Clinical trial NCT02833974: Effect of the GSK2245035 on the Allergen-induced Asthmatic Response
Official title: A Randomised, Double-blind, Placebo-controlled, Parallel Group, 8-week Treatment Study to Investigate the Safety, Pharmacodynamics, and Effect of the TLR7 Agonist, GSK2245035, on the Allergen-induced Asthmatic Response in Subjects With Mild Allergic Asthma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Asthma
Keywords: GSK2245035
TLR7 agonist
allergic asthma
FEV1
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2016-07-15
Enrollment: 36
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study will assess whether Toll like receptor 7 (TLR7)-mediated pharmacology, with intranasal (i.n.) GSK2245035 20 nanogram (ng) administered weekly for a period of 8 weeks, will lead to reduced allergic reactivity in the lower airways in subjects with mild allergic asthma.

This will be a randomised, double-blind (sponsor open), placebo-controlled, parallel group, 8-week treatment study.

The study will consist of a screening period of up to approximately 4 weeks (involving two screening visits), a blinded treatment period of 8 weeks, followed by a follow-up period of up to 3 months. The total duration of the study for each subject will therefore be a maximum of approximately 6 months.


Eligibility criteria: Inclusion Criteria

* Between 18 and 65 years of age inclusive, at the time of signing the informed consent.
* Diagnosis of asthma, as defined by the history of respiratory symptoms such as wheeze, shortness of breath, chest tightness and cough that vary over time and in intensity, together with variable expiratory airflow limitation for at least 6 months prior to screening
* Current asthma therapy. Intermittent short-acting beta-agonist (SABA) alone (on average for no more than 2 days per week)
* Positive skin prick test (3 mm or more greater than negative control) to common perennial or seasonal aeroallergen(s) (i.e., house dust mite, cat dander, grass pollen) at screening
* Pre-bronchodilator FEV1 \> 70 % predicted normal at Screening Visit 1
* EAR with \>=20 % FEV1 decrease between 5 and 30 minutes after the final allergen concentration is obtained at the screening bronchial allergen challenge (BAC) (decreases relative to the saline)
* LAR with three FEV1 decreases of \>= 15 % between 4 and 10 hours after the final allergen concentration is obtained at the screening bronchial allergen challenge, with two FEV1 decreases being at consecutive time points (decreases relative to the saline)
* Subjects who are current non-smokers (defined as no use of any tobacco products in the 6-month period preceding the screening visit) and have a pack history of \< 10 pack years. Number of pack years = (number of cigarettes per day/20) x number of years smoked
* Bodyweight \>= 45kilograms (kg)
* Male OR female of non-reproductive potential Male subjects with female partners of child bearing potential complying with contraception requirements from the time of first dose of study medication until the final follow-up visit: Vasectomy with documentation of azoospermia, male condom plus partner use of one of the following contraceptive options: Contraceptive subdermal implant, Intrauterine device or intrauterine system, Oral contraceptive, either combined or progestogen alone, Injectable progestogen, Contraceptive vaginal ring, Percutaneous contraceptive patches. This is an all-inclusive list of those methods that meet the following GSK definition of highly effective: having a failure rate of less than 1% per year when used consistently and correctly and, when applicable, in accordance with the product label. For non-product methods (e.g., male sterility), the investigator determines what is consistent and correct use. The GSK definition is based on the definition provided by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). The investigator is responsible for ensuring that subjects understand how to properly use these methods of contraception
* A female subject is eligible to participate if she is not pregnant, (as confirmed by a negative \[serum or urine\] human chorionic gonadotrophin \[hCG\] test), not lactating and where the following conditions applies: Non-reproductive potential: defined as pre-menopausal females with one of the following Documented tubal ligation, Documented hysteroscopic tubal occlusion procedure with follow-up confirmation of bilateral tubal occlusion, Hysterectomy, Documented Bilateral Oophorectomy. Postmenopausal defined as 12 months of spontaneous amenorrhea (in questionable cases a blood sample with simultaneous follicle stimulating hormone \[FSH\] and estradiol levels consistent with menopause \[refer to laboratory reference ranges for confirmatory levels\]). Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the highly effective contraception methods 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 enrolment
* Capable of giving signed informed consent

Exclusion Criteria

* Alanine transaminase (ALT) \>2xUpper Limit of Normal (ULN) and bilirubin \>1.5xULN (isolated bilirubin \>1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin \<35%)
* Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones)
* Heart rate corrected QT interval (QTc) \> 450 milliseconds (msec) or QTc \> 480 msec in subjects with Bundle Branch Block
* Asthma exacerbation requiring treatment with oral corticosteroids or hospitalization within 3 months prior to screening
* History of life-threatening asthma, defined as an asthma episode that required intubation and/or was associated with hypercapnea, respiratory arrest or hypoxic seizures within the last 10 years
* Evidence of concurrent respiratory diseases such as pneumonia, pneumothorax, atelectasis, pulmonary fibrotic disease, allergic bronchopulmonary aspergillosis, cystic fibrosis, bronchopulmonary dysplasia, or other respiratory abnormalities other than asthma
* Other concurrent diseases/abnormalities: A subject must not have any clinically significant, uncontrolled condition or disease state that, in the opinion of the investigator, would put the safety of the subject at risk through study participation or would confound the interpretation of the efficacy results if the condition/disease exacerbated during the study
* Respiratory tract infection that is not resolved within 2 weeks prior to screening
* Treatment with intranasal steroid, inhaled corticosteroid (ICS) with or without long-acting beta2-agonist (LABA), and treatment with non-ICS controller asthma medications (i.e., leukotriene modifier, methylxanthines) within 4 weeks prior to screening
* Use of long-acting antihistamines within 7 days' or short-acting antihistamines within 72 hours prior to the screening skin prick test
* Treatment with systemic corticosteroids within 6 weeks prior to screening
* Use of inhaled SABAs as rescue treatment on average for more than 2 days per week
* History of regular alcohol consumption within 6 months of the study defined as: An average weekly intake of \>14 units for males and females. One unit is equivalent to 8 gram (g) of alcohol: a half-pint (\~240 mililiter \[ml\]) of beer, 1 glass (125 ml) of wine or 1 (25 ml) measure of spirits
* Patient known to be intolerant to salbutamol or albuterol
* History of sensitivity to any of the study medications, or components thereof or a history of drug or other allergy that, in the opinion of the investigator or GSK Medical Monitor, contraindicates their participation
* Presence of hepatitis B surface antigen (HBsAg), positive hepatitis C antibody test result at screening or within 3 months prior to first dose of study treatment
* A positive pre-study drug/alcohol screen
* A positive test for Human Immunodeficiency Virus (HIV) antibody
* Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 56 day period
* The subject has participated in a clinical trial and has received an investigational product within the following time period prior to the first dosing day in the current study: 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer)
* Exposure to more than 4 investigational medicinal products within 12 months prior to the first dosing day

Primary outcomes:
measure: Late Asthmatic Response (LAR): Absolute Change From Saline in Minimum Forced Expiratory Volume in 1 Second (FEV1) Between 4-10 Hours Following Allergen Challenge One Week After Treatment
timeFrame: Week 9
measure: LAR: Absolute Change From Saline in Weighted Mean FEV1 Between 4-10 Hours Following Allergen Challenge One Week After Treatment
timeFrame: Week 9
Secondary outcomes:
measure: Early Asthmatic Response (EAR): Absolute Change From Saline in Minimum FEV1 Between 0-2 Hours Following Allergen Challenge One Week After Treatment
timeFrame: Week 9
measure: EAR: Absolute Change From Saline in Weighted Mean FEV1 Between 0-2 Hours Following Allergen Challenge One Week After Treatment.
timeFrame: Week 9
measure: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: Up to Week 20
measure: Number of Participants With Abnormal Peak Expiratory Flow (PEF)
timeFrame: Up to Week 12
measure: Number of Participants Receiving Rescue Medication
timeFrame: Up to Week 20
measure: Number of Participants With Hematology Values of Potential Clinical Concern
timeFrame: Up to Week 20
measure: Number of Participants With Clinical Chemistry Values of Potential Clinical Concern
timeFrame: Up to Week 8
measure: Number of Participants With Abnormal Urine Analysis Findings
timeFrame: Up to Week 8
Other outcomes:
Locations:
city: Frankfurt
country: Germany
facility: GSK Investigational Site
state: Hessen
city: Wiesbaden
country: Germany
facility: GSK Investigational Site
state: Hessen
city: Hannover
country: Germany
facility: GSK Investigational Site
state: Niedersachsen
city: Grosshansdorf
country: Germany
facility: GSK Investigational Site
state: Schleswig-Holstein
city: London
country: United Kingdom
facility: GSK Investigational Site
city: Manchester
country: United Kingdom
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Siddall H, Quint D, Pandya H, Powley W, Shabbir S, Hohlfeld JM, Singh D, Lee L. Intranasal GSK2245035, a Toll-like receptor 7 agonist, does not attenuate the allergen-induced asthmatic response in a randomized, double-blind, placebo-controlled experimental medicine study. PLoS One. 2020 Nov 9;15(11):e0240964. doi: 10.1371/journal.pone.0240964. eCollection 2020.