A Study of the Pharmacokinetics, Safety and Tolerability of Single Doses of VR647 Inhalation Suspension Administered Using the VR647 Inhalation System in Children With Wheezing, Reactive Airway Disease or Mild Asthma

Study Overview
=================
Brief Summary
-----------------
The primary objective of this study is to evaluate budesonide levels in the blood following inhalation of single doses of VR647 Inhalation Suspension in children with wheezing, reactive airway disease or mild asthma using a nebulizer, the VR647 Inhalation System. Secondary objectives include the evaluation of the safety and tolerability of VR647 Inhalation Suspension administered using the VR647 Inhalation System. The study consists of four visits; a screening visit (Visit 1), two dosing days (Visits 2 and 3) and a follow-up visit (Visit 4). On each dosing day a single dose of treatment will be administered. Treatment allocation at Visits 2 and 3 is determined by a balanced incomplete block design.

Official Title
-----------------
A Single-dose, Open-label, Randomized, Incomplete Block Design Trial to Characterize the Pharmacokinetics of VR647 Inhalation Suspension Delivered by the VR647 Inhalation System and Single Doses of Budesonide Delivered by a Conventional Jet Nebulizer in Pediatric Subjects Aged 4 to 8 Years With Wheezing, Reactive Airway Disease or Mild Asthma

Conditions
-----------------
Wheezing, Reactive Airway Disease, Mild Asthma

Intervention / Treatment
-----------------
* Combination Product: VR647 Inhalation Suspension (budesonide) 1 mg/2 mL delivered by the VR647 Inhalation System
* Combination Product: 1 mg/2 mL Pulmicort Respules delivered by a conventional jet nebulizer


Participation Criteria
=================
Eligibility Criteria
-----------------
Key Inclusion Criteria: Male or pre-menarchal female subjects. Aged 4 to 8 years, inclusive. Diagnosis of wheezing, reactive airway disease or mild asthma confirmed by a physician at least 3 months prior to screening. Wheezing, reactive airway disease or mild asthma controlled by intermittent or regular non-steroidal medications commonly used for asthma, such as short-acting β2-agonists (SABAs) or leukotriene receptor antagonists (LTRAs), for a minimum of 28 days prior to the Screening Visit. Body weight ≥15 kg. Subject is able to demonstrate the ability to use the VR647 Inhalation System and the conventional jet nebulizer effectively during training. Key Exclusion Criteria: Clinically relevant abnormality or medical condition (other than wheezing, reactive airway disease or mild asthma) identified at the screening assessment that, in the opinion of the investigator, could interfere with the objectives of the trial or the safety of the subject. The sponsor's medical officer should be consulted in case of any doubt. Life-threatening asthma, defined as a history of asthma episode(s) requiring intubation, and/or associated with hypercapnia, respiratory arrest, hypoxic seizures, or asthma-related syncopal episodes. Subjects currently using long-acting β2-agonists. Use of the following prescription medications within 28 days prior to the first treatment day: corticosteroids by any route and drugs that inhibit cytochrome P450 3A4.

Ages Eligible for Study
-----------------
Minimum Age: 4 Years
Maximum Age: 8 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: This is an open label, randomized, balanced, incomplete block design trial. Eligible subjects will be randomized to 1 of 12 treatment sequences (A,B), (A,C), (A,D), (B,A), (B,C), (B,D), (C,A), (C,B), (C,D), (D,A), (D,B) or (D,C), corresponding to the following treatment regimens: (A) 5 breaths of VR647 Inhalation Suspension delivered by the VR647 Inhalation System (B) 10 breaths of VR647 Inhalation Suspension delivered by the VR647 Inhalation System (C) 20 breaths of VR647 Inhalation Suspension delivered by the VR647 Inhalation System (D) 1 mg/2 mL Pulmicort Respules delivered by a conventional jet nebulizer nebulized to empty The treatment period comprises 2 dosing visits. Each subject will receive their first treatment regimen during Visit 2 and their second treatment regimen during Visit 3.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AB - VR647 5 breaths, then VR647 10 breaths<br>5 breaths of the VR647 Inhalation Suspension 1 mg/2 mL delivered by the VR647 Inhalation System followed by 10 breaths of the VR647 Inhalation Suspension 1 mg/2 mL delivered by the VR647 Inhalation System | Combination Product: VR647 Inhalation Suspension (budesonide) 1 mg/2 mL delivered by the VR647 Inhalation System<br>* The VR647 Inhalation System consists of the VR647 Inhalation System 1 control unit, a VR647 nebulizer handset, a mouthpiece and VR647 Smart Cards designed specifically for this trial.<br>|
| Experimental: AC - VR647 5 breaths, then VR647 20 breaths<br>5 breaths of the VR647 Inhalation Suspension 1 mg/2 mL delivered by the VR647 Inhalation System followed by 20 breaths of the VR647 Inhalation Suspension 1 mg/2 mL delivered by the VR647 Inhalation System | Combination Product: VR647 Inhalation Suspension (budesonide) 1 mg/2 mL delivered by the VR647 Inhalation System<br>* The VR647 Inhalation System consists of the VR647 Inhalation System 1 control unit, a VR647 nebulizer handset, a mouthpiece and VR647 Smart Cards designed specifically for this trial.<br>|
| Experimental: AD - VR647 5 breaths, then Pulmicort<br>5 breaths of the VR647 Inhalation Suspension 1 mg/2 mL delivered by the VR647 Inhalation System followed by 1 mg/2 mL Pulmicort Respules delivered by the conventional jet nebulizer nebulized to empty | Combination Product: VR647 Inhalation Suspension (budesonide) 1 mg/2 mL delivered by the VR647 Inhalation System<br>* The VR647 Inhalation System consists of the VR647 Inhalation System 1 control unit, a VR647 nebulizer handset, a mouthpiece and VR647 Smart Cards designed specifically for this trial.<br>Combination Product: 1 mg/2 mL Pulmicort Respules delivered by a conventional jet nebulizer<br>* Commercial Pulmicort Respules (budesonide inhalation suspension 1 mg/2 mL) delivered by a conventional jet nebulizer operated to sputtering.<br>|
| Experimental: BA - VR647 10 breaths, then VR647 5 breaths<br>10 breaths of the VR647 Inhalation Suspension 1 mg/2 mL delivered by the VR647 Inhalation System followed by 5 breaths of the VR647 Inhalation Suspension 1 mg/2 mL delivered by the VR647 Inhalation System | Combination Product: VR647 Inhalation Suspension (budesonide) 1 mg/2 mL delivered by the VR647 Inhalation System<br>* The VR647 Inhalation System consists of the VR647 Inhalation System 1 control unit, a VR647 nebulizer handset, a mouthpiece and VR647 Smart Cards designed specifically for this trial.<br>|
| Experimental: BC - VR647 10 breaths, then VR647 20 breaths<br>10 breaths of the VR647 Inhalation Suspension 1 mg/2 mL delivered by the VR647 Inhalation System followed by 20 breaths of the VR647 Inhalation Suspension 1 mg/2 mL delivered by the VR647 Inhalation System | Combination Product: VR647 Inhalation Suspension (budesonide) 1 mg/2 mL delivered by the VR647 Inhalation System<br>* The VR647 Inhalation System consists of the VR647 Inhalation System 1 control unit, a VR647 nebulizer handset, a mouthpiece and VR647 Smart Cards designed specifically for this trial.<br>|
| Experimental: BD - VR647 10 breaths, then Pulmicort<br>10 breaths of the VR647 Inhalation Suspension 1 mg/2 mL delivered by the VR647 Inhalation System followed by 1 mg/2 mL Pulmicort Respules delivered by the conventional jet nebulizer nebulized to empty | Combination Product: VR647 Inhalation Suspension (budesonide) 1 mg/2 mL delivered by the VR647 Inhalation System<br>* The VR647 Inhalation System consists of the VR647 Inhalation System 1 control unit, a VR647 nebulizer handset, a mouthpiece and VR647 Smart Cards designed specifically for this trial.<br>Combination Product: 1 mg/2 mL Pulmicort Respules delivered by a conventional jet nebulizer<br>* Commercial Pulmicort Respules (budesonide inhalation suspension 1 mg/2 mL) delivered by a conventional jet nebulizer operated to sputtering.<br>|
| Experimental: CA - VR647 20 breaths, then VR647 5 breaths<br>20 breaths of the VR647 Inhalation Suspension 1 mg/2 mL delivered by the VR647 Inhalation System followed by 5 breaths of the VR647 Inhalation Suspension 1 mg/2 mL delivered by the VR647 Inhalation System | Combination Product: VR647 Inhalation Suspension (budesonide) 1 mg/2 mL delivered by the VR647 Inhalation System<br>* The VR647 Inhalation System consists of the VR647 Inhalation System 1 control unit, a VR647 nebulizer handset, a mouthpiece and VR647 Smart Cards designed specifically for this trial.<br>|
| Experimental: CB - VR647 20 breaths, then VR647 10 breaths<br>20 breaths of the VR647 Inhalation Suspension 1 mg/2 mL delivered by the VR647 Inhalation System followed by 10 breaths of the VR647 Inhalation Suspension 1 mg/2 mL delivered by the VR647 Inhalation System | Combination Product: VR647 Inhalation Suspension (budesonide) 1 mg/2 mL delivered by the VR647 Inhalation System<br>* The VR647 Inhalation System consists of the VR647 Inhalation System 1 control unit, a VR647 nebulizer handset, a mouthpiece and VR647 Smart Cards designed specifically for this trial.<br>|
| Experimental: CD - VR647 20 breaths, then Pulmicort<br>20 breaths of the VR647 Inhalation Suspension 1 mg/2 mL delivered by the VR647 Inhalation System followed by 1 mg/2 mL Pulmicort Respules delivered by the conventional jet nebulizer nebulized to empty | Combination Product: VR647 Inhalation Suspension (budesonide) 1 mg/2 mL delivered by the VR647 Inhalation System<br>* The VR647 Inhalation System consists of the VR647 Inhalation System 1 control unit, a VR647 nebulizer handset, a mouthpiece and VR647 Smart Cards designed specifically for this trial.<br>Combination Product: 1 mg/2 mL Pulmicort Respules delivered by a conventional jet nebulizer<br>* Commercial Pulmicort Respules (budesonide inhalation suspension 1 mg/2 mL) delivered by a conventional jet nebulizer operated to sputtering.<br>|
| Experimental: DA - Pulmicort, then VR647 5 breaths<br>1 mg/2 mL Pulmicort Respules delivered by the conventional jet nebulizer nebulized to empty followed by 5 breaths of the VR647 Inhalation Suspension 1 mg/2 mL delivered by the VR647 Inhalation System | Combination Product: VR647 Inhalation Suspension (budesonide) 1 mg/2 mL delivered by the VR647 Inhalation System<br>* The VR647 Inhalation System consists of the VR647 Inhalation System 1 control unit, a VR647 nebulizer handset, a mouthpiece and VR647 Smart Cards designed specifically for this trial.<br>Combination Product: 1 mg/2 mL Pulmicort Respules delivered by a conventional jet nebulizer<br>* Commercial Pulmicort Respules (budesonide inhalation suspension 1 mg/2 mL) delivered by a conventional jet nebulizer operated to sputtering.<br>|
| Experimental: DB - Pulmicort, then VR647 10 breaths<br>1 mg/2 mL Pulmicort Respules delivered by the conventional jet nebulizer nebulized to empty followed by 10 breaths of the VR647 Inhalation Suspension 1 mg/2 mL delivered by the VR647 Inhalation System | Combination Product: VR647 Inhalation Suspension (budesonide) 1 mg/2 mL delivered by the VR647 Inhalation System<br>* The VR647 Inhalation System consists of the VR647 Inhalation System 1 control unit, a VR647 nebulizer handset, a mouthpiece and VR647 Smart Cards designed specifically for this trial.<br>Combination Product: 1 mg/2 mL Pulmicort Respules delivered by a conventional jet nebulizer<br>* Commercial Pulmicort Respules (budesonide inhalation suspension 1 mg/2 mL) delivered by a conventional jet nebulizer operated to sputtering.<br>|
| Experimental: DC - Pulmicort, then VR647 20 breaths<br>1 mg/2 mL Pulmicort Respules delivered by the conventional jet nebulizer nebulized to empty followed by 20 breaths of the VR647 Inhalation Suspension 1 mg/2 mL delivered by the VR647 Inhalation System | Combination Product: VR647 Inhalation Suspension (budesonide) 1 mg/2 mL delivered by the VR647 Inhalation System<br>* The VR647 Inhalation System consists of the VR647 Inhalation System 1 control unit, a VR647 nebulizer handset, a mouthpiece and VR647 Smart Cards designed specifically for this trial.<br>Combination Product: 1 mg/2 mL Pulmicort Respules delivered by a conventional jet nebulizer<br>* Commercial Pulmicort Respules (budesonide inhalation suspension 1 mg/2 mL) delivered by a conventional jet nebulizer operated to sputtering.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AUClast of Plasma Budesonide (VR647 Inhalation Suspension Delivered by the VR647 Inhalation System or Pulmicort Respules Delivered by a Conventional Jet Nebulizer). | AUClast is the area under the plasma concentration-time curve, from time 0 to the time of the last measurable concentration (Clast). | Pre-dose, and at 20 minutes, 40 minutes, 1.5, 3, 4, 6 and 8 hours after start of nebulization on Day 1 (Visit 2) and Day 8 (Visit 3). | 
| AUCinf of Plasma Budesonide (VR647 Inhalation Suspension Delivered by the VR647 Inhalation System or Pulmicort Respules Delivered by a Conventional Jet Nebulizer). | AUCinf is the area under the plasma concentration-time curve, from time 0 extrapolated to infinity. AUCinf is calculated as the sum of AUClast plus the ratio of the last measurable plasma concentration (Clast) to the elimination rate constant (λz). | Pre-dose, and at 20 minutes, 40 minutes, 1.5, 3, 4, 6 and 8 hours after start of nebulization on Day 1 (Visit 2) and Day 8 (Visit 3). | 
| Cmax of Plasma Budesonide (VR647 Inhalation Suspension Delivered by the VR647 Inhalation System or Pulmicort Respules Delivered by a Conventional Jet Nebulizer). | Cmax is the maximum observed concentration. | Pre-dose, and at 20 minutes, 40 minutes, 1.5, 3, 4, 6 and 8 hours after start of nebulization on Day 1 (Visit 2) and Day 8 (Visit 3). | 
| Tmax of Plasma Budesonide (VR647 Inhalation Suspension Delivered by the VR647 Inhalation System or Pulmicort Respules Delivered by a Conventional Jet Nebulizer). | Tmax is the time to reach Cmax. | Pre-dose, and at 20 minutes, 40 minutes, 1.5, 3, 4, 6 and 8 hours after start of nebulization on Day 1 (Visit 2) and Day 8 (Visit 3). | 
| Tlast of Plasma Budesonide (VR647 Inhalation Suspension Delivered by the VR647 Inhalation System or Pulmicort Respules Delivered by a Conventional Jet Nebulizer). | Tlast is the time of the last measurable concentration (Clast). | Pre-dose, and at 20 minutes, 40 minutes, 1.5, 3, 4, 6 and 8 hours after start of nebulization on Day 1 (Visit 2) and Day 8 (Visit 3). | 
| T1/2 of Plasma Budesonide (VR647 Inhalation Suspension Delivered by the VR647 Inhalation System or Pulmicort Respules Delivered by a Conventional Jet Nebulizer). | T1/2 is the apparent first-order terminal elimination half-life. | Pre-dose, and at 20 minutes, 40 minutes, 1.5, 3, 4, 6 and 8 hours after start of nebulization on Day 1 (Visit 2) and Day 8 (Visit 3). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Modified Patient Satisfaction and Preference Questionnaire (PASAPQ) Total Score (Q1 to Q8). | The PASAPQ is a validated multi-item measure of satisfaction and preference with inhaler devices. The modified PASAPQ consists of 10 questions. The first 8 questions generate the total score domain. Data from this questionnaire were listed by subject and summarized by treatment. The results from Questions 1 through 8 were added for each subject to generate the Total Score (n = Q1+Q2+Q3+Q4+Q5+Q6+Q7+Q8) and expressed as percentage of maximum total score (i.e., (n/56)*100). Questions 1 to 8 were answered using scores from 1 (i.e., very dissatisfied) to 7 (i.e., very satisfied). | Following dosing on Day 1 (Visit 2) and Day 8 (Visit 3). | 
| Mean Modified PASAPQ Performance Score | The PASAPQ is a validated multi-item measure of satisfaction and preference with inhaler devices; it was originally a 15-item questionnaire, with performance assessed over 7 items. The modified PASAPQ (mPASAPQ) has 10 questions, including only 4 from the performance domain; the 3 questions not included were dropped from the mPASAPQ as they were not applicable to patient population and device under study. Questions 1, 2, 6, and 7 were assessed, covering satisfaction with nebulizer reliability, ease of inhalation, use and treatment time. Although specified in the protocol, the mPASAPQ performance score was not summarized in the efficacy analysis. The results for each question are presented below, however it was not considered appropriate to analyze the performance domain, as it is not possible to verify the validity of the questionnaire utilising only 4 of the original 7 questions. Questions were answered using scores from 1 (i.e., very dissatisfied) to 7 (i.e., very satisfied). | Following dosing on Day 1 (Visit 2) and Day 8 (Visit 3). | 
| Mean Modified PASAPQ Satisfaction Score (Q9). | The PASAPQ is a validated multi-item measure of satisfaction and preference with inhaler devices. The modified PASAPQ consists of 10 questions. Question 9 asks for overall satisfaction with the device(s) used in the trial. Question 9 was answered using scores from 1 (i.e., very dissatisfied) to 7 (i.e., very satisfied). | Following dosing on Day 1 (Visit 2) and Day 8 (Visit 3). | 
| Mean Modified PASAPQ Score Indicating Willingness to Continue With the Device (Q10). | The PASAPQ is a validated multi-item measure of satisfaction and preference with inhaler devices. The modified PASAPQ consists of 10 questions. Question 10 asks about willingness to continue with the device(s) used in the trial. Parents/legal guardians were asked to indicate how willing they would be for their child to use the nebulizer used during the study, providing a number between 0 (unwilling) and 100 (willing). | Following dosing on Day 1 (Visit 2) and Day 8 (Visit 3). | 
| Changes in Vital Signs (Blood Pressure) | Mean values for blood pressure from pre-dose to 0.5 hours post-dose. | Baseline to Day 1 0.5 hours post-dose | 
| Changes in Vital Signs (Heart Rate) | Mean values for heart rate from pre-dose to 0.5 hours post-dose. | Baseline to Day 1 0.5 hours post-dose | 
| Changes in Vital Signs (Respiration Rate) | Mean values for respiratory rate from pre-dose to 0.5 hours post-dose. | Baseline to Day 1 0.5 hours post-dose | 
| Changes in Vital Signs (Temperature) | Mean values for temperature from pre-dose to 0.5 hours post-dose. | Baseline to Day 1 0.5 hours post-dose | 
| Changes in Physical Examination | Physical examination data were listed. The number of participants with a change in physical examination status (i.e. from normal to abnormal, or from abnormal to normal) is presented below. | Visit 1, and Day 8 of Visit 3. | 
| Use of Concomitant Medications | Number of subjects using concomitant medications. | Visit 1 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
mild asthma, budesonide, nebulizer, pediatric, pharmacokinetics