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    Clinical Trial Results:
    A Phase 3 randomised, double-blind, controlled trial of inhaled 7% hypertonic saline versus 0.9% isotonic saline for 48 weeks in patients with Cystic Fibrosis at 3-6 years of age in parallel with the North American SHIP clinical trial

    Summary
    EudraCT number
    2015-004143-39
    Trial protocol
    NL   BE   DK   FR   ES   IT  
    Global end of trial date
    22 Dec 2020

    Results information
    Results version number
    v1(current)
    This version publication date
    22 Sep 2022
    First version publication date
    22 Sep 2022
    Other versions
    Summary report(s)
    SHIP-CT publication

    Trial information

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    Trial identification
    Sponsor protocol code
    SHIP002
    Additional study identifiers
    ISRCTN number
    ISRCTN13083896
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    Toetsingonline: NL55240.078.15
    Sponsors
    Sponsor organisation name
    ErasmusMC
    Sponsor organisation address
    Wytemaweg, Rotterdam, Netherlands, 3015CN
    Public contact
    Program manager, Erasmus MC, 0031 010703668, j.vandeputtelaar@erasmusmc.nl
    Scientific contact
    Program manager, Erasmus MC, 0031 010703668, j.vandeputtelaar@erasmusmc.nl
    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
    29 Oct 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Dec 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Compare the difference in PRAGMA-CF total percent disease (%Dis) between HS and IS study arm at end of study (48 weeks), measured from standardized chest CT.
    Protection of trial subjects
    CT protocols used will be according to the As Low As Reasonably Achievable (ALARA) principle of radiation minimization in medical imaging. Thus, the lowest radiation dose will be used to obtain CTs of diagnostic quality for SHIP-CT outcomes. Based on the recent SCIFI project, we have acquired phantom scan data for a 5 year old patient that allows us to define for each participating centre the optimal balance between radiation dose and image quality. The median dose used by the SCIFI centres is in the order of 1 mGy for the TLC CT and 0.5 mGy for the FRC CT. The total dose for the FRC and TLC CT scans both at enrolment and end of study, depending on the type of scanner and software at the participating centre will be approximately 3 mGy. The risks related to this protocol are considered low [43, 44]. Some participating centres use biennial (Rotterdam, Leuven, Barcelona) or annual chest CT as part of routine annual clinical examination. Thus, for Rotterdam, Leuven, and Barcelona one extra CT will be added to the routine clinical protocol of biennial CTs. For. centres that do not use chest CT routinely, baseline and end of study CTs will be in addition to standard care. In order to minimize radiation exposure, patients should have had their last clinical chest CT at least 8 months prior to enrolment in the study, so that one of the scans will replace a routine CT scan. Each centre will have a recommended CT protocol from the Erasmus MC coordinating centre to optimally balance image quality against radiation dose. After the scan is made, key features of the protocol will be entered in the CRF by the sites. Images will be transferred to the LungAnalysis centre (as per the Study Manual) for the assessment of the protocol followed and to assess image quality. LungAnalysis will give feedback to the centres within 2 weeks following arrival of each CT.
    Background therapy
    Bronchodilator’s and delivery device: In order to minimize cough and bronchospasm associated with saline inhalation, participants will be pre-treated prior to each dose with a short-acting B2 bronchodilator, 2 puffs or as per local guidelines via metered dose inhaler via a valved holding chamber. In participants that do not tolerate the metered dose inhaler with spacer, a short-acting B2 bronchodilator may be delivered by nebulizer (distinct from the nebulizer used to administer study treatment).
    Evidence for comparator
    1.3. Results of the ISIS trial ISIS was a multicentre, randomised, double-blind, placebo-controlled trial conducted from 2009 to 2011 evaluating the efficacy and safety of 7% hypertonic saline versus isotonic saline (IS, control agent) inhaled twice daily for 48 weeks among children 4 to 60 months of age [7]. A total of 321 participants were enrolled at 30 sites in the United States and Canada. Enrolment was rapid, highlighting the enthusiasm for early intervention studies among providers and patients. There were no significant differences in the primary endpoint, pulmonary exacerbation rate, or any secondary clinical endpoints (height, weight, respiratory rate, oxygen saturation, cough, respiratory symptoms scores) between those randomised to HS vs IS. Seventy-three infants at 15 sites enrolled in a sub-study in which infant lung function tests were performed at the beginning and end of the treatment period. Among the 45 infants who had acceptable raised volume measurements at both visits, there was a significant difference between groups in the 48-week change in forced expiratory volume in 0.5 seconds: the mean change in FEV0.5 was 38 mL greater in the HS group compared to the IS group. In a second sub-study performed only in Toronto, MBW was performed at the beginning and end of the study in 27 participants; 25 (98%) had acceptable measurements at both time points. The change in LCI z-score over the treatment period was significantly greater in those randomised to HS vs. IS. Results of this study are detailed below. We hypothesize that the ISIS study failed to detect a treatment effect because the primary endpoint of pulmonary exacerbations was not sensitive to early, regional lung disease. The results of our two sub-studies, while preliminary and only hypothesis generating, suggest that HS may have an important effect on physiologic outcomes in these relatively asymptomatic young children. As stated in the editorial accompanying the ISIS publication [8
    Actual start date of recruitment
    01 Apr 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Belgium: 8
    Country: Number of subjects enrolled
    Denmark: 11
    Country: Number of subjects enrolled
    France: 12
    Country: Number of subjects enrolled
    Italy: 9
    Country: Number of subjects enrolled
    Australia: 11
    Country: Number of subjects enrolled
    United States: 37
    Country: Number of subjects enrolled
    Netherlands: 14
    Country: Number of subjects enrolled
    Spain: 14
    Worldwide total number of subjects
    116
    EEA total number of subjects
    68
    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)
    116
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    recruitment period: 6 oct 2016 until 6 january 2020

    Pre-assignment
    Screening details
    134 children screened for eligibility 2 ineligible or did not meet inclusion criteria: 1 acute respiratory infection; 1 already on hypertonic saline. 132 eligible for inclusion 4 did not complete enrolment visit: 1 withdrew consent; 1 reason for no enrolment visit unknown; 2 could not comply with CT training at screening and enrolment visit

    Period 1
    Period 1 title
    baseline period (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    • Access to the randomisation code will be strictly controlled. • Packaging and labeling of test and control treatments will be identical. • Only the following persons will have access to the blinded data: authorized CC personnel and the medical monitor. • The following perswill have access to the unblinded data: the PI of the CC, biostatistician and project manager of the CC, and members of the DSMB as appropriate.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    treatment group
    Arm description
    patients who received hypertonic saline
    Arm type
    Active comparator

    Investigational medicinal product name
    Hypertonic Saline
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for nebuliser solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Hypertonic/isotonic saline: Participants will be instructed to place 4 ml of study saline in the nebulizer and nebulize until sputtering or for 15 minutes, whichever occurs first. Any remaining, unused solution in the opened study drug vial will be discarded. Study drug will be inhaled twice daily, with pre- treatment prior to each dose with a short-acting beta2-agonist (B2) bronchodilator. Participants will be instructed to continue with study treatments until the final study visit.

    Arm title
    placebo group
    Arm description
    patients who received isotonic saline
    Arm type
    Placebo

    Investigational medicinal product name
    Isotonic saline
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for nebuliser solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Hypertonic/isotonic saline: Participants will be instructed to place 4 ml of study saline in the nebulizer and nebulize until sputtering or for 15 minutes, whichever occurs first. Any remaining, unused solution in the opened study drug vial will be discarded. Study drug will be inhaled twice daily, with pre- treatment prior to each dose with a short-acting beta2-agonist (B2) bronchodilator. Participants will be instructed to continue with study treatments until the final study visit.

    Number of subjects in period 1
    treatment group placebo group
    Started
    56
    60
    Completed
    49
    55
    Not completed
    7
    5
         perceived treatment as too great
    2
    -
         perceived treatment burden as too great
    -
    3
         intolerant of study drug
    2
    -
         Lost to follow-up
    3
    2

    Baseline characteristics

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    End points

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    End points reporting groups
    Reporting group title
    treatment group
    Reporting group description
    patients who received hypertonic saline

    Reporting group title
    placebo group
    Reporting group description
    patients who received isotonic saline

    Subject analysis set title
    Complete group
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    All subjects included in the study were analyzed according to the intention-to-treat method

    Primary: difference between groups int he percentage of total lung volume occupied by abnormal airways (PRAGMA-CF % disesase) measured by chest CT at 48 weeks.

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    End point title
    difference between groups int he percentage of total lung volume occupied by abnormal airways (PRAGMA-CF % disesase) measured by chest CT at 48 weeks.
    End point description
    End point type
    Primary
    End point timeframe
    Measured during the last study visit for each patient
    End point values
    treatment group placebo group Complete group
    Number of subjects analysed
    49
    55
    116
    Units: Percentage
        number (not applicable)
    49
    55
    116
    Statistical analysis title
    difference PRAGMA-CF
    Statistical analysis description
    The primary outcome, the difference between the treatment groups in PRAGMA-CF %Disease at 48 weeks, was investigated using a multiple linear regression model. We used %Disease at 48 weeks as the outcome and included treatment group, mean baseline %Disease value, and mean baseline age as the covariates in the model. The differences in %Bronchiectasis, %Trapped air, and LCI2·5 between the treatment groups at 48 weeks were assessed using the same approach. To assess change in LCI2·5 from
    Comparison groups
    placebo group v treatment group
    Number of subjects included in analysis
    104
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.05
    Method
    Regression, Linear
    Parameter type
    Mean difference (final values)
    Point estimate
    0.67
    Confidence interval
         level
    95%
         sides
    1-sided
         lower limit
    -
         upper limit
    1.08

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    collected during the study
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    1.0
    Reporting groups
    Reporting group title
    placebo group
    Reporting group description
    subject who received placebo during the study.

    Reporting group title
    treatment group
    Reporting group description
    all study participants who received hypertonic saline during the study

    Serious adverse events
    placebo group treatment group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    11 / 60 (18.33%)
    13 / 56 (23.21%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Respiratory, thoracic and mediastinal disorders
    pulmonary exacerbation
         subjects affected / exposed
    5 / 60 (8.33%)
    5 / 56 (8.93%)
         occurrences causally related to treatment / all
    5 / 5
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    cough
         subjects affected / exposed
    3 / 60 (5.00%)
    3 / 56 (5.36%)
         occurrences causally related to treatment / all
    6 / 6
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    nasal congestion
         subjects affected / exposed
    2 / 60 (3.33%)
    0 / 56 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    otitis / otitis media
         subjects affected / exposed
    2 / 60 (3.33%)
    0 / 56 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    2 / 60 (3.33%)
    0 / 56 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    infection - pseudomonas
         subjects affected / exposed
    3 / 60 (5.00%)
    0 / 56 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    placebo group treatment group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    48 / 60 (80.00%)
    42 / 56 (75.00%)
    Respiratory, thoracic and mediastinal disorders
    rhinorrhea
         subjects affected / exposed
    20 / 60 (33.33%)
    17 / 56 (30.36%)
         occurrences all number
    45
    38
    common cold or flu-like
         subjects affected / exposed
    11 / 60 (18.33%)
    10 / 56 (17.86%)
         occurrences all number
    15
    25
    General disorders and administration site conditions
    nasal congestion
         subjects affected / exposed
    25 / 60 (41.67%)
    25 / 56 (44.64%)
         occurrences all number
    63
    46
    Infections and infestations
    Fever
         subjects affected / exposed
    32 / 60 (53.33%)
    23 / 56 (41.07%)
         occurrences all number
    50
    48

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    the comparator IS might also have some effects on mucociliary clearance. use of chest CT as an outcome measure exposes the participants to ionising radiation. underestimated the volume of trapped air as exp scans were acquiredat FRC and not at RV
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