Clinical Study to Evaluate the Efficacy and Safety of VR506 Using a New Inhaler for the Treatment of Asthma

Study Overview
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Brief Summary
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To evaluate the clinical efficacy, safety, tolerability and dose-response relationship, using oral corticosteroid (OCS) modulation, of 3 different doses of VR506 using a twice daily regimen from a new dry powder inhaler (nDPI) for 16 weeks in subjects with severe persistent asthma requiring OCS therapy, i.e. Step 5 treatment as defined by modified Global Initiative for Asthma (GINA) guidelines 2011.

Official Title
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A Randomised Double-blind, Parallel Group, Dose-ranging Study to Evaluate the Efficacy and Safety of VR506 From a New Dry Powder Inhaler in Subjects With Severe Persistent Asthma Requiring Oral Corticosteroid Therapy.

Conditions
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Asthma

Intervention / Treatment
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* Drug: VR506


Participation Criteria
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Eligibility Criteria
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Inclusion: Written informed consent Adolescents aged 12-17 years & adults aged 18-65 years (both inclusive) Documented clinical history of severe asthma requiring prednisone/prednisolone therapy, high-intensity treatment ICS, OCS, LABA Stable OCS dose for ≥7 days before Screening Visit & during Screening Period. At least 80% compliant w/regular asthma medication per investigator at end of Screening Period Documented asthma reversibility within 5 yrs prior to/during Screening Period, or diagnosis of asthma that is incontrovertible per investigator Ability to use nDPI correctly, per investigator's review of completed inhaler operation checklist Ability to use eDiary correctly, assessed by investigator at end of Screening Period Ability to comply w/study procedures, including blood sampling Ability to perform technically satisfactory pulmonary function tests Available to complete all study visits before 12 noon BMI of 16-26 kg/m2 in adolescents and 18-32 kg/m2 in adults Oral PIF ≥40 L/min, using an appropriate device set to match resistance of inhaler Good health, except for presence of asthma, per medical history/physical examination Negative drug/alcohol/urine cotinine screen. Subjects must test negative for amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine, cotinine, ethanol & opiates (unless given as prescription medicine) Non-smokers or ex-smokers with a smoking history of less than 10 pack-yrs (e.g. <20 cigarettes per day for 10 years or <40 cigarettes per day for 5 years) & stopped smoking for at least 1 year prior to Screening Visit. Smoking will not be permitted throughout study Female subjects of child-bearing potential must be using medically acceptable forms of contraception [abstinence, hormonal (oral/implant/transdermal/injection), in use for ≥3 consecutive months before first dose of study medication, double barrier (condom w/spermicide, or diaphragm w/spermicide), IUD, or vasectomised partner (≥6 months since vasectomy)]. Exclusion: Regular use (≥3 times/wk) of topical steroids to treat dermatitis/rhinitis/allergic conjunctivitis, within 28 days of Screening Visit Subjects who have/who have had, an upper/lower respiratory tract infection within 28 days of Screening Visit Subjects w/brittle asthma Subjects w/asthma that required admission to an ICU and/or ventilation within previous 12 months Subjects whose comorbidities, per investigator's opinion, are major contributors to their respiratory symptoms (e.g. COPD, bronchiectasis, dysfunctional breathlessness, vocal cord dysfunction, gastro-oesophageal reflux) Previously/currently diagnosed as having Churg-Strauss syndrome Previously/currently diagnosed as having pulmonary eosinophilia History of lung cancer Subjects w/current diagnosis of HIV infection Active chronic hepatitis B or C infection Subjects who have clinically significant abnormality/finding from examination, tests, or history that may compromise subject safety, specifically any history of cardiac, renal or hepatic impairment Subjects with an abnormal ECG Persistent arterial hypotension, with average SBP readings of ≤95 mmHg Persistent elevation of blood pressure, with average SBP readings of ≥160 mmHg or average DBP readings of ≥100 mmHg Pregnant or lactating females Participation in another clinical study in 28 days prior to Screening Visit Evidence of clinically significant renal, hepatic, cardiac, pulmonary (apart from asthma) or metabolic dysfunction, e.g. diabetes mellitus, thyrotoxicosis, uncorrectable hypokalaemia, or predisposition to low levels of serum potassium Current/history of drug/alcohol abuse/dependence per WHO criteria Inability to communicate well w/investigator Donation of ≥450 mL of blood/blood products within previous 3 months prior to screening History of allergy/intolerance/contraindications to corticosteroids/lactose, or severe allergy to milk proteins Consumption of alcohol- or caffeine-containing foods/beverages from midnight before or during Screening Visit History of medically diagnosed chronic respiratory diseases other than asthma (e.g. chronic obstructive pulmonary disease, ABPA in the absence of asthma)

Ages Eligible for Study
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Minimum Age: 12 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: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Dose 1 VR506<br>VR506 inhalation powder delivered via a new dry powder inhaler device | Drug: VR506<br>* VR506 inhalation powder delivered via a new dry powder inhaler device<br>|
| Active Comparator: Dose 2 VR506<br>VR506 inhalation powder delivered via a new dry powder inhaler device | Drug: VR506<br>* VR506 inhalation powder delivered via a new dry powder inhaler device<br>|
| Active Comparator: Dose 3 VR506<br>VR506 inhalation powder delivered via a new dry powder inhaler device | Drug: VR506<br>* VR506 inhalation powder delivered via a new dry powder inhaler device<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Prednisone/Prednisolone Dose for Analysis (PDA) at End of Study (Week 16) | The mean asthma control prednisone/prednisolone dose at end of study (week 16) | 16 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Start of Treatment Baseline to End of Study (Week 16) for In-clinic Morning Pre-Dose Forced Expiratory Volume In 1 Second (FEV1) |  | Baseline and 16 weeks | 
| Mean Change From Start of Treatment Baseline to End of Study (Week 16) for Asthma Control Questionnaire (ACQ-5) Mean Total Score | Change from baseline to end of study (week 16) in 5 item asthma control questionnaire (ACQ-5) mean total score (range 0 (better) to 6 (worse)). The mean total score is calculated as the mean for each subject at each visit of 5 questions, each scored from 0 (better) to 6 (worse). | Baseline and 16 weeks | 
| Mean Change From Start of Treatment Baseline to End of Study (Week 16) for In-clinic Weekly Morning Pre-dose Peak Expiratory Flow (PEF) |  | Baseline and 16 weeks | 
| Mean Change From Start of Treatment Baseline to End of Study (Week 16) for Weekly Average Asthma Night-time Symptom Score | To measure the change from baseline to end of study for the weekly mean asthma night time symptom score, scored from 0 (not at all bothered) to 6 (severely bothered). | Baseline and 16 weeks | 
| Number of Participants With Withdrawals Due to Worsening of Asthma |  | 16 weeks | 
| Assessment of Acceptability of the Device | Percentage of subjects that overall found it very easy or fairly easy to use the inhaler, based on inhaler acceptability questionnaire | 16 weeks |