A Randomized, Double-blind, Placebo-controlled First Time Into Human Study to Investigate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Intranasal Dosing With GSK2245035, a TLR7 Agonist, in Healthy Volunteers and Allergic Rhinitics.
Inclusion Criteria
Inclusion Criteria for all subjects (parts 1 and 2)
- Healthy as determined by a responsible and experienced physician, based on a medical
evaluation including medical history,physical examination, laboratory testsand
cardiac monitoring. A subject with a clinical abnormality or laboratoryparameters
outside the reference range for the population being studied may be included only if
the Investigator agrees that the finding is unlikely to introduce additional risk
factors and will not interfere with the study procedures.
- Male between 18 and 55 years of age inclusive, at the time of signing the informed
consent.
- Male subjects with female partners of child-bearing potential must agree to use one
of the contraception methods listed in Section 8.1 of the protocol. This criterion
must be followed from the time of the first dose of study medication until one week
post-dosing.
- Body weight greater than or equal to 50 kilograms (kg) and Body Mass Index (BMI)
within the range 19 - 29.9 kilograms per square metre (kg/m2) inclusive.
- 12 lead Electrocardiogram without any clinically significant abnormality as judged by
the Investigator, and average QT interval (QTc), QT interval corrected for Basett
(QTcB) or QT interval corrected for Fredericia (QTcF) less than 450 milliseconds
- Aspartate transaminase (AST), alanine transamine (ALT), alkaline phosphatase and
bilirubin less than 1.5 x Upper Limit of Normal (ULN) (isolated bilirubin greater
than1.5 x ULN is acceptable if bilirubin is fractionated and direct bilirubin less
than 35%).
- Subjects have a screening pre-challenge Forced Expiratory Volume in 1 second (FEV1)
greater than or equal to 80% and a baseline FEV1/FVC greater than or equal to 70% of
the predicted value.
- Subjects should refrain from smoking between screening and the end of the study, and
have a negative test for cotinine/ carbon monoxide (CO) at pre-dose.
- Capable of giving written informed consent, which includes compliance with the
requirements and restrictions listed in the consent form.
- Available to complete all the required study measurements.
Inclusion Criteria for Allergic Rhinitics only (Part 2)
- History and diagnosis of symptomatic seasonal allergic rhinitis to pollen, for more
than 3 years.
- Positive skin allergy test (wheal greater than or equal to 4miliimetres) or
radioallergosorbent test (RAST) greater than or equal to Class 2, for pollen
allergens.
- Subjects have a Total Nasal Symptom Score (TNSS) score of greater than or equal to 3
during the current pollen season (Total nasal symptom score is the sum of nasal
congestion, rhinorrhoea, nasal itch and sneeze, each of which are scored on a scale
from 0 to 3).
Exclusion Criteria for all subjects (Parts 1 and 2):
- History of immunologic or haematologic deficiencies or diseases, except conditions
that in the opinion of the Investigator and the GSK Medical Monitor are unlikely to
introduce additional risk factors.
- Current diagnosis of asthma.
- Nasal conditions likely to affect the outcome of the study, i.e. nasal septal
perforation, nasal polyps, other nasal malformations or history of frequent
nosebleeds.
- History of haematologic, gastro-intestinal, hepatic, renal or other condition that
may influence the absorption, distribution, metabolism, excretion or action of the
drug.
- History of frequent headaches and/or migraine.
- A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody
result within 3 months of screening
- A positive test for Human Immunodeficiency Virus antibody
- A positive screening or pre-dose drug/alcohol screen, or a positive pre-dose smoking
test
- 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 grams (8g) of alcohol: a half-pint or
approximately 240 millilitres (240 mL) of beer, 1 glass (125 mL) of wine or 1 (25 mL)
measure of spirits.
- The subject has participated in a clinical trial and has received an investigational
product within 3 months prior to the first dosing day in the current study.
- Exposure to more than four new chemical entities within 6 months prior to the first
dosing day.
- History of drug or other allergy that, in the opinion of the Investigator or GSK
Medical Monitor, contraindicates participation in this study.
- Donation of blood or blood products in excess of 500 mL within a 90-day period.
- History of sensitivity to heparin or heparin-induced thrombocytopenia
- Unwillingness or inability to follow the procedures outlined in the protocol.
- Subject is mentally or legally incapacitated
Exclusion Criteria for healthy volunteers only (part 1)
- History of rhinitis, including allergic, non-allergic rhinitis and rhinosinusitis.
Subjects with recent upper respiratory tract infections (URTIs) will be allowed in
the study only if their nasal symptoms have been completely resolved for more than 3
weeks prior to screening.
- Use of prescription or non-prescription drugs, including vitamins, herbal and dietary
supplements (including St John's Wort) within 7 days (or 14 days if the drug is a
potential enzyme inducer) or 5 half-lives (whichever is longer) prior to entry to the
clinic, unless in the opinion of the Investigator and GSK Medical Monitor the
medication will not interfere with the study procedures or compromise subject safety.
Exclusion criteria for Allergic Rhinitics only (part 2)
- Subjects with recent upper respiratory tract infections (URTIs) will be allowed in
the study only if their nasal symptoms have been completely resolved for more than 3
weeks prior to screening.
- Use of prescription or non-prescription drugs, including vitamins, herbal and dietary
supplements (including St John's Wort) within 7 days (or 14 days if the drug is a
potential enzyme inducer) or 5 half-lives (whichever is longer) prior to entry into
the clinic, unless in the opinion of the Investigator and GSK Medical Monitor the
medication will not interfere with the study procedures or compromise subject safety.
Subjects using treatment for allergies and AR may participate in the study if they
remain free of medication for the following periods of time prior to entry into the
clinic:
- Nasal antihistamines: 48 hours
- Oral antihistamines A (cetirizine, fexofenadine, loratadine, desloratadine): 72
hours
- Oral antihistamines B (all others): 72 hours
- Nasal decongestants: 24 hours
- Oral decongestants: 24 hours
- Nasal glucocorticosteroids: 4 weeks
- Oral glucocorticosteroids: 12 weeks
- Oral leukotriene receptor antagonists: 7 days