Last updated: 07/17/2024 16:46:21
A study to investigate the safety and pharmacodynamics of repeat intranasal administration of the TLR7 agonist GSK2245035 in subjects with respiratory allergies
EudraCT ID
Not applicable
EU CT Number
Not applicable
Trial status
Study complete
Study complete
Trial overview
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
Trial description: 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.
Primary purpose:
Treatment
Trial design:
Single Group Assignment
Masking:
Double (Participant, Investigator)
Allocation:
Randomized
Primary outcomes:
Number of participants with adverse events (AEs) and serious adverse events (SAEs)
Timeframe: Up to Day 22
Mean systolic blood pressure (SBP) and diastolic blood pressure (DBP)
Timeframe: Pre-dose, 4, 6, 8, 10, 12, 18 and 24 hours post-dose of Day 1 (DV1), Day 8 (DV2), Day 15 (DV3) and Day 22 (DV4)
Mean heart rate at indicated time points
Timeframe: Pre-dose, 4, 6, 8, 10, 12, 18 and 24 hours post-dose of Day 1, Day 8, Day 15 and Day 22
Change from DV Baseline in body temperature
Timeframe: Baseline (pre-dose on Day 1 of each DV) and 4, 6, 8, 10, 12, 18 and 24 hours post-dose of Day 1, Day 8, Day 15 and Day 22
Number of participants with abnormal electrocardiogram (ECG)
Timeframe: Pre-dose, 8, 12 and 24 hours post-dose of Day 1, Day 8, Day 15 and Day 22
Number of participants with clinical chemistry abnormalities of potential clinical importance
Timeframe: Pre-dose, 10 and 24 hours post of day 1, 8, 15 and 22
Number of participants with hematology abnormalities of potential clinical importance
Timeframe: Pre-dose, 10 and 24 hours post of day 1, 8, 15 and 22
Number of participants with abnormal Urinalysis Dipstick Results
Timeframe: Pre-dose and 24 hours post of Day 1, 8, 15 and 22
Number of participants with abnormal nasal examination data
Timeframe: Pre-dose, 10 and 24 hours post-dose of Day 1, Day 8, Day 15 and Day 22
Assessment of Nasal tolerability endpoints- nasal symptoms using Visual analogue scale (VAS)
Timeframe: Pre-dose, 1, 4, 8, 12 and 24 hours post-dose of Day 1, Day 8, Day 15 and Day 22
Secondary outcomes:
Measurement of TLR7-induced blood PD biomarkers, including TLR7-induced cytokines- C-reactive protein (CRP)
Timeframe: 10 hours and 24 hours post-dose of Day 1, 8, 15 and 22
Measurement of TLR7-induced blood PD biomarkers, including TLR7-induced cytokines- interferon inducible protein 10 (IP-10)
Timeframe: 8 hours and 24 post-dose of Day 1, 8, 15 and 22
Measurement of TLR7-induced nasal PD biomarkers, including but not limited to IP-10, in nasal lavage fluid
Timeframe: 24 hours post-dose of Day 1, 8, 15 and 22
Measurement of cell counts and differential in nasal lavage fluid
Timeframe: Pre-dose and 24 hours post-dose of Day 1, 8, 15 and 22
Measurement of plasma GSK2245035 concentrations
Timeframe: Pre-dose, 5, 10, 20, 30 minutes, 1, 2, 4, 6, 8, 10, 12 and 24 hours post-dose of Day 1, 8, 15 and 22
Mean change in forced expiratory volume (FEV1)
Timeframe: Pre-dose, 10 and 24 hours post-dose of Day 1, 8, 15 and 22
Number of participants with daily rhinitis symptoms and daily asthma symptoms
Timeframe: Day 1, 8, 15 and 22
Mean change in daily morning peak expiratory flow (PEF) during the study period
Timeframe: Day -7 to Day 7 of DV 1, 2, 3 and 4
Assessment of exhaled nitric oxide (NO)
Timeframe: 0 and 24 hours post-dose of Day 1, 8, 15 and 22
Exploratory allergic biomarkers including but not limited to immunoglobulins and cytokines in nasal lavage fluid- Eosinophilic cationic protein (ECP) and tryptase
Timeframe: 0 hour and 24 hours post-dose of Day 1, 8, 15 and 22
Exploratory allergic biomarkers, including but not limited to immunoglobulins and cytokines, in blood and nasal lavage fluid and tissue- Eotaxin, IFNa, IFNg, IL10, IL12p70, IL13, IL2, IL4, IL5, MCP-1, MDC, TARC
Timeframe: 0 hours and 24 hours post-dose of Day 1, 8, 15 and 22
Exploratory allergic biomarkers, including but not limited to immunoglobulins and cytokines, in nasal lavage fluid- Timothy grass specific IgE and Total IgE
Timeframe: 0 hours and 24 hours post-dose of Day 1, 8, 15 and 22
Interventions:
Enrollment:
18
Primary completion date:
2013-27-09
Observational study model:
Not applicable
Time perspective:
Not applicable
Clinical publications:
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. Clinical Pharmacology & Therapeutics. 2015;98:369–380.
Medical condition
Asthma and Rhinitis
Product
GSK2245035
Collaborators
Program for Appropriate Technology in Health
Study date(s)
April 2012 to September 2013
Type
Interventional
Phase
2
Participation criteria
Sex
Female & Male
Age
18 - 62 years
Accepts healthy volunteers
Yes
- 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.
- 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.
Inclusion and exclusion 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
Trial location(s)
Study documents
Clinical study report
Available language(s): English
Protocol
Available language(s): English
Scientific result summary
Available language(s): English
If you wish to request for full study report, please contact - [email protected]
Results overview
Results posted on ClinicalTrials.gov
Recruitment status
Study complete
Actual primary completion date
2013-27-09
Actual study completion date
2013-27-09
Plain language summaries
Plain language summaries of clinical trial results for Phase 2-4 clinical trials that were initiated on or after January 2022 will be posted by GSK within one year following study completion.
Additional information about the trial
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