Evaluation of Efficacy, Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability of Glycopyrronium Bromide in Pediatric Asthma Patients Aged 6 to <12 Years
- Trial ID
- 2024-511382-11-00
- Protocol
- CQVM149C2201
- Sponsor
- Novartis Pharma AG
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the change from baseline in **trough forced expiratory volume in one second (FEV1)** at week 2 of each treatment period in children aged 6 to less than 12 years with **asthma**. This measurement is clinically relevant as it provides insight into the efficacy of the treatment in improving lung function, which is a critical aspect of asthma management.
Secondary objectives include:
- Characterizing systemic exposure following two doses of **glycopyrronium**.
- Evaluating the change from baseline in peak expiratory flow (PEF) rate at week 2 of each treatment period.
- Assessing the change from baseline in FEV1 at 30 minutes and 1 hour post-dose at week 2 of each treatment period.
- Evaluating the change from baseline in rescue medication use over each treatment period.
- Assessing the safety and tolerability of each treatment, including laboratory parameters such as blood glucose and serum potassium levels.
- Evaluating typical anti-muscarinic side effects, including dry mouth, fatigue, constipation, and urinary retention.
Participants
The clinical trial involves a total of **23 participants** diagnosed with **asthma**. The study population consists of both male and female children, aged between 6 and less than 12 years, who have a confirmed diagnosis of asthma for at least six months prior to screening. Participants are required to be on a stable dose of inhaled low-to-medium dose inhaled corticosteroids (ICS) with one additional controller for at least four weeks before the run-in period. The trial population was selected based on specific inclusion criteria, including the ability to demonstrate acceptable inhaler use technique and complete spirometry procedures. Participants must have a pre-bronchodilator forced expiratory volume in one second (FEV1) between 60% and 90% of the predicted normal at the beginning of the run-in and randomization. Additionally, a parent or legal guardian is required to assist with study procedures, including compliance with study medication and completion of an electronic participant diary. The trial includes both genders and considers the participants as a vulnerable population due to their age. Lifestyle considerations such as diet and physical activity are not specified in the available data.
Plans and Procedures
The clinical trial is designed as a **randomized**, double-blind, placebo-controlled, crossover study to evaluate the efficacy, pharmacokinetics, pharmacodynamics, safety, and tolerability of **glycopyrronium bromide** in children aged 6 to less than 12 years with **asthma**. The trial involves three treatment periods, each lasting two weeks, with a total estimated duration of the study extending until May 31, 2025. Participants will be randomly assigned to receive either the active treatment or a placebo in a sequence that ensures each participant receives both treatments at different times during the study.
The study will commence with a screening visit to confirm eligibility based on inclusion criteria such as age, confirmed diagnosis of asthma, and stable use of inhaled corticosteroids. Participants must demonstrate acceptable inhaler technique and have a documented history of **FEV1** reversibility. Following successful screening, participants will enter a run-in period to establish baseline measurements and ensure compliance with study procedures.
During each treatment period, participants will attend multiple study visits, including baseline, mid-treatment, and end-of-treatment assessments. These visits will involve spirometry to measure changes in **FEV1**, monitoring of pharmacokinetic parameters, and evaluation of safety through adverse event reporting, electrocardiograms, and laboratory tests. The primary endpoint is the change from baseline in trough **FEV1** at week 2 of each treatment period. Secondary endpoints include changes in peak expiratory flow rate, rescue medication use, and adverse events of special interest.
The expected length of participant involvement is approximately 12 weeks, including the screening, run-in, and treatment periods. Conditions that may lead to early termination from the study include non-compliance with study procedures, adverse events that compromise participant safety, or withdrawal of consent. The study aims to provide comprehensive data on the efficacy and safety of **glycopyrronium bromide** in the pediatric asthma population, contributing to the optimization of treatment strategies for this condition.
Treatment
The clinical trial involves the administration of several treatments, including both experimental and non-experimental medications. **Salbutamol** is utilized as an auxiliary treatment in the form of a suspension for inhalation. The active substance, salbutamol, is chemically derived and administered via inhalation. The maximum daily dose is 800 micrograms, with a total maximum dose of 14,500 micrograms over a treatment period of 145 days. The medication is delivered using a pressurized container that is integral with the medicinal product.
**NVA237**, containing the active substance **glycopyrronium bromide**, is the primary experimental treatment. It is provided as an inhalation powder in hard capsules, specifically designed for pediatric use. The maximum daily dose is one dosage form, with a total maximum dose of 28 dosage forms over a 28-day treatment period. Administration is facilitated by a Breezhaler device, a unit-dose dry powder inhalation device that is CE marked and classified as a Class IIa medical device. The device includes a protective cap, mouthpiece, and inhaler body, ensuring proper aerosolization and preventing capsule ingestion.
**Salmeterol xinafoate** is another auxiliary treatment, provided as an inhalation powder. The maximum daily dose is two dosage forms, with a total maximum dose of 168 dosage forms over an 84-day treatment period. The medication is administered using a pressurized container, which is an integral part of the medicinal product.
**Fluticasone propionate** is also used as an auxiliary treatment in the form of an inhalation powder. Similar to salmeterol xinafoate, the maximum daily dose is two dosage forms, with a total maximum dose of 168 dosage forms over an 84-day treatment period. Administration is conducted using a pressurized container integral to the medicinal product.
The study includes a **placebo** treatment, which is a generic inhalation powder in hard capsules. The placebo is designed to match the active dosage forms of NVA237 (12.5 µg and 25 µg) and consists of inactive excipients such as magnesium stearate and lactose monohydrate. These are encapsulated in hard non-gelatin capsules that match those used for the active drug product.
Efficacy
The efficacy of the clinical trial will be assessed primarily through the evaluation of the change from baseline in trough **Forced Expiratory Volume in one second (FEV1)** at week 2 of each treatment period. This primary endpoint is designed to measure the improvement in lung function in children with asthma, aged 6 to less than 12 years. Secondary endpoints include the steady-state pharmacokinetic concentration profiles and parameters for each glycopyrronium dose level, changes from baseline in Peak Expiratory Flow (PEF) rate averaged over 2 weeks, and changes in FEV1 at 30 minutes and 1 hour post-dose at week 2 of each treatment period. Additionally, the trial will monitor changes from baseline in rescue medication use over 2 weeks, adverse events, electrocardiograms, vital signs, and laboratory parameters such as blood glucose and serum potassium levels. Adverse events of special interest, typical of anti-muscarinic side effects, will also be recorded.
The efficacy parameters will be collected and analyzed at specified time points, including baseline, week 2, and throughout each treatment period. The trial employs validated spirometry procedures to measure FEV1 and PEF rates, ensuring accurate and reliable data collection. The use of inhalation devices such as the Breezhaler and Diskus/Accuhaler is integral to the administration of the investigational products, and participants must demonstrate acceptable inhaler use technique prior to randomization. The trial is structured as a double-blind, randomized, multiple-dose, crossover study with three treatments and three periods, ensuring robust assessment of the investigational product's efficacy in the target pediatric population.
Inclusion and Exclusion Criteria
Inclusion Criteria
- 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
- Confirmed documented diagnosis of asthma for at least 6 months prior to screening
- 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
- 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.
- Pre-Bronchodilator FEV1 >60% to <95% of predicted normal at beginning of run-in and randomization.
- 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.
- 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.
- A parent/legal guardian must be designated to complete all e-Diary entries and attend all clinical visits with the participant.
- 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.
- 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
- Systemic corticosteroid use for any reason within 3 months of run-in (visit 20).
- 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.
- 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.
- 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.
- 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.
- 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.
- 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).
- 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.
- Prior intubation for asthma.
- 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.
- 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.
- Participants with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption or diagnosed intolerance to lactose or milk products.
- 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.
- 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).
- 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).
- Participant who is a ward of the state or government.
- Participant is an immediate family member of the participating investigator, sub-investigator, study coordinator, or employee of the participating investigator.
- 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.
- 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.
- 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).
- History of Type I diabetes or uncontrolled Type II diabetes.
- Participants who, as per investigator's judgement, have any clinically significant abnormal lab values reported at Run-in (Visit 20).
- History of immunodeficiency diseases, including a positive Human Immunodeficiency Virus (HIV) test result (ELISA and Western blot).
- 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.
- Pregnant or nursing (lactating) females, including postmenarchal girl with a positive serum pregnancy test at Run-in.
- Participants who are sexually active at screening.
- Hemoglobin levels outside normal ranges and considered clinically significant as per investigator’s judgement at Run-in (Visit 20).
- 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.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Bulgaria | Recruiting | 29 Aug 2022 | 9 |
 Hungary | Recruiting | 29 Aug 2022 | 10 |
 Poland | Recruiting | 29 Aug 2022 | 5 |
 Spain | Recruiting | 29 Aug 2022 | 6 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
SALBUTAMOL | Other | — | INHALATION USE | 800 | 145 | SUB10422MIG |
SALMETEROL XINAFOATE | Other | — | INHALATION USE | 2 | 84 | SUB04314MIG |
FLUTICASONE PROPIONATE | Other | — | INHALATION USE | 2 | 84 | SUB02241MIG |
NVA237 | Test | INHALATION POWDER, HARD CAPSULE | INHALATION USE | 1 | 28 | PRD221949 |
NVA237 | Test | INHALATION POWDER, HARD CAPSULE | INHALATION USE | 1 | 28 | PRD221950 |
The Placebo is a generic Placebo, inhalation powder, hard capsule. It is used to match an active dosage forms (NVA237 12.5µg and NVA 237 25µg) in this clinical trial. The placebo comprises inactive excipients (magnesium stearate and lactose monohydrate) encapsulated in hard non-gelatin capsules matching those used for the active drug product. | Placebo | N/A | — | — | — | N/A |