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

• 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: La Jolla Pharmaceutical Company
• Information provided by (Responsible Party): La Jolla Pharmaceutical Company

Tracking Information

• First Submitted Date: January 1, 2015
• First Posted Date: January 14, 2015
• Results First Submitted Date: November 28, 2017
• Results First Posted Date: January 17, 2018
• Last Update Posted Date: March 27, 2018
• Study Start Date: March 2015
• Actual Primary Completion Date: December 1, 2016 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 15, 2018)

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 [ Time Frame: 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.

• Original Primary Outcome Measures (submitted: January 13, 2015): Increased mean arterial pressure (MAP) [ Time Frame: Day 1 ]
• Current Secondary Outcome Measures: Not Provided
• Original Secondary Outcome Measures (submitted: January 13, 2015): SOFA Score [ Time Frame: Day 2 ]
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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)
• 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.

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment

Condition

• Catecholamine-resistant Hypotension (CRH)
• Distributive Shock
• High Output Shock
• Sepsis

Intervention

• Drug: LJPC-501
  Treatment arm
  Other Name: angiotensin II
• Drug: Placebo
  PBO
  Other Name: 0.9% Sodium Chloride Solution USP

Study Arms

• Experimental: LJPC-501 (angiotensin II)
  Treatment arm
  Intervention: Drug: LJPC-501
• Placebo Comparator: Placebo (0.9% sodium chloride solution)
  Placebo arm
  Intervention: Drug: Placebo

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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: April 6, 2017): 344
• Original Estimated Enrollment (submitted: January 13, 2015): 315
• Actual Study Completion Date: February 18, 2017
• Actual Primary Completion Date: December 1, 2016 (Final data collection date for primary outcome measure)

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Belgium, Canada, Finland, France, Germany, New Zealand, Switzerland, United Kingdom, United States

Administrative Information

• NCT Number: NCT02338843
• Other Study ID Numbers: LJ501-CRH01
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: La Jolla Pharmaceutical Company
• Original Responsible Party: Same as current
• Current Study Sponsor: La Jolla Pharmaceutical Company
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

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

• PRS Account: La Jolla Pharmaceutical Company
• Verification Date: January 2018