Safety Study of GSK1995057 Given as Single and Repeat Intravenous Doses in Healthy Subjects.

Study Overview
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Brief Summary
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The main purpose of the study is to see how safe GSK1995057 is and how well it is tolerated after dosing. The study will also investigate how GSK1995057 is taken up, metabolised (chemically broken down), distributed through the body and excreted, and what some of the effects of the study drug are.

Detailed Description
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This study will be the first investigation of GSK1995057 in humans and is primarily designed to investigate safety and tolerability of single and repeat intravenously infused doses. The study will enrol healthy male subjects and healthy female subjects of non-child bearing potential and will also investigate immunogenicity, GSK1995057 distribution (pharmacokinetics), and potential impact on indicators of host immunity and normal immunological function. Safety, tolerability, immunogenicity, pharmacokinetic and pharmacodynamic data from this trial may facilitate further clinical investigations in healthy subjects dosed with GSK1995057 via the inhaled route, and ultimately clinical trials in patients with acute lung injury.

Official Title
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A Two-part, Randomised, Placebo-controlled Study to Investigate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamicsof Single and Repeat Doses of Intravenously Infused GSK1995057 in Healthy Subjects.

Conditions
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Respiratory Disorders

Intervention / Treatment
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* Drug: GSK1995057 single dose
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy as determined by a responsible and experienced physician. Male or female between 18 and 55 years of age inclusive A female subject is eligible to participate if she is of non-childbearing potential defined as pre-menopausal females with a documented tubal ligation, hysterectomy or bilateral oophorectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea and elevated FSH as per the local laboratory guidelines. Normal creatinine clearance values at screening Male subjects must agree to use one of the study specific contraception methods Body weight ≥ 50 kg and BMI within the range 19 - 29.9 kg/m2 (inclusive). Normal lung function at screening. Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form. Available to complete all study assessments. Able to read, comprehend and write English at a sufficient level to complete study elated materials. Exclusion Criteria: A history of Hepatitis B, Hepatitis C or HIV infection and/or a positive pre-study HIV, Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening Current or chronic history of liver disease, or known hepatic or biliary abnormalities. (With the exception of known Gilbert's syndrome or asymptomatic gallstones). A positive pre-study drug/alcohol screen. Evidence of previous or active mycobacterium tuberculosis complex infection Recent history of and/or a positive test for Toxoplasma consistent with active oxoplasmosis infection. A positive test for influenza A/B taken within 7 days before dosing. Current evidence or history of an influenza-like illness. Corrected QT interval (QTcF) >450msec from ECG readings. History of regular alcohol consumption within 6 months of the study defined as an average weekly intake of >21 units for males or >14 units for females. One unit is equivalent to 8 g of alcohol and the following can be used as a guide: a half-pint ( 240 ml) of beer, 1 glass (125 ml) of wine or 1 (25 ml) measure of spirits. The subject is unwilling to abstain from alcohol consumption from 24 hr prior to dosing until discharge from the clinic, and for 24 hr prior to all other out-patient clinic visits. Subjects with a smoking history of >10 cigarettes per day in the last 3 months. The subject has participated in a clinical trial and has received an investigational product within the following time period prior to the first dosing day in the current study: 90 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer) or exposure to more than four new chemical or biological entities within 12 months prior to the first dosing day. Subjects having received any type of vaccination within 3 weeks of the anticipated dosing start or are expected to be vaccinated within 3 weeks after the last dose. Current evidence of ongoing or acute infection, history of repeated or chronic significant infections or history of serious infection within three months of dosing. Subjects who have asthma or a history of asthma, COPD, other respiratory conditions or recurrent infections (a subject who suffered from childhood asthma but not as an adult may be included provided they fulfil other entry criteria). Subjects who have a known history of migraine headaches or are frequently suffering from other types of headaches which require medication (frequent defined as more than one headache in a fortnight). Use of prescription or non-prescription drugs (except simple analgesics), including vitamins, herbal and dietary supplements (including St John's Wort) within 7 days or 5 half-lives (whichever is longer) prior to the first dose of study medication, unless in the opinion of the Investigator and sponsors Medical Monitor the medication will not interfere with the study procedures or compromise subject safety. History of sensitivity to any of the study medications, or components thereof or a history of drug or other allergy including severe allergic reaction, angio-edema or anaphylaxis that, in the opinion of the investigator or sponsors Medical Monitor, contraindicates their participation. History of malignancy, except for adequately treated non-invasive cancer of the skin (basal or squamous cell) or cervical carcinoma in situ (>2 yrs prior to dosing). Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 3 month or 90 day period. Subject is unable to refrain from travelling to countries with a high prevalence of TB or other areas of prevalent infectious disease as judged by the investigator or the sponsors medical monitor from the start of screening until the final follow-up visit. Subject is mentally or legally incapacitated.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 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: Diagnostic
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: GSK1995057<br>Single intravenous dose | Drug: GSK1995057 single dose<br>* Single intravenous dose<br>|
| Placebo Comparator: Placebo<br>Single intravenous dose | Drug: Placebo<br>* Single intravenous dose<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Occurance of adverse events. | Number and type of adverse events recorded during study. | From start of screening until 84 days after completion of single dose (Part A subjects) or first dose (Part B subjects). | 
| Change from baseline in blood pressure. | Systolic and diastolic blood pressure values before and after dosing completion. | From start of screening until 28 days after completion of single or repeat dosing. | 
| Change from baseline in heart rate. | Heart rate before and after dosing completion. | From start of screening until 28 days after completion of single or repeat dosing. | 
| Change from baseline in respiration rate. | Respiration rate before and after dosing completion. | From start of screening until 28 days after completion of single or repeat dosing. | 
| Change from baseline in body temperature. | Body temperature before and after dosing completion. | From start of screening until 28 days after completion of single or repeat dosing. | 
| Change from baseline in heart function. | Holter recording. | For 24hrs during screening, then for 1 hour before dosing to 24 hours after dosing starts (in Part A subjects only, except for cohort 7). | 
| Change from baseline in heart function | Lead II cardiac telemetry. | From 1 hour before dosing to 12 hours after dosing starts for each dose. | 
| Change from baseline in heart function. | 12-lead ECG recording. | From start of screening until 28 days after completion of single or repeat dosing. | 
| Change from baseline in lung function. | FEV1 and FVC measurements. | From start of screening until 28 days after completion of single or repeat dosing. | 
| Change from baseline in laboratory safety data. | Clinical chemistry, haematology and routine urinalysis. | From start of screening until 28 days after completion of single or repeat dosing. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma pharmacokinetics of GSK1995057 | Levels of GSK1995057 in blood samples. | From the first day of dosing until 48 hours after the completion of dosing. | 
| Urine pharmacokinetics of GSK1995057 | Levels of GSK1995057 in urine samples from cohort 6 subjects only. | From 1 hour before the only dose until 48 hours after the dose. | 
| Bronchoalveolar lavage fluid (BALF) (saline flushed into and then collected from a lung) pharmacokinetics. | Levels of GSK1995057 in BALF from cohort 7 subjects only. | At 2 hrs after the completion of the only dose. | 
| Effect of GSK1995057 on host immunity and immunological function | Levels of pharmacodynamic and immune function biomarkers in blood samples. | From the day before dosing starts to 28 days after dosing completion. | 
| Effects of GSK1995057 on host immunity and immunological function | Levels of pharmacodynamic and immune function biomarkers in BALF from cohort 7 subjects only. | At 2 hrs after the completion of the only dose. | 
| Immunogenic effect of GSK1995057 | Levels of anti-GSK1995057 antibodies in blood samples | From the start of screening (cohorts 1-4 only) or from the day before the start of dosing until 84 days after the completion of single or repeat dosing. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Acute Lung Injury (ALI), Acute Respiratory Distress Syndrome (ARDS)