Evaluation of Danirixin (GSK1325756) Inhibition of CD11b Cell Surface Expression

A Single-Center In Vitro Study to Evaluate GSK1325756 Inhibition of CD11b Cell Surface Expression in Healthy Adults and Respiratory Syncytial Virus-Infected Children <2 Years (200591)

This study is to determine danirixin (GSK1325756) concentrations required to inhibit neutrophil activation in blood obtained from Respiratory Syncytial Virus (RSV)-infected children <2 years and healthy adults. The study will evaluate differences in neutrophil activation between RSV-infected children <2 years and healthy adults with escalating concentrations of Chemokine (C-X-C motif) Ligand 1 (CXCL1) and danirixin to determine if RSV-infected children and adult neutrophils are similarly activated by CXCL1 and inhibited by danirixin. This study will guide dose prediction to inhibit specific percentages of neutrophils in future pediatric RSV-infection studies. This single-center, in vitro study will consist of 2 parts. Approximately 24 subjects will be enrolled, including 12 healthy adults and 12 RSV-infected children <2 years.

Study Overview

• Status: Completed
• Conditions: Infections, Respiratory Syncytial Virus
• Intervention / Treatment: Other: CXCL1; Drug: Danirixin

• Study Type: Interventional
• Enrollment (Actual): 40
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • New York
    • Syracuse, New York, United States, 13210
      • GSK Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 64 years (Child, Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

Healthy Adults

• Male/females aged between 18 and 64 years of age inclusive, at the time of signing the informed consent
• Healthy as determined by a responsible and experienced physician, based on a medical evaluation including medical history and physical examination. A subject with a clinical abnormality parameter(s) which is not specifically listed in the inclusion or exclusion criteria, may be included only if the Investigator in consultation with the GSK Medical Monitor agree and document that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures.
• Body weight >= 45 kilograms (kg) and body mass index (BMI) within the range 18.5-32 kg/meter^2 (inclusive).
• A female subject is eligible to participate if she is not known to be pregnant by history or delivered within the past 3 months.
• Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.

RSV Infected Children

• Male/females aged <2 years, at the time of parent(s)/legal guardian(s) signing the informed consent.
• Healthy, except for current RSV-infection, as determined by a responsible and experienced physician, based on a medical evaluation including medical history and physical examination. A subject with a clinical abnormality parameter(s) which is not specifically listed in the inclusion or exclusion criteria, may be included only if the Investigator in consultation with the GSK Medical Monitor agree and document that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures.
• Body weight >= 3.5 kg
• Documented RSV-infection, either by RSV-antigen or RSV-PCR
• RSV-infection clinical symptom onset within 5 days of blood draw based on parent(s)/guardian(s) history.
• Parent(s)/legal guardian(s) of child capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.

Exclusion Criteria:

Healthy Adults

• Any clinical infection within the past 14 days per subject's history.
• Acute or chronic infectious/inflammatory diseases by history, including but not limited to, hepatitis B, hepatitis C, human immuno virus (HIV), inflammatory bowel disease, liver / biliary disease, pancreatitis, arthritis.
• Receiving systemic anti-inflammatory or immune modulating medications, including but not limited to, non-steroidal anti-inflammatory (NSAIDS) and glucocorticoids, within the past 14 days. All other medications are permitted.
• Any alcoholic beverage within 24 hours of blood collection and history of regular alcohol consumption within 6 months of the study defined as: an average weekly intake of >14 drinks for males or >7 drinks for females. One drink is equivalent to 12 gram (g) of alcohol: 12 ounces (360 mL) of beer, 5 ounces (150 mL) of wine or 1.5 ounces (45 mL) of 80 proof distilled spirits.
• Current smoking or history or regular use of tobacco- or nicotine-containing products within 6 months prior to screening.
• Strenuous exercise within 48 hours prior to the blood collection.
• Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 56 day period.
• The subject has participated in a clinical trial and has received an investigational product within the following time period prior to signing the informed consent in the current study: 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer).

RSV Infected Children

• A Child in Care: A child who has been placed under the control or protection of an agency, organization, institution or entity by the courts, the government or a government body, acting in accordance with powers conferred on them by law or regulation. A child in care can include a child cared for by foster parents or living in a care home or institution, provided that the arrangement falls within the definition above. A child in care does not include a child who is adopted or has an appointed legal guardian.
• Any clinical infection, besides current RSV infection, within the past 14 days per subject's history
• Acute or chronic infectious/inflammatory diseases by history, including but not limited to, hepatitis B, hepatitis C, HIV, liver / biliary disease, pancreatitis
• Receiving systemic anti-inflammatory or immune modulating medications, including but not limited to, NSAIDS and glucocorticoids, within the past 14 days. All other medications are permitted.
• Past medical history including prematurity <37 weeks, congenital heart disease, chronic lung disease, or immunodeficiency.
• Where participation in the study would result in withdrawal of blood or blood products in excess of 2 mL/kg for 24 hours before or after the study period.
• The subject has participated in a clinical trial and has received an investigational product within the following time period prior to parent(s)/guardian(s) signing the informed consent in the current study: 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part 1; Blood sample will be collected from the RSV-infected children <2 years and healthy adults participants. Escalating concentrations of CXCL1 will be added to whole blood in vitro and CD11b up regulation on peripheral blood neutrophils will be analyzed	Other: CXCL1; Escalating concentrations of CXCL1 will be added to whole blood in vitro. A CXCL1/CD11b upregulation concentration response curve will determine the concentration to be used in Part 2.
Experimental: Part 2; Blood sample will be collected from the RSV-infected children <2 years and healthy adults participants. Escalating concentrations of danirixin will be added to whole blood in vitro with a fixed concentration of CXCL1 to determine inhibition of CD11b expression on peripheral blood neutrophils	Other: CXCL1; Escalating concentrations of CXCL1 will be added to whole blood in vitro. A CXCL1/CD11b upregulation concentration response curve will determine the concentration to be used in Part 2.; Drug: Danirixin; Powdered form for in-vitro administration to blood sample

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent inhibition of Chemokine Ligand (CXCL1)-induced Cluster of Differentiation 11b expression on peripheral blood neutrophils in RSV-infected children <2 years and healthy adults after in vitro incubation with escalating concentrations of danirixin	Blood (1.5 milliliter [mL]) will be collected from a peripheral vein via indwelling catheter or direct venepuncture. Escalating concentrations of danirixin (0.03-100 micromoles) will be added to whole blood in vitro with a fixed concentration of CXCL1 to determine inhibition of Cluster of Differentiation 11b (CD11b) expression on peripheral blood neutrophils analyzed by Fluorescence-Activated Cell sorting (FACs).	Day 1

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
CD11b upregulation on peripheral blood neutrophils in RSV-infected children <2 years and healthy adults after in vitro incubation with escalating concentrations of CXCL1	Blood (1.0 mL) will be collected from a peripheral vein via indwelling catheter or direct venepuncture. Escalating concentrations of CXCL1 will be added to whole blood in vitro and CD11b upregulation on peripheral blood neutrophils will be analyzed by FACS	Day 1
Differences in percent inhibition of CXCL1-induced CD11b expression on peripheral blood neutrophils in RSV-infected children <2 years and healthy adults after in vitro incubation with escalating concentrations of danirixin	Inhibition of CD11b upregulation will be evaluated to determine if there is a similar concentration-response relationship between healthy adults and RSV-infected children	Day 1

Collaborators and Investigators

• Sponsor: GlaxoSmithKline

Study record dates

Study Major Dates

• Study Start (Actual): January 13, 2014
• Primary Completion (Actual): July 2, 2015
• Study Completion (Actual): July 2, 2015

Study Registration Dates

• First Submitted: January 9, 2014
• First Submitted That Met QC Criteria: July 24, 2014
• First Posted (Estimate): July 28, 2014

Study Record Updates

• Last Update Posted (Actual): May 9, 2017
• Last Update Submitted That Met QC Criteria: May 5, 2017
• Last Verified: May 1, 2017

More Information

Terms related to this study

• Keywords: Children; Neutrophils; Respiratory Syncytial Virus; Danirixin; CXCR2; CD11b; CXCL1
• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Diseases; Paramyxoviridae Infections; Mononegavirales Infections; Pneumovirus Infections; Respiratory Tract Infections; Respiratory Syncytial Virus Infections
• Other Study ID Numbers: 200591