An Investigation of the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of GSK2245035 in Healthy Volunteers and Allergic Rhinitics.
- Conditions
- Rhinitis, Allergic, Seasonal
- Interventions
- Drug: 20ng GSK2445053Drug: PlaceboDrug: 400ng GSK2445053Drug: 100ng GSK2445053Drug: 1000ng GSK2445053Drug: 4000ng GSK2445053Drug: 200ng GSK2445053Drug: 2000ng GSK2445053
- Registration Number
- NCT01480271
- Lead Sponsor
- GlaxoSmithKline
- Brief Summary
GSK2245035 is a highly selective Toll-like Receptor 7(TLR7) agonist capable of preferentially inducing the production of interferon alpha (IFNα) versus tumor necrosis factor alpha (TNFα). The aim of this FTIH study is to collect tolerability, pharmacokinetic (PK) and pharmacodynamic (PD) information to enable the identification of appropriate safe doses of intranasal (i.n) GSK2245035, associated with up-regulation of TLR7-mediated genes in the nasal milieu, for use in subsequent clinical drug development studies. There will be two parts to the study: Healthy Volunteers will be dosed in escalating single doses in Part 1, followed by Allergic Rhinitis (AR) subjects dosed similarly in Part 2.
- Detailed Description
This is a First Time in Human (FTIH) study to investigate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of single, escalating doses of intranasal (i.n.) GSK2245035 in healthy male volunteers (HVT) and male subjects with allergic rhinitis (AR). The safety and tolerability of single i.n. GSK2245035 dosing will be assessed and established in HVT before the initiation of evaluation in AR.
GSK2245035 is a highly selective Toll-like Receptor 7 (TLR7) agonist capable of preferentially inducing the production of IFNα rather than TNFα. Activation of TLR7 is known to result in upregulation of co-stimulatory signals on antigen-presenting cells and in generation of pro-inflammatory mediators that can shift bystander immune responses towards a Helper T-cell Type 1/ Regulatory T cell (Th1/Treg) phenotype and therefore reduce the magnitude of Helper T-cell Type 2 (Th2) reactivity. In this context, it is proposed that i.n. GSK2245035 administration may alter the airways immune environment in a way that results in long-lasting control of AR symptoms and potentially disease remission through persistent modification of the underlying aberrant Th2 responsiveness to aeroallergens.
The aim of this study is to collect tolerability, PK and PD information to enable the identification of appropriate safe doses of i.n. GSK2245035, associated with up-regulation of TLR7-mediated genes in the nasal milieu, for use in subsequent clinical drug development studies. The study will be divided in to two parts. Part 1, involving only healthy volunteers, will consist of 8 cohorts receiving doses from 2 nanograms (2 ng) to 4000ng or a placebo dose. Administration within each cohort will be staggered so that two subjects (one receiving drug and one placebo) will be dosed and monitored for 24 hours before any subsequent doses.
Screening for part 2 of the study will begin once data from cohort 4 in part 1 has been found to be satisfactory. Part 2 will involve subjects with Allergic Rhinitis and be divided into three cohorts receiving doses between 20ng and 4000ng or a placebo dose.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- Male
- Target Recruitment
- 61
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Part 1 Cohort 1 GSK2445053 2 ng GSK2445053 2ng GSK2245053 Part 1 Cohort 2 GSK2445053 20ng GSK2445053 20ng GSK2445053 Part 1 Cohort 4 Placebo Placebo Placebo Part 1 Cohort 3 Placebo Placebo Placebo Part 1 Cohort 2 Placebo Placebo Placebo Part 1 Cohort 1 Placebo Placebo Placebo Part 1 Cohort 5 GSK245053 400ng GSK2445053 400ng GSK2445053 Part 1 Cohort 3 GSK2245053 100ng GSK2445053 100ng GSK2445053 Part 1 Cohort 5 Placebo Placebo Placebo Part 1 Cohort 6 GSK2445053 1000ng GSK2445053 1000ng GSK2245053 Part 1 Cohort 7 Placebo Placebo Placebo Part 1 Cohort 8 GSK2445053 4000ng GSK2445053 4000ng GSK2445053 Part 1 Cohort 4 GSK2445053 200ng GSK2445053 200ng GSK2445053 Part 1 Cohort 6 Placebo Placebo Placebo Part 1 Cohort 7 GSK2445053 2000ng GSK2445053 2000ng GSK2445053 Part 1 Cohort 8 Placebo Placebo Placebo
- Primary Outcome Measures
Name Time Method Nasal Tolerability From screening until follow-up Nasal examination and nasal symptom to assess nasal tolerability of single escalating doses of GSK2245035 in subjects with Allergic Rhinitis
TLR7-associated Biomarkers From pre-dose until 3 days post-dose Evaluation of the induction of TLR7-induced blood biomarkers in the nasal lavage and nasal tissues of individuals with AR following single GSK2245035 administration versus placebo.
Safety From screening until follow-up General safety endpoints, including AEs, vital signs, 12-lead ECG, body temperature and clinical laboratory safety tests to evaluate the safety and nasal tolerability of single escalation doses of GSK2245035 in healthy volunteers and individuals with Allergic Rhinitis.
- Secondary Outcome Measures
Name Time Method Correlation Evaluation From pre-dose until 3 days post-dose To evaluate the correlation between GSK2245035 dose - systemic PK - PD blood biomarkers - PD nasal biomarkers in healthy volunteer and subjects with Allergic Rhinitis.
Systemic PK From pre-dose until 3 days post-dose Standard single dose derived plasma PK parameters for GSK2245035 in healthy volunteers and individuals with Allergic Rhinitis
Trial Locations
- Locations (1)
GSK Investigational Site
🇳🇱Zuidlaren, Netherlands