| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Body processes [G] - Circulatory and Respiratory Physiological Phenomena [G09] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10003553 |
| E.1.2 | Term | Asthma |
| E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To evaluate the clinical efficacy, safety and tolerability of VR475 1 mg/2 ml twice daily given for 52 weeks compared to placebo. |
|
| E.2.2 | Secondary objectives of the trial |
-To evaluate the clinical efficacy, safety and tolerability of VR475 1 mg/2 ml compared to conventionally nebulised budesonide 1 mg/2 ml twice daily;
-To investigate the dose-response relationship of VR475;
-To evaluate any change from Baseline to End-of-Treatment in OCS dose in those subjects receiving OCS at Baseline. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Adolescents aged 12 to 17 years (inclusive) and adults aged 18 to 74 years (inclusive). For those countries where local regulations permit enrolment of adults only, subject recruitment will be restricted to those who are ≥ 18 years of age;
2.FEV1 reversibility (increase of at least 12% in absolute FEV1 and 200 ml from pre-bronchodilator value within 15-30 minutes after the use of inhaled bronchodilator) at the Screening or Randomisation Visits or during past 24 months;
A positive airways hyper-responsiveness test (fall in FEV1 from baseline of ≥20% with standard doses of methacholine or histamine, or ≥15% with standardized hyperventilation, hypertonic saline or mannitol challenge) during the past 24 months is also acceptable;
3.High dose inhaled glucocorticosteroid at a total daily dose of ≥500 μg of fluticasone proprionate DPI or equivalent for at least 3 months prior to the Screening Visit;
4. Treatment with at least a second asthma controller medication (i.e. not a short acting β-agonist [SABA]) for at least 3 months prior to the Screening Visit;
5. FEV1 <80% of predicted value at the Screening and Randomisation Visits;
6. ACQ-5 score (symptom-only version) of 1.5 or higher at the Screening and Randomisation Visits;
7. Subjects with a previously confirmed history of at least two clinically significant asthma exacerbations defined as those requiring treatment or increased treatment with oral/systemic corticosteroids for at least 3 days and/or requiring hospitalisation and/or visit to an emergency department for an exacerbation in the 12 months prior to the Screening Visit, despite the use of high-dose ICS and additional controller medication (or Symbicort SMART) at the time the exacerbation occurred;
8. Written informed consent obtained from the subject or subject’s parents/legal representatives (according to local regulations) and written or verbal assent by the subject (when appropriate), prior to participation in the study;
9. A negative pregnancy test must be available for any women of childbearing potential at the Screening and Randomisation Visits (prior to randomisation to one of the treatment groups);
10. Subjects able to read, comprehend and write at a level sufficient to complete study-related materials. |
|
| E.4 | Principal exclusion criteria |
1. Asthma exacerbation or significant change in asthma treatment within the 4 weeks prior to the Screening Visit or during the Screening Period;
2. Abnormal lab values for biochemistry tests during the Screening Period that may indicate impaired ability to metabolise and/or excrete budesonide (aspartate transaminase [AST], alanine transaminase [ALT] > 3 times upper limit of normal range, serum creatinine > 1.5 times upper limit of normal range).
3.Current smokers or subjects with a recent smoking history (less than 6 months before randomisation) of ≥10 pack years (number of pack years = number of cigarettes per day / 20 x number of years smoked);
4.Presence of a clinically important lung condition other than asthma. This includes, but is not limited to, current infection, bronchiectasis, pulmonary fibrosis, bronchopulmonary aspergillosis or diagnoses of emphysema or chronic bronchitis (chronic obstructive pulmonary disease other than asthma) or a history of lung cancer;
5.Subjects with a diagnosis of active malignancy or in the process of investigation for a suspected malignancy. Subjects with a past medical history of malignancy can be allowed in the trial if in remission and provided anyone with a diagnosis of a recurrent malignant tumour or having received treatment for a malignancy within 12 months prior to the Screening Visit are excluded;
6.Subjects with a known immunodeficiency (e.g. human immunodeficiency virus),) or receiving immunosuppressant and/or immune modulating therapy (e.g. rheumatoid arthritis) other than that explained by the use of corticosteroids taken as therapy for asthma;
7. Subjects who have clinically significant cardiovascular, endocrine, autoimmune, metabolic, neurological, renal, gastrointestinal, hepatic, haematological or any other system abnormalities that were uncontrolled with standard treatment and which in the investigator’s opinion places the subject at undue risk by participating in the study;
8. History of substance abuse that may impair or risk the subject’s full participation in the study, in the judgment of the investigator;
9. Treatment with other investigational treatment within 4 weeks prior to the Screening Visit;
10. Regular oral/systemic corticosteroids for the treatment of conditions other than asthma in the 3 months prior to the Screening Visit;
11. History of allergy or adverse experience with budesonide or any of the excipients of budesonide nebuliser suspension (see VR475 Investigator’s Brochure 2016);
12. Use of a monoclonal antibody for the treatment of asthma within the 6 months prior to the Screening Visit;
13.Pregnant or lactating females. or females who are planning to become pregnant during the study.
14. Subjects with features suggestive of Cushing's syndrome;
15. Subjects who have failed screening twice before in this study or who have completed this study;
16. Treatment with the following medications during the Screening Period: benzodiazepines, barbiturates and opiates (except at prescription doses for analgesia and/or insomnia), new or non-maintenance immunotherapy, methotrexate, oral gold, dapsone or i.v. ƴ globulin, monoclonal antibodies, anti-IgE treatment, b-blockers, macrolides (either as a chronic therapy or as an antimicrobial treatment for infection) and any investigational treatment other than the study medication. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The annualised rate of clinically significant exacerbations during the Treatment Period. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
-Time to first clinically significant exacerbation;
-Change in in-clinic pre bronchodilator FEV1 from baseline during the Treatment Period;
-Change in in-clinic forced expiratory flow between 25% and 75% of FVC [FEF25-75]) from Baseline during Treatment Period;
-Change in ACQ-5 scores from baseline during the Treatment Period.
- Proportion of subjects without a clinically significant exacerbation;
- Annualized exacerbation rate (all exacerbations);
- Time to first exacerbation (all exacerbations);
- Proportion of subjects without an exacerbation (all exacerbations);
- Change in OCS dose from baseline to End-of-Treatment/ Week 52, in subgroup of OCS users at baseline;
- Proportion of OCS users with 50 % or 100 % OCS dose reductions from baseline to End-of-Treatment/ Week 52;
- Total OCS dosage;
- Total OCS/ systemic corticosteroid dosage given for exacerbations;
- Change in in-clinic pulmonary function test (PFT) assessments (FEV1 % predicted, forced vital capacity {FVC}) from baseline during the Treatment Period;
- Change in am and pm PEF from baseline during the Treatment Period;
- Change in reliever medication use from baseline during the Treatment Period;
- Change in symptom-free days from baseline during the Treatment Period;
- Change in reliever-medication-free days from baseline during the Treatment Period;
- Change in uncontrolled asthma days from baseline during the Treatment Period;
- Change in night-time awakenings due to asthma from baseline during the Treatment Period;
- Changes in scores from EQ-5D questionnaire from baseline during the Treatment Period;
- Changes in AQLQ + 12 scores from baseline during the Treatment Period. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Baseline to End-of-Treatment/Week 52 |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Budesonide nebuliser suspension 1 mg/2 ml (open-label) delivered by the PARI BOY® Inhalation System |
|
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 13 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 103 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Bulgaria |
| Germany |
| Greece |
| Hungary |
| Philippines |
| Poland |
| Romania |
| Serbia |
| Ukraine |
| United Kingdom |
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| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The definition of the end of the clinical phase of the study is when the last subject’s follow-up telephone call has been carried out. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
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