A Study to Investigate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single Doses of Inhaled GSK1995057
A Study to Investigate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single Doses of Inhaled GSK1995057
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.
Inclusion Criteria:

 -  Healthy as determined by a responsible and experienced physician, based on a medical
 evaluation including medical history, physical examination, laboratory tests nd
 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 considers that the finding is unlikely to introduce additional risk
 factors and will not interfere with the study procedures. The investigator may discuss
 with GSK medical monitor as required.

 -  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 or hysterectomy; or postmenopausal defined as
 12 months of spontaneous amenorrhoea [in questionable cases a blood sample with
 simultaneous follicle stimulating hormone (FSH) greater than 40 MlU/ml and oestradiol
 less than 40 pg/ml (less than 140 pmol/L) is confirmatory]. Females on hormone
 replacement therapy (HRT) and whose menopausal status is in doubt will be required to
 discontinue HRT to allow confirmation of post-menopausal status prior to study
 enrollment. For most forms of HRT, at least 2-4 weeks will elapse between the
 cessation of therapy and the blood draw; this interval depends on the type and dosage
 of HRT. Following confirmation of their post-menopausal status, they can resume use of
 HRT during the study without use of a contraceptive method. Male subjects must agree
 to use one of the contraception methods listed in the protocol. This criterion must be
 followed from the time of the first dose of study medication until the last follow-up
 visit.

 -  Normal creatinine clearance values at screening (calculated from serum creatinine by a
 predicting equation using Cockcroft-Gault formula), normal serum creatinine value as
 defined by the local reference laboratory, normal urine microscopy and no significant
 proteinuria on dipstick testing.

 -  Body weight greater than and equal to 50 kg and BMI within the range 19 - 29.9 kg/m2
 (inclusive).

 -  No evidence of previous or active TB infection and a negative QuantiFERON TB Gold test
 taken within 7 days of dosing, and negative medical history with respect to active or
 latent mycobacterium tuberculosis complex infection.

 -  Normal spirometry (FEV1 greater than and equal to 85% of predicted, FEV1/FVC ratio
 greater than and equal to 70%) at screening. Predictions should be according to ECCS
 equations, and race corrections should be made for non-caucasians.

 -  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.

 -  Subjects who are able to use the inhaler device correctly.

 -  Able to read, comprehend and write English at a sufficient level to complete study
 related 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.

 -  History of and/or a positive test for toxoplasmosis consistent with active
 toxoplasmosis infection at the time of enrollment.

 -  A positive RT-PCR test for influenza A/B.

 -  Current evidence or history of an influenza-like illness as defined by fever (greater
 than 380C) and two or more of the following symptoms within the last 7 days: cough,
 sore throat, runny nose, sneezing, limb/joint pain, headache, vomiting/diarrhoea in
 the absence of a known cause, other than influenza.

 -  Corrected QT interval (QTc) >450msec.

 -  History of regular alcohol consumption within 6 months of the study defined as an
 average weekly intake of greater than 21 units for males or greater than 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 (approximately 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 greater than 5 cigarettes per day in the last 3
 months (Part 1); smokers are not eligible to take part in Part 2.