A Study to Investigate the Safety Tolerability Pharmacokinetics, and Pharmacodynamics of Inhaled and Intravenous GSK2862277 in Healthy Volunteers

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

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.

Study Overview

• Status: Completed
• Conditions: Respiratory Disorders
• Intervention / Treatment: Drug: Single IV dose of GSK2862277; Drug: Matching placebo single dose IV infusion; Drug: Single IH dose of GSK2862277; Drug: Matching placebo single dose IH; Drug: Repeat IV dose of GSK2862277; Drug: Matching placebo repeat dose IV infusion; Drug: Repeat IH dose selected of GSK2862277 from Part 2; Drug: Matching placebo repeat dose IH

• Study Type: Interventional
• Enrollment (Actual): 54
• Phase: Phase 1

Contacts and Locations

Study Locations

• United Kingdom
  • Middlesex
    • Harrow, Middlesex, United Kingdom, HA13UJ
      • GSK Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Single Group Assignment
• Masking: Single

Number of Arms

11

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part 1: Cohort 1a; Single IV dose of GSK2862277 as a continuous infusion over 2 hours.	Drug: Single IV dose of GSK2862277; GSK2862277 solution available in a 40 mg vial for IV administration.
Experimental: Part 1: Cohort 1b; Single IV dose of GSK2862277 as a continuous infusion over 3 hours.	Drug: Single IV dose of GSK2862277; GSK2862277 solution available in a 40 mg vial for IV administration.
Experimental: Part 1: Cohort 1c; Single IV dose of GSK2862277 as a continuous infusion over 3 hours.	Drug: Single IV dose of GSK2862277; GSK2862277 solution available in a 40 mg vial for IV administration.
Experimental: Part 2: Cohort 2a GSK2862277; Single IV dose of GSK2862277 as a continuous infusion over 1 hour.	Drug: Single IV dose of GSK2862277; GSK2862277 solution available in a 40 mg vial for IV administration.
Experimental: Part 2: Cohort 2a Placebo; Matching placebo will be administered as a continuous IV infusion over 1 hour.	Drug: Matching placebo single dose IV infusion; Matching placebo solution available for IV administration.
Experimental: Part 2: Cohort 2b GSK2862277; Single IH dose of GSK2862277.	Drug: Single IH dose of GSK2862277; GSK2862277 nebulised solution available in a 40 mg vial for IH administration.
Experimental: Part 2: Cohort 2b Placebo; Matching placebo will be administered.	Drug: Matching placebo single dose IH; Matching placebo nebulised solution available for IH administration.
Experimental: Part 3: Cohort 3a GSK2862277; IV dose of GSK2862277 (decided from Part 2) as a continuous infusion over 1 hour for daily 5 days.	Drug: Repeat IV dose of GSK2862277; GSK2862277 solution available in a 40 mg vial for IV administration.
Experimental: Part 3: Cohort 3a Placebo; Matching placebo will be administered as IV infusion over 1 hour daily for 5 days.	Drug: Matching placebo repeat dose IV infusion; Matching placebo solution available for IV administration.
Experimental: Part 3: Cohort 3b GSK2862277; Repeat IH dose of GSK2862277 (decided from Part 2) daily for 5 days.	Drug: Repeat IH dose selected of GSK2862277 from Part 2; GSK2862277 nebulised solution available in a 40 mg vial for IH administration.
Experimental: Part 3: Cohort 3b Placebo; Matching placebo will be administered as IH daily for 5 days.	Drug: Matching placebo repeat dose IH; Matching placebo nebulised solution available for IH administration.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	Safety and tolerability parameters will include recording of adverse events (AEs), throughout the study.	Up to 42 days
Safety and tolerability of repeat IV or IH dose of GSK2862277 assessed by number of subjects with AEs in Part 3	Safety and tolerability parameters will include recording of AEs, throughout the study.	Up to 42 days
Safety and tolerability of single IV or IH dose of GSK2862277 assessed by laboratory tests in Part 1 and Part 2	Laboratory tests will include haemogram, clinical chemistry, urine examination.	Up to 42 days
Safety and tolerability of repeat IV or IH dose of GSK2862277 as assessed by laboratory tests in Part 3	Laboratory tests will include haemogram, clinical chemistry, urine examination.	Up to 42 days
Safety and tolerability of single IV or IH dose of GSK2862277 assessed by vital signs in Part 1 and Part 2	Vital signs will include blood pressure (BP), heart rate respiration rate and body temperature.	Up to 42 days
Safety and tolerability of repeat IV or IH dose of GSK2862277 assessed by vital signs in Part 3	Vital signs will include BP, heart rate respiration rate and body temperature.	Up to 42 days
Safety and tolerability of single IV or IH dose of GSK2862277 assessed by ECG in Part 1 and Part 2	Safety data will include electrocardiogram (ECG) readings obtained at each timepoint during the study.	Up to 42 days
Safety and tolerability of repeat IV or IH dose of GSK2862277 assessed by ECG in Part 3	Safety data will include ECG readings obtained at each timepoint during the study.	Up to 42 days
Safety and tolerability of single IV or IH dose of GSK2862277 assessed by spirometry monitoring in Part 1 and Part 2	Spirometry monitoring will include forced expiratory volume in one second (FEV1) and forced vital capacity (FVC).	Up to 42 days
Safety and tolerability of repeat IV or IH dose of GSK2862277 assessed by spirometry monitoring in Part 3	Spirometry monitoring will include FEV1 and FVC.	Up to 42 days
Safety and tolerability of single IV dose of GSK2862277 as assessed by measurement of plasma cytokines in Part 1	Blood samples will be collected for assessment of plasma cytokines.	Up to 42 days
Immunogenicity in subjects receiving single IV or IH dose of GSK2862277 in Part 1 and Part 2	Presence of anti GSK2862277 binding antibodies will be evaluated.	Up to 60 days
Immunogenicity in subjects receiving repeat IV or IH dose of GSK2862277 in Part 3	Presence of anti GSK2862277 binding antibodies will be evaluated.	Up to 60 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetic (PK) parameters in subjects receiving single IV or IH dose of GSK2862277 in Part 1 and Part 2	The blood samples will be collected for plasma concentrations of GSK2862277.	Up to 48 hours post dose
PK parameters in subjects receiving repeat IV dose of GSK2862277 in Part 3 Cohort 3a	The blood samples will be collected for plasma concentrations of GSK2862277.	Up to 48 hours post last dose
PK parameters in subjects receiving repeat IH dose of GSK2862277 in Part 3 Cohort 3b	The blood samples will be collected for plasma concentrations of GSK2862277	Up to 48 hours post last dose
PK parameters in subjects receiving single IV dose of GSK2862277 in Part 1	The PK parameters will be compared with historic GSK1995057 PK data in Part 1	Up to 48 hours post last dose
Pharmacodynamic and immune function biomarkers in serum of subjects receiving single IV or IH dose of GSK2862277 in Part 1 and Part 2	The pharmacodynamic and immune function biomarkers in serum.	Up to 48 hours post last dose
Pharmacodynamic and immune function biomarkers in serum of subjects receiving repeat IV or IH dose of GSK2862277in Part 3	The pharmacodynamic and immune function biomarkers in serum.	Up to 48 hours post last dose
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	IL-8 expression in ex vivo whole blood essay (WBA).	Up to 12 hours post dose
Composite of urine parameters in subjects receiving single IV 2 mg/kg dose of GSK2862277 in Part 2 in Cohort 2a	The urine samples will be collected for urine concentrations of GSK2862277.	Up to 48 hours post dose

Collaborators and Investigators

• Sponsor: GlaxoSmithKline

Publications and helpful links

General Publications

• 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.

Helpful Links

• Researchers can use this site to request access to anonymised patient level data and/or supporting documents from clinical studies to conduct further research.

Study record dates

Study Major Dates

• Study Start (Actual): February 22, 2013
• Primary Completion (Actual): October 25, 2013
• Study Completion (Actual): October 25, 2013

Study Registration Dates

• First Submitted: February 14, 2013
• First Submitted That Met QC Criteria: March 21, 2013
• First Posted (Estimate): March 26, 2013

Study Record Updates

• Last Update Posted (Actual): May 15, 2017
• Last Update Submitted That Met QC Criteria: May 12, 2017
• Last Verified: May 1, 2017

More Information

Terms related to this study

• Keywords: healthy volunteer; Lung injury; TNFR1; domain antibody
• Additional Relevant MeSH Terms: Respiration Disorders; Respiratory Tract Diseases; Physiological Effects of Drugs; Immunologic Factors; Antibodies, Monoclonal
• Other Study ID Numbers: 116343

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Patient-level data for this study will be made available through www.clinicalstudydatarequest.com following the timelines and process described on this site.

Study Data/Documents

1. Dataset Specification
   Information identifier: 116343
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
2. Individual Participant Data Set
   Information identifier: 116343
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
3. Clinical Study Report
   Information identifier: 116343
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
4. Annotated Case Report Form
   Information identifier: 116343
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
5. Informed Consent Form
   Information identifier: 116343
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
6. Statistical Analysis Plan
   Information identifier: 116343
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
7. Study Protocol
   Information identifier: 116343
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register