Clinical trial NCT00850642: GSK2190915 Moderate to Severe Asthma Study
Official title: The Efficacy of Orally Administered GSK2190915 as an add-on to Current Therapy in Subjects With Moderate to Severe Asthma Who Have Elevated Sputum Neutrophils
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Asthma
Keywords: Sputum cell counts
Neutrophils
Severe Asthma
ICS
Inhaled corticosteroids
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2009-02-25
Enrollment: 7
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: A randomised, double-blind, placebo-controlled, parallel group study to evaluate the effect of treatment with GSK2190915, a FLAP inhibitor, as add-on to current inhaled corticosteroid therapy in patients with moderate to severe asthma with elevated sputum neutrophils.


Eligibility criteria: Inclusion Criteria:

A subject will be eligible for inclusion in this study only if all of the following criteria apply:

* Males and females aged 18 to 65 years inclusive.
* Body mass index within the range 18.5-37.0 kilograms/metre2 (kg/m2).
* An established clinical history of Asthma in accordance with the definition by the GINA Guidelines \[GINA, 2006\]. Subjects should have at screening or within the last year documented reversibility (\>12 %) to short acting bronchodilator, or positive methacholine challenge, or positive histamine challenge (PC20 \<8mg/ml).
* A female subject is eligible to participate if she is of: non-childbearing potential defined as pre-menopausal females with documented (medical report verification) hysterectomy or double oophrectomy or postmenopausal defined as 12 months of spontaneous amenorrhea or 6 months of spontaneous amenorrhea with serum FSH levels \> 40 mIU/mL and estradiol \< 40 pg/ml (\<140 pmol/L) or 6 weeks postsurgical bilateral oophorectomy with or without hysterectomy; childbearing potential and agrees to use one of the contracception methods listed in Section 8.1 for an appropriate period of time prior to the start of dosing and until 3 months after last dose.
* Male subjects must agree to use one of the contraception methods listed in Section 8.1. This criterion must be followed from the time of the first dose of study medication until 3 months after the last dose.
* Subject with moderate to severe asthma with forced expiratory volume in one second (FEV1) ≥ 50% of predicted.
* Subject who are on regular inhaled corticosteroids without or in combination with a regular long acting Beta 2 Agonist. The dose should be stable for at least 4 weeks before screening.
* Subjects who are taking a minimum of FP 250mg BID or equivalent.
* Persistent sputum neutrophilia defined by sputum neutrophils ≥ 65% with TTC \< 15 million cells/g with no evidence of eosinophilia (sputum eosinophils \< 2%). Persistent is defined as the criteria being met at screening (or within the 6 months preceding screening) and on visit 1.
* Signed and dated written informed consent is obtained from the subject
* The subject is able to understand and comply with the protocol requirements, instructions and protocol-stated restrictions.

Exclusion Criteria:

A subject will not be eligible for inclusion in this study if any of the following criteria apply:

* Past or present disease, which as judged by the investigator or medical monitor, may affect the outcome of this study. These diseases include, but are not limited to, cardiovascular disease, malignancy, gastrointestinal disease, hepatic disease, renal disease, haematological disease, neurological disease, endocrine disease or pulmonary disease (excluding asthma but including but not confined to chronic bronchitis, emphysema, bronchiectasis, eosinophilic bronchitis or pulmonary fibrosis).
* Clinically significant abnormalities in safety laboratory analysis at screening.
* Subject has uncontrolled hypertension or is hypertensive at screening. Hypertension at screening is defined as persistent systolic BP \>150 mmHg or diastolic BP \> 90mmHg.
* History of asthma exacerbations or acute intercurrent respiratory illness (viral respiratory syndrome, bronchitis, pneumonia) for a four week period before the screening visit
* History of life-threatening asthma, defined as an asthma episode that required intubations and/or was associated with hypercapnoea, respiratory arrest and/or hypoxic seizures.
* Subject is unable to abstain from taking prescription or non-prescription drugs (including vitamins and dietary or herbal supplements) including non-steroidal anti-inflammatory drugs (NSAIDs), anti-depressant drugs, anti-histamines and anti-asthma, anti-rhinitis or hay fever medication, with the exception of ICS, LABA and short action beta agonists, from 14 days before screening until the follow-up visit unless in the opinion of the Investigator and sponsor the medication will not interfere with the study
* Administration of oral or injectable steroids within 6 weeks of screening.
* The subject has participated in a study with a new molecular entity during the previous 3 months or has participated in 4 or more clinical studies in the previous 12 months prior to the first dosing day.
* Administration of anti -leukotrienne therapies for 14 days before screening and during the study.
* Administration of any vaccinations within 1 month of screening or during the study.
* Administration of biological therapies within 3 months of the screening visit or during the study
* Subject is undergoing allergen desensitisation therapy.
* Administration of OATP1B1 substrates from 2 weeks before dosing, and until all follow-up assessments are completed.
* There is a risk of non-compliance with study procedures.
* History of blood donation (500 mL) within 3 months of starting the clinical study.
* The subject regularly drinks more than 28 units of alcohol in a week if male, or 21 units per week if female. One unit of alcohol is defined as a medium (125 ml) glass of wine, half a pint (250 ml) of beer or one measure (25 ml) of spirits.
* The subject has a screening QTc value of \>450msec, PR interval outside the range 120 to 220msec or an ECG that is not suitable for QT measurements (e.g. poorly defined termination of the T-wave).
* The subject has tested positive for hepatitis C antibody or hepatitis B surface antigen.
* The subject has tested positive for HIV antibodies.
* The subject has a positive pre-study urine drug or urine or breath alcohol screen. A minimum list of drugs that will be screened for include Amphetamines, Barbituates, Cocaine, Opiates, Cannabinoids and Benzodiazepines.

Primary outcomes:
measure: The Numbers of Neutrophils in Induced Sputum-Absolute Neutrophil Count
timeFrame: Day -9 to -7, Day 1, Day 12 and follow-up (Day 24-28)
measure: Percentage of Neutrophils in Induced Sputum
timeFrame: Day -9 to -7, Day 1, Day 12 and follow-up (Day 24-28)
Secondary outcomes:
measure: Assessment of FEV1 on Visit 2, 3 and Visit 4
timeFrame: Visit 2 (Day 1), visit 3 (Day 5 to 7) and visit 4 (Day 12)
measure: Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: From visit 1 (Day -7 to Day -9) to upto follow-up (upto Day 28)
measure: Number of Participants With Vital Sign of Potential Clinical Concern (PCC)
timeFrame: Visit 2 (Day 1) to Upto follow-up (Day 28)
measure: Number of Participants With Abnormal Electrocardiogram (ECG) Findings
timeFrame: Visit 2 (Day 1) to Upto follow-up (Day 28)
measure: Number of Participants With Clinical Chemistry Values of PCC
timeFrame: Visit 2 (Day 1) to Upto follow-up (Day 28)
measure: Number of Participants With Hematology Values of PCC
timeFrame: Visit 2 (Day 1) to Upto follow-up (Day 28)
measure: Plasma Concentration of GSK2190915
timeFrame: At Day 1, pre-dose; Day 1, 2 hour; Day 12, pre-dose; and Day 12, 2 hour
measure: Percentage Change From Baseline Urine LTE4 Biomarker
timeFrame: Day 1 and Day 12
measure: Percentage Change From Baseline of LTB4 Biomarker in Plasma
timeFrame: Day 1 and Day 12
measure: Concentration of LTB4 in Sputum
timeFrame: Day 1 and Day 12
measure: Concentration of Interleukin (IL)-17 and High-sensitivity C-reactive Protein (hsCRP) in Blood
timeFrame: Day 1 and Day 12
measure: Assessment of Established Markers of Anti-inflammatory Activity in Sputum: the Measurements Will Include IL-17, Neutrophil Elastase, Myeloperoxidase and IL-8
timeFrame: Day 1 and Day 12
measure: Asthma Control Questionnaire (ACQ) Assessment
timeFrame: At Day 1, Day 5 to 7 and Day 12
Other outcomes:
Locations:
city: Hamilton
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Kingston
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Montreal
country: Canada
facility: GSK Investigational Site
state: Quebec
city: Sainte-Foy
country: Canada
facility: GSK Investigational Site
state: Quebec
city: Glasgow
country: United Kingdom
facility: GSK Investigational Site
state: Lanarkshire
city: Leicester
country: United Kingdom
facility: GSK Investigational Site
state: Leicestershire
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: