Intravenous AII for the Treatment of Severe Hypotension in High Output Shock: A Pilot Study (ATHOS)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Lakhmir Chawla, George Washington University
ClinicalTrials.gov Identifier:
NCT01393782
First received: July 12, 2011
Last updated: February 18, 2014
Last verified: February 2014
  Purpose

The investigators propose a dose finding study to determine the feasibility of Angiotensin II (AII) to increase mean arterial pressure in high-output shock. If AII can be shown to increase mean arterial pressure, this could lead to future pharmacologic development based on the AII hormonal pathway. The investigators propose a 20 patient, randomized, placebo-controlled, blinded study in the treatment of high-output shock. Patients with high-output shock and a cardiovascular SOFA (sequential organ failure score) score of > 4 will be eligible. In addition, patients must already be receiving cardiac output monitoring and have a cardiac index > 2.4 L/min/ 1.73 m2. Patients will be randomized to intravenous AII or saline in a blinded fashion. There will be 10 patients in each arm. This is a safety and dose finding feasibility study. The investigators are starting with a small cohort consistent with similar types of studies. The investigators estimate that ten patients in each arm will generate a basis for determining if there is sufficient signal for AII to improve blood pressure at the doses outlined. The primary endpoint in the study will be the effect of AII on the standing dose of norepinephrine which is required to maintain a MAP of 65 mmHg. Secondary endpoints will be the effect of AII on urine output, serum lactate, and creatinine clearance. 30 day post dose mortality will also be assessed. Subjects discharged prior to day 30 will be contacted by telephone for this assessment.


Condition Intervention Phase
Septic Shock
Drug: Angiotensin II
Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Intravenous AII for the Treatment of Severe Hypotension in High Output Shock: A Pilot Study

Resource links provided by NLM:


Further study details as provided by George Washington University:

Primary Outcome Measures:
  • Efficacy [ Time Frame: 6 hours ] [ Designated as safety issue: No ]
    The primary endpoint in the study will be the effect of AII on the standing dose of norepinephrine which is required to maintain a MAP of 65 mmHg.


Secondary Outcome Measures:
  • Biomarkers [ Time Frame: 6 hours ] [ Designated as safety issue: No ]
    Secondary endpoints will be the effect of AII on urine output, serum lactate, and creatinine clearance.

  • Mortality [ Time Frame: 30 days ] [ Designated as safety issue: No ]
    30 day post dose mortality will be assessed. Subjects discharged prior to day 30 will be contacted by telephone for this assessment.


Enrollment: 20
Study Start Date: July 2011
Study Completion Date: January 2014
Primary Completion Date: January 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Angiotensin
The angiotensin arm will receive angiotensin II acetate at an initial dose of 20ng/kg/min, titratable during the study (6 hours) for MAP goals as outlined in the protocol.
Drug: Angiotensin II
All patients will have their vasopressors titrated to a mean arterial pressure (MAP) of 65 mm of Hg (standard MAP goal in the ICU for patients suffering from shock). Patients will then be randomized to control or IV AII. In the interventional arm, AII will start at a dose of 20ng/kg/min; the dose can then be titrated up to 30ng/kg/min, and then to 40ng/kg/min. The intervention will last for 6 hours. Each patient will start with the assigned starting dose indicated above. After the first hour, if the patient is still requiring standing norepinephrine (the standard vasopressor for the treatment of shock in the GW ICU), the dose of the control/interventional drug can be increased 50%. After the second hour, if the patient is still requiring a standing dose of norepinephrine, the control/interventional can be increased again to twice the initial dose. At the end of 6 hours, the study drug will be titrated off.
Placebo Comparator: Control
Control patients will receive placebo intravenously equal in duration, color and volume to the intervention arm's angiotensin II.
Drug: Angiotensin II
All patients will have their vasopressors titrated to a mean arterial pressure (MAP) of 65 mm of Hg (standard MAP goal in the ICU for patients suffering from shock). Patients will then be randomized to control or IV AII. In the interventional arm, AII will start at a dose of 20ng/kg/min; the dose can then be titrated up to 30ng/kg/min, and then to 40ng/kg/min. The intervention will last for 6 hours. Each patient will start with the assigned starting dose indicated above. After the first hour, if the patient is still requiring standing norepinephrine (the standard vasopressor for the treatment of shock in the GW ICU), the dose of the control/interventional drug can be increased 50%. After the second hour, if the patient is still requiring a standing dose of norepinephrine, the control/interventional can be increased again to twice the initial dose. At the end of 6 hours, the study drug will be titrated off.

  Eligibility

Ages Eligible for Study:   21 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. High-output shock
  2. Cardiovascular SOFA score of > 4
  3. Cardiac Index > 2.4 liters/min/BSA 1.73m2
  4. Indwelling arterial line already present as part of standard care
  5. Age > 21 years of age
  6. Signed consent form
  7. Use of indwelling urinary catheter as standard care expected at least for 12 hours during the study interventions

Exclusion Criteria:

  1. Patients with acute coronary syndrome
  2. Patients with a known history of vasospasm
  3. Patients with a history of asthma
  4. Patients currently experiencing bronchospasm
  5. Patients with active bleeding with an anticipated need for > 4 units of PRBC or Hemoglobin < 7g/dL or any other condition that would contraindicate drawing serial blood samples
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01393782

Locations
United States, District of Columbia
GW University
Washington, District of Columbia, United States, 20037
Sponsors and Collaborators
George Washington University
Investigators
Principal Investigator: Lakhmir Chawla, MD GW University
  More Information

No publications provided

Responsible Party: Lakhmir Chawla, Associate Professor of Medicine, George Washington University
ClinicalTrials.gov Identifier: NCT01393782     History of Changes
Other Study ID Numbers: 111016
Study First Received: July 12, 2011
Last Updated: February 18, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by George Washington University:
high output shock
distributive shock
warm shock
septic shock
pressor
angiotensin
ATII
vasopressor

Additional relevant MeSH terms:
Shock
Shock, Septic
Hypotension
Pathologic Processes
Sepsis
Infection
Systemic Inflammatory Response Syndrome
Inflammation
Vascular Diseases
Cardiovascular Diseases
Angiotensin II
Vasoconstrictor Agents
Cardiovascular Agents
Therapeutic Uses
Pharmacologic Actions

ClinicalTrials.gov processed this record on October 19, 2014