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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Respiratory Disorders

Intervention / Treatment
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* 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


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: Single


Arms and Interventions

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

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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healthy volunteer, TNFR1, domain antibody, Lung injury