A 5-way Treatment Period Trial of Single Doses of Intranasal GSK256066 in Patients With Rhinitis

Study Overview
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Brief Summary
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This current study is planned as a dedicated pharmacodynamic (effect of drug on the body) study to investigate the dose response in rhinitic subjects at doses where GSK256066 has been proven to work (200mcg) or expected to (50mcg) work. This study also aims to investigate the lower end of the predicted therapeutic range.

Official Title
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A Randomised, Open, Placebo-controlled 5-way Crossover Trial of Single Doses of Intranasal GSK256066 in Subjects With Seasonal Allergic Rhinitis (SAR).

Conditions
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Rhinitis, Allergic, Seasonal

Intervention / Treatment
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* Drug: GSK256066


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The subject is healthy. Body mass index less than 29.0 kg/m² , weight range of 55.0kg (females 50kg) to 95.0kg inclusive. They have a history of hayfever (repeated yearly episodes). They have a positive skin prick test for grass pollen at or within the 12 months preceding the screening visit. They have a positive radioallergosorbent test for grass pollen at or within the 12 months preceding the screening visit. non-smokers. They must have a baseline FEV1>80% predicted and a baseline FEV1(maximum recorded value)/ forced vital capacity (FVC) (maximum recorded value)>70% They are capable of giving informed consent They are available to complete all study measurements. Exclusion Criteria: Pregnant or nursing females. Women of childbearing potential who are unwilling or unable to use an appropriate method of contraception. The subject has structural nasal abnormalities or nasal polyposis. Any respiratory disease other than mild stable asthma that is controlled with occasional use of as-needed short-acting beta-agonists and associated with normal lung function. The subject has a history of drug or other allergy that may contraindicate participation. The subject has participated in a study with a new molecular entity during the previous 4 months or in any clinical study in the previous 3 months The subject is concurrently participating in another clinical study and is exposed to an investigational or a non-investigational drug or device. The subject has a screening QTc value >450msec, PR interval outside the range 120 to 240msec or an ECG that is not suitable for QT measurements.In addition subjects will be excluded if they have a history of atrial and ventricular arrhythmia. The subject has a supine blood pressure that is persistently higher than 140/90 millimetres of mercury (mmHg) at screening. The subject has donated a unit of blood (450mL) within the previous 3 months or intends to donate within 3 months of completing the study. The subject is currently taking regular (or a course of) medication whether prescribed or not, including steroids, vitamins, and herbal remedies (e.g. St. John's Wort). Paracetamol (<2g/day) and occasional as needed use of short-acting beta agonists is permitted. Past or present disease which may affect study. outcome The subject regularly, or on average, drinks more than 4 units of alcohol per day - where 1 unit = ½ pint of beer (284mL), or 1 glass of wine (125mL), or 1 measure of spirit (25mL). The subject is at risk of non-compliance with the study procedures/restrictions. The subject has Hepatitis B, Hepatitis C, or HIV virus.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment


Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: GSK256066|nan|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Messenger Ribonucleic Acid (mRNA) Concentrations as a Measure of Gene Expression | The effect of GSK256066 on ribonucleic acid (RNA) levels indicative of Phosphodiesterase-4 (PDE4) inhibition in nasal scrape samples and on protein biomarkers of PDE4 inhibition in lavage samples was evaluated. Nasal lavage and scrapes were taken 2 to 3 hour post morning dose; bilateral nasal lavage was conducted before the scrape. Nasal scrape samples were taken from alternate nostrils. The novel RNA markers presented are cAMP responsive element modulator (CREM), dual specificity phosphatase 1(DUSP1), fos-like antigen 2(FOSL2), insulin receptor substrate 2 (IRS2), nuclear receptor subfamily 4, group A, member 2 (NR4A2), Phosphodiesterase-4A (PDE4A), Regulator of G-protein signalling 1 (RGS1), Serine/threonine protein kinase SNF1 like kinase (SNF1LK). Nasal lavage cytospins were stained with a SNF1LK specific monoclonal antibody by indirect immunofluorescence. Adjusted Geometric Mean and Standard error logs are presented. | Day 1 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Forced Expiratory Volume in One Second (FEV1) | The FEV1 is the volume of air forcefully exhaled in 1 second. The highest FEV1 value amongst the three recorded FEV1 readings was used for all FEV1 calculations. FEV1 was recorded pre-dose and at follow-up. | Up to 9 weeks | 
| Mean Diastolic Blood Pressure (DBP) and Systolic Blood Pressure (SBP) Over Study Period | Vital signs included SBP and DBP. SBP and DBP were measured pre-dose. The measurements were taken at 5 minutes interval during each treatment period. Vital signs measurements were made with the participant in a supine position having rested in this position for at least 5 minutes before the first reading at each time point. Measurements that deviated substantially from previous readings were repeated immediately. | Up to 9 weeks | 
| Mean Heart Rate Over Study Period | Vital signs included heart rate. Heart rate was measured pre-dose. The measurements were taken at 5 minutes interval during each treatment period. Vital signs measurements were made with the participant in a supine position having rested in this position for at least 5 minutes before the first reading at each time point. Measurements that deviated substantially from previous readings were repeated immediately. | Up to 9 weeks | 
| Change From Baseline in Electrocardiogram (ECG) Values | Electrocardiogram variables evaluated included PR interval, QRS duration, QT interval, QT corrected by Bazett's formula (QTcB), QT corrected by Fridericia's formula (QTcF) and RR interval. ECG was performed pre-dose, one hour and four hour post-dose. The ECG measurements were made with the participant in a supine position having rested in this position for at least 10 minutes before each time-point. Baseline was defined as the pre-dose measurement on Day 1. Change from Baseline was calculated by subtracting Baseline values from post-Baseline values | Baseline (Day 1) to 9 weeks | 
| Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE) | AE is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. For marketed medicinal products, this also includes failure to produce expected benefits (i.e., lack of efficacy), abuse or misuse. SAE is any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or is a congenital anomaly/birth defect or is medically significant. | Up to 9 weeks | 
| Number of Participants With Hematology Values of Potential Clinical Concern | Blood samples for hematology were taken before dosing. Whole blood samples were collected and processed according to the local procedures at site. The samples were transferred to the local laboratory for analysis. The participants with hematology of potential clinical concern are reported. The potential clinical concern ranges (low and high) were given as: for white blood cell count (clinical concern range: 3 to 20 giga cells/liter), neutrophils (normal range: 2.1 to 10.0 giga cells/liter), hemoglobin (clinical concern upper value: >180 grams/liter). Only those parameters for which at least one value of potential clinical concern was reported are summarized. | Up to 9 weeks | 
| Number of Participants With Clinical Chemistry Values of Potential Clinical Concern | Blood samples for clinical chemistry were taken before dosing. Whole blood samples were collected and processed according to the local procedures at site. The samples were transferred to the local laboratory for analysis. The participants with clinical chemistry values of potential clinical concern are reported. The potential clinical concern ranges (low and high) were given as: for total bilirubin levels (clinical concern upper value: >31 micromole/liter) and inorganic phosphorus level (normal range: 0.7-1.5 millimole/liter). | Up to 9 weeks | 
| Area Under the Plasma Drug Concentration Versus Time Curve (AUC0-last) of GSK256066 | The pharmacokinetics (PK) of GSK256066 were assessed in plasma by determining AUC(0-last). All participants who received at least one dose of the active investigational product provided at least one sample for plasma PK analysis. Blood samples for PK were collected pre-dose, 15 minutes, 30 minutes, 1, 2, 3 and 4 hours post-dose and analyzed for GSK256066. AUC (0-last) was not calculable for any participant at 1 mcg GSK256066 dose. | Pre-dose, 15 minutes, 30 minutes, 1, 2, 3 and 4 hours post-dose on Day 1 | 
| AUC (0-last) of Active Metabolite GSK614917 | The PK of GSK256066 were assessed in plasma by determining AUC(0-last). All participants who received at least one dose of the study drug provided at least one sample for plasma PK analysis. AUC (0-last) was not calculable in any participant at the 1, 10 or 50 mcg GSK256066 dose. | Pre-dose, 15 minutes, 30 minutes, 1, 2, 3 and 4 hours post-dose on Day 1 | 
| Maximum Observed Plasma Drug Concentration (Cmax) of GSK256066 | The PK of GSK256066 were assessed in plasma by determining Cmax. All participants who received at least one dose of the study drug provided at least one sample for plasma PK analysis. Blood samples for PK were collected pre-dose, 15 minutes, 30 minutes, 1, 2, 3 and 4 hours post-dose and analyzed for GSK256066. | Pre-dose, 15 minutes, 30 minutes, 1, 2, 3 and 4 hours post-dose on Day 1 | 
| Cmax of Active Metabolite GSK614917 | The PK of GSK614917 were assessed in plasma by determining AUC(0-last). All participants who received at least one dose of the study drug provided at least one sample for plasma PK analysis. C max was not calculable for any participant at the 1 mcg GSK256066 dose. | Pre-dose, 15 minutes, 30 minutes, 1, 2, 3 and 4 hours post-dose on Day 1 | 
| Time to Maximum Observed Plasma Drug Concentration (Tmax) and Time to Last Observed Plasma Drug Concentration (Tlast) of GSK256066 | The PK of GSK256066 were assessed in plasma by determining Tmax and Tlast. All participants who received at least one dose of the study drug provided at least one sample for plasma PK analysis. Blood samples for PK were collected pre-dose, 15 minutes, 30 minutes, 1, 2, 3 and 4 hours post-dose and analyzed for GSK256066. | Pre -dose, 15 minutes, 30 minutes, 1, 2, 3 and 4 hours post-dose on Day 1 | 
| Tmax and Tlast of Active Metabolite GSK614917 | The PK of GSK614917 were assessed in plasma by determining Tmax and Tlast. All participants who received at least one dose of the study drug provided at least one sample for plasma PK analysis. Tmax and Tlast could not be determined for any participant at the 1 mcg GSK256066 dose. | Pre-dose, 15 minutes, 30 minutes, 1, 2, 3 and 4 hours post-dose on Day 1 | 
| Nasal Lavage Concentrations of GSK256066 | Nasal lavage samples were taken 2 -3 hour post morning dose and analyzed for GSK256066. Quantifiable levels of GSK256066 were observed in nasal lavage samples obtained 2-3 hours post-dose. | Day 1 | 
| Mean Levels of Total Vasodilator Stimulated Phosphoprotein (VASP) Protein, Phosphorylated(Phospho)157 VASP (pVASP) and phospho239 VASP in Lavage Cells | Nasal lavage were taken 2 to 3 hour post morning dose; bilateral nasal lavage was conducted before the scrape. Nasal lavage samples were analyzed to explore the effects of GSK256066 on novel protein biomarkers including pVASP. Markers indicative of PDE4 inhibition such as VASP protein levels and phospho157 VASP were also measured in this study, in lavage cells, following positive data in an enabling study which showed increases in such protein levels in participants with allergic rhinitis following a single intranasal dose of salbutamol. Nasal lavage data from earlier studies showed that pVASP157 is the best marker and not pVASP239. pVASP239 was therefore not collected or analyzed as planned. | Day 1 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Seasonal allergic rhinitis,, hayfever