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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
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

SHIP002

ISRCTN number

ISRCTN13083896

US NCT number

WHO universal trial number (UTN)

Other trial identifiers

Toetsingonline: NL55240.078.15

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

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

29 Oct 2021

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

22 Dec 2020

Was the trial ended prematurely?

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

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country