A Study to Investigate the Safety and Pharmacodynamics of Repeat Intranasal Administration of the TLR7 Agonist GSK2245035 in Subjects With Respiratory Allergies

NCT01607372 | Completed Phase 2

• 1 other identifier: 116392
• Study Type: interventional
• Target: 18
• Locations: 1 country
• Sites: 1

Brief Summary

GSK2245035 is a highly selective Toll-like receptor 7 (TLR7) agonist that stimulates preferentially the induction of type I interferons. Intranasal (i.n.) administration of GSK2245035 in humans causes immune changes in the upper airways milieu that may alter bystander immune responsiveness to aeroallergens and contribute to reduction of allergic reactivity in subjects with respiratory allergies. The purpose of this study is to examine the safety and pharmacodynamics (PD) of repeat dosing with i.n. GSK2245035 in subjects with respiratory allergies. The safety and pharmacodynamic response of four weekly administrations of escalating doses of i.n. GSK2245035 will be investigated and the maximum tolerated dose will be established. The study will be conducted in patients with symptomatic allergic rhinitis and mild asthma. The overall duration of the study will be up to a maximum of approximately 122 days considering 90 days screening period, 22 days treatment period and 10 days follow-up period.

Conditions

Asthma and Rhinitis

Keywords

TLR7 agonist, Respiratory Allergies, Allergic Rhinitis, Mild Allergic Asthma, Repeat Dose Safety, Reduction of Allergic Reactivity

Outcome Measures

Primary Outcomes (10)

• Number of participants experiencing adverse events (AEs)

  An AE is any untoward medical occurrence in a patient or clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.

  Up to 122 Days

• Hematology parameters as a safety measure

  The hematology parameters included are platelet count, red blood cell (RBC) count, white blood cell (WBC) count, reticulocyte count, hemoglobin, hematocrit, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), neutrophils, lymphocytes, monocytes, eosinophils, basophils.

  Up to 112 Days

• Clinical Chemistry parameters as a safety measure

  Clinical chemistry parameters included are blood urea nitrogen (BUN), creatinine, glucose, potassium, C-Reactive protein (CRP) potassium, chloride, total carbon dioxide, calcium, total and direct bilirubin, Aspartate transaminase (AST), Alanine transaminase (ALT), alkaline phosphatase, uric acid, protein and albumin

  Up to 112 Days

• Urinalysis parameters as a safety measure

  Urinalysis parameters included are specific gravity, potential of hydrogen (pH), glucose, protein, blood and ketones by dipstick, microscopic examination (if blood or protein is abnormal)

  Up to 112 Days

• Body temperature

  Up to 112 Days

• Systolic and diastolic blood pressure (BP)

  Up to 112 Days

• Pulse rate

  Up to 112 Days

• ECG parameters

  A 12 lead electrocardiogram (ECG) will be measured using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and QTc intervals.

  Up to 112 Days

• Nasal examination

  Visual nasal examination will be conducted by a trained physician

  Up to 112 Days

• Nasal symptoms assessment

  Nasal tolerability symptoms itching, discomfort, post-nasal drip, rhinorrhoea, obstruction will be assessed using a Visual analogue score system

  Up to 23 Days

Secondary Outcomes (10)

• FEV1 assessment

  Up to 112 Days

• TLR7-induced blood PD biomarkers, including TLR7-induced cytokines

  Up to 23 Days

• TLR7-induced nasal PD biomarkers, including but not limited to induced protein (IP)-10, i.n. nasal lavage fluid

  Up to 23 Days

• Daily rhinitis symptoms and use of medication diaries during the study period

  Up to 122 Days

• Daily asthma symptoms and use of medication diaries during the study period

  Up to 122 Days

Study Arms (4)

GSK2245035 - 40 ng or placebo

EXPERIMENTAL

Subjects will receive GSK2245035 - 40 nanogram (ng) or placebo once per week for four treatment weeks. There will be washout period of 7 days between treatment periods. GSK medical monitor will review all available clinical and laboratory safety data and decide if subjects can proceed to the next scheduled dosing cohort.

Drug: GSK2245035; Device: Type 1 amber glass bottle; Other: Placebo

GSK2245035 - 80 ng or placebo

EXPERIMENTAL

Subjects will receive GSK2245035 - 80 ng or placebo once per week for four treatment weeks. There will be washout period of 7 days between treatment periods. GSK medical monitor will review all available clinical and laboratory safety data and decide if subjects can proceed to the next scheduled dosing cohort.

Drug: GSK2245035; Device: Type 1 amber glass bottle; Other: Placebo

GSK2245035 - 120 ng or placebo

EXPERIMENTAL

Subjects will receive GSK2245035 - 120 ng or placebo once per week for four treatment weeks. There will be washout period of 7 days between treatment periods. GSK medical monitor will review all available clinical and laboratory safety data and decide if subjects can proceed to the next scheduled dosing cohort.

Drug: GSK2245035; Device: Type 1 amber glass bottle; Other: Placebo

GSK2245035 - 160 ng or placebo

EXPERIMENTAL

Subjects will receive GSK2245035 - 160 ng or placebo once per week, for four treatment weeks. There will be washout period of 7 days between treatment periods.

Drug: GSK2245035; Device: Type 1 amber glass bottle; Other: Placebo

Interventions

GSK2245035 DRUG

GSK2245035 nasal spray solution. A solution formulation in saline, preserved with Benzalkonium Chloride and Disodium Edetate

GSK2245035 - 120 ng or placebo; GSK2245035 - 160 ng or placebo; GSK2245035 - 40 ng or placebo; GSK2245035 - 80 ng or placebo

Type 1 amber glass bottle DEVICE

fitted with a metered Valios VP7 pump

GSK2245035 - 120 ng or placebo; GSK2245035 - 160 ng or placebo; GSK2245035 - 40 ng or placebo; GSK2245035 - 80 ng or placebo

Placebo OTHER

As for GSK2245035 nasal spray solution except for omission of the active ingredient

GSK2245035 - 120 ng or placebo; GSK2245035 - 160 ng or placebo; GSK2245035 - 40 ng or placebo; GSK2245035 - 80 ng or placebo

Eligibility Criteria

• Age: 18 Years - 62 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Good general health, as determined by a responsible and experienced physician, based on a medical evaluation, including medical history, physical examination, laboratory tests and 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 agrees that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures.
• Males between 18 and 62 years of age inclusive.
• Male subjects with female partners of child-bearing potential 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 four days after the last dosing.
• Females between 18 and 62 years of age inclusive, if they are of non-childbearing potential, defined as pre-menopausal females with a documented tubal ligation or hysterectomy, or postmenopausal, defined as 12 months of spontaneous amenorrhea (in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) greater than 40 MlU/ml and estradiol less than 40 pg/ml (less than 147 pmol/L) is confirmatory). Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the contraception methods in the protocol if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrollment. For most forms of HRT, at least 2-4 weeks should 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.
• Body weight greater than and equal to 50 kilogram (kg) and body mass index (BMI) within the range 19 - 35 kg/meter square (m\^2) (inclusive).
• Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.
• Available to complete all required study measurements.
• Documented history of Symptomatic perennial allergic rhinitis and mild asthma driven by house dust mite (HDM) for more than 3 years, that does not require regular use of inhaled steroids. Subjects with symptomatic perennial allergic rhinitis and mild asthma driven by house dust mite (HDM) will need to have a positive skin allergy test (wheal ≥ 3 millimeter \[mm\]) or RAST (≥ class 2) to house dust mite allergens. (However, an allergen radio allergosorbent test \[RAST\] or skin test can be omitted if a subject provides clear evidence confirmed by a physician of an analogous positive test within the last 3 years).

You may not qualify if:

• History of immunological disorders or other diseases (including, but not limited to, malignancy, cardiovascular, gastro-intestinal, hepatic, renal, haematological, neurological, endocrine or pulmonary disease) that in the opinion of the investigator and GSK medical monitor may pose additional risk factors
• Nasal conditions that according to the opinion of the investigator may affect the outcome of the study, i.e. nasal septal perforation, nasal polyps, other nasal malformations or history of frequent nosebleeds.
• Respiratory tract infection within 4 weeks prior to the first dosing.
• A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening
• A positive test for HIV antibody
• A positive screening or pre-dose drug/alcohol screen
• History of regular alcohol consumption within 6 months of the study defined as: an average weekly intake of greater than 14 drinks for males or greater than 7 drinks for females. One drink is equivalent to 12 grams (g) of alcohol: 12 ounces (360 millileter \[mL\]) of beer, 5 ounces (150 mL) of wine or 1.5 ounces (45 mL) of 80 proof distilled spirits.
• Participation in a clinical trial with receipt of an investigational product within 3 months prior to the first dosing day.
• 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 56-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.
• History of severe asthma

Sponsors & Collaborators

• GlaxoSmithKline: lead
• PATH: collaborator

Study Sites (1)

GSK Investigational Site

Toronto, Ontario, M5V 2T3, Canada

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

• 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

Asthma; Rhinitis; Rhinitis, Allergic

Interventions

GSK2245035

Condition Hierarchy (Ancestors)

Bronchial Diseases; Respiratory Tract Diseases; Lung Diseases, Obstructive; Lung Diseases; Respiratory Hypersensitivity; Hypersensitivity, Immediate; Hypersensitivity; Immune System Diseases; Respiratory Tract Infections; Infections; Nose Diseases; Otorhinolaryngologic Diseases

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 29, 2012
• First Posted: May 30, 2012
• Study Start: April 1, 2012
• Primary Completion: September 1, 2013
• Study Completion: September 1, 2013
• Last Updated: January 30, 2017

Record last verified: 2017-01

Data Sharing

• IPD Sharing: Will share

Locations

CA (1)