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

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

Status

Completed

Phases

Phase 1

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT03421730

Enrollment

Registered

2018-02-05

Start date

2017-12-18

Completion date

2018-03-27

Last updated

2019-10-21

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Mild Asthma, Reactive Airway Disease, Wheezing

Keywords

mild asthma, budesonide, nebulizer, pediatric, pharmacokinetics

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.

Interventions

COMBINATION_PRODUCTVR647 Inhalation Suspension (budesonide) 1 mg/2 mL delivered by the VR647 Inhalation System

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.

COMBINATION_PRODUCT1 mg/2 mL Pulmicort Respules delivered by a conventional jet nebulizer

Commercial Pulmicort Respules (budesonide inhalation suspension 1 mg/2 mL) delivered by a conventional jet nebulizer operated to sputtering.

Study design

Allocation

RANDOMIZED

Intervention model

CROSSOVER

Primary purpose

TREATMENT

Masking

NONE

Masking description

This is an open label trial.

Intervention 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.

Eligibility

Sex/Gender

ALL

Age

4 Years to 8 Years

Healthy volunteers

Inclusion 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.

Design outcomes

Primary

Measure	Time frame	Description
AUClast of Plasma Budesonide (VR647 Inhalation Suspension Delivered by the VR647 Inhalation System or Pulmicort Respules Delivered by a Conventional Jet Nebulizer).	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).	AUClast is the area under the plasma concentration-time curve, from time 0 to the time of the last measurable concentration (Clast).
AUCinf of Plasma Budesonide (VR647 Inhalation Suspension Delivered by the VR647 Inhalation System or Pulmicort Respules Delivered by a Conventional Jet Nebulizer).	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 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).
Cmax of Plasma Budesonide (VR647 Inhalation Suspension Delivered by the VR647 Inhalation System or Pulmicort Respules Delivered by a Conventional Jet Nebulizer).	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 is the maximum observed concentration.
Tmax of Plasma Budesonide (VR647 Inhalation Suspension Delivered by the VR647 Inhalation System or Pulmicort Respules Delivered by a Conventional Jet Nebulizer).	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 is the time to reach Cmax.
Tlast of Plasma Budesonide (VR647 Inhalation Suspension Delivered by the VR647 Inhalation System or Pulmicort Respules Delivered by a Conventional Jet Nebulizer).	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 is the time of the last measurable concentration (Clast).
T1/2 of Plasma Budesonide (VR647 Inhalation Suspension Delivered by the VR647 Inhalation System or Pulmicort Respules Delivered by a Conventional Jet Nebulizer).	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 is the apparent first-order terminal elimination half-life.

Secondary

Measure	Time frame	Description
Changes in Vital Signs (Respiration Rate)	Baseline to Day 1 0.5 hours post-dose	Mean values for respiratory rate from pre-dose to 0.5 hours post-dose.
Changes in Vital Signs (Temperature)	Baseline to Day 1 0.5 hours post-dose	Mean values for temperature from pre-dose to 0.5 hours post-dose.
Mean Modified Patient Satisfaction and Preference Questionnaire (PASAPQ) Total Score (Q1 to Q8).	Following dosing on Day 1 (Visit 2) and Day 8 (Visit 3).	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).
Use of Concomitant Medications	Visit 1	Number of subjects using concomitant medications.
Changes in Physical Examination	Visit 1, and Day 8 of Visit 3.	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.
Mean Modified PASAPQ Performance Score	Following dosing on Day 1 (Visit 2) and Day 8 (Visit 3).	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).
Mean Modified PASAPQ Satisfaction Score (Q9).	Following dosing on Day 1 (Visit 2) and Day 8 (Visit 3).	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).
Mean Modified PASAPQ Score Indicating Willingness to Continue With the Device (Q10).	Following dosing on Day 1 (Visit 2) and Day 8 (Visit 3).	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).
Changes in Vital Signs (Blood Pressure)	Baseline to Day 1 0.5 hours post-dose	Mean values for blood pressure from pre-dose to 0.5 hours post-dose.
Changes in Vital Signs (Heart Rate)	Baseline to Day 1 0.5 hours post-dose	Mean values for heart rate from pre-dose to 0.5 hours post-dose.

Countries

United States

Participant flow

Pre-assignment details

Seventeen subjects were enrolled and randomized to 1 of 12 crossover treatment sequences AB, AC, AD, BA, BC, BD, CA, CB, CD, DA, DB or DC. However, data were analyzed (and presented) by individual treatment only (i.e. A, B, C and D), not per treatment sequence. Fifteen subjects received at least 1 study treatment; 13 subjects completed the trial.

Participants by arm

Arm	Count
Overall Treatment Baseline measures were not analysed by arm or comparison group, so they are presented for the total number of subjects enrolled in the study who received at least one dose of treatment.	15
Total	15

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002	FG003	FG004	FG005	FG006	FG007	FG008	FG009	FG010	FG011
First Intervention (Day 1, Visit 2)	Withdrawal by subject or legal guardian	0	2	0	0	0	0	0	0	0	0	0	0
Washout (Days 4 to 10)	Withdrawal by subject or legal guardian	0	0	0	0	2	0	0	0	0	0	0	0

Baseline characteristics

Characteristic	Overall Treatment
Age, Continuous	82.6 months STANDARD_DEVIATION 14.05
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	15 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants
Race (NIH/OMB) Asian	0 Participants
Race (NIH/OMB) Black or African American	9 Participants
Race (NIH/OMB) More than one race	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants
Race (NIH/OMB) White	6 Participants
Sex: Female, Male Female	8 Participants
Sex: Female, Male Male	7 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk	EG004 affected / at risk
deaths Total, all-cause mortality	0 / 7	0 / 8	0 / 6	0 / 7	0 / 15
other Total, other adverse events	1 / 7	1 / 8	1 / 6	0 / 7	2 / 15
serious Total, serious adverse events	0 / 7	0 / 8	0 / 6	0 / 7	0 / 15

Outcome results

Primary

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).

Time frame: 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).