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    Clinical Trial Results:
    Triple Modality Functional Magnetic Resonance Lung Imaging in Cystic Fibrosis and Non-CF Bronchiectasis

    Summary
    EudraCT number
    		 2019-003052-36
    Trial protocol
    		 GB  
    Global end of trial date
    31 Dec 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    24 Jan 2025
    First version publication date
    24 Jan 2025
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    19067
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University of Nottingham
    Sponsor organisation address
    University of Nottingham, E-Floor, Yang Fujia Building, Jubilee Campus, Wollaton Road, Nottingham, United Kingdom, NG8 1BB
    Public contact
    Head of Research Integrity, Governance and Compliance, The University of Nottingham, sponsor@nottingham.ac.uk
    Scientific contact
    Head of Research Integrity, Governance and Compliance, The University of Nottingham, sponsor@nottingham.ac.uk
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    31 Dec 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 Dec 2023
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Dec 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the value of novel MRI techniques to image the lungs of people with CF and bronchiectasis. Our main aims are to see how they compare to current measurements of lung function/structure and check that they give us useful information. Overall, we hope to identify the best MRI scanning methods for assessment of these lung diseases and employ those techniques in future clinical trials. In CF, there is great interest in newer treatments that can improve lung function. At present, we use relatively simple measures such as blowing tests to assess and monitor the efficacy of these therapies. These measurements may not always be sensitive enough to detect changes in the lungs, so newer tests that are more sensitive are required. The lung disease in bronchiectasis is similar to CF and so studying both patient groups will highlight the utility of lung MRI in a broader population. Following this study, we aim to run a clinical trial that will use our lung MRI scanning expertise.
    Protection of trial subjects
    Safety monitoring during hyperpolarised Xe scanning
    Background therapy
    		 None
    Evidence for comparator
    		 Pilot study, no comparators used.
    Actual start date of recruitment
    01 Jan 2020
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 20
    Worldwide total number of subjects
    20
    EEA total number of subjects
    0
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    3
    Adults (18-64 years)
    17
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Nottingham, UK Recruitment from Jan1st 2020-Dec 31st 2023

    Pre-assignment
    Screening details
    		 After consent, the following were performed: Relevant past medical history and current medical records Physical examination Pregnancy test St George’s Respiratory Questionnaire CFQ-R QoL questionnaire Height and weight Spirometry (post bronchodilator) Full lung function tests Blood pressure Pulse ox. at rest ECG Sputum samples

    Period 1
    Period 1 title
    Baseline
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 HP Xe Imaging
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Hyperpolarised Xenon
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Medicinal gas, compressed
    Routes of administration
    Inhalation use
    Dosage and administration details
    The IMP (hp 129Xe) was administered via inhalation from a Tedlar bag via an inhalation tube in the hpXe arm. The maximum volume of hp 129Xe per scan was 1L for adults. IMP was administered in the cystic fibrosis arm of the study

    Arm title
    		 Cystic fibrosis
    Arm description
    		 -
    Arm type
    		 Proton scan

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		HP Xe Imaging Cystic fibrosis
    Started
    8
    12
    Completed
    8
    12
    Period 2
    Period 2 title
    Completion of scan
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 HP Xe Imaging
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Hyperpolarised Xenon
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Medicinal gas, compressed
    Routes of administration
    Inhalation use
    Dosage and administration details
    The IMP (hp 129Xe) was administered via inhalation from a Tedlar bag via an inhalation tube in the hpXe arm. The maximum volume of hp 129Xe per scan was 1L for adults. IMP was administered in the cystic fibrosis arm of the study

    Arm title
    		 Cystic fibrosis
    Arm description
    		 -
    Arm type
    		 Proton scan

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 2
    		HP Xe Imaging Cystic fibrosis
    Started
    8
    12
    Completed
    8
    12

    Baseline characteristics

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    End points

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    End points reporting groups
    Reporting group title
    HP Xe Imaging
    Reporting group description
    		 -

    Reporting group title
    Cystic fibrosis
    Reporting group description
    		 -
    Reporting group title
    HP Xe Imaging
    Reporting group description
    		 -

    Reporting group title
    Cystic fibrosis
    Reporting group description
    		 -

    Primary: successful completion of imaging

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    End point title
    		 successful completion of imaging [1]
    End point description
    Safety monitoring during Xe scanning
    End point type
    Primary
    End point timeframe
    during MR scanning plus 24 hour follow up
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This is a binary outcome variable; all subjects successfully completed imaging.
    End point values
    		 HP Xe Imaging HP Xe Imaging
    Number of subjects analysed
    8 [2]
    8 [3]
    Units: oxygen saturations
        number (not applicable)
    8
    8
    Notes
    [2] - Oxygen saturation pre-scan
    [3] - Oxygen saturation monitored throughout and following scan
    Statistical analysis title
    		 Xe gas transfer
    Statistical analysis description
    The primary outcome of this arm of this study was whether longitudinal change could be measured in xenon gas transfer (RBC:M), lung microstructure (LmD), lung ventilation (VDP) and lung perfusion (PBV, PBF and MTT) across the post Covid cohort. Changes in metrics with time were assessed using mixed-effect linear regression, which were set up using a random intercept model using IBM SPSS Statistics 27 (SPSS, New York, USA). Results were meta analysed as part of a national post-COVID study.
    Comparison groups
    HP Xe Imaging v HP Xe Imaging
    Number of subjects included in analysis
    16
    Analysis specification
    Pre-specified
    Analysis type
    		 other [4]
    P-value
    		 > 0.05 [5]
    Method
    		 Friedmans with bonferroni correction
    Parameter type
    		 Mean difference (final values)
    Point estimate
    2.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.6
         upper limit
    		 7.2
    Variability estimate
    Standard error of the mean
    Notes
    [4] - measure of lung ventilation
    [5] - compared with established range in previously studied normal volunteers (not part of this study)

    Primary: image quality from proton scans

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    End point title
    		 image quality from proton scans [6]
    End point description
    Abnormal ventilation determined using proton scanning protocol
    End point type
    Primary
    End point timeframe
    during scan
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Satisfactory images were obtained from all subjects to allow further analyses to be undertaken.
    End point values
    		 Cystic fibrosis Cystic fibrosis
    Number of subjects analysed
    12 [7]
    12 [8]
    Units: % abnormal ventilation
        number (not applicable)
    12
    12
    Notes
    [7] - Pre-scan
    [8] - Scan completion
    Statistical analysis title
    		 VOLVE
    Statistical analysis description
    ventilation measured using VOLVE protocol
    Comparison groups
    Cystic fibrosis v Cystic fibrosis
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 other [9]
    P-value
    		 > 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 VOLVE
    Point estimate
    0.44
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.36
         upper limit
    		 0.54
    Variability estimate
    Standard error of the mean
    Notes
    [9] - VOLVE analysis

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    Jan 1st 2020-Dec 31st 2023
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    hp Xe
    Reporting group description
    		 imaging with hp Xe

    Reporting group title
    proton imaging
    Reporting group description
    		 proton imaging in subjects with cystic fibrosis

    Serious adverse events
    		 hp Xe proton imaging
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 12 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 hp Xe proton imaging
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: As this was purely an imaging study no adverse events were seen.

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 Jun 2020
    1) Addition of a new cohort of patients (n=20) who have viral-induced lung disease due to previous covid-19 infection or other significant previous respiratory virus infection (e.g. influenza) 2) Aerosol generating procedures (namely: full lung function tests and lung clearance index) have been made optional, given the current covid-19 outbreak 3) The number of measurements performed at each study visit has been redefined as a minimum of one and maximum of four from the following: xenon MRI, oxygen-enhanced MRI, UTE MRI and lung clearance index) 4) Addition of an extra MRI scanning platform - 7 Tesla Philips Achieva MRI scanner (only used for adult participants)
    05 May 2021
    Addition of one additional calibration 129Xe scan per study visit (using a smaller volume of 129Xe than full dose scans) to help optimise image quality. Total dosing of hyperpolarized xenon now up to 2.1L (from 2L) compared to previous version of protocol. Test dose of non-hyperpolarized xenon only required for 1st study visit and protocol adjusted to reflect this
    13 Aug 2021
    1) Use of both natural abundance and isotopically enriched 129Xe for MRI scanning. a. Both the protocol (version 5.1) and investigator brochure (version 2.0) were updated to reflect the use of the two formulations of 129Xe b. The investigator brochure was also updated to accurately reflect manufacturing/batch release processes for both calibration and full doses of hyperpolarized 129Xe. 2) Addition to the protocol of sharing anonymised data with research teams at the University of Sheffield and University of Oxford. 3) Addition of dynamic contrast enhanced (DCE) lung MRI as an optional modality. 4) Altered timing of study visits

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    20 Mar 2020
    scanning suspended during Covid pandemic from March 2020-August 2020
    03 Aug 2020

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    data analysed then used as part of meta analysis with other centres as part of Xmas study (publication submitted)

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/38819593
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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