. 19. Patients who are known to be pregnant at the time of Screening.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 | Hour 3 | 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. |
Countries
Australia, Belgium, Canada, Finland, France, Germany, New Zealand, Switzerland, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| LJPC-501 (Angiotensin II) Treatment arm
LJPC-501: Treatment arm | 163 |
| Placebo (0.9% Sodium Chloride Solution) Placebo arm
Placebo: PBO | 158 |
| Total | 321 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 1 |
| Overall Study | Death | 40 | 53 |
| Overall Study | Discontinued prior to randomizat | 1 | 0 |
| Overall Study | Physician Decision | 1 | 0 |
| Overall Study | Subject Recovered | 0 | 2 |
| Overall Study | Withdrawal by Subject | 0 | 2 |
Baseline characteristics
| Characteristic | Placebo (0.9% Sodium Chloride Solution) | Total | LJPC-501 (Angiotensin II) |
|---|---|---|---|
| Age, Continuous | 65 years | 64 years | 63 years |
| APACHE II Score | 29 points | 28 points | 27 points |
| Body Mass Index (BMI) BMI < 30 | 84 Participants | 176 Participants | 92 Participants |
| Body Mass Index (BMI) BMI ≥ 30 | 71 Participants | 140 Participants | 69 Participants |
| Cause of Shock Other | 4 Participants | 10 Participants | 6 Participants |
| Cause of Shock Other, potentially sepsis | 11 Participants | 31 Participants | 20 Participants |
| Cause of Shock Pancreatitis | 2 Participants | 2 Participants | 0 Participants |
| Cause of Shock Sepsis | 132 Participants | 259 Participants | 127 Participants |
| Cause of Shock Vasoplegia | 9 Participants | 19 Participants | 10 Participants |
| Mean Arterial Pressure (MAP) | 66.3 mmHg | 66.3 mmHg | 66.3 mmHg |
| Region of Enrollment Australia | 19 Participants | 43 Participants | 24 Participants |
| Region of Enrollment Belgium | 1 Participants | 1 Participants | 0 Participants |
| Region of Enrollment Canada | 10 Participants | 36 Participants | 26 Participants |
| Region of Enrollment Finland | 2 Participants | 7 Participants | 5 Participants |
| Region of Enrollment France | 1 Participants | 6 Participants | 5 Participants |
| Region of Enrollment Germany | 1 Participants | 1 Participants | 0 Participants |
| Region of Enrollment New Zealand | 5 Participants | 9 Participants | 4 Participants |
| Region of Enrollment United Kingdom | 9 Participants | 18 Participants | 9 Participants |
| Region of Enrollment United States | 110 Participants | 200 Participants | 90 Participants |
| Sex: Female, Male Female | 55 Participants | 126 Participants | 71 Participants |
| Sex: Female, Male Male | 103 Participants | 195 Participants | 92 Participants |
| Vasopressor Dose | 0.34 mcg/kg/min | 0.34 mcg/kg/min | 0.33 mcg/kg/min |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 75 / 163 | 85 / 158 |
| other Total, other adverse events | 110 / 163 | 108 / 158 |
| serious Total, serious adverse events | 99 / 163 | 106 / 158 |
Outcome results
Primary
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
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
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| LJPC-501 (Angiotensin II) | 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 | 114 Participants |
| Placebo (0.9% Sodium Chloride Solution) | 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 | 37 Participants |
p-value: <0.00195% CI: [4.76, 13.3]Regression, Logistic