| 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 | 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 |
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| 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 |
| ● Evaluate the effects of UMEC 62.5 mcg and UMEC 31.25 mcg on lung function (trough FEV1) versus placebo after 24 weeks of treatment. |
|
| E.2.2 | Secondary objectives of the trial |
| ● Evaluate the effects of UMEC 62.5 mcg and UMEC 31.25 mcg on lung function (3hours post dose FEV1) versus placebo after 24 weeks of treatment. ● To evaluate the safety and tolerability of UMEC 62.5 mcg and UMEC 31.25 mcg compared to placebo. ●To evaluate other efficacy assessments of UMEC 62.5 mcg and UMEC 31.25 mcg compared to placebo. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
| Participants are eligible to be included in the study only if all of the following criteria apply: AGE 1. Age: 18 years of age or older at the time of signing the informed consent. TYPE OF PARTICIPANT AND DISEASE CHARACTERISTICS 2. Diagnosis: Participants with a diagnosis of asthma as defined by the National Institutes of Health at least 6 months prior to Visit 0. 3. Asthma Control: ACQ-6 total score of >0.75 at Visit 1. 4. Current Asthma Maintenance Therapy: Participants are eligible if they have required daily ICS therapy ≥ 100 mg/day fluticasone propionate (FP, or equivalent) with or without LABA or LAMA for at least 12 weeks prior to Visit 0 and there have been no changes in maintenance asthma medications during the 4 weeks immediately prior to Visit 0. Examples of acceptable doses of commonly prescribed ICS medication will be provided in the Study Reference Manual (SRM). Dosing regimen (once or twice daily to equal the total daily dose) should be restricted to the current local product labels. 5. Spirometry: Both of the following: a. A best pre-bronchodilator morning (AM) FEV1 ≤90% of the predicted normal value. Predicted values will be based upon the ERS Global Lung Function Initiative. b. A best post-bronchodilator FEV1/ forced vital capacity (FVC) ≥0.7 at Visit 1. 6. Reversibility of Disease: Airway reversibility is 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 participant 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 participant successfully demonstrate airway reversibility (defined as ≥12% and ≥200 mL increase in FEV1 between 20 and 60 minutes following 4 inhalations of albuterol/salbutamol aerosol) at the second attempt then, provided that all other eligibility criteria assessed at Visit 1 are met, the participant may enter the 2-week run-in period (see Section 9.1.3 of study protocol). 7. Short-Acting β2 Agonists (SABAs): 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 8. Gender: a. Male participants b. Female participants: A female participant is eligible to participate if she is not pregnant (see Appendix 5 of study protocol), not breastfeeding, and at least one of the following conditions applies: • Not a woman of childbearing potential (WOCBP) as defined in Appendix 5 of study protocol OR • A WOCBP who agrees to follow the contraceptive guidance in Appendix 5 of study protocol during the treatment period and for at least 5 days after the last dose of study treatment. INFORMED CONSENT 9. Informed Consent: Able to give written informed consent prior to participation in the study, which will include the ability to comply with the requirements and restrictions listed in the consent form and in this protocol. Participants must be able to read, comprehend, and write at a level sufficient to complete study related materials. |
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| E.4 | Principal exclusion criteria |
Participants are excluded from the study if any of the following criteria apply: MEDICAL CONDITIONS 1. Pneumonia: Chest X-ray documented pneumonia in the 12 weeks prior to Visit 1. 2. Asthma Exacerbation: Any severe asthma exacerbation, defined as deterioration of asthma requiring the use of systemic corticosteroids (oral, parenteral or depot) within 12 weeks of Visit 1, or an inpatient hospitalisation or emergency department visit due to asthma that required systemic corticosteroids within 12 weeks of Visit 1. 3. Concurrent Respiratory Disease: Current evidence of pneumonia, pneumothorax, atelectasis, pulmonary fibrotic disease, bronchopulmonary dysplasia, chronic bronchitis, emphysema, chronic obstructive pulmonary disease, lung cancer, or other respiratory abnormalities other than asthma. 4. Pregnancy: Women who are pregnant or lactating or are planning on becoming pregnant during the study. 5. Risk Factors for Pneumonia: Immune suppression (e.g., HIV, Lupus) or other risk factors for pneumonia (e.g., neurological disorders affecting control of the upper airway, such as Parkinson’s Disease, Myasthenia Gravis). Patients at potentially high risk (e.g., very low BMI, severely malnourished, or very low FEV1) will only be included at the discretion of the Investigator. 6. Other diseases/abnormalities: Participants with historical or current evidence of clinically significant cardiovascular, neurological, psychiatric, renal, hepatic, immunological, gastrointestinal, urogenital, nervous system, musculoskeletal, skin, sensory, endocrine (including uncontrolled diabetes or thyroid disease) 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 participant 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 (with the exception of Gilbert’s syndrome or asymptomatic gallstones). Note: Chronic stable hepatitis B and C are acceptable if the participant otherwise meets entry criteria 8. Clinically significant ECG abnormality: Evidence of a clinically significant abnormality in the 12- lead ECG performed during screening or run-in (refer to study protocol for details). 9. Unstable or life threatening cardiac disease: participants 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 (NYHA) Class IV Heart failure 10. Antimuscarinic effects: Participants 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: Participants with carcinoma that has not been in complete remission for at least 5 years. Participants 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 participant has been considered cured by treatment. 12. Questionable validity of consent: Participants 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. PRIOR/CONCOMITANT THERAPY 13. Medication prior to spirometry: Participants who are medically unable to withhold their albuterol/salbutamol for the 6-hour period required prior to spirometry testing at each study visit. PRIOR/CONCURRENT CLINICAL STUDY EXPERIENCE/RELEVANT HABITS 14. Tobacco Use: Current smoker or a smoking history of ≥10 pack years (e.g., 20 cigarettes/day for 10 years). A participant may not have used inhaled tobacco products within the past 12 months (i.e., cigarettes, cigars or pipe tobacco). 15. Drug/alcohol abuse: Participants with a known or suspected history of alcohol or drug abuse within the last 2 years. This includes marijuana,
which is considered an
abused drug. Diagnostic assessments 16. Allergy or Hypersensitivity: A history of allergy or hypersensitivity to any corticosteroid, anticholinergic/muscarinic receptor antagonist, beta2-agonist, lactose/milk protein or magnesium stearate. Other Exclusions 17. Non-compliance: (refer to study protocol for details). 18. Affiliation with investigator site: (refer to study protocol for details). 19. Inability to read: In the opinion of the Investigator, any participant who is unable to read and/or would not be able to complete study related materials. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| ● Mean change from baseline in clinic trough FEV1 at Week 24. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
| ● Mean change from baseline in clinic FEV1 at 3 hours post dose at Week 24 ● To evaluate the safety and tolerability of UMEC 62.5 mcg and UMEC 31.25 mcg compared to placebo ● To evaluate other efficacy assessments of UMEC 62.5 mcg and UMEC 31.25 mcg compared to placebo |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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| 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 | 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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 | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| 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 | 17 |
| 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 |
| Canada |
| European Union |
| Russian Federation |
| 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 | 0 |
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 12 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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