Asthma
Conditions
Brief summary
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.
Interventions
DRUGVR506
VR506 inhalation powder delivered via a new dry powder inhaler device
Sponsors
Vectura Limited
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
12 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Prednisone/Prednisolone Dose for Analysis (PDA) at End of Study (Week 16) | 16 weeks | The mean asthma control prednisone/prednisolone dose at end of study (week 16) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change From Start of Treatment Baseline to End of Study (Week 16) for Asthma Control Questionnaire (ACQ-5) Mean Total Score | Baseline and 16 weeks | 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). |
| 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 In-clinic Morning Pre-Dose Forced Expiratory Volume In 1 Second (FEV1) | Baseline and 16 weeks | — |
| Number of Participants With Withdrawals Due to Worsening of Asthma | 16 weeks | — |
| Assessment of Acceptability of the Device | 16 weeks | Percentage of subjects that overall found it very easy or fairly easy to use the inhaler, based on inhaler acceptability questionnaire |
| Mean Change From Start of Treatment Baseline to End of Study (Week 16) for Weekly Average Asthma Night-time Symptom Score | Baseline and 16 weeks | 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). |
Countries
Bulgaria, Germany, Hungary, Poland, Romania, Ukraine, United Kingdom, United States
Participant flow
Pre-assignment details
197 subjects were randomised and 196 received at least one dose of study drug; 1 subject was randomised but not treated.
Participants by arm
| Arm | Count |
|---|---|
| Dose 1 VR506 50 mcg VR506 inhalation powder delivered via a new dry powder inhaler device
VR506: VR506 inhalation powder delivered via a new dry powder inhaler device | 62 |
| Dose 2 VR506 250 mcg VR506 inhalation powder delivered via a new dry powder inhaler device
VR506: VR506 inhalation powder delivered via a new dry powder inhaler device | 71 |
| Dose 3 VR506 500 mcg VR506 inhalation powder delivered via a new dry powder inhaler device
VR506: VR506 inhalation powder delivered via a new dry powder inhaler device | 63 |
| Total | 196 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 1 |
| Overall Study | Could not use e-diary correctly | 0 | 1 | 1 |
| Overall Study | Lack of Efficacy | 0 | 4 | 0 |
| Overall Study | Lost to Follow-up | 0 | 0 | 1 |
| Overall Study | Non-compliance on using e-diary | 0 | 0 | 1 |
| Overall Study | OCS bursts occured, discontinued in line | 1 | 0 | 0 |
| Overall Study | Randomised without baseline values | 0 | 0 | 1 |
| Overall Study | Treatment period withdrawal criteria met | 4 | 8 | 9 |
| Overall Study | Withdrawal by Subject | 0 | 2 | 1 |
Baseline characteristics
| Characteristic | Dose 1 VR506 50 mcg | Dose 2 VR506 250 mcg | Dose 3 VR506 500 mcg | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 62 Participants | 70 Participants | 63 Participants | 195 Participants |
| Region of Enrollment Bulgaria | 6 participants | 7 participants | 6 participants | 19 participants |
| Region of Enrollment Germany | 4 participants | 3 participants | 3 participants | 10 participants |
| Region of Enrollment Hungary | 3 participants | 3 participants | 4 participants | 10 participants |
| Region of Enrollment Poland | 15 participants | 18 participants | 16 participants | 49 participants |
| Region of Enrollment Romania | 16 participants | 17 participants | 16 participants | 49 participants |
| Region of Enrollment Ukraine | 15 participants | 18 participants | 14 participants | 47 participants |
| Region of Enrollment United Kingdom | 1 participants | 1 participants | 0 participants | 2 participants |
| Region of Enrollment United States | 2 participants | 4 participants | 4 participants | 10 participants |
| Sex: Female, Male Female | 40 Participants | 45 Participants | 42 Participants | 127 Participants |
| Sex: Female, Male Male | 22 Participants | 26 Participants | 21 Participants | 69 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 62 | 0 / 71 | 0 / 63 |
| other Total, other adverse events | 21 / 62 | 33 / 71 | 25 / 63 |
| serious Total, serious adverse events | 0 / 62 | 0 / 71 | 0 / 63 |
Outcome results
Primary
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)
Time frame: 16 weeks
Population: The Full Analysis Set (FAS) was analyzed, however 7 subjects are not included because they had no OCS dose adjustment assessment post-randomisation, and baseline values were not carried forward.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dose 1 VR506 50 mcg | Mean Prednisone/Prednisolone Dose for Analysis (PDA) at End of Study (Week 16) | 4.55 mg | Standard Deviation 6.85 |
| Dose 2 VR506 250 mcg | Mean Prednisone/Prednisolone Dose for Analysis (PDA) at End of Study (Week 16) | 4.31 mg | Standard Deviation 7.38 |
| Dose 3 VR506 500 mcg | Mean Prednisone/Prednisolone Dose for Analysis (PDA) at End of Study (Week 16) | 3.97 mg | Standard Deviation 6.21 |
p-value: 0.772ANCOVA
Secondary
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
Time frame: 16 weeks
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Dose 1 VR506 50 mcg | Assessment of Acceptability of the Device | Missing | 1 Participants |
| Dose 1 VR506 50 mcg | Assessment of Acceptability of the Device | Fairly easy | 21 Participants |
| Dose 1 VR506 50 mcg | Assessment of Acceptability of the Device | Very easy | 40 Participants |
| Dose 2 VR506 250 mcg | Assessment of Acceptability of the Device | Fairly easy | 21 Participants |
| Dose 2 VR506 250 mcg | Assessment of Acceptability of the Device | Very easy | 49 Participants |
| Dose 2 VR506 250 mcg | Assessment of Acceptability of the Device | Missing | 1 Participants |
| Dose 3 VR506 500 mcg | Assessment of Acceptability of the Device | Very easy | 38 Participants |
| Dose 3 VR506 500 mcg | Assessment of Acceptability of the Device | Missing | 4 Participants |
| Dose 3 VR506 500 mcg | Assessment of Acceptability of the Device | Fairly easy | 21 Participants |
Secondary
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).
Time frame: Baseline and 16 weeks
Population: Full Analysis Set was analyzed, but number of patients represents subjects with both start of treatment baseline value and end of treatment value where a Last Observation Carried Forward (LOCF) approach was used to impute values of missing post-baseline visits; 1 subject had no post-dose ACQ-5 assessment, baseline value was not carried forward.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dose 1 VR506 50 mcg | Mean Change From Start of Treatment Baseline to End of Study (Week 16) for Asthma Control Questionnaire (ACQ-5) Mean Total Score | -0.67 score on a scale | Standard Deviation 0.98 |
| Dose 2 VR506 250 mcg | Mean Change From Start of Treatment Baseline to End of Study (Week 16) for Asthma Control Questionnaire (ACQ-5) Mean Total Score | -0.77 score on a scale | Standard Deviation 1.15 |
| Dose 3 VR506 500 mcg | Mean Change From Start of Treatment Baseline to End of Study (Week 16) for Asthma Control Questionnaire (ACQ-5) Mean Total Score | -0.39 score on a scale | Standard Deviation 0.89 |
p-value: 0.066ANCOVA
Secondary
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)
Time frame: Baseline and 16 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dose 1 VR506 50 mcg | 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) | 0.06 Liters | Standard Deviation 0.4 |
| Dose 2 VR506 250 mcg | 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) | 0.02 Liters | Standard Deviation 0.31 |
| Dose 3 VR506 500 mcg | 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) | 0.06 Liters | Standard Deviation 0.35 |
p-value: 0.891ANCOVA
Secondary
Mean Change From Start of Treatment Baseline to End of Study (Week 16) for In-clinic Weekly Morning Pre-dose Peak Expiratory Flow (PEF)
Time frame: Baseline and 16 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dose 1 VR506 50 mcg | Mean Change From Start of Treatment Baseline to End of Study (Week 16) for In-clinic Weekly Morning Pre-dose Peak Expiratory Flow (PEF) | 2 L/min | Standard Deviation 45.7 |
| Dose 2 VR506 250 mcg | Mean Change From Start of Treatment Baseline to End of Study (Week 16) for In-clinic Weekly Morning Pre-dose Peak Expiratory Flow (PEF) | 20.1 L/min | Standard Deviation 51.7 |
| Dose 3 VR506 500 mcg | Mean Change From Start of Treatment Baseline to End of Study (Week 16) for In-clinic Weekly Morning Pre-dose Peak Expiratory Flow (PEF) | 6.1 L/min | Standard Deviation 53.5 |
p-value: 0.063ANCOVA
Secondary
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).
Time frame: Baseline and 16 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dose 1 VR506 50 mcg | Mean Change From Start of Treatment Baseline to End of Study (Week 16) for Weekly Average Asthma Night-time Symptom Score | -0.3 score on a scale | Standard Deviation 1 |
| Dose 2 VR506 250 mcg | Mean Change From Start of Treatment Baseline to End of Study (Week 16) for Weekly Average Asthma Night-time Symptom Score | -0.6 score on a scale | Standard Deviation 1 |
| Dose 3 VR506 500 mcg | Mean Change From Start of Treatment Baseline to End of Study (Week 16) for Weekly Average Asthma Night-time Symptom Score | -0.2 score on a scale | Standard Deviation 1 |
p-value: 0.054ANCOVA
Secondary
Number of Participants With Withdrawals Due to Worsening of Asthma
Time frame: 16 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dose 1 VR506 50 mcg | Number of Participants With Withdrawals Due to Worsening of Asthma | 4 Participants |
| Dose 2 VR506 250 mcg | Number of Participants With Withdrawals Due to Worsening of Asthma | 11 Participants |
| Dose 3 VR506 500 mcg | Number of Participants With Withdrawals Due to Worsening of Asthma | 8 Participants |
p-value: 0.168Fisher Exact
p-value: 0.363Fisher Exact
p-value: 0.805Fisher Exact