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Trial registered on ANZCTR


Registration number
ACTRN12618001032246
Ethics application status
Approved
Date submitted
10/06/2018
Date registered
20/06/2018
Date last updated
21/06/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Impulse oscillometry for the diagnosis of bronchiolitis obliterans syndrome
Scientific title
Impulse oscillometry for the diagnosis of bronchiolitis obliterans syndrome
Secondary ID [1] 295156 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Chronic lung allograft dysfunction 308265 0
Chronic graft-versus-host disease of the lung (bronchiolitis obliterans) 308266 0
Condition category
Condition code
Respiratory 307280 307280 0 0
Other respiratory disorders / diseases
Blood 307281 307281 0 0
Other blood disorders
Inflammatory and Immune System 307368 307368 0 0
Other inflammatory or immune system disorders

Intervention/exposure
Study type
Observational
Patient registry
False
Target follow-up duration
Target follow-up type
Description of intervention(s) / exposure
This prospective diagnostic study seeks to determine whether impulse oscillometry may provide a more sensitive diagnostic tool for the diagnosis of chronic lung allograft dysfunction (both bronchiolitis obliterans and restrictive allograft syndrome subtypes) and, separately, chronic graft-versus-host disease of the lung in allogeneic haematopoietic stem cell transplant recipients (bronchiolitis obliterans).

Participants will perform impulse oscillometry (IOS) prior to performing spirometry as ordered by their treating clinicians as surveillance for chronic lung allograft dysfunction or bronchiolitis obliterans in the case of allogeneic haematopoietic stem cell transplant patients. Patients typically undergo spirometry at least three-monthly. Patients will be observed for a minimum of 12 months and a maximum of 60 months.

IOS is a simple test with no risks to the patient which involves minimal to no discomfort. It involves the subject placing their mouth over a mouthpiece and forming a seal. The subject then breathes normally and while this is occurring the machine delivers a range of impulses into the respiratory system at different frequencies. The entire procedure takes only around 2 minutes.
Intervention code [1] 301495 0
Diagnosis / Prognosis
Comparator / control treatment
The reference test is spirometry which remains the gold-standard test for the diagnosis of chronic lung allograft dysfunction and chronic graft-versus-host disease of the lung in allogeneic haematopoietic stell cell transplant recipients.
Control group
Active

Outcomes
Primary outcome [1] 306234 0
Small airway resistance (resistance at 5 Hz minus resistance at 20 Hz)
Timepoint [1] 306234 0
Paired recordings of spirometry and impulse oscillometry will be taken every 3 months for the duration of the study (nominally set at up to five years).

As chronic lung allograft dysfunction and bronchiolitis obliterans in allogeneic haematopoietic stem cell transplantation are unpredictable diseases that may develop at any point late post-transplantation, it is not considered essential that all patients are observed for the full 5 year duration of the study which has been arbitrarily determined. The minimum period of useful observation is considered to be 12 months.
Primary outcome [2] 306342 0
Area under the reactance curve from 5 Hz to resonant frequency (AX)
Timepoint [2] 306342 0
Paired recordings of spirometry and impulse oscillometry will be taken every 3 months for the duration of the study (nominally set at up to five years).

As chronic lung allograft dysfunction and bronchiolitis obliterans in allogeneic haematopoietic stem cell transplantation are unpredictable diseases that may develop at any point late post-transplantation, it is not considered essential that all patients are observed for the full 5 year duration of the study which has been arbitrarily determined. The minimum period of useful observation is considered to be 12 months.
Primary outcome [3] 306343 0
Reactance at 5 Hz
Timepoint [3] 306343 0
Paired recordings of spirometry and impulse oscillometry will be taken every 3 months for the duration of the study (nominally set at up to five years).

As chronic lung allograft dysfunction and bronchiolitis obliterans in allogeneic haematopoietic stem cell transplantation are unpredictable diseases that may develop at any point late post-transplantation, it is not considered essential that all patients are observed for the full 5 year duration of the study which has been arbitrarily determined. The minimum period of useful observation is considered to be 12 months.
Secondary outcome [1] 347933 0
Reactance at 5Hz on inspiration minus reactance at 5 Hz on expiration
Timepoint [1] 347933 0
Paired recordings of spirometry and impulse oscillometry will be taken every 3 months for the duration of the study (nominally set at up to five years).

As chronic lung allograft dysfunction and bronchiolitis obliterans in allogeneic haematopoietic stem cell transplantation are unpredictable diseases that may develop at any point late post-transplantation, it is not considered essential that all patients are observed for the full 5 year duration of the study which has been arbitrarily determined. The minimum period of useful observation is considered to be 12 months.
Secondary outcome [2] 348232 0
Predictive value of changes in impulse oscillometry for the future development of bronchiolitis obliterans (whether in lung transplant or allogeneic haematopoietic stem cell transplant recipients) and / or restrictive allograft syndrome
Timepoint [2] 348232 0
Analysis of data upon completion of study. The analysis will be performed as follows:

Receiver operating characteristic (ROC) curves will be analysed for each different IOS parameter (in the form of percentage of predicted value) as a predictor of a future diagnosis of BOS / RAS or a worsening of pre-existing BOS / RAS at each available time interval (e.g. each IOS parameter, both as static values as well as any change in each IOS parameter over time, will be assessed against the spirometrically-defined point of change in BOS / RAS category to a maximum of 24 months prior to that point of change).

In order to avoid bias that may arise from the comparison of IOS data as continuous variables against the arbitrarily categorical variable of BOS / RAS severity, similar ROC curves will be analysed for the predictive value of FEV1 as a continuous variable (in the form of percentage of predicted value) and resulting areas under the curves will be numerically and graphically contrasted against results from the IOS parameter analysis. The same analysis will be performed for MMEF25-75 separately.

Predicting the development of BOS / RAS is more imperative for future research into disease aetiology and therapeutics than is excluding the condition; consequently we identify the sensitivity of IOS to be more important than its specificity. Therefore our a priori targets for IOS to be considered clinically useful are as follows:

- Sensitivity of greater than or equal to 85% for a BOS / RAS diagnosis or categorical worsening greater than or equal to 6 months before standard diagnostic criteria
- Specificity of greater than or equal to 75% for a BOS / RAS diagnosis or categorical worsening greater than or equal to 6 months before standard diagnostic criteria

Confidence intervals (95%) will be provided for all reported sensitivities and specificities.

Eligibility
Key inclusion criteria
- Bilateral Lung transplant recipient
- 18 years old or more

OR:

- Allogeneic haematopoietic stem cell transplant recipient
- 18 years old or more
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
In lung transplant recipients, allograft dysfunction from causes other than BOS or RAS, including:
- BOS / RAS overlap
- Active non-BOS alloinflammatory processes (e.g. acute cellular rejection, lymphocytic bronchiolitis and antibody-mediated rejection)
- Active allograft infection
- Mechanical impediment:
- Known upper / large airway obstructive pathology (e.g. anastomotic stricture or stricture to level of segmental bronchus)
- Pleural complications such as pneumothorax, infection or pleural effusion
- Neuromuscular deficits (e.g. diaphragmatic paralysis)
- Uncontrolled cardiac failure of any cause
- Recurrent of primary disease in allograft

In allogeneic haematopoietic stem cell transplant recipients, lung dysfunction from causes other than bronchiolitis obliterans including:

- Active pulmonary infection
- Mechanical impediment:
- Known upper / large airway obstructive pathology
- Pleural complications such as pneumothorax, infection or pleural effusion
- Neuromuscular deficits (e.g. diaphragmatic paralysis)
- Uncontrolled cardiac failure of any cause
- Pre-existing lung disease that is more than mild in severity (either obstructive or restrictive)

Study design
Purpose
Natural history
Duration
Longitudinal
Selection
Defined population
Timing
Prospective
Statistical methods / analysis
Our first and third hypotheses will be tested by comparing IOS results at all time points between the following groups:

- Lung transplant patients without lung dysfunction
- Allogeneic HSCT patients without lung dysfunction
- Lung transplant patients with BOS
- Allogeneic HSCT patients with BOS
- Lung transplant patients with RAS

All hypotheses will be tested by monitoring serial IOS results in individual patients over time and comparing these with spirometric data and new BOS / RAS or more severe BOS / RAS.

In the prospective phase of our study, we will seek to perform PFTs and IOS on each enrolled patient three-monthly; if a patient does not have matched PFTs / IOS for greater than 6 months, this period will be excluded from prospective analysis regarding hypotheses two and four.

Statistical analysis

Analysis examining hypotheses one and three:

Lung transplant and allogeneic HSCT patients will be analysed separately with respect to the testing of hypotheses one and three. IOS parameters (Rrs5-20, AX, Xrs5 and the differential between Xrs5insp and Xrs5exp) will be used to predict FEV1 and, separately, MMEF25-75 in separate linear mixed-effects models adjusting for repeated measurements over time.

Given the significant variation in normal values for all pulmonary function tests parameters, IOS characteristics as a percentage of the predicted value will also be examined as predictors of FEV1 and, separately, MMEF25-75 once again using linear mixed-effects models. Predicted values for both IOS and spirometry will be based on lung transplant recipient biometrics and not those of the donor, as is standard convention in spirometry.

Agreement between IOS results from spirometrically equivalent lung transplant and allogeneic HSCT patients with BOS will be tested using linear mixed-effects models, only for those patients with BOS in at least one of the time periods. The outcome will be IOS parameters (one at a time) and interaction will be FEV1 versus being in the lung transplant or allogeneic HSCT group. Repeated measures over time will be accounted for. A significant interaction would indicate a significant difference in relationship between IOS results and FEV1 between the lung transplant and allogeneic HSCT groups. The same analysis will be performed for MMEF25-75 separately.

Analysis examining hypotheses two and four:

If substantial agreement between IOS results for spirometrically equivalent lung transplant and allogeneic HSCT patients with BOS is demonstrated in the initial analysis (a priori requirement is interaction p value greater than or equal to 0.10 for all models), then these groups may be analysed collectively in the predictive analysis described below.

Receiver operating characteristic (ROC) curves will be analysed for each different IOS parameter (in the form of percentage of predicted value) as a predictor of a future diagnosis of BOS / RAS or a worsening of pre-existing BOS / RAS at each available time interval (e.g. each IOS parameter, both as static values as well as any change in each IOS parameter over time, will be assessed against the spirometrically-defined point of change in BOS / RAS category to a maximum of 24 months prior to that point of change).

In order to avoid bias that may arise from the comparison of IOS data as continuous variables against the arbitrarily categorical variable of BOS / RAS severity, similar ROC curves will be analysed for the predictive value of FEV1 as a continuous variable (in the form of percentage of predicted value) and resulting areas under the curves will be numerically and graphically contrasted against results from the IOS parameter analysis. The same analysis will be performed for MMEF25-75 separately.

Predicting the development of BOS / RAS is more imperative for future research into disease aetiology and therapeutics than is excluding the condition; consequently we identify the sensitivity of IOS to be more important than its specificity. Therefore our a priori targets for IOS to be considered clinically useful are as follows:

- Sensitivity of greater than or equal to 85% for a BOS / RAS diagnosis or categorical worsening greater than or equal to 6 months before standard diagnostic criteria
- Specificity of greater than or equal to 75% for a BOS / RAS diagnosis or categorical worsening greater than or equal to 6 months before standard diagnostic criteria

Confidence intervals (95%) will be provided for all reported sensitivities and specificities.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
SA
Recruitment hospital [1] 11118 0
The Royal Adelaide Hospital - Adelaide
Recruitment postcode(s) [1] 22931 0
5000 - Adelaide

Funding & Sponsors
Funding source category [1] 299746 0
Hospital
Name [1] 299746 0
Department of Thoracic Medicine, Royal Adelaide Hospital
Address [1] 299746 0
Royal Adelaide Hospital
1 Port Road
Adelaide SA 5000
Country [1] 299746 0
Australia
Primary sponsor type
Individual
Name
Dr Thomas Crowhurst
Address
Department of Thoracic Medicine
Royal Adelaide Hospital
1 Port Road
Adelaide SA 5000
Country
Australia
Secondary sponsor category [1] 299083 0
None
Name [1] 299083 0
Address [1] 299083 0
Country [1] 299083 0
Other collaborator category [1] 280173 0
Individual
Name [1] 280173 0
A/Prof Chien-Li Holmes-Liew
Address [1] 280173 0
Department of Thoracic Medicine
Royal Adelaide Hospital
1 Port Road
Adelaide SA 5000
Country [1] 280173 0
Australia
Other collaborator category [2] 280174 0
Individual
Name [2] 280174 0
Dr Sonya Johnston
Address [2] 280174 0
Department of Thoracic Medicine
Royal Adelaide Hospital
1 Port Road
Adelaide SA 5000
Country [2] 280174 0
Australia
Other collaborator category [3] 280175 0
Individual
Name [3] 280175 0
Dr Aeneas Yeo
Address [3] 280175 0
Department of Thoracic Medicine
Royal Adelaide Hospital
1 Port Road
Adelaide SA 5000
Country [3] 280175 0
Australia
Other collaborator category [4] 280189 0
Individual
Name [4] 280189 0
Professor Mark Holmes
Address [4] 280189 0
Royal Adelaide Hospital
1 Port Road
Adelaide SA 5000
Country [4] 280189 0
Australia
Other collaborator category [5] 280190 0
Individual
Name [5] 280190 0
Lauren Bussell
Address [5] 280190 0
Royal Adelaide Hospital
1 Port Road
Adelaide SA 5000
Country [5] 280190 0
Australia
Other collaborator category [6] 280191 0
Individual
Name [6] 280191 0
Dr David Yeung
Address [6] 280191 0
Royal Adelaide Hospital
1 Port Road
Adelaide SA 5000
Country [6] 280191 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 300636 0
Central Adelaide Local Health Network Human Research Ethics Committee
Ethics committee address [1] 300636 0
Royal Adelaide Hospital
1 Port Road
Adelaide SA 5000
Ethics committee country [1] 300636 0
Australia
Date submitted for ethics approval [1] 300636 0
07/06/2018
Approval date [1] 300636 0
19/06/2018
Ethics approval number [1] 300636 0
R20180610

Summary
Brief summary
This is a prospective diagnostic study which aims to determine whether impulse oscillometry may enable the earlier detection of chronic lung allograft dysfunction and / or bronchiolitis obliterans after allogeneic haematopoietic stem cell transplantation.

Our prospective diagnostic study seeks to explore two primary and two secondary hypotheses:

Primary hypotheses:

1. As a disease of the small airways, BOS (whether in the context of lung transplant or allogeneic HSCT) will manifest changes on IOS as follows:

1.1 Small airway resistance (represented by Rrs5-Rrs20) will be increased
1.2 AX will be increased
1.3 Xrs5 will be more negative
1.4 In more severe disease with significant airflow limitation, there will be a significant difference between Xrs5insp and Xrs5exp in normal quiet breathing

2. BOS will be detectable via IOS before it is evident via standard diagnostic criteria

Secondary hypotheses:

3. RAS will also cause an increase in AX and a more negative Xrs5 but will be distinguishable from BOS on IOS due to the following:

3.1 Rrs5-Rrs20 will be normal
3.2 There will be no significant difference between Xrs5insp and Xrs5exp in normal quiet breathing

4. RAS will be detectable via IOS before it is evident via standard diagnostic criteria
Trial website
None
Trial related presentations / publications
None
Public notes

Contacts
Principal investigator
Name 84290 0
Dr Thomas Crowhurst
Address 84290 0
Department of Thoracic Medicine
Royal Adelaide Hospital
1 Port Road
Adelaide SA 5000
Country 84290 0
Australia
Phone 84290 0
+61439810678
Fax 84290 0
Email 84290 0
thomas.crowhurst@gmail.com
Contact person for public queries
Name 84291 0
Dr Thomas Crowhurst
Address 84291 0
Department of Thoracic Medicine
Royal Adelaide Hospital
1 Port Road
Adelaide SA 5000
Country 84291 0
Australia
Phone 84291 0
+61439810678
Fax 84291 0
Email 84291 0
thomas.crowhurst@gmail.com
Contact person for scientific queries
Name 84292 0
Dr Thomas Crowhurst
Address 84292 0
Department of Thoracic Medicine
Royal Adelaide Hospital
1 Port Road
Adelaide SA 5000
Country 84292 0
Australia
Phone 84292 0
+61439810678
Fax 84292 0
Email 84292 0
thomas.crowhurst@gmail.com

No information has been provided regarding IPD availability
Summary results
No Results