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

A Phase 3, Placebo-Controlled, Randomized, Double-Blind, Multi-Center Study of LJPC-501 in Patients With Catecholamine-Resistant Hypotension (CRH)

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.

Study Overview

• Status: Completed
• Conditions: Sepsis; Catecholamine-resistant Hypotension (CRH); Distributive Shock; High Output Shock
• Intervention / Treatment: Drug: LJPC-501; Drug: Placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 344
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • Adelaide, Australia, 5000
    • Royal Adelaide Hospital
  • Australian Capital Territory
    • Garran, Australian Capital Territory, Australia, 2605
      • Canberra Hospital
  • New South Wales
    • New Lambton Heights, New South Wales, Australia, 2305
      • John Hunter Hospital
    • Penrith, New South Wales, Australia, 2751
      • Nepean Hospital
    • St Leonards, New South Wales, Australia, 2065
      • Royal North Shore Hospital
  • Queensland
    • Auchenflower, Queensland, Australia, 4066
      • The Wesley Hospital
    • Herston, Queensland, Australia, 4029
      • Royal Brisbane & Women's Hospital
    • Southport, Queensland, Australia, 4215
      • Gold Coast University Hospital
    • Woolloongabba, Queensland, Australia, 4102
      • Princess Alexandra Hospital
  • South Australia
    • Bedford Park, South Australia, Australia, 5042
      • Flinders Medical Centre
  • Tasmania
    • Hobart, Tasmania, Australia, 7000
      • Royal Hobart Hospital
  • Victoria
    • Clayton, Victoria, Australia, 3168
      • Monash Medical Centre
    • Frankston, Victoria, Australia, 3199
      • Frankston Hospital
    • Heidelberg, Victoria, Australia, 3084
      • Austin Hospital
    • Melbourne, Victoria, Australia, 3065
      • St. Vincent's Hospital
    • Parkville, Victoria, Australia, 3050
      • Royal Melbourne Hospital
  • Western Australia
    • Murdoch, Western Australia, Australia, 6150
      • Fiona Stanley Hospital
    • Perth, Western Australia, Australia, 6000
      • Royal Perth Hospital
• Belgium
  • Antwerp, Belgium, 2650
    • UZ Antwerpen
  • Brussel, Belgium, 1090
    • UZ Brussel
  • Brussels, Belgium, 1020
    • Brugmann University Hospital
  • Bruxelles, Belgium, 1070
    • Erasme University Hospital
  • Gent, Belgium, 9000
    • UZ Gent
• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 2T9
      • South Health Campus & Rockyview General Hospital
    • Edmonton, Alberta, Canada, T6G 2B7
      • University of Alberta Hospital
    • Edmonton, Alberta, Canada, T5H 3V9
      • Royal Alexandra Hospital
  • British Columbia
    • Vancouver, British Columbia, Canada, V6Z 1Y6
      • St. Paul's Hospital
    • Victoria, British Columbia, Canada, V8R 1J8
      • Royal Jubilee Hospital
    • Victoria, British Columbia, Canada, V8Z 6R5
      • Victoria General Hospital
  • Ontario
    • Kingston, Ontario, Canada, K7I 2V7
      • Kingston General Hospital
    • Ottawa, Ontario, Canada, KIH 8L6
      • The Ottawa Hospital - Civic Campus
    • Ottawa, Ontario, Canada, KIH 8L6
      • The Ottawa Hospital - General Campus
    • Toronto, Ontario, Canada, M5B1W8
      • St. Michael's Hospital
• Finland
  • Helsinki, Finland, 00290
    • Helsinki University Central Hospital
  • Kuopio, Finland, 70210
    • Kuopio University Hospital
  • Tampere, Finland, 33520
    • Tampere University Hospital
  • Turku, Finland, 20521
    • Turku University Hospital
• France
  • Besancon, France, 25030
    • Jean Minjoz Hospital
  • Lille Cedex, France, 59037
    • Hospital Roger Salengro, CHRU de Lille
  • Nice, France, 06202
    • CHU Nice
  • Pessac, France, 33604
    • Bordeaux Hospital University Center
• Germany
  • Berlin, Germany, 10117
    • University Medical Center, Berlin
  • Münster, Germany, 48149
    • University Hospital Münster
• New Zealand
  • Auckland
    • Grafton, Auckland, New Zealand, 1023
      • Auckland City Hospital
    • Otahuhu, Auckland, New Zealand
      • Middlemore Hospital
  • Wellington
    • Newtown, Wellington, New Zealand, 6021
      • Wellington Hospital
• Switzerland
  • Bern, Switzerland, CH-3010
    • Bern University Hospital
• United Kingdom
  • Birmingham, West Midlands, United Kingdom, B15 2WB
    • Queen Elizabeth Hospital
  • Bristol, United Kingdom, BS2 8HW
    • Bristol Royal Infirmary
  • Cambridge, United Kingdom, CB2 0QQ
    • Addenbrooke's Hospital
  • Hull, United Kingdom, HU3 2JZ
    • Hull Royal Infirmary
  • London, United Kingdom, E1 1BB
    • Royal London Hospital
  • London, United Kingdom, W6 8RF
    • Charing Cross Hospital
  • London, United Kingdom, SE1 7EH
    • St. Thomas Hospital
  • London, United Kingdom, SW17 0QT
    • St. George's University Hospital
  • London, United Kingdom, W6 8RF
    • Hammersmith Hospital
  • Merseyside, United Kingdom, L7 8XP
    • Royal Liverpool Hospital
  • Northampton, United Kingdom, NN1 5BD
    • Northampton General Hospital
  • Plymouth, United Kingdom, PL6 8DH
    • Derriford Hospital
  • Hampshire
    • Southampton, Hampshire, United Kingdom, SO16 6YD
      • Southampton General Hospital
  • Norfolk
    • Norwich, Norfolk, United Kingdom, NR4 7UY
      • Norfolk and Norwich University Hospitals
  • Tyne And Wear
    • Sunderland, Tyne And Wear, United Kingdom, SR4 7TP
      • Sunderland Royal Hospital
  • West Midlands
    • Birmingham, West Midlands, United Kingdom, B9 5SS
      • Birmingham Heartlands Hospital
• United States
  • Alabama
    • Mobile, Alabama, United States, 36608
      • Pulmonary Associates of Mobile, PC
  • Arizona
    • Phoenix, Arizona, United States, 85054
      • Mayo Clinic Arizona
  • California
    • Loma Linda, California, United States, 92354
      • Loma Linda University Medical Center
    • Los Angeles, California, United States, 90095
      • University of California, Los Angeles
    • Los Angeles, California, United States, 90033
      • Keck Hospital of USC
    • Los Angeles, California, United States, 90033
      • Los Angeles County + University of Southern California Medical Center
    • Orange, California, United States, 92868
      • University of California, Irvine Medical Center
    • Sacramento, California, United States, 95817
      • University of California, Davis
  • Florida
    • Gainesville, Florida, United States, 32610
      • University of Florida
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University
    • Augusta, Georgia, United States, 30909
      • Joseph M. Still Research Foundation, Inc.
  • Idaho
    • Idaho Falls, Idaho, United States, 83404
      • Eastern Idaho Regional Medical Center
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Methodist Hospital, Indiana University Health Physicians
  • Kentucky
    • Hazard, Kentucky, United States, 41701
      • Kentucky Lung Clinic
    • Louisville, Kentucky, United States, 40292
      • University of Louisville
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • University of Maryland Medical Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Beth Israel Deaconess Medical Center
    • Boston, Massachusetts, United States, 02115
      • Brigham and Women's Hospital
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Henry Ford Hospital
  • Minnesota
    • Minneapolis, Minnesota, United States, 55415
      • Hennepin County Medical Center
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
    • Saint Paul, Minnesota, United States, 55101
      • St. Paul Regions Hospital
  • Missouri
    • Saint Louis, Missouri, United States, 63104
      • Saint Louis University
  • Nevada
    • Las Vegas, Nevada, United States, 89109
      • Sunrise Hospital/eStudySite
  • New Jersey
    • Englewood, New Jersey, United States, 07631
      • Englewood Hospital & Medical Center
    • New Brunswick, New Jersey, United States, 08901
      • Rutgers Robert Wood Johnson Medical Center
  • New York
    • Bronx, New York, United States, 10467
      • Montefiore Medical Center
    • Bronx, New York, United States, 10461
      • Montefiore Medical Center, Weiler Division
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
    • Durham, North Carolina, United States, 27704
      • Duke Regional Hospital
    • Greensboro, North Carolina, United States, 27403
      • Moses Cone Health
    • Greensboro, North Carolina, United States, 27403
      • Wesley Long Hospital
  • Ohio
    • Cincinnati, Ohio, United States, 45267
      • University of Cincinnati Medical Center
    • Cleveland, Ohio, United States, 44195
      • The Cleveland Clinic Foundation
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic - Fairview Hospital
    • Columbus, Ohio, United States, 43215
      • Riverside Methodist Hospital
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • University of Oklahoma Medical Center
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health & Sciences University
  • Pennsylvania
    • Allentown, Pennsylvania, United States, 18103
      • Lehigh Valley Health Network
    • Danville, Pennsylvania, United States, 17822
      • Geisinger Medical Center
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Penn Presbyterian Medical Center
    • Pittsburgh, Pennsylvania, United States, 15261
      • University of Pittsburgh Medical Center
  • Tennessee
    • Chattanooga, Tennessee, United States, 37408
      • Erlanger Hospital
    • Chattanooga, Tennessee, United States, 37408
      • Memorial Hospital
  • Texas
    • Dallas, Texas, United States, 75246
      • Baylor University
    • Fort Worth, Texas, United States, 76104
      • John Peter Smith Hospital - JPS Health Network
    • San Antonio, Texas, United States, 78234
      • U.S. Army Military Medical Center
  • Virginia
    • Falls Church, Virginia, United States, 22042
      • Inova Fairfax Hospital
    • Richmond, Virginia, United States, 23298
      • Virginia Commonwealth University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: LJPC-501 (angiotensin II); Treatment arm	Drug: LJPC-501; Treatment arm; Other Names: angiotensin II
Placebo Comparator: Placebo (0.9% sodium chloride solution); Placebo arm	Drug: Placebo; PBO; Other Names: 0.9% Sodium Chloride Solution USP

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Hour 3

Collaborators and Investigators

• Sponsor: La Jolla Pharmaceutical Company
• Investigators: Study Director: George F Tidmarsh, MD, PhD, La Jolla Pharmaceutical Company

Publications and helpful links

General Publications

• 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.
• 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.
• 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. Erratum In: Am J Cardiovasc Drugs. 2019 Apr;19(2):227.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start: March 1, 2015
• Primary Completion (Actual): December 1, 2016
• Study Completion (Actual): February 18, 2017

Study Registration Dates

• First Submitted: January 1, 2015
• First Submitted That Met QC Criteria: January 13, 2015
• First Posted (Estimate): January 14, 2015

Study Record Updates

• Last Update Posted (Actual): March 27, 2018
• Last Update Submitted That Met QC Criteria: February 27, 2018
• Last Verified: January 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Shock; Hypotension; Vasoconstrictor Agents; Angiotensin II
• Other Study ID Numbers: LJ501-CRH01