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: The patient has persistent asthma with a FEV1 ≥
40% and ≤85% of the value predicted for age, height, sex, and race as
per the National Health and Nutrition Examination Survey III (NHANES
III) reference values at the screening visit (SV).
b. Current Asthma Therapy: Permitted asthma therapies are detailed in
the protocol. Patients will be required to have a treatment regimen that
includes a short-acting β2-agonist (SABA; albuterol/salbutamol) for use
as needed for a minimum of 8 weeks before the SV. The patient is
required to have a qualifying dose of inhaled corticosteroid (ICS) as part
of their asthma management plan, either as ICS monotherapy or as an
ICS/LABA combination, for a minimum of 1 months before providing
consent. Patients on ICS/LABA combination therapy will require a
prescreening visit in order to change to a comparable dose of ICS
monotherapy. The ICS component of the patient's asthma therapy
should be stable for a minimum of 1 month before the informed consent
is signed. Qualifying doses of ICS are listed in the protocol. Appropriate
medication washouts are noted under the 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 is signed (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 for at least 30 days before the ICF is signed.
g. The patient is able to perform acceptable and repeatable spirometry
consistent with the ATS/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.
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 studyrelated
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.
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 packyears
or more (a pack-year is defined as smoking 1 pack of
cigarettes/day for 1 year). The patient must 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: A patient who
develops 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 AUEC0-12h) 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 daily trough evening PEF over the 12-week treatment period
• change from baseline in the AQLQ(S) (patients ≥18 years of age only) or PAQLQ(S) (patients
12-17 years of age only) score at week 12 or at endpoint
• time to meeting alert criteria for worsening asthma during the 12-week treatment period
• time to patient withdrawal for worsening asthma during 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 (median and mean) to 15% and 12% improvement from baseline in FEV1 postdose at TV1 in the serial spirometry subset
• time to patient withdrawal for worsening asthma during the 12-week treatment period
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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 | 23 |
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 | |
E.8.9.1 | In the Member State concerned months | 5 |
E.8.9.1 | In the Member State concerned days | 1 |
E.8.9.2 | In all countries concerned by the trial months | 7 |
E.8.9.2 | In all countries concerned by the trial days | 20 |