A Randomised, Double Blind, Placebo Controlled, 4 Period, Incomplete Block, Crossover Study Assessing the Dose-response Curve of Fluticasone Propionate in an Antigen Challenge Chamber

Study Overview
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Brief Summary
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This is a single-centre, randomised, double-blind, four-period, incomplete block, crossover study, with 8 days repeat dosing of intranasal Fluticasone Propionate (25, 50, 100, 200ug) and/or placebo in the Vienna Challenge Chamber in subjects with allergic rhinitis.

Official Title
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A Randomised, Double Blind, Placebo Controlled, 4 Period, Incomplete Block, Crossover Study to Assess the Dose-response Curve of Intranasal Fluticasone Propionate (25, 50, 100 and 200 μg, Once Daily for 8 Days) in the Vienna Challenge Chamber for the Purpose of Investigating the Sensitivity

Conditions
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Rhinitis, Allergic, Perennial, Allergic Rhinitis

Intervention / Treatment
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* Drug: Fluticasone propionate
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The subject is healthy with the exception of seasonal allergic rhinitis. Healthy as determined by a responsible physician, based on a medical evaluation including history, physical examination, laboratory tests, 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 considers that the finding will not introduce additional risk factors and will not interfere with the study procedures. Males and females who are aged between 18 and 65 years of age. A female is eligible to enter and participate in the study if she is of: Non-childbearing potential (i.e., physiologically incapable of becoming pregnant), including any female who is post menopausal. For the purposes of this study, post menopausal is defined as 1 year without menses (FSH/LH will be also tested to confirm menopausal status); or Child bearing potential, has a negative pregnancy test (urine) at entry, and agrees to one of the following acceptable contraceptive methods when used consistently and correctly (i.e., in accordance with the approved product label and the instructions of a physician for the duration of the study - screening visit to follow-up contact): Complete abstinence from intercourse from the first visit, throughout the trial and for a minimum of 7 days after the completion of the trial; or Male partner was sterile prior to the female subject's entry into the study, or Implants of levonorgestrel inserted for at least 1 month prior to the study Injectable progestogen administered for at least 1 month prior to the study Oral contraceptive (combined or progestogen only) administered for a least one monthly cycle prior to study medication administration; or The contraceptive transdermal patch, such as norelgestromin / ethinyl estradiol transdermal system (if the subject is less than 89kg); or Double-barrier method - spermicide plus a mechanical barrier (e.g., spermicide plus a male condom or a spermicide and female diaphragm . Condom and occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository; or An intrauterine device (IUD) or intrauterine system (IUS), inserted by a qualified physician, Subjects who are current non-smokers, who have not used any inhaled tobacco products (snuff is permitted) in the 12 month period preceding the screening visit and who have a pack history of less than 10 pack years. Pack years = Number of cigarettes per day x Number of years smoked 20 They exhibit a moderate response to up to 1500 grass pollen grains/m3 after 2 hours in the Vienna Challenge Chamber, which is defined as a nasal symptom score of at least 6. (Nasal symptom score is the sum of nasal obstruction, rhinorrhoea, nasal itch and sneeze, each of which are scored on a scale from 0 to 3) They have a positive skin prick test (wheal ³ 4mm) for grass pollen at or within the 12 months preceding the screening visit. They have a positive RAST (Radioallergosorbent Test) (³ class 2) for grass pollen at or within the 12 months preceding the screening visit. They have a TNSS score (Total Nasal Symptom Score)of less than 3 and a score of no more than 1 for any single symptom of the TNSS prior to the screening allergen challenge. There are no conditions or factors that would make the subject unlikely to be able to stay in the trial Able to provide written informed consent. The subject is able to understand and comply with the protocol requirements, instructions and protocol-stated restrictions. Demonstrated ability to use the intranasal device in a satisfactory and repeatable manner. Exclusion Criteria: As a result of medical interview, physical examination or screening investigations, the principle investigator or delegate physician deems the subject unsuitable for the study. Subjects must not have a systolic blood pressure above 150 mmHg or a diastolic pressure above 90 mmHg unless the Investigator confirms that it is satisfactory for their age. The subject has been treated for or diagnosed with depression within six months of screening or has a history of significant psychiatric illness. Pregnant or nursing females. Women of childbearing potential who are unwilling or unable to use an appropriate method of contraception as outlined (Inclusion Criteria 2) On examination the subject is found to have any structural nasal abnormalities or nasal polyposis, a history of frequent nosebleeds, recent nasal surgery or recent (within 2 weeks) or ongoing upper respiratory tract infection which in the Responsible Physician's opinion renders the subject unsuitable for participation in the study. 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 is likely to be unable to abstain from salbutamol use for 8 hours before a challenge. The subject has a screening QTcB value >450msec (based on single or average QTc value of triplicate ECGs obtained over a brief recording period), PQ interval outside the range 120 to 200msec or an ECG that is not suitable for QT measurements (e.g. poorly defined termination of the T-wave). In addition subjects will be excluded if they have a history of atrial or ventricular arrhythmia. The subject has a history of drug or other allergy that, in the opinion of the physician responsible, contraindicates their participation. 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 physician responsible, contraindicates their participation. The subject has taken prescription or non-prescription drugs, within 7 days prior to the first dose of study medication, unless in the opinion of the Investigator and Sponsor the medication will not interfere with the study procedures or compromise subject safety. History of alcohol/drug abuse or dependence within 12 months of the study. Abuse of alcohol defined as an average weekly intake of greater than 21 units or an average daily intake of greater than 3 units (males) or defined as an average weekly intake of greater than 14 units or an average daily intake of greater than 2 units (females). 1 unit is equivalent to a half-pint (220mL) of beer or 1 (25ml) measure of spirits or 1 glass (125ml) of wine). The subject has participated in a clinical trial and has received a drug or a new chemical entity within 30 days or 5 half-lives, or twice the duration of the biological effect of any drug (whichever is longer) prior to the first dose of current study medication. Exposure to more than four new chemical entities within 12 months prior to the first dosing day. The subject has donated a unit of blood (450 mL) within the previous 16 weeks or intends to donate within 16 weeks after completing the study. A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening. The subject has tested positive for HIV antibodies (if tested according to site Standard Operating Procedures). The subject has a positive pre-study urine drug/ urine alcohol screen. A minimum list of drugs that will be screened for include Amphetamines, Barbiturates, Cocaine, Opiates, Cannabinoids (THC) and Benzodiazepines.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* Placebo comparator<br>|
| Experimental: Fluticasone propionate 25ug<br> | Drug: Fluticasone propionate<br>* Corticosteriod, with anti-inflammatory effects<br>|
| Experimental: Fluticason propionate 50ug<br> | Drug: Fluticasone propionate<br>* Corticosteriod, with anti-inflammatory effects<br>|
| Experimental: Fluticasone propionate 100ug<br> | Drug: Fluticasone propionate<br>* Corticosteriod, with anti-inflammatory effects<br>|
| Experimental: Flutciasone propionate 200ug<br> | Drug: Fluticasone propionate<br>* Corticosteriod, with anti-inflammatory effects<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Weighted Mean Total Nasal Symptom Score (TNSS) at 2-5 Hours Post-dose (1-4 Hours Post-start of Challenge [PSC]) in the Vienna Challenge Chamber (VCC) | The TNSS (score of 0-12), defined as the sum of the symptom scores for nasal obstruction, rhinorrhea, nasal itch, and sneeze (each scored on 0-3 scale [0=none, 1=mild, 2=moderate, 3=severe]) was measured at pre-challenge, and then every 15 minutes from 0.25 to 4 hours PSC. In the VCC, aerosolized allergen is administered in a sealed chamber to evaluate the efficacy of antihistamines/other treatments. Weighted mean TNSS was calculated by dividing the value of the area under the response time curve between 1 and 4 hours (calculated by trapezoidal rule) by the time interval of available data. | Day 8 of each study period (Periods 1-4); up to Day 158 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Weighted Mean Nasal Airflow at 2-5 Hours Post-dose (1-4 Hours Post-start of Challenge) | Allergic rhinitis decreases the passage of air through the nose (nasal airflow) by increasing the nasal airway resistance. Rhinomanometry is used as an objective measurement of airway resistance. Nasal airflow was measured using active anterior rhinomanometry at pre-challenge, and then every 30 minutes from 0.5 to 4 hours post start of VCC. Weighted mean nasal airflow was calculated by dividing the value of the area under the response time curve between 1 and 4 hours (calculated by trapezoidal rule) by the time interval of available data. | Day 8 of each study period (Periods 1-4); up to Day 158 | 
| Weighted Mean Nasal Secretion at 2-5 Hours Post-dose (1-4 Hours Post-start of Challenge) | Nasal secretion was measured by weighing tissues used by participants. Wet tissue weight assessments were made pre-challenge, and then every 30 minutes from 0.5 to 4 hours post start of challenge chamber throughout the study. Weighted mean nasal secretion was calculated by dividing the value of the area under the response time curve between 1 and 4 hours (calculated by trapezoidal rule) by the time interval of available data. | Day 8 of each study period (Periods 1-4); up to Day 158 | 
| Weighted Mean Eye Symptom Score at 2-5 Hours Post-dose (1-4 Hours Post-start of Challenge) | The eye symptom score (total score of 0 [none] to 9 [severe]) was calculated as the sum of the symptom scores for watery eyes, itchy eyes, and red eyes, each of which was scored on a categorical scale from 0 to 3 (0=none, 1=mild, 2=moderate, 3=severe), and was measured at pre-challenge, and then every 15 minutes from 0.25 to 4 hours post-start of challenge chamber. Weighted mean eye symptom score was calculated by dividing the value of the area under the response time curve between 1 and 4 hours (calculated by trapezoidal rule) by the time interval of available data. | Day 8 of each study period (Periods 1-4); up to Day 158 | 
| Weighted Mean Global Symptom Score (GSS) at 5 Hours Post-dose (1-4 Hours Post-start of Challenge) | GSS (total score=0-30) is calculated as the sum of sneeze, nasal itch, rhinorrhea, nasal obstruction, cough, itchy throat, itchy ears, watery eyes, itchy eyes, and red eyes SSs, each of which was scored on a categorical scale from 0 to 3 (0=none, 1=mild, 2=moderate, 3=severe), as was measured at pre-challenge, and then every 15 mins from 0.25 to 4 hours post-start of challenge chamber. Weighted mean global symptom score was evaluated by dividing the value of the area under the response time curve between 1 and 4 hours (calculated by trapezoidal rule) by the time interval of available data. | Day 8 of each study period (Periods 1-4); up to Day 158 | 
| Glucocorticoid (GC) Receptor Biomarker Levels in Nasal Epithelial Scraping Samples: CCL2 | AROS Applied Biotechnology (AB) analyzed the nasal epithelial scrapings of participants and generated TaqMan (type of chemistry developed by AB to detect polymerase chain reaction [PCR] products) messenger ribonucleic acid (mRNA) biomarker expression data for CCL2, a steroid-responsive gene. Preliminary analysis of the mRNA abundance data was performed by Discovery Statistics. mRNA abundance data were normalized to the scores of GAPDH and 18S housekeeping genes. B-actin was not used. CCL2 data are presented by period to show the treatment-by-period interaction. ng, nanograms. | Day 1 (pre-dose) and Day 8 of each study period (Periods 1-4); up to Day 158 | 
| Glucocorticoid (GC) Receptor Biomarker Levels in Nasal Epithelial Scraping Samples: 18S, B-actin, DUSP_1_T1, FKBP5, GAPDH, GILZ, PLAU, PTGS2, and RGS2 | AROS Applied Biotechnology (AB) analyzed the nasal epithelial scrapings of participants and generated TaqMan (type of chemistry developed by AB to detect polymerase chain reaction [PCR] products) messenger ribonucleic acid (mRNA) biomarker expression data for 7 steroid-responsive genes (DUSP_1_TI, FKBP5, GILZ, PLAU, CCL2, PTGS2, and RGS2) and 3 housekeeping reference genes (GAPDH, 18S, and b-actin). Preliminary analysis of the mRNA abundance data was performed by Discovery Statistics. mRNA abundance data were normalized to the scores of GAPDH and 18S housekeeping genes. B-actin was not used. | Day 1 (pre-dose) and Day 8 of each study period (Periods 1-4); up to Day 158 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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fluticasone propionate, Vienna Challenge Chamber, glucocorticosteroids, allergic rhinitis