ClinicalTrials.gov
ClinicalTrials.gov Menu

Effects of 20,000 EU of Clinical Center Reference Endotoxin (CCRE) Versus Placebo(ENDOHEART) (Endoheart)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT03623022
Recruitment Status : Recruiting
First Posted : August 9, 2018
Last Update Posted : December 4, 2018
Sponsor:
Collaborators:
Environmental Protection Agency (EPA)
RTI International
United States Department of Defense
Information provided by (Responsible Party):
University of North Carolina, Chapel Hill

Brief Summary:
To determine the systemic inflammatory effects of inhaled endotoxin and associated alterations in cardiovascular function. Subjects will undergo an exposure to inhaled endotoxin in a crossover fashion with normal saline inhalation. Blood samples and sputum samples will be taken before and after inhalation challenge to measure markers of systemic inflammation. Cardiovascular measures, including a heart rate variability monitor, flow mediated dilation of the brachial artery and left ventricular stain will also be measured.

Condition or disease Intervention/treatment Phase
Healthy Drug: Clinical Center Reference Endotoxin (CCRE) Drug: Normal saline Phase 1

Detailed Description:
The purpose of this study is to determine the systemic inflammatory effects of inhaled endotoxin and associated alterations in cardiovascular function. The investigators have previously found that inhalation of 20,000 Endotoxin Units (EU) of CCRE increases the neutrophil content of the blood; this dose can then be employed to screen populations for enhanced susceptibility to the systemic and cardiovascular inflammatory effect of inhaled endotoxin. Endotoxin is a commonly encountered bioaerosol and component of particulate matter (PM), a prevalent indoor and outdoor air pollutant [1-3]. For reasons that remain unclear, some individuals appear to be more susceptible to the inflammatory effects of inhaled endotoxin than are others, possibly owing to single nucleotide polymorphisms in the Toll-like receptor 4 (TLR4) gene that influence TLR4 signaling and function [4-6]. Exposure to PM is associated with increased cardiovascular morbidity and mortality [7]. PM exposure has been specifically linked with increases in blood pressure [8,9]. Susceptible individuals represent a population of particular interest for further mechanistic studies of the effects of endotoxin and for therapeutic trials. Systemic inflammatory response to inhaled endotoxin will be determined by measuring change in peripheral blood neutrophil counts, a biomarker of systemic inflammation, following inhaled CCRE vs placebo. Blood pressure, heart rate variability (HRV), vascular stiffness (by flow mediated dilation, or FMD) and left ventricular strain (LVS) will be measured before and after CCRE or placebo exposure to investigate the effect of endotoxin-induced systemic inflammation on cardiovascular function.

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 16 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention Model Description: Subjects will undergo an exposure to inhaled endotoxin in a crossover fashion with normal saline inhalation.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: The pharmacy will in charge of the randomization key, all others are blinded.
Primary Purpose: Other
Official Title: Effects of 20,000 EU of Clinical Center Reference Endotoxin (CCRE) Versus Placebo on Systemic and Cardiovascular Inflammatory Responses in Mild Asthmatics and Healthy Volunteers
Actual Study Start Date : October 17, 2018
Estimated Primary Completion Date : September 2021
Estimated Study Completion Date : September 2021

Arm Intervention/treatment
Experimental: Endotoxin, then Normal Saline

Endotoxin challenge: Subjects will undergo inhalation of 20,000 EU CCRE. The Clinical Center Reference Endotoxin (CCRE) will be inhaled by subjects as a nebulized preparation using an ultrasonic nebulizer until the challenge solution is completely spent (generally 10 minutes).

Following a washout of 2 weeks to 3 months the participant will undergo a Saline Challenge: Subjects will undergo inhalation of 0.9% sodium chloride. The Normal saline will be inhaled by subjects as a nebulized preparation using an ultrasonic nebulizer until the challenge solution is completely spent (generally 10 minutes).

Drug: Clinical Center Reference Endotoxin (CCRE)
subjects will undergo an exposure to inhaled endotoxin through a nebulizer for approximately 10 minutes.
Other Name: Endotoxin

Drug: Normal saline
subjects will undergo an exposure to inhaled normal saline through a nebulizer for approximately 10 minutes
Other Name: 0.9% sodium Chloride (NACL)

Experimental: Normal Saline, then Endotoxin

Saline Challenge: Subjects will undergo inhalation of 0.9% sodium chloride. The Normal saline will be inhaled by subjects as a nebulized preparation using an ultrasonic nebulizer until the challenge solution is completely spent (generally 10 minutes).

Following a washout of 2 weeks to 3 months the participant will undergo an Endotoxin challenge: Subjects will undergo inhalation of 20,000 EU CCRE. The CCRE will be inhaled by subjects as a nebulized preparation using an ultrasonic nebulizer until the challenge solution is completely spent (generally 10 minutes).

Drug: Clinical Center Reference Endotoxin (CCRE)
subjects will undergo an exposure to inhaled endotoxin through a nebulizer for approximately 10 minutes.
Other Name: Endotoxin

Drug: Normal saline
subjects will undergo an exposure to inhaled normal saline through a nebulizer for approximately 10 minutes
Other Name: 0.9% sodium Chloride (NACL)




Primary Outcome Measures :
  1. Change in Left Ventricular Strain [ Time Frame: 15 minutes and 4 hrs after inhalation ]
    Comparing pre and post results before and after endotoxin vs normal saline inhalations

  2. Change in Flow Mediated Dilation [ Time Frame: 15 minutes and 4 hrs after inhalation ]
    Comparing pre and post results before and after endotoxin vs normal saline inhalations


Secondary Outcome Measures :
  1. Percent Change in sputum Polymorphonuclear Neutrophils (PMNs) [ Time Frame: 6 hrs after inhalation ]
    post differences in % change comparing saline to endotoxin

  2. Percent Change in Blood Polymorphonuclear Neutrophils (PMNs) [ Time Frame: 5 hours and 30 minutes after inhalation ]
    post differences in % change comparing saline to endotoxin



Information from the National Library of Medicine

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, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years to 50 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Adult volunteers with no more than mild asthma
  • Age 18-50 years, inclusive, of both sexes
  • Demonstrate an increase in peripheral blood PMNs of 20% (compared to baseline values) following inhalation of 20,000 EU of CCRE.
  • Negative pregnancy test for females who are not s/p hysterectomy with oophorectomy
  • Normal lung function, defined as (NHanes III predicted set):

    1. Forced Vital Capacity (FVC) of > 80 % of that predicted for gender, ethnicity, age and height
    2. Forced Expiratory Volume in the first second of the exhale (FEV1) of > 80 % of that predicted for gender, ethnicity, age and height
    3. FEV1/FVC ratio of > .75 of that predicted for gender, ethnicity, age and height
  • Oxygen saturation of > 93%, and blood pressure within the following limits: (Systolic between 150 - 90, Diastolic between 90-60 mm Hg)

Exclusion Criteria:

  • Any chronic medical condition considered by the PI as a contraindication to the exposure study including significant cardiovascular disease, diabetes requiring medication, chronic renal disease, or chronic thyroid disease.
  • Physician directed emergency treatment for asthma exacerbation within the preceding 3 months.
  • Exacerbation of asthma more than 2x/week that would be characteristic of a person of moderate or severe persistent asthma as outlined in the current NHLBI guidelines for diagnosis and management of asthma.
  • Nighttime symptoms of cough or wheeze greater than 1x/week at baseline (not during a clearly recognized viral induced asthma exacerbation) which would be characteristic of a person of moderate or severe persistent asthma as outlined in the current NHLBI guidelines for diagnosis and management of asthma
  • Daily requirement for albuterol due to asthma symptoms (cough, wheeze, chest tightness) which would be characteristic of a person of moderate or severe persistent asthma as outlined in the current NHLBI guidelines for diagnosis and management of asthma. (Not to include prophylactic use of albuterol prior to exercise).
  • History of intubation for asthma
  • Daily use of NSAIDs, or inability to withhold NSAIDs for 4 days prior to dosing.
  • Use of medications that may impact the results of the study to include, but not limited to, systemic corticosteroids, beta blockers.
  • Cigarette smoking > 1 pack per month.
  • Body Mass Index >35 kg/m2.
  • Pregnant or breast feeding women
  • Subjects who are employed within the past 6 months in an occupation with high risk for endotoxin exposure, such as grain storage sites or swine containment.
  • Any acute, non-chronic medical condition requiring treatment, such as bronchitis, pneumonia or febrile illness within the prior 4 weeks.
  • Participation in studies involving new molecular entities or an experimental environmental exposure in the past 4 weeks.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03623022


Contacts
Contact: Carole A Robinette, MS 919 966-5638 carole_robinette@med.unc.edu
Contact: Martha Almond, RRT 919 966-0759 malmond@med.unc.edu

Locations
United States, North Carolina
EPA Human Studies Facility Recruiting
Chapel Hill, North Carolina, United States, 27599
Contact: Judy Smith    919-966-0773    judith_smith@med.unc.edu   
Contact: Carole Robinette, MS    9199665638    carole_robinette@med.unc.edu   
Principal Investigator: Michelle Hernandez, MD         
Sponsors and Collaborators
University of North Carolina, Chapel Hill
Environmental Protection Agency (EPA)
RTI International
United States Department of Defense
Investigators
Principal Investigator: Michelle Hernandez, MD University of North Carolina, Chapel Hill

Responsible Party: University of North Carolina, Chapel Hill
ClinicalTrials.gov Identifier: NCT03623022     History of Changes
Other Study ID Numbers: 17-3351
First Posted: August 9, 2018    Key Record Dates
Last Update Posted: December 4, 2018
Last Verified: December 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by University of North Carolina, Chapel Hill:
healthy