| 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 | 17.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10003565 |
| E.1.2 | Term | Asthmatic |
| E.1.2 | System Organ Class | 100000004855 |
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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 |
| The primary objective is to demonstrate the therapeutic non-inferiority of the bronchodilator responses (area under the time curve of forced expiratory volume in 1 second [AUC-FEV1]) over 12 hours of the salmeterol component (50 µg) of a novel SAL/FP combination dry powder inhaler product (PulmoJet 50 µg/250 µg SAL/FP; test) with the respective mid-strength of the European reference product (Seretide Diskus; reference). |
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| E.2.2 | Secondary objectives of the trial |
Secondary objectives are:
• To compare the bronchodilator dose responses AUC-FEV1 over 12 hours between the salmeterol components of 2 doses (12.5 µg and 50 µg) of a novel SAL/FP combination dry powder inhaler product (PulmoJet; test) and with the respective mid-strength of the European reference product (Seretide Diskus; reference) in order to assess assay sensitivity.
• To assess and compare the duration and maximum bronchodilator responses in forced expiratory volume in 1 second (FEV1) between the salmeterol component of 2 doses (12.5 µg and 50 µg) of a novel SAL/FP combination dry powder inhaler product (PulmoJet; test) and with the respective mid-strength of the European reference product (Seretide Diskus; reference).
• To assess the local and systemic tolerability and safety of the investigational treatments.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Body weight of ≥50 kg for adults, ≥ 30 kg for adolescents, and body mass index between ≥18 and ≤30 kg/m2.
2.Baseline FEV1 of 50% to 85% of predicted normal for adults (age, sex, and height), and 60% to 90% of predicted normal for adolescents (after abstinence from SABA treatment larger than 6 hours).
3.Subjects must demonstrate bronchodilator reversibility of at least 15% and at least 250 mL increase in FEV1 15 to 30 minutes after 400 µg salbutamol at screening. If the level of reversibility is not achieved at screening, 1 repeat measurement of reversibility is allowed during the run-in period at least 24 hours prior to Visit 2.
4.Subjects must demonstrate FEV1 stability prior to any treatment period: FEV1 at pre dose randomization (baseline 1st treatment period) must be within ± 10% of the screening value. FEV1 between individual baselines before each treatment period must be within ±10% of baseline of 1st treatment period. All baseline FEV1 values will be determined by the mean of 2 pre-dose spirometries.
5.Female subjects must be either at least 1 year post-menopausal, surgically sterile (defined as having a hysterectomy or tubal ligation), or practicing a medically approved and highly effective method of contraception. Women of childbearing potential must have a negative pregnancy test at Screening Visit (Visit 1) and be using at least 2 months before the screening visit, at least one medically approved and highly effective method of birth control defined as those which result in a low failure rate (i.e., less than 1% per year) when used consistently and correctly such as implants, injectables, oral contraceptives combined with at least one barrier method, hormonal intrauterine devices, sexual abstinence or vasectomy of the partner. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods), declaration of abstinence for the duration of the study, and withdrawal are not acceptable methods of contraception.
6.Having provided written informed consent after the subject has been informed both verbally and in writing about the scope and objectives of the study, the methods employed, and the anticipated benefits and potential risks and discomfort to which he / she may be exposed. For adolescent subjects, the informed consent by the subject’s parent / legal guardian assent (if possible also by the subject) must be given in written form after being provided with detailed information about the nature, risks and scope of the clinical trial as well as the expected desirable and adverse effects of the drug. |
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| E.4 | Principal exclusion criteria |
1.History of clinically relevant allergies or idiosyncrasies to fluticasone propionate, salmeterol, lactose, or any other inactive ingredient(s) of the investigational products.
2.History of any other significant drug hypersensitivity or other significant allergic diathesis. Subjects with uncomplicated seasonal allergic rhinitis can be accepted if expected allergy season is clearly outside enrolment / treatment period. Active allergic rhinitis is excluded.
3.History of life-threatening asthma or severe asthma exacerbation requiring hospitalization within the last 12 months before screening.
4.Asthma exacerbation requiring a treatment course of systemic (i.e., oral or parenteral) corticosteroids within the 3 months before screening or ≥ 3 courses within the last 12 months before screening.
5.Lactating or pregnant female, or female of child-bearing potential not employing highly effective contraception (methods with a Pearl Index lower than 1% are regarded as highly-effective), or female planning to become pregnant during study participation. A male subject planning to father a child during study participation.
6.Clinical significant diseases, conditions, or illnesses at screening, that might interfere with the study methodologies, objectives, or safety of the subject.
7.Acute or chronic viral, bacterial or fungal airway infections, including laryngeal infections, mouth and throat infections, and hoarseness 4 weeks prior to screening and during run-in.
8.Other clinically relevant chronic or acute infectious illnesses or febrile infections within 4 weeks prior to start of the study and during run-in.
9.Current uncontrolled arterial hyper- or hypotension as evidenced by measured blood pressure values at screening.
10.Electrocardiogram abnormalities of clinical relevance, in particular abnormal prolongations of QT / QTc- or PR-interval (i.e., QTc Fridericia ≥ 450 ms, PR ≥ 220 ms) or heart rate of ≤ 45 or ≥ 90 beats/minute (at rest).
11.Clinical chemical, hematological or any other laboratory parameters clinically relevant outside the normal range considering in particular: hypokalemia, hypoglycemia, hyperglycemia or pathological glucose tolerance (minor deviations of laboratory values from the normal range may be accepted, if judged by the Investigator to have no clinical relevance).
12.Positive results in any of the virology tests for human immunodeficiency virus (HIV)-antibody (Ab), hepatitis C virus antibodies (HCV-Ab) and hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBc-Ab) (if positive to be verified by test for HBc-IgM).
13.Use of medications containing β-adrenoceptor agonists or β-adrenoceptor blockers within the past 7 days before Screening Visit 1 and throughout study participation.
14.Use of medium- or long-acting anti-cholinergic / -muscarinic bronchodilators such as ipratropium, tiotropium, and inhaled LABAs within the 48 hours before Screening Visit 1 and throughout study participation.
15.Use of oral/parenteral corticosteroids within the past 3 months before screening, Visit 1.
16.Ongoing immunotherapy (e.g., omalizumab) during the last 3 months or planned start of immunotherapy within the study period.
17. The use of other prior and concomitant medications as specified in the protocol.
18.Subject shows evidence for current alcohol abuse or history of illicit drug abuse.
19.Subject receives concomitant medications not (yet) stabilized on a maintenance dose (i.e., treatments undergoing current up-titration or down-tapering steps).
20.Subject was previously enrolled into the current study.
21.Subject is the Investigator in the current study, or a first-degree relative of a study Investigator, or is employee of a clinical study site or the Sponsor.
22.Subject participated in a previous clinical study with another investigational product within the last 30 days (or 6 half-lives, whichever is longer) prior to the start of the study or subject participates in a concurrent study.
23.Subject has donated blood within the last 30 days prior to the start of the study.
24.Subject is considered unable or unwilling to co-operate adequately, i.e., to follow study procedures and investigator instructions adequately (e.g., language difficulties).
25.Subject is a "vulnerable" individual (e.g., person is kept in detention).
26.Subject is anticipated to be not available for scheduled study visits / procedures. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Baseline adjusted AUC-FEV1 calculated from time zero to 12 hours (AUC0-12h): 0 hours pre-dose (approximately taken at 0.75 and 0.25 pre-dose) and 0,5, 1, 2, 3, 4, 6, 8, 10, 11, and 12 hours post-dose) after single dose treatment of 1 inhalation. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| FEV1 at 0 hours pre-dose (the mean of 2 separate spirometries performed for logistical reasons about 45 and 15 minutes pre-dose) and 0.5, 1, 2, 3, 4, 6, 8, 10, 11, and 12 hours post-dose. |
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| E.5.2 | Secondary end point(s) |
•The maximum baseline-adjusted FEV1 will be compared between the treatments using a t-test.
•Duration of effective bronchodilatation (i.e., duration of increase in FEV1 ≥ 15% from baseline over a 12-hour observation period) after single-dose treatment of 1 inhalation.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| FEV1 at 0 hours pre-dose (the mean of 2 separate spirometries performed for logistical reasons about 45 and 15 minutes pre-dose) and 0.5, 1, 2, 3, 4, 6, 8, 10, 11, and 12 hours post-dose. |
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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 | Yes |
| 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) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
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| E.7.2 | Therapeutic exploratory (Phase II) | No |
| 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 | No |
| E.8.1.6 | Cross over | Yes |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 10 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| 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
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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 | 0 |
| E.8.9.1 | In the Member State concerned months | 8 |
| 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 | 8 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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