Systemic Inflammatory Response to CCRE

NCT02847247 | Completed Phase 1 FDA Drug

• 1 other identifier: 15-1458
• Study Type: interventional
• Target: 25
• Locations: 1 country
• Sites: 1

Brief Summary

Purpose: The purpose of this study is to classify volunteers as endotoxin-responders or non-responders following inhalation of 20,000 EU Clinical Center Reference Endotoxin (CCRE). Endotoxin is a commonly encountered bioaerosol and component of indoor and outdoor air pollution. 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. These susceptible individuals represent a population of particular interest for further mechanistic studies of the effects of endotoxin and for therapeutic trials. Susceptibility to inhaled endotoxin will be determined by measuring change in peripheral blood neutrophil counts, a biomarker of systemic inflammation, following inhaled CCRE. In our previous work, the investigators have found that inhalation of 20,000 EU CCRE is well tolerated and induces measurable increase in neutrophil content of peripheral blood in susceptible individuals. Our hope is that this CCRE inhalation protocol can be employed to screen large populations for susceptibility to the inflammatory effect of inhaled endotoxin.

Conditions

Healthy

Keywords

healthy

Outcome Measures

Primary Outcomes (1)

• Change in peripheral blood PMNs

  The objective of this study is to identify endotoxin responders, characterized by an increase in post-CCRE peripheral blood polymorphonuclear (PMN)s compared to that day's baseline values of \> 20%. Thus, there will be two data points for this cohort, blood PMNs at baseline and PMNs 6 hours following 20,000 endotoxin units (EU) of CCRE.

  6 hrs post exposure

Study Arms (1)

CCRE

EXPERIMENTAL

20,000 EU of CCRE (Clinical Center Reference Endotoxin)

Drug: CCRE

Interventions

CCRE DRUG

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).

Also known as: endotoxin, lipopolysaccharide (LPS)

CCRE

Eligibility Criteria

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

You may qualify if:

• Subjects must be 18-50 years of age to be eligible for study participation
• Subjects must be willing to and able to provide informed consent and participate in all study procedures
• Normal lung function, defined as (Knudson 1976/1984 predicted set):
• \. Forced Vital Capacity (FVC) of \> 80% of that predicted for gender, ethnicity, age and height
• \. Forced Expiratory Volume in the first second (FEV1) of \> 80% of that predicted for gender, ethnicity, age and height
• \. FEV1/FVC ratio of \> 0.75 of that predicted for gender, ethnicity, age and height
• Oxygen saturation of \> 94% Normal blood pressure (Systolic between 150 - 90, Diastolic between 90-60 mm Hg)
• Symptom Score (defined in section "f") no greater than 6 (out of a possible 24) for total symptom score with a value no greater than 2 for any one score.

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.
• Moderate or Severe asthma
• 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.
• BMI\>35.
• Pregnant or breast feeding women will not be included.
• 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.
• Subjects will be deferred after any acute, non-chronic medical condition requiring treatment, such as bronchitis, pneumonia or febrile illness for a minimum of 4 weeks after complete resolution of symptoms.

Sponsors & Collaborators

• University of North Carolina, Chapel Hill: lead
• Environmental Protection Agency (EPA): collaborator

Study Sites (1)

Environmental Protection Agency Human Studies facility

Chapel Hill, North Carolina, 27599, United States

Location

MeSH Terms

Interventions

Endotoxins; Lipopolysaccharides

Intervention Hierarchy (Ancestors)

Bacterial Toxins; Toxins, Biological; Biological Factors; Glycoconjugates; Carbohydrates; Polysaccharides, Bacterial; Polysaccharides; Lipids; Antigens, Bacterial; Antigens

Study Officials

• Michelle Hernandez, MD

  UNC

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: OTHER
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 25, 2016
• First Posted: July 28, 2016
• Study Start: December 11, 2017
• Primary Completion: August 6, 2019
• Study Completion: August 6, 2019
• Last Updated: September 20, 2019

Record last verified: 2019-09

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)