Clinical trial NCT01818024: A Study to Investigate the Safety Tolerability Pharmacokinetics, and Pharmacodynamics of Inhaled and Intravenous GSK2862277 in Healthy Volunteers
Official title: A Three Part, Randomised, Placebo-controlled Study to Investigate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Single and Repeat Doses of Inhaled and Intravenous GSK2862277 in Healthy Volunteers
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Respiratory Disorders
Keywords: healthy volunteer
TNFR1
domain antibody
Lung injury
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2013-03-26
Enrollment: 54
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This will be a 3 part study to investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of single and repeat doses of GSK2862277 administered via inhalation (IH) or intravenous (IV) routes in healthy subjects.

Part 1 of this study will involve an initial assessment of safety, tolerability and pharmacokinetics of GSK286227, via single escalating intravenous doses, compared to a predecessor molecule, GSK1995057. After completion of Part 1 an interim data review will occur which will assess key comparability criteria to inform progression to Part 2 of the study.

Part 2 of the study will involve single doses of GSK2862277 at a level predicted to be at or close to therapeutic dose levels. Part 2 will investigate both intravenous and inhaled routes of administration, in sequential manner, respectively. An interim data review will also occur after completion of Part 2, where all data accumulated previously will be assessed to examine appropriateness to progress to Part 3.

Part 3 of the study will involve 5 days of repeat dosing via both inhaled and intravenous routes using the same dose administered in Part 2.


Eligibility criteria: Inclusion Criteria:

* Male or female between 18 and 65 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, physical examination, laboratory tests and cardiac monitoring. A subject with a clinical abnormality or laboratory parameters outside the reference range for the population being studied may be included only if the Investigator and the GSK Medical Monitor agree that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures.
* Subject is positive at screening for HAVH autoantibodies against GSK1995057 (Part 1 only).
* A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening
* A positive pre-study drug/alcohol screen.
* A positive test for human immunodeficiency virus (HIV) antibody.
* Exposure to more than four new chemical entities within 12 months prior to the first dosing day.

Exclusion Criteria:

* A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening
* A positive pre-study drug/alcohol screen.
* A positive test for human immunodeficiency virus (HIV) antibody.
* Exposure to more than four new chemical entities within 12 months prior to the first dosing day

Primary outcomes:
measure: Safety and tolerability of single IV or IH dose of GSK2862277 assessed by number of subjects with adverse events (AE)s in Part 1 and Part 2
timeFrame: Up to 42 days
measure: Safety and tolerability of repeat IV or IH dose of GSK2862277 assessed by number of subjects with AEs in Part 3
timeFrame: Up to 42 days
measure: Safety and tolerability of single IV or IH dose of GSK2862277 assessed by laboratory tests in Part 1 and Part 2
timeFrame: Up to 42 days
measure: Safety and tolerability of repeat IV or IH dose of GSK2862277 as assessed by laboratory tests in Part 3
timeFrame: Up to 42 days
measure: Safety and tolerability of single IV or IH dose of GSK2862277 assessed by vital signs in Part 1 and Part 2
timeFrame: Up to 42 days
measure: Safety and tolerability of repeat IV or IH dose of GSK2862277 assessed by vital signs in Part 3
timeFrame: Up to 42 days
measure: Safety and tolerability of single IV or IH dose of GSK2862277 assessed by ECG in Part 1 and Part 2
timeFrame: Up to 42 days
measure: Safety and tolerability of repeat IV or IH dose of GSK2862277 assessed by ECG in Part 3
timeFrame: Up to 42 days
measure: Safety and tolerability of single IV or IH dose of GSK2862277 assessed by spirometry monitoring in Part 1 and Part 2
timeFrame: Up to 42 days
measure: Safety and tolerability of repeat IV or IH dose of GSK2862277 assessed by spirometry monitoring in Part 3
timeFrame: Up to 42 days
measure: Safety and tolerability of single IV dose of GSK2862277 as assessed by measurement of plasma cytokines in Part 1
timeFrame: Up to 42 days
measure: Immunogenicity in subjects receiving single IV or IH dose of GSK2862277 in Part 1 and Part 2
timeFrame: Up to 60 days
measure: Immunogenicity in subjects receiving repeat IV or IH dose of GSK2862277 in Part 3
timeFrame: Up to 60 days
Secondary outcomes:
measure: Pharmacokinetic (PK) parameters in subjects receiving single IV or IH dose of GSK2862277 in Part 1 and Part 2
timeFrame: Up to 48 hours post dose
measure: PK parameters in subjects receiving repeat IV dose of GSK2862277 in Part 3 Cohort 3a
timeFrame: Up to 48 hours post last dose
measure: PK parameters in subjects receiving repeat IH dose of GSK2862277 in Part 3 Cohort 3b
timeFrame: Up to 48 hours post last dose
measure: PK parameters in subjects receiving single IV dose of GSK2862277 in Part 1
timeFrame: Up to 48 hours post last dose
measure: Pharmacodynamic and immune function biomarkers in serum of subjects receiving single IV or IH dose of GSK2862277 in Part 1 and Part 2
timeFrame: Up to 48 hours post last dose
measure: Pharmacodynamic and immune function biomarkers in serum of subjects receiving repeat IV or IH dose of GSK2862277in Part 3
timeFrame: Up to 48 hours post last dose
measure: Change from baseline in IL-8 expression in ex vivo WBA in subjects receiving single IV 0.05 mg/kg dose of GSK2862277 in Part 1 in Cohort1c
timeFrame: Up to 12 hours post dose
measure: Composite of urine parameters in subjects receiving single IV 2 mg/kg dose of GSK2862277 in Part 2 in Cohort 2a
timeFrame: Up to 48 hours post dose
Other outcomes:
Locations:
city: Harrow
country: United Kingdom
facility: GSK Investigational Site
state: Middlesex
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Cordy JC, Morley PJ, Wright TJ, Birchler MA, Lewis AP, Emmins R, Chen YZ, Powley WM, Bareille PJ, Wilson R, Tonkyn J, Bayliffe AI, Lazaar AL. Specificity of human anti-variable heavy (VH ) chain autoantibodies and impact on the design and clinical testing of a VH domain antibody antagonist of tumour necrosis factor-alpha receptor 1. Clin Exp Immunol. 2015 Nov;182(2):139-48. doi: 10.1111/cei.12680. Epub 2015 Sep 11.