Clinical trial NCT02338843: A Phase 3 Study of LJPC-501 in Patients With Catecholamine-Resistant Hypotension
Official title: A Phase 3, Placebo-Controlled, Randomized, Double-Blind, Multi-Center Study of LJPC-501 in Patients With Catecholamine-Resistant Hypotension (CRH)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Catecholamine-resistant Hypotension (CRH)
Distributive Shock
High Output Shock
Sepsis
Lead sponsor: La Jolla Pharmaceutical Company
Sponsor class: INDUSTRY
First posted: 2015-01-14
Enrollment: 344
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: 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
timeFrame: Hour 3
Secondary outcomes:
Other outcomes:
Locations:
city: Mobile
country: United States
facility: Pulmonary Associates of Mobile, PC
state: Alabama
city: Phoenix
country: United States
facility: Mayo Clinic Arizona
state: Arizona
city: Loma Linda
country: United States
facility: Loma Linda University Medical Center
state: California
city: Los Angeles
country: United States
facility: Keck Hospital of USC
state: California
city: Los Angeles
country: United States
facility: Los Angeles County + University of Southern California Medical Center
state: California
city: Los Angeles
country: United States
facility: University of California, Los Angeles
state: California
city: Orange
country: United States
facility: University of California, Irvine Medical Center
state: California
city: Sacramento
country: United States
facility: University of California, Davis
state: California
city: Gainesville
country: United States
facility: University of Florida
state: Florida
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Augusta
country: United States
facility: Joseph M. Still Research Foundation, Inc.
state: Georgia
city: Idaho Falls
country: United States
facility: Eastern Idaho Regional Medical Center
state: Idaho
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Indianapolis
country: United States
facility: Methodist Hospital, Indiana University Health Physicians
state: Indiana
city: Hazard
country: United States
facility: Kentucky Lung Clinic
state: Kentucky
city: Louisville
country: United States
facility: University of Louisville
state: Kentucky
city: Baltimore
country: United States
facility: University of Maryland Medical Center
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Brigham and Women's Hospital
state: Massachusetts
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Detroit
country: United States
facility: Henry Ford Hospital
state: Michigan
city: Minneapolis
country: United States
facility: Hennepin County Medical Center
state: Minnesota
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Saint Paul
country: United States
facility: St. Paul Regions Hospital
state: Minnesota
city: Saint Louis
country: United States
facility: Saint Louis University
state: Missouri
city: Las Vegas
country: United States
facility: Sunrise Hospital/eStudySite
state: Nevada
city: Englewood
country: United States
facility: Englewood Hospital & Medical Center
state: New Jersey
city: New Brunswick
country: United States
facility: Rutgers Robert Wood Johnson Medical Center
state: New Jersey
city: Bronx
country: United States
facility: Montefiore Medical Center, Weiler Division
state: New York
city: Bronx
country: United States
facility: Montefiore Medical Center
state: New York
city: Durham
country: United States
facility: Duke Regional Hospital
state: North Carolina
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Greensboro
country: United States
facility: Moses Cone Health
state: North Carolina
city: Greensboro
country: United States
facility: Wesley Long Hospital
state: North Carolina
city: Cincinnati
country: United States
facility: University of Cincinnati Medical Center
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic - Fairview Hospital
state: Ohio
city: Cleveland
country: United States
facility: The Cleveland Clinic Foundation
state: Ohio
city: Columbus
country: United States
facility: Riverside Methodist Hospital
state: Ohio
city: Oklahoma City
country: United States
facility: University of Oklahoma Medical Center
state: Oklahoma
city: Portland
country: United States
facility: Oregon Health & Sciences University
state: Oregon
city: Allentown
country: United States
facility: Lehigh Valley Health Network
state: Pennsylvania
city: Danville
country: United States
facility: Geisinger Medical Center
state: Pennsylvania
city: Philadelphia
country: United States
facility: Penn Presbyterian Medical Center
state: Pennsylvania
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh Medical Center
state: Pennsylvania
city: Chattanooga
country: United States
facility: Erlanger Hospital
state: Tennessee
city: Chattanooga
country: United States
facility: Memorial Hospital
state: Tennessee
city: Dallas
country: United States
facility: Baylor University
state: Texas
city: Fort Worth
country: United States
facility: John Peter Smith Hospital - JPS Health Network
state: Texas
city: San Antonio
country: United States
facility: U.S. Army Military Medical Center
state: Texas
city: Falls Church
country: United States
facility: Inova Fairfax Hospital
state: Virginia
city: Richmond
country: United States
facility: Virginia Commonwealth University Medical Center
state: Virginia
city: Garran
country: Australia
facility: Canberra Hospital
state: Australian Capital Territory
city: New Lambton Heights
country: Australia
facility: John Hunter Hospital
state: New South Wales
city: Penrith
country: Australia
facility: Nepean Hospital
state: New South Wales
city: St Leonards
country: Australia
facility: Royal North Shore Hospital
state: New South Wales
city: Auchenflower
country: Australia
facility: The Wesley Hospital
state: Queensland
city: Herston
country: Australia
facility: Royal Brisbane & Women's Hospital
state: Queensland
city: Southport
country: Australia
facility: Gold Coast University Hospital
state: Queensland
city: Woolloongabba
country: Australia
facility: Princess Alexandra Hospital
state: Queensland
city: Bedford Park
country: Australia
facility: Flinders Medical Centre
state: South Australia
city: Hobart
country: Australia
facility: Royal Hobart Hospital
state: Tasmania
city: Clayton
country: Australia
facility: Monash Medical Centre
state: Victoria
city: Frankston
country: Australia
facility: Frankston Hospital
state: Victoria
city: Heidelberg
country: Australia
facility: Austin Hospital
state: Victoria
city: Melbourne
country: Australia
facility: St. Vincent's Hospital
state: Victoria
city: Parkville
country: Australia
facility: Royal Melbourne Hospital
state: Victoria
city: Murdoch
country: Australia
facility: Fiona Stanley Hospital
state: Western Australia
city: Perth
country: Australia
facility: Royal Perth Hospital
state: Western Australia
city: Adelaide
country: Australia
facility: Royal Adelaide Hospital
city: Antwerp
country: Belgium
facility: UZ Antwerpen
city: Brussels
country: Belgium
facility: Brugmann University Hospital
city: Brussel
country: Belgium
facility: UZ Brussel
city: Bruxelles
country: Belgium
facility: Erasme University Hospital
city: Gent
country: Belgium
facility: UZ Gent
city: Calgary
country: Canada
facility: South Health Campus & Rockyview General Hospital
state: Alberta
city: Edmonton
country: Canada
facility: Royal Alexandra Hospital
state: Alberta
city: Edmonton
country: Canada
facility: University of Alberta Hospital
state: Alberta
city: Vancouver
country: Canada
facility: St. Paul's Hospital
state: British Columbia
city: Victoria
country: Canada
facility: Royal Jubilee Hospital
state: British Columbia
city: Victoria
country: Canada
facility: Victoria General Hospital
state: British Columbia
city: Kingston
country: Canada
facility: Kingston General Hospital
state: Ontario
city: Ottawa
country: Canada
facility: The Ottawa Hospital - Civic Campus
state: Ontario
city: Ottawa
country: Canada
facility: The Ottawa Hospital - General Campus
state: Ontario
city: Toronto
country: Canada
facility: St. Michael's Hospital
state: Ontario
city: Helsinki
country: Finland
facility: Helsinki University Central Hospital
city: Kuopio
country: Finland
facility: Kuopio University Hospital
city: Tampere
country: Finland
facility: Tampere University Hospital
city: Turku
country: Finland
facility: Turku University Hospital
city: Besancon
country: France
facility: Jean Minjoz Hospital
city: Lille Cedex
country: France
facility: Hospital Roger Salengro, CHRU de Lille
city: Nice
country: France
facility: CHU Nice
city: Pessac
country: France
facility: Bordeaux Hospital University Center
city: Berlin
country: Germany
facility: University Medical Center, Berlin
city: Münster
country: Germany
facility: University Hospital Münster
city: Grafton
country: New Zealand
facility: Auckland City Hospital
state: Auckland
city: Otahuhu
country: New Zealand
facility: Middlemore Hospital
state: Auckland
city: Newtown
country: New Zealand
facility: Wellington Hospital
state: Wellington
city: Bern
country: Switzerland
facility: Bern University Hospital
city: Southampton
country: United Kingdom
facility: Southampton General Hospital
state: Hampshire
city: Norwich
country: United Kingdom
facility: Norfolk and Norwich University Hospitals
state: Norfolk
city: Sunderland
country: United Kingdom
facility: Sunderland Royal Hospital
state: Tyne And Wear
city: Birmingham
country: United Kingdom
facility: Birmingham Heartlands Hospital
state: West Midlands
city: Birmingham, West Midlands
country: United Kingdom
facility: Queen Elizabeth Hospital
city: Bristol
country: United Kingdom
facility: Bristol Royal Infirmary
city: Cambridge
country: United Kingdom
facility: Addenbrooke's Hospital
city: Hull
country: United Kingdom
facility: Hull Royal Infirmary
city: London
country: United Kingdom
facility: Royal London Hospital
city: London
country: United Kingdom
facility: St. Thomas Hospital
city: London
country: United Kingdom
facility: St. George's University Hospital
city: London
country: United Kingdom
facility: Charing Cross Hospital
city: London
country: United Kingdom
facility: Hammersmith Hospital
city: Merseyside
country: United Kingdom
facility: Royal Liverpool Hospital
city: Northampton
country: United Kingdom
facility: Northampton General Hospital
city: Plymouth
country: United Kingdom
facility: Derriford Hospital
Study officials:
affiliation: La Jolla Pharmaceutical Company
name: George F Tidmarsh, MD, PhD
role: STUDY_DIRECTOR
References:
citation: Bellomo R, Forni LG, Busse LW, McCurdy MT, Ham KR, Boldt DW, Hastbacka J, Khanna AK, Albertson TE, Tumlin J, Storey K, Handisides D, Tidmarsh GF, Chawla LS, Ostermann M. Renin and Survival in Patients Given Angiotensin II for Catecholamine-Resistant Vasodilatory Shock. A Clinical Trial. Am J Respir Crit Care Med. 2020 Nov 1;202(9):1253-1261. doi: 10.1164/rccm.201911-2172OC.
citation: Bellomo R, Wunderink RG, Szerlip H, English SW, Busse LW, Deane AM, Khanna AK, McCurdy MT, Ostermann M, Young PJ, Handisides DR, Chawla LS, Tidmarsh GF, Albertson TE. Angiotensin I and angiotensin II concentrations and their ratio in catecholamine-resistant vasodilatory shock. Crit Care. 2020 Feb 6;24(1):43. doi: 10.1186/s13054-020-2733-x.
citation: Senatore F, Jagadeesh G, Rose M, Pillai VC, Hariharan S, Liu Q, McDowell TY, Sapru MK, Southworth MR, Stockbridge N. FDA Approval of Angiotensin II for the Treatment of Hypotension in Adults with Distributive Shock. Am J Cardiovasc Drugs. 2019 Feb;19(1):11-20. doi: 10.1007/s40256-018-0297-9.
citation: Khanna A, English SW, Wang XS, Ham K, Tumlin J, Szerlip H, Busse LW, Altaweel L, Albertson TE, Mackey C, McCurdy MT, Boldt DW, Chock S, Young PJ, Krell K, Wunderink RG, Ostermann M, Murugan R, Gong MN, Panwar R, Hastbacka J, Favory R, Venkatesh B, Thompson BT, Bellomo R, Jensen J, Kroll S, Chawla LS, Tidmarsh GF, Deane AM; ATHOS-3 Investigators. Angiotensin II for the Treatment of Vasodilatory Shock. N Engl J Med. 2017 Aug 3;377(5):419-430. doi: 10.1056/NEJMoa1704154. Epub 2017 May 21.
citation: Schmull S, Wang Z, Gao L, Lv J, Li J, Xue S. Angiotensins and Their Receptors in Cardiac and Vascular Injury. Curr Hypertens Rev. 2016;12(3):170-180. doi: 10.2174/1573402112666160302101545.