Try our beta test site
IMPORTANT: Listing of a study on this site does not reflect endorsement by the National Institutes of Health. Talk with a trusted healthcare professional before volunteering for a study. Read more...

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

This study has been completed.
Sponsor:
Collaborator:
PATH
Information provided by (Responsible Party):
GlaxoSmithKline
ClinicalTrials.gov Identifier:
NCT01607372
First received: March 29, 2012
Last updated: January 27, 2017
Last verified: January 2017

March 29, 2012
January 27, 2017
April 2012
September 2013   (Final data collection date for primary outcome measure)
  • Number of participants experiencing adverse events (AEs) [ Time Frame: Up to 122 Days ]
    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.
  • Hematology parameters as a safety measure [ Time Frame: Up to 112 Days ]
    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.
  • Clinical Chemistry parameters as a safety measure [ Time Frame: Up to 112 Days ]
    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
  • Urinalysis parameters as a safety measure [ Time Frame: Up to 112 Days ]
    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)
  • Body temperature [ Time Frame: Up to 112 Days ]
  • Systolic and diastolic blood pressure (BP) [ Time Frame: Up to 112 Days ]
  • Pulse rate [ Time Frame: Up to 112 Days ]
  • ECG parameters [ Time Frame: Up to 112 Days ]
    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.
  • Nasal examination [ Time Frame: Up to 112 Days ]
    Visual nasal examination will be conducted by a trained physician
  • Nasal symptoms assessment [ Time Frame: Up to 23 Days ]
    Nasal tolerability symptoms itching, discomfort, post-nasal drip, rhinorrhoea, obstruction will be assessed using a Visual analogue score system
  • To evaluate the safety and tolerability of repeat doses of i.n. GSK2245035 administered once per week or every 4 days [ Time Frame: 4 weeks (Part 1); 8 weeks (Part 2) ]
    General safety endpoints, including AE, vital signs, body temperature, 12-lead ECG and clinical laboratory parameters. Nasal tolerability endpoints, including nasal examination and assessment of nasal symptoms
  • To evaluate the effect of treatment with 8 doses of i.n. GSK2245035 on total and individual nasal symptoms elicited by the allergen challenge exposure compared to placebo [ Time Frame: 8 weeks (Part 2) ]
    Total nasal symptoms score (TNSS) elicited by allergen challenge exposure. Individual nasal symptoms, including nasal congestion, rhinorrhea, sneezing and nasal itch, elicited by allergen challenge exposure
  • To evaluate the duration of a positive treatment effect with 8 doses of i.n. GSK2245035 on total and individual nasal symptoms elicited by allergen challenge exposure compared to placebo [ Time Frame: 8 weeks (Part 2) ]
    Total nasal symptoms score (TNSS) elicited by allergen challenge exposure. Individual nasal symptoms, including nasal congestion, rhinorrhea, sneezing and nasal itch, elicited by allergen challenge exposure
Complete list of historical versions of study NCT01607372 on ClinicalTrials.gov Archive Site
  • FEV1 assessment [ Time Frame: Up to 112 Days ]
    To evaluate the effect of four repeat doses of i.n. GSK2245035 administered once per week on lung function, as measured by Forced expiratory volume in one second FEV1
  • TLR7-induced blood PD biomarkers, including TLR7-induced cytokines [ Time Frame: Up to 23 Days ]
    To evaluate the induction of TLR7-associated blood PD biomarkers following administration of i.n. GSK2245035 once per week
  • TLR7-induced nasal PD biomarkers, including but not limited to induced protein (IP)-10, i.n. nasal lavage fluid [ Time Frame: Up to 23 Days ]
    To evaluate the induction of TLR7-associated nasal PD biomarkers following administration of repeat doses of i.n. GSK2245035 once per week
  • Daily rhinitis symptoms and use of medication diaries during the study period [ Time Frame: Up to 122 Days ]
  • Daily asthma symptoms and use of medication diaries during the study period [ Time Frame: Up to 122 Days ]
  • Daily morning peak expiratory flow (PEF) during the study period [ Time Frame: Up to 112 Days ]
  • Exhaled NO assessment [ Time Frame: Up to 23 Days ]
  • Cell counts and differential in nasal lavage [ Time Frame: Up to 23 Days ]
  • Exploratory allergic biomarkers including but not limited to immunoglobulins and cytokines in blood and nasal lavage fluid and tissue [ Time Frame: Up to 23 Days ]
  • Plasma GSK2245035 concentrations [ Time Frame: Up to 23 Days ]
  • FEV1 assessment [ Time Frame: 4 weeks (Part 1) ]
    To evaluate the effect of four repeat doses of i.n. GSK2245035 administered once per week or every four days on lung function, as measured by FEV1
  • TLR7-induced blood PD biomarkers, including TLR7-induced cytokines [ Time Frame: 4 weeks (Part 1); 8 weeks (Part 2) ]
    To evaluate the induction of TLR7-associated blood PD biomarkers following administration of i.n. GSK2245035 once per week or every four days
  • TLR7-induced nasal PD biomarkers, including but not limited to IP-10, in nasal lavage fluid [ Time Frame: 4 weeks (Part 1); 8 weeks (Part 2) ]
    To evaluate the induction of TLR7-associated nasal PD biomarkers following administration of repeat doses of i.n. GSK2245035 once per week or every four days
  • Daily rhinitis symptoms and use of medication diaries during the study period [ Time Frame: 4 weeks (Part 1); 8 weeks (Part 2) ]
  • Daily asthma symptoms and use of medication diaries during the study period [ Time Frame: 4 weeks (Part 1) ]
  • Daily morning peak expiratory flow (PEF) during the study period [ Time Frame: 4 weeks (Part 1) ]
  • Exhaled NO assessment in Part 1, exhaled NO following allergen challenge exposure in Part 2 [ Time Frame: 4 weeks (Part 1); 8 weeks (Part 2) ]
  • Cell counts and differential in nasal lavage [ Time Frame: 4 weeks (Part 1); 8 weeks (Part 2) ]
  • Exploratory allergic biomarkers including but not limited to immunoglobulins and cytokines in blood and nasal lavage fluid and tissue [ Time Frame: 4 weeks (Part 1) ]
  • Allergic blood biomarkers including but not limited to immunoglobulins [ Time Frame: 8 weeks (Part 2) ]
  • Weight of nasal secretions elicited during allergen challenge exposure [ Time Frame: 8 weeks (Part 2) ]
  • Assessment of nasal flow following allergen challenge exposure [ Time Frame: 8 weeks (Part 2) ]
  • Allergic nasal biomarkers including but not limited to cytokines, chemokines and immunoglobulins in nasal fluid and/or tissue following allergen challenge exposure [ Time Frame: 8 weeks (Part 2) ]
  • Plasma GSK2245035 concentrations [ Time Frame: 4 weeks (Part 1); 8 weeks (Part 2) ]
Not Provided
Not Provided
 
A Study to Investigate the Safety and Pharmacodynamics of Repeat Intranasal Administration of the TLR7 Agonist GSK2245035 in Subjects With Respiratory Allergies
A Randomized, Double Blind, Placebo-controlled Study to Investigate the Safety and Pharmacodynamics of Repeat Intranasal Administration of the TLR7 Agonist GSK2245035 in Subjects With Respiratory Allergies
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.
Not Provided
Interventional
Phase 2
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: Participant, Investigator
Primary Purpose: Treatment
Asthma and Rhinitis
  • Drug: GSK2245035
    GSK2245035 nasal spray solution. A solution formulation in saline, preserved with Benzalkonium Chloride and Disodium Edetate
  • Device: Type 1 amber glass bottle
    fitted with a metered Valios VP7 pump
  • Other: Placebo
    As for GSK2245035 nasal spray solution except for omission of the active ingredient
  • Experimental: GSK2245035 - 40 ng or placebo
    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.
    Interventions:
    • Drug: GSK2245035
    • Device: Type 1 amber glass bottle
    • Other: Placebo
  • Experimental: GSK2245035 - 80 ng or placebo
    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.
    Interventions:
    • Drug: GSK2245035
    • Device: Type 1 amber glass bottle
    • Other: Placebo
  • Experimental: GSK2245035 - 120 ng or placebo
    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.
    Interventions:
    • Drug: GSK2245035
    • Device: Type 1 amber glass bottle
    • Other: Placebo
  • Experimental: GSK2245035 - 160 ng or placebo
    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.
    Interventions:
    • Drug: GSK2245035
    • Device: Type 1 amber glass bottle
    • Other: Placebo
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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
18
September 2013
September 2013   (Final data collection date for primary outcome measure)

Inclusion Criteria:

  • 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).

Exclusion Criteria:

  • 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
  • Serious asthma exacerbation requiring hospital visit and/ or treatment with oral steroids or high doses of inhaled steroids within 6 weeks prior to screening
  • History of treatment with allergen-specific immunotherapy
  • Pre-bronchodilator FEV1 less than and equal to 70% of predicted at 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 first dosing, unless in the opinion of the investigator and GlaxoSmithKline (GSK) medical monitor the medication will not interfere with the study procedures or compromise subject safety. Paracetamol is an exception and will be permitted at daily doses of up to 4 g from screening to follow-up. During the dosing visits Paracetamol can be used, if needed, only if the investigator allows it.
  • Subjects using steroid treatment for allergic rhinitis and/or asthma may participate in the study if they can remain free of medication throughout the study period starting from the following periods of time prior to first dosing: Nasal steroids: 4 weeks; Oral steroids: 12 weeks; Inhaled steroids: 4 weeks
  • Subjects using other medications for their allergic rhinitis and/or asthma on an as needed basis may participate in the study if they can abstain from: Xanthines (including theophylline, but not including caffeine), anticholinergics, cromoglycates, leukotriene antagonists, 5-lipoxygenase inhibitors and longacting inhaled beta-agonists from 1 week prior to screening and throughout the study Na; Nasal antihistamines: 48 hours prior each dosing; Oral antihistamines: 76 hours prior each dosing; Nasal decongestants: 24 hours prior each dosing; Oral decongestants: 24 hours prior each dosing; Short acting inhaled beta-agonists: 48 hours prior each dosing
Sexes Eligible for Study: All
18 Years to 62 Years   (Adult)
Yes
Contact information is only displayed when the study is recruiting subjects
Canada
 
 
NCT01607372
116392
No
Not Provided
Yes
Patient-level data for this study will be made available through www.clinicalstudydatarequest.com following the timelines and process described on this site.
GlaxoSmithKline
GlaxoSmithKline
PATH
Study Director: GSK Clinical Trials GlaxoSmithKline
GlaxoSmithKline
January 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP