1: Compare the differences in the PRAGMA-CF score: the volume proportion of the lung with structural airways disease (%Dis), measured from chest CT images at 48 weeks between treatment arms 2: Compare the differences in PRAGMA-CF subscores: the…
ID
Source
Brief title
Condition
- Congenital and hereditary disorders NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The difference in PRAGMA-CF %Dis between HS and IS study arm at end of study
(48 weeks), measured from standardized chest CT.
Secondary outcome
Longitudinal change in airway disease (%Dis), bronchiectasis (%Bx) trapped air
(%TA), and airway dimensions, as well as the proportion of patients with
bronchiectasis progression established by %BX and AA-system, airway wall
thickness established by the AA-system, from baseline to end of study as
established by PRAGMA-CF and the AA-system, on chest CTs*
Longitudinal change in LCI from baseline to 48 weeks measured by N2 MBW
Protocol defined pulmonary exacerbation rate
Health-related quality of life as measured by the modified parent-reported
CFQ-R for preschoolers (excluding European sites)
Background summary
There is growing interest in early initiation of therapies to prevent or delay
the progression of lung disease in cystic fibrosis (CF). Absence of functional
CF transmembrane regulator (CFTR) in the airway epithelium results in depletion
of water from the airway surface and impaired mucociliary clearance, leading to
a favourable environment for chronic infection and inflammation. Thus,
restoration of salt and water balance in the airways of patients with CF is the
goal of many therapeutic strategies. Ivacaftor, a CFTR potentiator, has
demonstrated substantial efficacy, but targets specific gating mutations that
only affect ~4% of patients with CF worldwide. Other mutation-specific CFTR
modulators are being developed, but it may be years before these therapeutics
are available to the youngest patients with CF. In the meantime, inhaled 7%
hypertonic saline (HS) is an attractive agent to ameliorate airway surface
liquid tonicity and improve mucociliary clearance.
Cystic Fibrosis Foundation Therapeutics (CFFT) and the National Institute of
Health recently sponsored a randomised, controlled trial of HS (active agent)
vs. 0.9% isotonic saline (IS, control agent) in patients with CF <6 years of
age (the Infant Study of Inhaled Saline (ISIS) trial). There was no significant
difference in the primary endpoint, pulmonary exacerbation rate, over the
48-week treatment period. However, there was evidence of possible treatment
effects in two smaller sub-studies that assessed physiologic measures. In a
subgroup of 45 participants <17 months of age at baseline, the change in the
forced expiratory volume in 0.5 seconds (FEV0.5) measured by infant pulmonary
function testing was significantly greater in those randomised to HS than IS.
The second study assessed ventilation inhomogeneity measured by multiple breath
washout (MBW). MBW has been shown to be highly feasible in young children, and
its main endpoint, the lung clearance index (LCI), has been shown to be
sensitive to detecting early lung disease and identifying response to treatment
in CF. In a subgroup of 25 Toronto participants in the ISIS trial, the change
in LCI over the 48-week treatment period was significantly greater in those
randomised to HS than IS. In a previous study, the Toronto group had also
demonstrated a significant treatment effect of HS on LCI in school-age children
with CF who had normal spirometry. Given its feasibility, sensitivity and
non-invasive nature as well as the recent ISIS findings, LCI is a promising
endpoint to assess treatment response in young children with CF, however, it is
unclear whether LCI is sensitive enough to reflect relevant structural changes
of CF lung disease.
Several observational studies have shown that CF patients* *6 years of age have
clinically silent airway damage. A plausible explanation for the lack of an
observed treatment effect in the ISIS study is that the pulmonary exacerbation
endpoint was not sensitive enough to detect early, regional lung disease in
these outwardly healthy children. Given the positive trends observed for FEV0.5
and LCI in the two ISIS sub-studies, physiologic measures rather than clinical
endpoints may be more suitable to detect treatment effects in young children.
LCI measurements in preschool children have a higher success rate and greater
sensitivity than spirometry, and commercial equipment that can be used in a
multi-centre trial is now available.
The primary hypothesis of the SHIP study (SHIP001) which runs in North America,
is that compared to IS, HS will improve the LCI, a measure of ventilation
heterogeneity, during the 48 week treatment period among preschool children
with CF. The SHIP-CT study will use a near identical study design as the SHIP
study, with similar eligibility criteria and treatment arms, to determine
whether HS reduces structural lung disease as measured by chest computed
tomography (CT), in addition to stabilizing or improving functional outcomes as
measured by LCI. Thus, we aim to conduct a randomised, double-blind, controlled
trial of inhaled HS vs. IS for 48 weeks in patients with CF 3-6 years of age in
parallel with the North American SHIP clinical trial.
In SHIP-CT, we will evaluate treatment effects of HS relative to IS on measures
of structural lung disease obtained from chest computed tomography (CT) using a
novel scoring system sensitive to early lung changes, the Perth-Rotterdam
Annotated Grid Morphometric Analysis method for CF (PRAGMA-CF), that quantifies
the volume percentage of diseased airways (%Dis), bronchiectasis (%Bx), and
trapped air (%TA). As a secondary evaluation of structural airway damage, we
will use an image analysis system to measure airway dimensions relative to
adjacent arteries (AA-system). Longitudinal changes in CT measures will also be
compared to changes in lung function measured by LCI and to clinical outcomes.
Our primary hypothesis is that HS will reduce structural lung disease as
assessed by the PRAGMA-CF computed tomography score relative to IS during the
48 week treatment period.
Study objective
1: Compare the differences in the PRAGMA-CF score: the volume proportion of the
lung with structural airways disease (%Dis), measured from chest CT images at
48 weeks between treatment arms
2: Compare the differences in PRAGMA-CF subscores: the volume proportions of
the lung with bronchiectasis (%Bx) and trapped air (%TA), as well as airway
dimensions measured from chest CT images at 48 weeks between treatment arms
3: Compare the change in LCI, measured by N2 MBW, from baseline to 48 weeks
between treatment arms.
4: Elucidate the longitudinal relationships between measures of structural lung
disease evaluated by chest CT (PRAGMA-CF (%Dis, %Bx, %TA) and airway
dimensions), LCI measured by multiple breath washout and clinical outcomes
(pulmonary exacerbations, health-related quality of life) over the 48-week
treatment period.
Study design
Multicentre, randomised, double-blind, controlled, parallel group trial
Intervention
Participants will be randomised 1:1 to receive 4 ml 7% HS (treatment arm) vs.
4 ml 0.9% IS (control arm) administered twice daily via jet nebulizer for 48
weeks.
Study burden and risks
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 enrollment and end of study, depending on the type of scanner and
software at the participating centre will be 2 mSv. The risks related to this
protocol are considered low [43, 44].
Some participating centres use biennial (Rotterdam, Leuven, Barcelona) or
annual (Perth, Melbourne) 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 Perth and Melbourne
no extra CTs will be needed. For the other 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 enrollment in the study, so that
one of the scans will replace a routine CT scan. To allow centres to optimally
time the first study CT in relation to the last routine CT, a specified number
of patients will be allocated to each centre and 18 months is allowed for
enrolment.
Each centre will have a recommended CT protocol from the ErasmusMC 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.
Wytemaweg 80
Rotterdam 3015 CN
NL
Wytemaweg 80
Rotterdam 3015 CN
NL
Listed location countries
Age
Inclusion criteria
Diagnosis of CF as evidenced by one or more clinical feature consistent with the CF phenotype or positive CF newborn screen AND one or more of the following criteria: a) A documented sweat chloride * 60 mEq/L by quantitative pilocarpineiontophoresis (QPIT) b) A documented genotype with two disease-causing mutations in the CFTR gene ;Informed consent by parent or legal guardian;Age * 36 months and *72 months at Screening visit ;Ability to comply with medication use, study visits and study procedures as judged by the site investigator;***Ability to execute a technician controlled or spirometer controlled chest CT scan***????
Exclusion criteria
Chest CT within 8 months prior to the Screening visit;Acute intercurrent respiratory infection, defined as an increase in cough, wheezing, or respiratory rate with onset within 3 weeks preceding Screening or Enrolment visit;Acute wheezing at Screening or Enrollment visit ;Oxygen saturation < 95% (<90% at centres above 4000 feet elevation) at Screening or Enrollment visit ;Other major organ dysfunction, excluding pancreatic dysfunction;Physical findings that would compromise the safety of the participant or the quality of the study data as determined by site investigator;Investigational drug use within 30 days prior to Screening or Enrolment visit;Treatment with inhaled hypertonic saline at any concentration within 30 days prior to Screening or Enrolment visit;Start of any additional inhaled saline solution at any concentration, or other hydrating agent such as mannitol or mucolytic drug such as dornase alpha within 30 days prior or following the Screening or Enrollment visit;Chronic lung disease not related to CF ;Inability to tolerate first dose of study treatment at the Enrolment visit
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2015-004143-39-NL |
| CCMO | NL55240.078.15 |