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

NCT03623022 | Completed Phase 1 FDA Drug

• 1 other identifier: 17-3351
• Study Type: interventional
• Target: 15
• Locations: 1 country
• Sites: 1

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.

Conditions

Healthy

Keywords

healthy

Outcome Measures

Primary Outcomes (2)

• Change in Left Ventricular Strain

  Comparing pre and post results before and after endotoxin vs normal saline inhalations

  15 minutes and 4 hrs after inhalation

• Change in Flow Mediated Dilation

  Comparing pre and post results before and after endotoxin vs normal saline inhalations

  15 minutes and 4 hrs after inhalation

Secondary Outcomes (2)

• Percent Change in sputum Polymorphonuclear Neutrophils (PMNs)

  6 hrs after inhalation

• Percent Change in Blood Polymorphonuclear Neutrophils (PMNs)

  5 hours and 30 minutes after inhalation

Study Arms (2)

Endotoxin, then Normal Saline

EXPERIMENTAL

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); Drug: Normal saline

Normal Saline, then Endotoxin

EXPERIMENTAL

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); Drug: Normal saline

Interventions

Clinical Center Reference Endotoxin (CCRE) DRUG

subjects will undergo an exposure to inhaled endotoxin through a nebulizer for approximately 10 minutes.

Also known as: Endotoxin

Endotoxin, then Normal Saline; Normal Saline, then Endotoxin

Normal saline DRUG

subjects will undergo an exposure to inhaled normal saline through a nebulizer for approximately 10 minutes

Also known as: 0.9% sodium Chloride (NACL)

Endotoxin, then Normal Saline; Normal Saline, then Endotoxin

Eligibility Criteria

• Age: 18 Years - 50 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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):
• Forced Vital Capacity (FVC) of \> 80 % of that predicted for gender, ethnicity, age and height
• Forced Expiratory Volume in the first second of the exhale (FEV1) of \> 80 % of that predicted for gender, ethnicity, age and height
• 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)

You may not qualify if:

• 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.

Sponsors & Collaborators

• University of North Carolina, Chapel Hill: lead
• Environmental Protection Agency (EPA): collaborator
• RTI International: collaborator
• United States Department of Defense: collaborator

Study Sites (1)

EPA Human Studies Facility

Chapel Hill, North Carolina, 27599, United States

Location

MeSH Terms

Interventions

Endotoxins; Saline Solution; Sodium Chloride

Intervention Hierarchy (Ancestors)

Bacterial Toxins; Toxins, Biological; Biological Factors; Crystalloid Solutions; Isotonic Solutions; Solutions; Pharmaceutical Preparations; Chlorides; Hydrochloric Acid; Chlorine Compounds; Inorganic Chemicals; Sodium Compounds

Study Officials

• Michelle Hernandez, MD

  University of North Carolina, Chapel Hill

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: The pharmacy will in charge of the randomization key, all others are blinded.
• Purpose: OTHER
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Subjects will undergo an exposure to inhaled endotoxin in a crossover fashion with normal saline inhalation.

Study Record Dates

• First Submitted: August 6, 2018
• First Posted: August 9, 2018
• Study Start: October 17, 2018
• Primary Completion: September 17, 2019
• Study Completion: September 17, 2019
• Last Updated: September 20, 2019

Record last verified: 2019-09

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)