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
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EudraCT number |
2015-004143-39 |
Trial protocol |
NL BE DK FR ES IT |
Global end of trial date |
22 Dec 2020
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Results information
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Results version number |
v1(current) |
This version publication date |
22 Sep 2022
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First version publication date |
22 Sep 2022
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Other versions |
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Summary report(s) |
SHIP-CT publication |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
SHIP002
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Additional study identifiers
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ISRCTN number |
ISRCTN13083896 | ||
US NCT number |
- | ||
WHO universal trial number (UTN) |
- | ||
Other trial identifiers |
Toetsingonline: NL55240.078.15 | ||
Sponsors
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Sponsor organisation name |
ErasmusMC
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Sponsor organisation address |
Wytemaweg, Rotterdam, Netherlands, 3015CN
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Public contact |
Program manager, Erasmus MC, 0031 010703668, j.vandeputtelaar@erasmusmc.nl
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Scientific contact |
Program manager, Erasmus MC, 0031 010703668, j.vandeputtelaar@erasmusmc.nl
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
29 Oct 2021
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
22 Dec 2020
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Was the trial ended prematurely? |
No
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General information about the trial
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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.
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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.
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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
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Netherlands: 14
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Country: Number of subjects enrolled |
Spain: 14
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Country: Number of subjects enrolled |
Belgium: 8
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Country: Number of subjects enrolled |
Denmark: 11
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Country: Number of subjects enrolled |
France: 12
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Country: Number of subjects enrolled |
Italy: 9
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Country: Number of subjects enrolled |
Australia: 11
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Country: Number of subjects enrolled |
United States: 37
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Worldwide total number of subjects |
116
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EEA total number of subjects |
68
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
116
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
0
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
recruitment period: 6 oct 2016 until 6 january 2020 | ||||||||||||||||||||||||
Pre-assignment
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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
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Period 1 title |
baseline period (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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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.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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treatment group | ||||||||||||||||||||||||
Arm description |
patients who received hypertonic saline | ||||||||||||||||||||||||
Arm type |
Active comparator | ||||||||||||||||||||||||
Investigational medicinal product name |
Hypertonic Saline
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Concentrate for nebuliser solution
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Routes of administration |
Inhalation use
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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.
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Arm title
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placebo group | ||||||||||||||||||||||||
Arm description |
patients who received isotonic saline | ||||||||||||||||||||||||
Arm type |
Placebo | ||||||||||||||||||||||||
Investigational medicinal product name |
Isotonic saline
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Concentrate for nebuliser solution
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Routes of administration |
Inhalation use
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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.
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End points reporting groups
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Reporting group title |
treatment group
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Reporting group description |
patients who received hypertonic saline | ||
Reporting group title |
placebo group
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Reporting group description |
patients who received isotonic saline | ||
Subject analysis set title |
Complete group
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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
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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 |
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End point type |
Primary
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End point timeframe |
Measured during the last study visit for each patient
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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
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Comparison groups |
placebo group v treatment group
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Number of subjects included in analysis |
104
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Analysis specification |
Pre-specified
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Analysis type |
other | ||||||||||||||||
P-value |
< 0.05 | ||||||||||||||||
Method |
Regression, Linear | ||||||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||||||
Point estimate |
0.67
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Confidence interval |
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level |
95% | ||||||||||||||||
sides |
1-sided
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lower limit |
- | ||||||||||||||||
upper limit |
1.08 |
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Adverse events information
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Timeframe for reporting adverse events |
collected during the study
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
1.0
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Reporting groups
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Reporting group title |
placebo group
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Reporting group description |
subject who received placebo during the study. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
treatment group
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Reporting group description |
all study participants who received hypertonic saline during the study | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? No | |||
Interruptions (globally) |
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Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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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 |