| Eligibility |
Inclusion criteria
Participants eligible for inclusion in this study must meet all of the following criteria:
1. Male and female adolescent subjects aged from equal to or greater than 12 years old to
less than 18 years old at Screening visit.
2. 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 greater than 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 equal to or greater than 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 equal to or greater than 60 % and < 90 % of the predicted
normal value for the subject according to ATS/ERS 2019 criteria after withholding
bronchodilators (see Table 6-8) at both Run-in and before randomization.
Withholding period of bronchodilators prior to spirometry:
- SABA for equal to or greater than 6 hours
- FDC or free combinations of ICS/LABA for equal to or greater than 48 hours
- SAMA for equal to or greater than 8 hours
- Xanthines equal to or greater than 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 but should be started only once the repeat
spirometry was qualified by spirometry overread, if all inclusions at Run-in are
successful in case of necessary repeat of Runin.
- 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.
9. Subjects who demonstrate an increase in FEV1 of equal to or greater than 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
adhoc 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
rescreened.
Run-in medication can be dispensed at Run-in visit but should be started by the
patient only if reversibility is met and all other elligibility 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 equal to or greater than 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.
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
rescreened 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.
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.
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 as per investigator
judgement or abnormal liver chemistry results (i.e. ALT, AST, total bilirubin,
alkaline phosphatase, GGT and albumin above the upper limit of normal) 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 hypoand 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 or
baseline prior to randomization (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 to sympathomimetic 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 6-9.
21. Subjects receiving any asthma-related medications in the classes specified in Table
6-8 unless they undergo the required washout period and follow the adjustment to
treatment program.
22. Subjects receiving medications in the classes listed in Table 6-10 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 (including female pediatric patients who are menarchal or who become
menarchal during the study), 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 subject). Periodic abstinence (e.g., calendar, ovulation, symptothermal,
post-ovulation methods) and withdrawal are not acceptable methods of
contraception
- Barrier methods of contraception: Condom or Occlusive cap (diaphragm or
cervical/vault caps). For UK: 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) In case of use of oral contraception females should
have been stable on the same pill for a minimum of 3 months before taking
investigational drug. 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.
32. Use of Long Acting Muscarinic Antagonist (LAMA) within 3 months prior to Screening.
33. History or presence of impaired renal function as indicated by clinically significant
abnormal creatinine or blood urea nitrogen (BUN) and/or urea values, or abnormal
urinary constituents (e.g. albuminuria) according to investigator's judgement.
- Evidence of urinary obstruction, or difficulty in voiding
- Evidence of congenital renal abnormalities with an established effect on renal
function
- Calculated eGFR <60 mL/min/1.73m2 using the Bedside Schwartz formula
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