Clinical trial NCT01607372: A Study to Investigate the Safety and Pharmacodynamics of Repeat Intranasal Administration of the TLR7 Agonist GSK2245035 in Subjects With Respiratory Allergies
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Asthma and Rhinitis
Keywords: TLR7 agonist, Respiratory Allergies, Allergic Rhinitis, Mild Allergic Asthma, Repeat Dose Safety, Reduction of Allergic Reactivity
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
Collaborators: name: PATH
First posted: 2012-05-30
Enrollment: 18
Sex: ALL
Minimum age (years): 18
Maximum age (years): 62
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.


Eligibility criteria: 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

Primary outcomes:
measure: Number of participants experiencing adverse events (AEs)
timeFrame: Up to 122 Days
measure: Hematology parameters as a safety measure
timeFrame: Up to 112 Days
measure: Clinical Chemistry parameters as a safety measure
timeFrame: Up to 112 Days
measure: Urinalysis parameters as a safety measure
timeFrame: Up to 112 Days
measure: Body temperature
timeFrame: Up to 112 Days
measure: Systolic and diastolic blood pressure (BP)
timeFrame: Up to 112 Days
measure: Pulse rate
timeFrame: Up to 112 Days
measure: ECG parameters
timeFrame: Up to 112 Days
measure: Nasal examination
timeFrame: Up to 112 Days
measure: Nasal symptoms assessment
timeFrame: Up to 23 Days
Secondary outcomes:
measure: FEV1 assessment
timeFrame: Up to 112 Days
measure: TLR7-induced blood PD biomarkers, including TLR7-induced cytokines
timeFrame: Up to 23 Days
measure: TLR7-induced nasal PD biomarkers, including but not limited to induced protein (IP)-10, i.n. nasal lavage fluid
timeFrame: Up to 23 Days
measure: Daily rhinitis symptoms and use of medication diaries during the study period
timeFrame: Up to 122 Days
measure: Daily asthma symptoms and use of medication diaries during the study period
timeFrame: Up to 122 Days
measure: Daily morning peak expiratory flow (PEF) during the study period
timeFrame: Up to 112 Days
measure: Exhaled NO assessment
timeFrame: Up to 23 Days
measure: Cell counts and differential in nasal lavage
timeFrame: Up to 23 Days
measure: Exploratory allergic biomarkers including but not limited to immunoglobulins and cytokines in blood and nasal lavage fluid and tissue
timeFrame: Up to 23 Days
measure: Plasma GSK2245035 concentrations
timeFrame: Up to 23 Days
Other outcomes:
Locations:
city: Toronto
country: Canada
facility: GSK Investigational Site
state: Ontario
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: 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.