An Investigation of the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of GSK2245035 in Healthy Volunteers and Allergic Rhinitics.

NCT01480271 | Completed Phase 1

• 1 other identifier: 114450
• Study Type: interventional
• Target: 61
• Locations: 1 country
• Sites: 1

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.

Conditions

Rhinitis, Allergic, Seasonal

Keywords

Allergic Rhinitis; Healthy Volunteers; Single Dose Escalation; TLR7 agonist; First Time in Human Study

Outcome Measures

Primary Outcomes (3)

• Safety

  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.

  From screening until follow-up

• Nasal Tolerability

  Nasal examination and nasal symptom to assess nasal tolerability of single escalating doses of GSK2245035 in subjects with Allergic Rhinitis

  From screening until follow-up

• TLR7-associated Biomarkers

  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.

  From pre-dose until 3 days post-dose

Secondary Outcomes (2)

• Systemic PK

  From pre-dose until 3 days post-dose

• Correlation Evaluation

  From pre-dose until 3 days post-dose

Study Arms (16)

Part 1 Cohort 1 GSK2445053

EXPERIMENTAL

2ng GSK2245053

Drug: 2 ng GSK2445053

Part 1 Cohort 1 Placebo

PLACEBO COMPARATOR

Placebo

Drug: Placebo

Part 1 Cohort 2 GSK2445053

EXPERIMENTAL

20ng GSK2445053

Drug: 20ng GSK2445053

Part 1 Cohort 2 Placebo

PLACEBO COMPARATOR

Placebo

Drug: Placebo

Part 1 Cohort 3 GSK2245053

EXPERIMENTAL

100ng GSK2445053

Drug: 100ng GSK2445053

Part 1 Cohort 3 Placebo

PLACEBO COMPARATOR

Placebo

Drug: Placebo

Part 1 Cohort 4 GSK2445053

EXPERIMENTAL

200ng GSK2445053

Drug: 200ng GSK2445053

Part 1 Cohort 4 Placebo

PLACEBO COMPARATOR

Placebo

Drug: Placebo

Part 1 Cohort 5 GSK245053

EXPERIMENTAL

400ng GSK2445053

Drug: 400ng GSK2445053

Part 1 Cohort 5 Placebo

PLACEBO COMPARATOR

Placebo

Drug: Placebo

Part 1 Cohort 6 GSK2445053

EXPERIMENTAL

1000ng GSK2245053

Drug: 1000ng GSK2445053

Part 1 Cohort 6 Placebo

PLACEBO COMPARATOR

Placebo

Drug: Placebo

Part 1 Cohort 7 GSK2445053

EXPERIMENTAL

2000ng GSK2445053

Drug: 2000ng GSK2445053

Part 1 Cohort 7 Placebo

PLACEBO COMPARATOR

Placebo

Drug: Placebo

Part 1 Cohort 8 GSK2445053

EXPERIMENTAL

4000ng GSK2445053

Drug: 4000ng GSK2445053

Part 1 Cohort 8 Placebo

PLACEBO COMPARATOR

Placebo

Drug: Placebo

Interventions

2 ng GSK2445053 DRUG

2ng GSK2445053 administered intranasally

Part 1 Cohort 1 GSK2445053

20ng GSK2445053 DRUG

20ng GSK2445053 administered intranasally

Part 1 Cohort 2 GSK2445053

100ng GSK2445053 DRUG

100ng GSK2445053 administered intranasally

Part 1 Cohort 3 GSK2245053

200ng GSK2445053 DRUG

200ng GSK2445053 administered intranasally

Part 1 Cohort 4 GSK2445053

400ng GSK2445053 DRUG

400ng GSK2445053 administered intranasally

Part 1 Cohort 5 GSK245053

1000ng GSK2445053 DRUG

1000ng GSK2445053 administered intranasally

Part 1 Cohort 6 GSK2445053

2000ng GSK2445053 DRUG

2000ng GSK2445053 administered intranasally

Part 1 Cohort 7 GSK2445053

4000ng GSK2445053 DRUG

4000ng GSK2445053 administered intranasally

Part 1 Cohort 8 GSK2445053

Placebo DRUG

Placebo administered intranasally

Part 1 Cohort 1 Placebo; Part 1 Cohort 2 Placebo; Part 1 Cohort 3 Placebo; Part 1 Cohort 4 Placebo; Part 1 Cohort 5 Placebo; Part 1 Cohort 6 Placebo; Part 1 Cohort 7 Placebo; Part 1 Cohort 8 Placebo

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: male
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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.
• 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.
• 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).

You may not qualify if:

• 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.

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (1)

GSK Investigational Site

Zuidlaren, 9471 GP, Netherlands

Location

Related Publications (1)

• Tsitoura D, Ambery C, Price M, Powley W, Garthside S, Biggadike K, Quint D. Early clinical evaluation of the intranasal TLR7 agonist GSK2245035: Use of translational biomarkers to guide dosing and confirm target engagement. Clin Pharmacol Ther. 2015 Oct;98(4):369-80. doi: 10.1002/cpt.157.

  PMID: 26044169 DERIVED

Related Links

• Results for study 114450 can be found on the GSK Clinical Study Register.
• Researchers can use this site to request access to anonymised patient level data and/or supporting documents from clinical studies to conduct further research.

MeSH Terms

Conditions

Rhinitis, Allergic, Seasonal; Rhinitis, Allergic

Condition Hierarchy (Ancestors)

Rhinitis; Nose Diseases; Respiratory Tract Diseases; Respiratory Hypersensitivity; Otorhinolaryngologic Diseases; Hypersensitivity, Immediate; Hypersensitivity; Immune System Diseases

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 23, 2011
• First Posted: November 28, 2011
• Study Start: May 30, 2011
• Primary Completion: September 30, 2011
• Study Completion: September 30, 2011
• Last Updated: June 28, 2017

Record last verified: 2017-06

Data Sharing

• IPD Sharing: Will share

Locations

NL (1)