Efficacy, Pharmacokinetics, Pharmacodynamics, Safety and Tolerability of Glycopyrronium (Bromide) in Children (6 to Less Than 12 Years) With Asthma

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Novartis Pharma AG

Participant type

Pediatric, Patients

Age range

0-17 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Respiratory Tract Diseases [C08]

Trial duration

29 Aug 2022 → ongoing

Decision date (initial)

2024-06-14

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

External identifiers

EU CT number

2024-511382-11-00

EudraCT number

2021-004972-32

ClinicalTrials.gov

NCT05222529

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacodynamic, Safety, Others, Efficacy, Dose response, Pharmacokinetic

Evaluate the change from baseline in trough forced expiratory volume in one second (FEV1) at week 2 of each treatment period.

Secondary objectives 6

1. Characterize systemic exposure following 2 doses of glycopyrronium (GLY)
2. Evaluate the change from baseline in peak expiratory flow (PEF) rate at week 2 of each treatment period
3. Evaluate the change from baseline in FEV1 at 30 min and 1 hour post dose at week 2 of each treatment period
4. Evaluate the change from baseline in rescue medication use over each treatment period
5. Evaluate the safety and tolerability of each treatment, including in laboratory parameters including blood glucose and serum potassium
6. Assess typical anti-muscarinic side effects (including dry mouth, fatigue, constipation, and urinary retention)

Conditions and MedDRA coding

Asthma

Regulatory references

EMA paediatric investigation plan (PIP)

EMEA-001812-PIP01-15

Plan to share IPD

Yes

IPD plan description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 10

1. Male and female children with asthma, with age from equal or more than 6 years to less than 12 years at the time of study entry
2. Confirmed documented diagnosis of asthma for at least 6 months prior to screening
3. Signed informed consent by parents(s)/legal guardian(s) and assent by the pediatric participant (depending on local requirements) must be obtained prior to participation in the study
4. Participant on stable dose of inhaled low-to-medium dose ICS (up to Budesonide ((Dry Powder Inhaler) DPI) 400ug daily or equivalent) with one additional controller for at least 4 weeks prior to run-in.
5. Pre-Bronchodilator FEV1 >60% to <95% of predicted normal at beginning of run-in and randomization.
6. FEV1 reversibility, done using up to 4 puffs of SABA (up to 400μg salbutamol or 360μg albuterol) at Run-in visit (Visit 20): increase > and/or = 12% (performed according to American Thoracic Society (ATS)/European Respiratory Society (ERS) 2019 guidelines.All participants must perform a reversibility test at start of Run-in. If reversibility is not demonstrated at Run-in, reversibility may be repeated once more during run-in, within 5 days of the initial visit. If reversibility is still not demonstrated after repeat testing, documentation of historical reversibility (protocol defined criteria of reversibility demonstrated within past 2 years as per medical records) is accepted. If documentation of historical reversibility is not available, patients must be screen failed. The use of a spacer is authorized at Run-in for the reversibility test only.
7. Demonstrated acceptable inhaler use technique for Diskus/Accuhaler (prior to run-in and Breezhaler (prior to randomization) and be able to complete spirometry procedures prior to randomization.
8. A parent/legal guardian must be designated to complete all e-Diary entries and attend all clinical visits with the participant.
9. Parents/legal guardian must be willing and able to assist the child with the procedures outlined in the protocol. Eg, compliance with study medication, completion of electronic participant diary.
10. Female participants of child-bearing potential, who might become sexually active, must be informed of the need to prevent pregnancy during the study. The effective 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 that have comparable efficacy (failure rate <1%), for example hormone vaginal ring or transdermal hormone contraception. 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.

Exclusion criteria 28

1. Systemic corticosteroid use for any reason within 3 months of run-in (visit 20).
2. Participants on low-to-medium mono ICS alone (i.e. up to 400 µg Budesonide (DPI) per day or equivalent, without another controller) prior to screening (visit 1) are not allowed.
3. Participants requiring six or more puffs of rescue medication per day on more that two consecutive days in the four weeks prior to screening (Visit 1) and/or in the four weeks prior to the run-in visit (Visit 20). In case of an asthma deterioration occurring in the four weeks prior to screening (Visit 1) and/or in the four weeks prior to the run-in visit (Visit 20), the visit must be postponed.
4. Participants who have had an asthma attack/exacerbation requiring a) systemic corticosteroids (SCS) or b) hospitalization or c) emergency room visit, within 3 months prior to screening (Visit 1), or more that 3 separate exacerbations in the 12 months preceding the screening visit. If participants experience an asthma attack/exacerbation requiring SCS or hospitalization between Screening and Day 1, they may be re-screened 3 months after recovery from the exacerbation.
5. Participants receiving any medications in the classes specified in Table 6-5 and Table 6-6 unless they undergo the required wash-out period prior to Screening (Visit 1) or Run-in (Visit 20), as specified, and follow the adjustment through the treatment period.
6. History or presence [at Run-in visit (Visit 20)] of impaired renal function as indicated by clinically significantly abnormal creatinine or blood urea nitrogen (BUN) and/or urea values, or abnormal urinary constituents (e.g., albuminuria) or moderate to severe renal impairment (as defined by a creatinine clearance or eGFR <60 mL/min/1.73 m2 body surface area (BSA) lasting for 3 months) with or without kidney damage.
7. Participants with a known narrow-angle glaucoma, bladder dysfunction, bladder outlet obstruction or any other conditions where anticholinergic treatment is contraindicated prior to Screening (Visit 1).
8. Evidence of unstable disease within 4 weeks prior to Screening (Visit 1) that in the opinion of the investigator would put the safety of the participant at risk through study participation or would confound the interpretation of the results if the condition/disease exacerbated during the study.
9. Prior intubation for asthma.
10. Participants who, in the opinion of the investigator, are not able to be compliant with study treatments, properly use study drug devices (e.g., peak flow meter, devices to capture participant reported outcomes (PROs)), or who have any medical or mental disorder, situation, or diagnosis which could interfere with the proper completion of the protocol requirements.
11. History of hypersensitivity to any ingredients of the study drugs including fluticasone, glycopyrronium and salmeterol. This includes any known hypersensitivity or intolerance to the excipients, including lactose.
12. Participants with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption or diagnosed intolerance to lactose or milk products.
13. Parent/guardian has a history of psychiatric disease, intellectual deficiency, substance abuse, or other condition (e.g., inability to read, comprehend and write) which will limit the validity of consent for their child to participate in this study.
14. Participants with a history of long QT syndrome or whose corrected QT interval (QTc) measured either at start of Run-in or at Baseline (prior to randomization) (Fridericia method) is prolonged (> 450 msec for boys and girls) and confirmed by a central assessor (these participants should not be rescreened).
15. Participants who have a clinically significant ECG abnormality as per the investigator’s judgement either at start of Run-in or at baseline (prior to randomization).
16. Participant who is a ward of the state or government.
17. Participant is an immediate family member of the participating investigator, sub-investigator, study coordinator, or employee of the participating investigator.
18. History of malignancy of any organ (including lung cancer), treated or untreated within the past 5 years prior to Screening (Visit 1), whether there is evidence of local recurrence of metastases or not.
19. History of chronic lung disease other than asthma prior to Screening (Visit 1) e.g., sarcoidosis, interstitial lung disease, cystic fibrosis, or any chronic condition of the respiratory tract which in the opinion of the investigator may interfere with study evaluation or optimal participation in the study.
20. Suspected or documented active infections (bacterial, viral, fungal, mycobacterial, or other, including active SARS-CoV-2, tuberculosis, or atypical mycobacterial disease) of the upper or lower respiratory tract, sinus or middle ear that is not resolved within 6 weeks of Screening (Visit 1).
21. History of Type I diabetes or uncontrolled Type II diabetes.
22. Participants who, as per investigator's judgement, have any clinically significant abnormal lab values reported at Run-in (Visit 20).
23. History of immunodeficiency diseases, including a positive Human Immunodeficiency Virus (HIV) test result (ELISA and Western blot).
24. Any surgical or medical condition which might significantly alter the absorption, distribution, metabolism, or excretion of drugs, or which may jeopardize the participant in case of participation in the study.
25. Pregnant or nursing (lactating) females, including postmenarchal girl with a positive serum pregnancy test at Run-in.
26. Participants who are sexually active at screening.
27. Hemoglobin levels outside normal ranges and considered clinically significant as per investigator’s judgement at Run-in (Visit 20).
28. Female participants of childbearing potential (e.g., are menstruating) who do not agree to abstinence or, if they become sexually active during study participation, do not agree to the use of contraception as defined in the inclusion criteria. No additional exclusions may be applied by the investigator, to ensure that the study population will be representative of all eligible participants.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Change from Baseline in trough FEV1 at week 2 of each treatment period

Secondary endpoints 5

1. Steady state pharmacokinetic (PK) concentration profiles and parameters for each glycopyrronium dose level as feasible
2. Change from Baseline (morning and evening) in PEF rate averaged over 2 weeks of each treatment period
3. Change from Baseline in FEV1 at 30 min and 1 hour post dose at week 2 of each treatment period
4. Change from baseline in rescue medication use over 2 weeks of each treatment period 1. Adverse events (AEs), electrocardiograms (ECGs), vital signs 2. Laboratory parameters including blood glucose and serum potassium levels
5. Adverse events of special interest (AESI) typical of anti-muscarinic side effects (including dry mouth, fatigue, constipation, and urinary retention)

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Placebo 1

Auxiliary 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Novartis Pharma AG

Sponsor organisation

Novartis Pharma AG

Address

Lichtstrasse 35

City

Basel

Postcode

4056

Country

Switzerland

Scientific contact point

Organisation

Novartis Pharma AG

Contact name

Novartis Pharma Arzneimittel GmbH

Public contact point

Organisation

Novartis Pharma AG

Contact name

Novartis Pharma Arzneimittel GmbH

Third parties 15

Locations

4 EU/EEA countries · 15 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 61 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

6 submissions — initial application plus substantial / non-substantial modifications