GSK1995057 is a fully human, single domain antibody directed against the TNFR1 receptor. The purpose of this study is to investigate the safety, tolerability and pharmacokinetics of inhaled GSK1995057 in healthy subjects. The study will be in two parts. Part 1 is a single-dose escalating design of 5 sequential cohorts of healthy subjects. Part 2 is a single-dose, parallel group design comprising 2 groups of healthy subjects assessing the effect of GSK1995057 on lung inflammation following inhaled LPS challenge. Actual dose administered in Part 2 will be determined from emerging safety and PK data from Part 1 and Study TFR110951.
This study will be a randomised, placebo-controlled study to investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of single doses of inhaled GSK1995057 in healthy subjects. The study consists of 2 parts with a total of 6 cohorts. Part 1 will be conducted singleblind and Part 2 will be conducted single-blind with restrictions (i.e. subject and investigator only). The GSK Study Team and site pharmacist will remain unblinded to treatment allocation. Cohorts 1, 2, 3 and 4 (in Part 1) will receive a single inhaled dose of GSK1995057 or placebo. Cohort 5 will receive a single inhaled dose of GSK1995057 and in addition will have a bronchoalveolar lavage (BAL) sampling procedure conducted approximately 30 minutes post GSK1995057 dose. Subjects in Cohort 6 (Part 2) will be randomised to receive a high dose of GSK1995057 or placebo followed by an inhaled LPS challenge and BAL sampling procedure. Subjects will be required to visit the clinic over the course of 28 days after their dosing period for a follow up. Further visits for immunogenicity sampling may be conducted at 56 and 84 days post-first dose for subjects who show changes indicating a positive ADA response after dosing. Doses levels stipulated within the protocol are target doses based on predictions using the PK/PD model described in Section 1.2.2 of the clinical protocol. Part 1 will commence first and following acceptable safety and tolerability data will allow initiation of Part 2. All cohorts will participate in a single study session only.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
OTHER
Masking
SINGLE
Enrollment
53
inhaled dose (volume based on cohort)
BAL
50 μg
Sucrose, glycine, sodium dihydrogen phosphate and polysorbate 80 (volume to match active dose)
GSK Investigational Site
Belfast, United Kingdom
GSK Investigational Site
Harrow, United Kingdom
Safety and tolerability of ascending single inhaled doses of GSK1995057
Adverse event reporting, Laboratory safety data (clinical chemistry, hematology, urinalysis), Vital signs (blood pressure, heart rate, respiration rate, body temperature), ECG monitoring, Spirometry monitoring (FEV1, FVC)
Time frame: 56 Days
Levels and specificity of anti-GSK1995057 binding antibodies.
Presence of anti GSK1995057 binding antibodies. Where binding antibodies aredetected, levels and specificity of the antibodies will be evaluated
Time frame: Up to 84 Days
Plasma pharmacokinetics of ascending single inhaled doses of GSK1995057
Plasma concentrations of GSK1995057 and derived pharmacokinetic parameters in normal healthy subjects following single administration (all except Cohort 5).
Time frame: 3 days
Urine pharmacokinetics of single inhaled doses of GSK1995057
Urine concentrations of GSK1995057 and derived pharmacokinetic parameters in normal healthy subjects following a single administration (Part 1, except Cohort 5).
Time frame: 3 Days
Concentration of GSK1995057 in lung epithelial lining fluid after inhalation of a single dose
Bronchoalveolar lavage (BAL) concentrations of GSK1995057 and derived lung deposition parameters in normal healthy subjects following a single administration (Cohorts 5 \& 6 only). Bronchoalveolar lavage (BAL) concentrations of urea (Cohorts 5 \& 6 only).
Time frame: 1 Day
Effect of single inhaled doses of GSK1995057 on biomarkers
Pharmacodynamic and immune function biomarkers in serum (these may include but are not limited to sTNFR1 (free and total) and IL-6) (all except Cohort 5).
Time frame: 3 Days
Effect of single inhaled doses of GSK1995057 on biomarkers in BAL
Bronchoalveolar lavage (BAL) neutrophil counts at 6 h post LPS exposure (Cohort 5). Other pharmacodynamic and immune function biomarkers in BAL (these may include but are not limited to TNFα and IL-6) (Cohort 5).
Time frame: 1 Day
To explore the GSK1995057 PK-PD relationship
Pharmacodynamic and immune function biomarkers in serum and BALF (these may include but are not limited to sTNFR1 (free and total) and IL-6). Bronchoalveolar lavage (BAL) concentrations of GSK1995057 and derived lung deposition parameters in normal healthy subjects following a single administration (Cohort 5 and 6 only). Bronchoalveolar lavage (BAL) concentrations of urea (Cohorts 5 and 6 only). Change from baseline in IL-8 expression in ex vivo whole blood assay (WBA).
Time frame: 1 Day
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