| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
| 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 effects of FF/UMEC/VI
on lung function compared with FF/VI
after 24 weeks of treatment |
|
| E.2.2 | Secondary objectives of the trial |
-To evaluate the efficacy of FF/UMEC/VI compared with FF/VI
-To evaluate the safety of FF/UMEC/VI compared with FF/VI
-To evaluate other efficacy assessments of FF/UMEC/VI compared with FF/VI |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
| The PK sub study aims to include approximately 20% of trial participants. Details of the sub study are included in the main trial protocol. The objective is to evaluate the systemic exposure of FF, UMEC and VI following FF/UMEC/VI |
|
| E.3 | Principal inclusion criteria |
AGE
1. 18 years of age or older at the time of signing the informed consent.
TYPE OF SUBJECT AND DIAGNOSIS INCLUDING DISEASE SEVERITY
2. Diagnosis: Subjects with a diagnosis of asthma as defined by the National Institutes of Health at least one year prior to Visit 0.
3. Symptomatic: Subjects with inadequately controlled asthma despite ICS/LABA maintenance therapy at Visit 1.
4. Asthma Control: A documented non-routine healthcare visit due to acute asthma symptoms in the 1 year prior to Visit 1.
5. Current Asthma Maintenance Therapy: Subjects are eligible if they have required daily ICS/LABA for at least 12 weeks prior to Visit 0 with no changes to maintenance asthma medications during the 6 weeks immediately prior to Visit 0 (including no changes to a stable total dose of ICS of >250 mcg/day fluticasone proprionate
Examples of acceptable doses of commonly prescribed ICS and LABA or ICS/LABA combination medication is provided in the Study Reference Manual (SRM). Dosing regimen should be restricted to the current local product labels.
6. Spirometry:
A best pre-bronchodilator morning FEV1 ≥30% and <80% of the predicted normal value at Visit 1. Predicted values will be based upon the European Respiratory Society Global Lung Function Initiative
7. Reversibility of Disease: airway reversibility defined as ≥12% and ≥200 mL increase in FEV1 between 20 and 60 minutes following 4 inhalations of albuterol/salbutamol aerosol at Visit 1.
Note: If the subject does not meet the above reversibility criteria at Visit 1 then the reversibility assessment may be repeated once within 7 days of Visit 1 if either criteria a) or b) are met:
a) ≥9% increase in FEV1 between 20 and 60 minutes following 4 inhalations of albuterol/salbutamol aerosol at Visit 1.
b) Documented evidence of a reversibility assessment within 1 year prior to Visit 1 which demonstrated a post-bronchodilator increase in FEV1 of ≥12% and ≥200 mL.
Should the subject successfully demonstrate airway reversibility at the second attempt then, provided that all other eligibility criteria assessed at Visit 1 are met, the subject may enter the 3-week runin period
8. Short-Acting β2 Agonists: All subjects must be able to replace their current SABA inhaler with albuterol/salbutamol aerosol inhaler at Visit 1 as needed for the duration of the study. Subjects must be judged capable of withholding albuterol/salbutamol for at least 6 hours prior to study visits.
SEX
9. Male or Eligible Female, defined as having documentation of non-reproductive potential or reproductive potential. |
|
| E.4 | Principal exclusion criteria |
CONCURRENT CONDITIONS/MEDICAL HISTORY (INCLUDES LIVER
FUNCTION AND QTc INTERVAL)
1. Pneumonia: Chest X-ray documented pneumonia in the 6 weeks prior to Visit 1.
2. Asthma Exacerbation: Any asthma exacerbation requiring a change in maintenance asthma therapy in the 6 weeks prior to Visit 1.
Note: Subjects who experience an asthma exacerbation in the 6 weeks prior to Visit 1 are not explicitly excluded at Visit 1 provided that, at the Investigator’s discretion, the subject’s condition is stable and they are considered appropriate for enrolment into this study of up to 12 months’ duration.
3. Chronic Obstructive Pulmonary Disease: Subjects with the diagnosis of chronic obstructive pulmonary disease, as per Global Initiative for Chronic Obstructive Lung Disease guidelines, including all of the following:
-History of exposure to risk factors;
AND
-A post-albuterol/salbutamol FEV1/Forced Vital Capacity ratio of <0.70 and a post-albuterol/salbutamol FEV1 of ≤70% of predicted normal values;
AND
-Onset of disease ≥40 years of age
4. Concurrent respiratory disorders: Subjects with current evidence of pneumonia, active tuberculosis, lung cancer, significant bronchiectasis, sarcoidosis, lung fibrosis, pulmonary hypertension, interstitial lung diseases or other active pulmonary diseases or abnormalities other than asthma.
5. Risk Factors for Pneumonia: immune suppression or other risk factors for pneumonia Patients at potentially high risk will only be included at the discretion of the Investigator.
6. Other diseases/abnormalities: Subjects with historical or current evidence of clinically significant cardiovascular, neurological, psychiatric, renal, hepatic, immunological, gastrointestinal, urogenital, nervous system, musculoskeletal, skin, sensory, endocrine or hematological abnormalities that are uncontrolled. Significant is defined as any disease that, in the opinion of the Investigator, would put the safety of the subject at risk through participation, or which would affect the efficacy or safety analysis if the disease/condition exacerbated during the study.
7. Unstable liver disease as defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminaemia, esophageal or gastric varices or persistent jaundice, cirrhosis, known biliary abnormalities. Note: Chronic stable hepatitis B and C are acceptable if the subject otherwise meets entry criteria
8. Clinically significant ECG abnormality: Evidence of a clinically significant abnormality in the 12-lead ECG performed during screening. The Investigator will determine the clinical significance of each abnormal ECG finding in relation to the subject’s medical history and exclude subjects who would be at undue risk by participating in the trial. An abnormal and clinically significant finding is defined as a 12-lead tracing that is interpreted as, but not limited to, any of the following:
-Atrial Fibrillation with rapid ventricular rate >120 beats per minute (BPM);
-Sustained or nonsustained ventricular tachycardia;
-Second degree heart block Mobitz type II and third degree heart block (unless
pacemaker or defibrillator had been inserted);
-QTcF ≥500 msec in patients with QRS <120 msec and QTcF ≥530 msec in patients with QRS ≥120 msec
9. Unstable or life threatening cardiac disease: subjects with any of the following at Screening (Visit 1) would be excluded:
-Myocardial infarction or unstable angina in the last 6 months
-Unstable or life threatening cardiac arrhythmia requiring intervention in the last 3 months
-New York Heart Association Class IV Heart failure
10. Antimuscarinic effects: Subjects with a medical condition such as narrow-angle glaucoma, urinary retention, prostatic hypertrophy or bladder neck obstruction should only be included if in the opinion of the Investigator the benefit outweighs the risk
and that the condition would not contraindicate study participation.
11. Cancer: Subjects with carcinoma that has not been in complete remission for at least 5 years. Subjects who have had carcinoma in situ of the cervix, squamous cell carcinoma and basal cell carcinoma of the skin would not be excluded based on the 5 year waiting period if the subject has been considered cured by treatment.
12. Questionable validity of consent: Subjects with a history of psychiatric disease, intellectual deficiency, poor motivation or other conditions that will limit the validity of informed consent to participate in the study.
CONCOMITANT MEDICATIONS/TREATMENTS
13. Medication prior to spirometry: Subjects who are medically unable to withhold their albuterol/salbutamol for the 6-hour period required prior to spirometry testing at each study visit
Refer to protocol for criteria under the following headings:
-RELEVANT HABITS
-CONTRAINDICATIONS
-DIAGNOSTIC ASSESSMENTS AND OTHER CRITERIA
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Mean change from baseline in trough Forced Expiratory Volume in 1 second (FEV1) at Week 24
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| E.5.1.1. The primary analysis will be at 24 weeks. Data will be summarised at all timepoints where collected. |
|
| E.5.2 | Secondary end point(s) |
-Annualized rate of moderate/severe asthma exacerbations
-Mean change from baseline in clinic FEV1 at 3 hours post study treatment at Week 24
-Mean change from baseline in ACQ-7 total score at Week 24
-Mean change from baseline in St. George's Respiratory Questionnaire (SGRQ) total score at Week 24
-Mean change from baseline in Evaluating Respiratory Symptoms (E-RS) total score over the first 24 weeks of the treatment period
-Incidence and type of adverse events (AEs)
-Electrocardiogram (ECG) measurements
-Vital signs
-Clinical hematological and chemistry parameters |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
E.5.2.1. For all endpoints except annualized rate of moderate/severe asthma exacerbations the primary
analysis will be at week 24.
For the annualized rate of moderate/severe asthma exacerbations endpoint all available data up until week 52 will be included in the primary analysis
Data will be summarised for all end points at all timepoints where collected. |
|
| 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 | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| 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 | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
|
| E.8.2.4 | Number of treatment arms in the trial | 6 |
| 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 | 10 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 106 |
| 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 |
| Australia |
| Canada |
| Germany |
| Italy |
| Japan |
| Korea, Democratic People's Republic of |
| Netherlands |
| Poland |
| Romania |
| Russian Federation |
| South Africa |
| Spain |
| Sweden |
| United Kingdom |
| United States |
|
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 11 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 11 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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