| 5.1 Inclusion criteria
Participants eligible for inclusion in this study must meet all of the following criteria:
1. Male and female adolescent subjects aged from ≥ 12 years old to less than 18 years old at
screening visit.
2. Signed informed consent must be obtained prior to participation in the study. Written and
signed informed consent by parent(s)/legal guardian(s) for the pediatric participant and assent by
the pediatric participant (depending on local requirements) must be obtained before any
study-specific assessment is performed.
3. Patients with a documented diagnosis of persistent asthma (according to GINA 2022) for a period
of at least 1 year prior to screening.
4. Subjects who have used high dose ICS with LABA in combination for asthma for at least 3 months
and at stable doses for at least 1 month prior to screening.
5. Subjects must be symptomatic / inadequately controlled according to the investigator's opinion
despite treatment with high stable doses of ICS with LABA in combination before screening.
6. A history of one or more documented severe asthma exacerbations within the 12 months prior to
screening that required either:
• Treatment with systemic corticosteroids (tablets, suspension or injection). OR
• Hospitalization (defined as an in subject stay or >24-hour stay in an observation area in the
emergency room of other equivalent facility).
NOTES: Investigators must use appropriate means to ensure the accuracy of the subject’s
exacerbation history (subject history at screening documented in source notes, pharmacy records,
hospital records, or chart records are acceptable).
7. Subjects must have ACQ-5 score ≥ 1.5 at end of run-in visit prior to randomization (prior
to double-blind treatment) and qualify for treatment with high dose LABA/ICS/LAMA.
8. Pre-bronchodilator FEV1 ≥ 60 % and < 90 % of the predicted normal value for the subject
according to ATS/ERS 2019 criteria after withholding bronchodilators (see Table 6-7) at both run-in
and before randomization.
Withholding/washout period of bronchodilators prior to spirometry:
• SABA for ≥ 6 hours
• FDC or free combinations of ICS/LABA for ≥ 48 hours
• Short acting anticholinergics (SAMA) for ≥ 8 hours
• Xanthines ≥ 7 days
NOTES:
• In case of combination ICS/LABA at screening, ICS alone should be continued until run-in
visit.
• Wash-out period of each drug should be adhered to as above and should not be longer. If wash-out
period is considered to be longer please contact the Novartis Medical Monitor.
• A one-time repeat of percent predicted FEV1 (pre-bronchodilator FEV1) is allowed at
run-in as well as before randomization. Repeat of run-in spirometry can be done later on the same
day/visit (only to retest FEV1 criteria, not for reversibility, and before any salbutamol/albuterol
inhalation) or in an ad-hoc visit to be scheduled on a later date (within 5 days of original
run-in) that would provide sufficient time to receive confirmation from the spirometry data central
reviewer of the validity of the assessment before randomization. Run-in medication can be dispensed
at run-in visit however the dispensed medication should only be started by the patient if
reversibility is met as per ATS/ERS criteria and if all other eligibility criteria as per protocol
are met.
• A one-time re-screen is allowed in case the subjects fail to meet the criteria at the repeat,
provided the subjects return to their previous treatment until re-screening. In this circumstance,
subjects are not required to go back on prior medication for 1 full month duration as outlined in
inclusion criterion 4. Some participants will not be eligible for re-screening, depending on the
cause of screen failure. See Section 5.3 for further detail.
9. Subjects who demonstrate an increase in FEV1 of ≥ 12% and 200 mL within 15 to 30 minutes after
administration of 200-400 μg salbutamol/180-360 μg albuterol (or equivalent dose) at run-in visit.
All subjects must perform a reversibility test at run-in visit that will be evaluated by central
overread.
If reversibility is not demonstrated at run-in visit, or the assessment was evaluated as
unacceptable by the central overread then:
• Spirometry assessment to demonstrate reversibility should be repeated once in an ad- hoc visit
to be schedule preferably within 5 days. The reversibility test cannot be repeated on the same day
because of the wash-out period of salbutamol/albuterol.
• Subjects may be permitted to enter the study with historical evidence of reversibility that was
performed according to ATS/ERS guidelines within 2 years prior to screening.
• Alternatively, subjects may be permitted to enter the study with a historical positive
broncho-provocation test that was performed within 2 years prior to screening.
If reversibility is not demonstrated at run-in visit (or after repeated assessment at ad-hoc visit
within 5 days) with acceptable spirometry quality as per overread and historical evidence of
reversibility/broncho-provocation is not available (or was not performed according to ATS/ERS
guidelines) subjects must be screen failed and cannot be re- screened.
Run-in medication can be dispensed at run-in visit however the dispensed medication should only be
started by the patient if reversibility is met as per ATS/ERS criteria and if all other eligibility
criteria as per protocol are met.
Spacer devices are permitted during reversibility testing only. The Investigator or delegate may
decide whether to use spacer or not for the reversibility testing.
10. Subjects must meet all the following criteria at end of run-in visit prior to randomization:
• Subjects must demonstrate acceptable inhaler devices (as per investigator judgement), peak flow
meter, and spirometry techniques during the run-in period (from beginning to end of run-in).
• Subjects must demonstrate ≥ 70% compliance with the asthma controller ICS/LABA
during the run-in period based on their inhaler use count. 70% compliance is defined as medication
taken in 70% of the days in that period.
• Subjects must demonstrate ≥ 70% compliance with required use of the eDiary during the run-in
period. 70% compliance is defined as completing the daily eDiary for 70% of the days (either
morning or evening, including at least 7 morning and 7 evening eDiaries) during the run-in period.
Female patients of child-bearing potential, who are or might become sexually active, need to
prevent pregnancy during the study by effective contraception.
The effective contraception methods are:
• Barrier method: Condom or Occlusive cap (diaphragm or cervical/vault caps). For UK: with
spermicidal foam/gel/film/cream/vaginal suppository.
• Use of oral, injected or implanted hormonal methods of contraception or placement of an
intrauterine device (IUD) or intrauterine system (IUS) or other forms of hormonal contraception
that have comparable efficacy (failure rate <1%), for example hormone vaginal ring or trans dermal
patch.
The decision on the contraceptive method should be reviewed at least every 3 months to evaluate the
individual need and compatibility of the method chosen.
|
5.2 Exclusion criteria
Participants meeting any of the following criteria are not eligible for inclusion in this study.
1. Subjects who have smoked or inhaled tobacco products within the 6 months period prior to
screening, or who have a smoking history of greater than 10 pack years (Note:1 pack is equivalent
to 20 cigarettes. 10 pack years = 1 pack /day x 10 yrs., or ½ pack/day x 20 yrs.) or use of
nicotine inhalers such as e-cigarettes at the time of screening.
2. Subjects who have had an asthma attack/exacerbation requiring systemic steroids OR
hospitalization (> 24 hours) OR emergency room visit (≤ 24 hours) within 6 weeks of screening. If
subjects experience an asthma attack/exacerbation requiring systemic steroids or emergency room
visit between screening and end of run-in they may be re- screened 6 weeks after recovery from the
exacerbation.
3. Subjects who have ever required intubation for a severe asthma attack/exacerbation.
4. Subjects who have a clinical condition which is likely to be worsened by ICS administration
(e.g. glaucoma, cataract and fragility fractures) who are according to investigator's medical
judgment at risk participating in the study. Subjects with narrow- angle glaucoma, bladder-neck
obstruction or severe renal impairment or urinary retention.
5. Subjects who have had a respiratory tract infection or asthma worsening as determined by
investigator within 4 weeks prior to screening or between screening and end of run-in. Subjects may
be re-screened 4 weeks after recovery from their respiratory tract infection or asthma worsening.
6. Subjects with evidence upon visual inspection (laboratory culture is not required) of
clinically significant (in the opinion of investigator) oropharyngeal candidiasis at end of run-in
or earlier, with or without treatment. Subjects may be re-screened once their candidiasis has been
treated and has resolved.
7. Subjects with any chronic conditions affecting the upper respiratory tract (eg.7. Subjects with any chronic conditions affecting the upper respiratory tract (eg. chronic
sinusitis) which in the opinion of the investigator may interfere with the study evaluation or
optimal participation in the study.
8. Subjects with a history of chronic lung diseases other than asthma, including (but not limited
to) sarcoidosis, interstitial lung disease, cystic fibrosis, clinically significant bronchiectasis
and active tuberculosis.
9. Subjects with type I diabetes or uncontrolled type II diabetes.
10. Subjects who have a clinically significant laboratory abnormality before the end of run-in.
11. Use of other investigational drugs within 30 days or 5 half-lives of enrollment, or until the
expected pharmacodynamic effect has returned to baseline, whichever is longer.
12. Subjects who, either in the judgment of the investigator or the responsible Novartis personnel,
have a clinically significant condition such as (but not limited to) unstable ischemic heart
disease, New York Heart Association (NYHA) Class III/IV left ventricular failure arrhythmia,
uncontrolled hypertension, cerebrovascular disease, psychiatric disease, neuro-degenerative
diseases or other neurological diseases, uncontrolled hypo- and hyper-thyroidism and other
autoimmune diseases, hypokalemia, hyperadrenergic state, or ophthalmologic disorder or subjects
with a medical condition that might compromise subject safety or compliance, interfere with
evaluation, or preclude completion of the study.
Subjects with paroxysmal (e.g., intermittent) atrial fibrillation are excluded. Subjects with
persistent atrial fibrillation as defined by continuous atrial fibrillation for at least 6 months
and controlled with a rate control strategy (i.e., selective beta blockers, calcium channel
blocker, pacemaker placement, digoxin or ablation therapy) for at least 6 months may be considered
for inclusion. In such subjects, atrial fibrillation must be present at the run-in visit with a
resting ventricular rate < 100/min. At run-in visit the atrial fibrillation must be confirmed by
central reading.
13. Subjects with a history of myocardial infarction (this should be confirmed clinically by the
investigator) within the previous 12 months.
14. Concomitant use of agents known to prolong the QTc interval unless it can be permanently
discontinued for the duration of study.
15. Subjects with a history of long QT syndrome or whose QTc measured at run-in (Fridericia method)
is prolonged (> 450 msec for males and > 460 msec for females) and confirmed by a central assessor
or inability to determine the QTcF interval (these subjects should not be re-screened).
16. Subjects who have a clinically significant ECG abnormality at run-in visit and at any time
during the run-in period (including unscheduled ECG). ECG evidence of myocardial infarction at
run-in (via central reader) should be clinically assessed by the investigator with supportive
documentation.
17. History of malignancy of any organ system (other than localized basal cell carcinoma of the
skin or in-situ cervical cancer), treated or untreated, within the past 5 years, regardless of
whether there is evidence of local recurrence or metastases.
18. Subjects with a history of hypersensitivity or intolerance to any of the study drugs (including
excipients) or to similar drugs within the class including untoward reactions tosympathomimetic amines or inhaled medication or any component thereof. This criteria
also applies to rescue and run-in medications.
19. Subjects who have not achieved an acceptable spirometry result at run-in in accordance with
American Thoracic Society/European Respiratory Society (ATS/ERS) criteria for acceptability and
repeatability. Repeat spirometry may be allowed in an ad-hoc visit scheduled as close as possible
from the first attempt (but not on the same day) if the spirometry did not qualify due to ATS/ERS
criteria at run-in. If the subjects fail the repeat assessment, the subjects may be re-screened
once, provided the subjects return to their prior treatment until re-screened.
20. Subjects receiving any medications in the classes listed in Table 6-8 .
21. Subjects receiving any asthma-related medications in the classes specified
in Table 6-7 and Table 6-8unless they undergo the required washout period and follow the adjustment
to treatment program.
22. Subjects receiving medications in the classes listed in Table 6-9 should be excluded unless the
medication has been stabilized for the specified period and the stated conditions have been met.
23. Subjects with severe narcolepsy and/or insomnia.
24. Subjects on Maintenance Immunotherapy (desensitization) for allergies for less than 3 months
prior to run-In or subjects on Maintenance Immunotherapy for more than 3 months prior to end of
run-in visit but expected to change throughout the course of the study.
25. Subjects who are serving a custodial sentence, do not have a permanent residence or who are
detained under local mental health legislation/regulations.
26. Subjects who are directly associated with any members of the study team or their family
members.
27. Subjects unable to use the Breezhaler® dry powder inhaler or the Girohaler® inhaler as per
investigator 's judgement. Spacer devices are not permitted for rescue medication.
28. History of alcohol or other substance abuse.
29. Subjects with a known history of non-compliance to medication or who were unable or unwilling
to complete a subject diary or who are unable or unwilling to use Electronic Peak Flow with e-diary
device.
30. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female
after conception and until the termination of gestation, confirmed by a positive hCG laboratory
test at run-in.
31. Women of child-bearing potential, defined as all women physiologically capable of becoming
pregnant, unless they are using effective methods of contraception during dosing of study
treatment. Effective contraception methods include:
• Total abstinence (when this is in line with the preferred and usual lifestyle of the
participant. Periodic abstinence (e.g. calendar, ovulation, symptothermal, post- ovulation methods)
and withdrawal are not acceptable methods of contraception
• Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy),
total hysterectomy, or bilateral tubal ligation at least six weeks before taking investigational
drug. In case of oophorectomy alone, only when thereproductive status of the woman has been confirmed by follow up hormone level
assessment
Male sterilization (at least 6 months prior to screening). For female participants on the study,
the vasectomized male partner should be the sole partner for that participant
Barrier methods of contraception: Condom or Occlusive cap (e.g. diaphragm or cervical/vault caps).
For studies being conducted in the UK add: with spermicidal foam/gel/film/cream/vaginal suppository
Use of oral (estrogen and progesterone), injected or implanted hormonal methods of contraception or
other forms of hormonal contraception that have comparable efficacy (failure rate <1%), for
example, hormone vaginal ring or transdermal hormone contraception or placement of an intrauterine
device (IUD) or intrauterine system (IUS)
|
Adolescent: 13 Year(s)-17 Year(s),Child: 6 Year-12 Year |
12 Year(s) |
18 Year(s) |
Both |