Dose-Related Inflammatory Effects of Intravenous Endotoxin in Humans

NCT02789241 | Completed Phase 1

• 1 other identifier: Pro00070829
• Study Type: interventional
• Target: 23
• Locations: 1 country
• Sites: 1

Brief Summary

The purpose of this study is to evaluate 4-dose levels of CCRE Lot 94332B1 (0.6, 1.0, 2.0, and 4.0 ng/kg). This study is known as, an "endotoxin challenge." Thousands of healthy subjects worldwide over the last 20 years have participated in endotoxin challenge studies as part of clinical research and clinical drug development programs. This study will only test the safety and tolerability of CCRE Lot 94332B1.

Conditions

Healthy

Keywords

Endotoxin; healthy; volunteers; males; females

Outcome Measures

Primary Outcomes (8)

• Change in heart rate

  Safety will be assessed by measuring heart rate.

  Baseline, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, 5, 5.25, 5.5, 5.75, 6, 6.5, 7, 7.5, 8, 9, 10, 11, 12, and 24 hours after the LPS administration

• Number of treatment emergent adverse events (TEAEs)

  every 15 minutes for up to 6 hours

• Change in blood pressure

  Safety will be assessed by measuring blood pressure

  Baseline, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, 5, 5.25, 5.5, 5.75, 6, 6.5, 7, 7.5, 8, 9, 10, 11, 12, and 24 hours after the LPS administration

• Change in ECG parameters

  Baseline, 1, 2, 4, 8, and 24 hours after LPS administration

• Change in respiratory rate

  Safety will be assessed by measuring respiratory rate

  Baseline, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, 5, 5.25, 5.5, 5.75, 6, 6.5, 7, 7.5, 8, 9, 10, 11, 12, and 24 hours after the LPS administration

• Change in body temperature

  Safety will be assessed by measuring body temperature

  Baseline, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, 5, 5.25, 5.5, 5.75, 6, 6.5, 7, 7.5, 8, 9, 10, 11, 12, and 24 hours after the LPS administration

• Change in Pulse Oximetry

  Safety will be assessed by measuring pulse oximetry

  Baseline, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, 5, 5.25, 5.5, 5.75, 6, 6.5, 7, 7.5, 8, 9, 10, 11, 12, and 24 hours after the LPS administration

• Dose-Response Comparison

  Comparisons between the LPS doses and their responses will be assessed

  Baseline, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 24 hours after LPS administration.

Secondary Outcomes (11)

• Change in Patient Health Questionnaire (PHQ-9)

  Baseline, 2-6, and 24 hours after LPS administration.

• Change in Affect Rating Scale

  Baseline, 2-6, and 24 hours after LPS administration.

• Change in plasma pro-inflammatory cytokines

  Baseline, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 24 hours after LPS administration.

• Change in RNA

  Baseline, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 24 hours after LPS administration.

• Change in hsC-reactive protein

  Baseline, and at approximately 24 hours after LPS administration.

Study Arms (2)

Endotoxin (LPS)

EXPERIMENTAL

The safety and tolerability will be assessed at different doses that will consist of 4 groups; each consisting of 4 subjects receiving endotoxin (LPS). Group 1 will test the low dose of LPS (0.6 ng/kg); Group 2 will test the 1.0 ng/kg dose; Group 3 will test the 2.0 ng/kg dose and Group 4 will test the 4.0 ng/kg dose.

Biological: Endotoxin

Placebo

PLACEBO COMPARATOR

The trial will consist of 4 groups each group will have 2 subjects receiving Placebo (normal saline)\].

Other: Placebo

Interventions

Endotoxin BIOLOGICAL

Reference Endotoxin is a purified LPS prepared from Escherichia coli O:113 (US Standard Reference Endotoxin); Clinical Center Reference Endotoxin (CCRE) Lot #94332B1 manufactured and vialed under GMP guidelines by List Biological Labs, Inc., 540 Division St., Campbell, CA 95008, for the Pharmacy Development Service, Clinical Center, National Institutes of Health, Bethesda, MD, USA. The material has been approved by the FDA (Food and Drug Administration) for 'Investigational Use Only'. This specific Lot from List Biological Labs specified for use in this study contains 1 mcg/vial.

Also known as: LPS, Lipopolysaccharide, Reference Endotoxin, CCRE, CCRE Lot 94332B1

Endotoxin (LPS)

Placebo OTHER

Normal saline will be administered as the control to evaluate the effects on the biomarkers over time and to compare the responses following LPS to those following the control injection of normal saline.

Also known as: Normal Saline (NS), Control

Placebo

Eligibility Criteria

• Age: 18 Years - 40 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Healthy men and women between the ages of 18-40 years, inclusive, at the time of Informed Consent. Healthy is defined as no clinically relevant abnormalities identified by a detailed medical history, full physical examination, including blood pressure and pulse rate measurement, 12-lead ECG or clinical laboratory tests.
• Agreement by female subjects with reproductive potential to be using an adequate method of contraception and agrees to continue using this method for the duration of the study. Female subjects must also agree to the use of TWO reliable methods of contraception following receiving study drug; if sexually active, which can include: condoms, spermicidal gel, diaphragm, hormonal or non-hormonal intrauterine device, surgical sterilization, an oral contraceptive pill (OCP), and depot progesterone injections.
• Body Mass Index (BMI) of 18-32 kg/m2 and a total body weight \>50 kg (110 lb), but \<95 kg.
• The subject has demonstrably adequate veins for IV catheter insertion.
• Evidence of a personally signed and dated informed consent document indicating that the subject (or a legal representative) has been informed of all the pertinent aspects of the study.
• Subjects who are willing and able to comply with the scheduled visits, laboratory tests, and other study procedures.
• Male subjects agree that they \[or their female partner(s)\] will use an acceptable contraceptive regimen throughout the duration of the study. Acceptable contraception for a subject (or female partner) is being surgically sterilized; or willing to use condoms plus contraceptive foam or jelly (with all female partners who are not surgically sterilized).
• The subject has the ability and willingness to comply with protocol requirements during the study, including fasting and refraining from alcohol, nicotine and caffeine consumption from 48h prior to check-in until discharge from the unit.
• On the morning of endotoxin, Study Day 1, prior to dosing, the subject must have a normal stable baseline body temperature defined as the average of three consecutive oral temperatures (recorded, repeatedly, approximately every 10-15 seconds) between 97.0 degrees F (36.1°C) and 98.8 degrees F (37.1°C) and do not differ by \>0.4 degrees F (\>0.2 degrees C).
• The subject has a high probability for compliance with and completion of the study.

You may not qualify if:

• Evidence or history of clinically significant dental (presence of abscess), hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurologic, or allergic disease.
• A positive urine drug test for cannabinoids, amphetamines, barbiturates, cocaine, opiates, benzodiazepines, phencyclidine, and/or methadone and alcohol (breathalyzer) test at either Screening or Day -1.
• History or evidence of habitual use of tobacco- or nicotine-containing products within 3 months of screening.
• A positive serum pregnancy test (females only) at Screening or a positive urine pregnancy test at check-in.
• Subjects who have previously received endotoxin (LPS) within the previous 6 months or known hypersensitivity to endotoxin at any time.
• Subjects who have experienced cold/flu symptoms (i.e., runny nose, cough, and/or fever) or received any antibiotic treatment within 30 days or has undergone a surgical procedure within 60 days prior of the endotoxin challenge
• History of recurrent or chronic infections of any type such as tuberculosis, sinusitis, urinary tract infection, respiratory tract or dental (abscess) infection, etc. Also excluded are subjects with recurrent oral or genital herpes, recurrent herpes zoster, or any infection otherwise judged by the investigator to have the potential for exacerbation by participation in the study.
• History of syncope or symptoms of lightheadedness associated with blood draws
• History of regular alcohol consumption exceeding 7 drinks/week for females or 14 drinks/week for males (1 drink = 5 ounces (150 mL) of wine or 12 ounces (360 mL) of beer or 1.5 ounces (45 mL) of hard liquor) within 6 months of Screening or history of drug use within 12 months prior to study drug administration, which the Investigator considers abusive.
• Treatment with an investigational drug within 30 days (or as determined by the local requirement) or 5 half-lives, whichever is longer, preceding the first dose of study medication. Also, if received an immunosuppressive drug or had received a vaccination within 3 months of Day 1
• Screening supine BP \>140 or \<100 mm Hg (systolic), or \>90 or \<60 mmHg (diastolic); following at least 5 minutes of rest. If BP is \>140 or \<100 mm Hg (systolic), or \>90 or \<60 mm Hg (diastolic), the BP should be repeated two more times and the median of the three systolic and the median of the three diastolic BP values should be used to determine the subject's eligibility. If either of the median values is outside of the criteria above, the subject is excluded.
• Resting heart rate (HR) at screening or check-in on Day -1 \<50 bpm (beats per minute) following at least 10 minutes of rest from either vital signs or ECGs. If HR is \<50 bpm, the HR should be repeated two more times and the median of the three HR values should be used to determine the subject's eligibility. If the median value is \<50 bpm, the subject is excluded.
• lead ECG demonstrating HR \< 50 bpm, QTc \>450 or a QRS interval \>120 msec at screening of check-in. If the heart rate or QTc exceeds 450 msec, or QRS exceeds 120 msec, the ECG should be repeated two more times and the median of the three QTc values should be used to determine the subject's eligibility. If the median value for any of these parameters is outside the limit specified, the subject is excluded.
• Use of prescription or nonprescription drugs and dietary supplements, especially those with anti-inflammatory properties (e.g. fish oil, turmeric, etc.) within 7 days or 5 half-lives (whichever is longer) prior to receiving endotoxin. Limited use of non-prescription medications that are not believed to affect subject safety or the overall results of the study may be permitted on a case-by-case basis. Use of any steroidal or non-steroidal anti-inflammatory drug (NSAID) within 7 days or 5 half-lives (whichever is longer) of admission of each period is specifically prohibited due to potential confounding effects on the study PD endpoints
• History of frequent headaches (\>2 per month) or migraines or headaches from an absence of caffeine from coffee, tea, chocolate, or other caffeine-related substances

Sponsors & Collaborators

• Robert J Noveck, M.D.: lead
• Foundation for the National Institutes of Health: collaborator

Study Sites (1)

Duke Early Phase Clinical Research (DEPRU)

Durham, North Carolina, 27710, United States

Location

MeSH Terms

Interventions

Endotoxins; Lipopolysaccharides; Saline Solution

Intervention Hierarchy (Ancestors)

Bacterial Toxins; Toxins, Biological; Biological Factors; Glycoconjugates; Carbohydrates; Polysaccharides, Bacterial; Polysaccharides; Lipids; Antigens, Bacterial; Antigens; Crystalloid Solutions; Isotonic Solutions; Solutions; Pharmaceutical Preparations

Study Officials

• Robert J Noveck, MD, PhD

  Medical Director, Duke Early Phase Clinical Research (DEPRU)

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Associate Professior and Co-Director, Division of Clinical Pharmacology and Medical Director, Duke Clinical Research Unit

Study Record Dates

• First Submitted: May 27, 2016
• First Posted: June 2, 2016
• Study Start: August 1, 2016
• Primary Completion: October 1, 2016
• Study Completion: October 1, 2016
• Last Updated: April 11, 2017

Record last verified: 2017-04

Data Sharing

• IPD Sharing: Will share

Locations

US (1)