| 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 | 18.0 |
| 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 |
| The primary objective of this study is to evaluate the efficacy of Fp MDPI and FS MDPI when administered over 12 weeks in patients 12 years of age and older with persistent asthma |
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| E.2.2 | Secondary objectives of the trial |
| The secondary objectives of the study are as follows: To evaluate the efficacy of Fp MDPI and FS MDPI based on patient reported outcomes and secondary efficacy measures. To evaluate the safety and tolerability of Fp MDPI and FS MDPI in patients with asthma over 12 weeks |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Severity of Disease: Patient has persistent asthma with a FEV1 ≥40% and ≤85% of the value predicted for age, height, sex, and race as per the NHANES III reference values at the screening visit.
b.Current Asthma Therapy: Permitted asthma therapies detailed in the protocol. Patients required to have a treatment regimen that includes a short-acting β2-agonist for use as needed for a minimum of 8 weeks before SV. Patient required to have a low dose or mid-dose inhaled corticosteroid as part of their asthma management plan for a minumum of 1 month before consent. Patients on ICS/LABA combination therapy will require a prescreening visit in order to change to a comparable dose of ICS monotherapy(Section 3.11.1). ICS component of the patient’s asthma therapy should be stable for a minimum of 1 month before providing informed consent. Qualifying doses of ICS are listed in the protocol. Appropriate medication washouts noted under prohibited medications section.
c.Reversibility of Disease: The patient has demonstrated at least 15% reversibility (all patients) and at least 200 mL increase from baseline FEV1 (patients age 18 and older) within 30 minutes after 2-4 inhalations of albuterol/salbutamol hydrofluoroalkane (HFA) metered-dose inhaler (MDI) (90 mcg ex-actuator) or equivalent at the SV. Reversibility values of 14.50-14.99 will be rounded to 15. Note: Patients who do not qualify for the study due to failure to meet reversibility will be permitted to perform a retest once within 7 days or will be a screen failure and permitted to rescreen once at least 7 days after the date of first screening.
d.Written informed consent/assent is obtained. For adult patients (age 18 years and older, or as applicable per local regulations), the written informed consent form (ICF) must be signed and dated by the patient before conducting any study-related procedure. For minor patients (ages 12 to 17 years, or as applicable per local regulations), the written ICF must be signed and dated by the parent/legal guardian and the written assent form must be signed and dated by the patient (if applicable) before conducting any study-related procedure. Note: Age requirements are as specified by local regulations.
e.The patient is a male or female 12 years of age or older, as of the visit when the ICF/assent form issigned (SV or prescreening visit, as applicable). In countries where the local regulations or the regulatory status of study drug permit enrolment of adult patients only, patients must be 18 years of age and older, as of the date of the ICF/assent form. f.Asthma diagnosis: The patient has a diagnosis of asthma as defined by the NIH. The asthma diagnosis has been present for a minimum of 3 months and has been stable (defined as no exacerbations and no changes in medication) for at least 30 days before providing informed consent.
g.The patient is able to perform acceptable and repeatable spirometry consistent with the American Thoracic Society (ATS)/European Respiratory Society Task Force (ERS) 2005 criteria. FVC repeatability will not be required.
h.The patient is able to perform PEF with a handheld peak flow meter. i.The patient is able to use a MDI device without a spacer device and a MDPI device. j.The patient is able to withhold (as judged by the investigator) his or her regimen of ICS or study drug, and rescue medication for at least 6 hours before the SV and before all treatment visits where spirometry is performed.
k.The patient/parent/legal guardian/caregiver is capable of understanding the requirements, risks, and benefits of study participation, and, as judged by the investigator, capable of giving informed consent/assent and being compliant with all study requirements (eg, dose schedules, visit schedules, procedures, and record keeping).
l.SABAs: All patients must be able to replace their current SABA with albuterol/salbutamol HFA MDI inhalation aerosol at the SV for use as needed for the duration of the study. Patients should withhold all inhaled SABA bronchodilators for at least 6 hours prior to all study visits.
m.If female, the patient is currently not pregnant, breastfeeding, or attempting to become pregnant (for 30 days before the SV and throughout the duration of the study and for 30 days after the patient’s last visit), or is of nonchildbearing potential (defined in protocol) OR, if of childbearing potential, has a negative serum pregnancy test and is willing to commit to using a consistent and acceptable method of birth control (defined in the protocol) OR, if of childbearing potential, is not sexually active or has a negative serum pregnancy test, and is willing to commit to using a consistent and acceptable method of birth control as defined above for the duration of the study, in the event she becomes sexually active. If male and sexually active, the patient is willing to commit to an acceptable method of birth control for the duration of the study or exclusively has same-sex partners. |
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| E.4 | Principal exclusion criteria |
The patient has a history of a life-threatening asthma exacerbation that is defined for this protocol as an asthma episode that required intubation and/or was associated with hypercapnea, respiratory arrest, or hypoxic seizures.
b. The patient is pregnant or lactating, or plans to become pregnant during the study period or for 30 days after the patient’s last study-related visit (for eligible patients only, if applicable). Eligible female patients unwilling to employ appropriate contraceptive measures to ensure that pregnancy will not occur during the study will be excluded. Any patient becoming pregnant during the study will be withdrawn from the study.
c. The patient has participated as a randomized patient in any investigational drug study within the 30 days (starting from the final follow-up visit of that study) preceding the SV (or prescreening visit, as applicable) or plans to participate in another investigational drug study at any time during this study.
d. The patient has previously participated as a randomized patient in a study of Fp MDPI or FS MDPI. Applicable studies are listed in Section 1.5.
e. The patient has a known hypersensitivity to any corticosteroid, salmeterol, or any of the excipients in the study drug or rescue medication formulation (ie, lactose).
f. The patient has been treated with any known strong cytochrome P450 (CYP) 3A4 inhibitors (eg, azole antifungals, ritonavir, or clarithromycin) within 30 days before the SV or plans to be treated with any strong CYP3A4 inhibitor during the study.
g. The patient has been treated with any of the prohibited medications during the prescribed (per protocol) washout periods before the SV.
h. The patient currently smokes or has a smoking history of 10 pack-years or more (a pack-year is defined as smoking 1 pack of cigarettes/day for 1 year). The patient may not have used tobacco products within the past year (eg, cigarettes, cigars, chewing tobacco, or pipe tobacco).
i. The patient has a culture-documented or suspected bacterial or viral infection of the upper or lower respiratory tract, sinus, or middle ear that has not resolved at least 2 weeks before the SV. Note: Patients who develop an upper respiratory tract infection (URI) or lower respiratory tract infection (LRI) during the run-in period will be made a screen failure and may rescreen 2 weeks after symptoms resolve.
j. The patient has a history of alcohol or drug abuse within 2 years preceding the SV.
k. The patient has had an asthma exacerbation requiring systemic corticosteroids within 30 days before the SV, or has had any hospitalization for asthma within 2 months before the SV.
l. Initiation or dose escalation of immunotherapy (administered by any route) is planned during the study period. However, patients who initiated immunotherapy 90 days or more before the SV and have been on a stable (maintenance) dose for 30 days or more before the SV may be considered for inclusion.
m. The patient has used immunosuppressive medications within 4 weeks before the SV.
n. The patient is unable to tolerate or unwilling to comply with the appropriate washout periods and withholding of all applicable medications.
o. The patient has untreated oral candidiasis at the SV. Patients with clinical visual evidence of oral candidiasis who agree to receive treatment and comply with appropriate medical monitoring may enter the study. Note: Azole antifungals are prohibited.
p. The patient has a history of a positive test for human immunodeficiency virus (HIV), active hepatitis B virus, or hepatitis C infection.
q. The patient is either an employee or an immediate relative of an employee of the clinical investigational center.
r. A member of the patient’s household is participating in the study at the same time. However, after the enrolled patient completes or discontinues participation in the study, another patient from the same household may be screened.
s. The patient has a disease/condition that in the medical judgment of the investigator would put the safety of the patient at risk through participation or that could affect the efficacy or safety analysis if the disease/condition worsened during the study (listed in the protocol).
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| E.5 End points |
| E.5.1 | Primary end point(s) |
• Change from baseline in trough (morning predose and pre-rescue bronchodilator) FEV1 at week 12 (TV9)
• standardized baseline-adjusted area under the effect curve for forced expiratory volume in 1 second from time zero to 12 hours postdose (FEV1 AUC0-12) at week 12 (TV9), analyzed for the subset of approximately 300 patients who perform postdose serial spirometry |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Trough FEV1 will be measured in the AM before the AM dose, for those patients that perform serial spirometry those measurements will be immediately after the AM dose given in the investigational site. |
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| E.5.2 | Secondary end point(s) |
•change from baseline in the weekly average of the daily trough morning PEF over the 12-week treatment period
•change from baseline in the weekly average of the total daily asthma symptom score (the total daily asthma symptom score is the average of the daytime and nighttime scores) over weeks 1 to 12
•change from baseline in the weekly average of total daily (24-hour) use of albuterol/salbutamol inhalation aerosol (number of inhalations) over weeks 1 to 12
•time to patient withdrawal for worsening asthma during the 12-week treatment period
• change from baseline in the AQLQ(S) (patients ≥18 years of age only) score at week 12 or at endpoint |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Secondary Efficacy Measures and Endpoints:
Recorded in patient diary daily throughout 12 week study treatment period
Safety Measures and Endpoints:
This will be monitored throughout the 12 week treatment period through the patient
diary and at all visits (visits 1 to visit 9) |
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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 | Yes |
| 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 | No |
| E.8.2.4 | Number of treatment arms in the trial | 5 |
| 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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 65 |
| 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 |
| Czech Republic |
| Germany |
| Hungary |
| Poland |
| Russian Federation |
| South Africa |
| Ukraine |
| United States |
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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
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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 | 1 |
| E.8.9.1 | In the Member State concerned months | 0 |
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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