Forced Vital Capacity

Sixty-two experienced centres (managing at least 40 SSc patients) from 18 countries in North America, Europe and Asia participated in the study between 2008 and 2011. Patients aged ≥18 years with a diagnosis of SSc (American College of Rheumatology criteria,18 (link) including patients with other connective tissue diseases who met these criteria) of >3 years’ duration from first non-Raynaud's symptom and a predicted DLCO of <60% (to enrich for a higher likelihood of PAH), were included. Patients were excluded if they had pulmonary hypertension (PH) confirmed by RHC prior to enrolment, were receiving recognised advanced PH therapy, had a forced vital capacity (FVC) <40% of predicted, renal insufficiency, previous evidence of clinically relevant left heart disease, or were pregnant.
Patients were classified as either non-PH, or WHO group 1 PH (PAH), WHO group 2 PH (PH due to left heart disease), or WHO group 3 PH (PH due to lung disease/hypoxia), according to current guidelines.10
19 WHO group 3 definition was based on Study Scientific Committee consensus applying a conservative interpretation of the literature to minimise misclassification of patients with evident lung disease as PAH. Classification definitions are summarised in figure 1.

Ecleralimab is formulated as a PulmoSol engineered powder in hard capsules and delivered to the lungs via a Breezhaler dry powder inhaler device, all provided by Novartis (Basel, Switzerland). Based on clinical and nonclinical safety data, a starting dose of 4 mg administered once daily for 12 weeks was expected to provide adequate pulmonary exposure to assess pharmacodynamic effects against allergen-induced airway responses. Each randomised subject received a single inhaled dose of ecleralimab or placebo on day 1 at the investigational site. Subsequent daily dosing began on day 3 provided no safety concerns were identified in the 48 h following the initial dose. Dosing was self-administered during the morning at home or at the study site during scheduled visits up to and including day 84. MIC and AIC testing commenced at least 1 h after dosing. Compliance to study treatment was recorded by the subject in a diary and assessed at each visit using blister pack counts and the diary.
13 visits were scheduled during the 12-week treatment period, including two allergen challenge triads (MIC–AIC–MIC) at days 41–43 and days 83–85. Safety, pharmacokinetics and pharmacodynamics assessments were also performed. To enter the treatment period, subjects needed to demonstrate return to baseline with FEV₁ ≥70% predicted, and FEV₁ and forced vital capacity were to be within 10% and the methacholine PC₂₀ not more than 1 doubling concentration lower than the values measured at day −15 during screening.
MIC was conducted during screening (to qualify subjects for the study), pre-treatment on day 1, and 24 h pre-AIC and 24 h post-AIC, as previously described [21 (link)], until a 20% decrease in FEV₁ occurred. The methacholine PC₂₀ was calculated from the log concentration versus response curve.
AIC was conducted during screening and again at day 42 and day 84 as previously reported (see supplementary material) [22 (link)]. At screening, doubling concentrations of commercially available aero-allergen extracts (table 1) were inhaled at 12-min intervals until a ≥20% decrease in FEV₁ was reached. FEV₁ was then measured at regular intervals for 7 h to identify subjects with positive LAR. Allergen concentrations administered on days 42 and 84 were the same as those administered at screening. EAR and LAR were reported as time-adjusted area of percentage decrease in FEV₁ (EAR AUC_0–2h and LAR AUC_3–7h), maximum percentage decrease in FEV₁ (EAR% and LAR%) and minimum FEV₁ (EAR_min and LAR_min).
Sputum was induced before the start of treatment on day 1, and during each allergen challenge triad at 24 h pre-allergen and at 7 and 24 h post-allergen, and processed using a method modified from Pizzichiniet al. [23 (link)].
Fractional exhaled nitric oxide (F_ENO) was sampled before each MIC, beginning on day −1 and also at 7 h post-allergen (prior to 7 h spirometry), using a Niox VERO (Aerocrine, Stockholm, Sweden) F_ENO testing device. Peripheral blood eosinophils were also assessed.
Safety assessments included physical examinations, systems review, open-ended health inquiry, ECGs, vital signs, haematology, blood chemistry, urinalysis, and monitoring of adverse events (AEs) and serious AEs (SAEs). Subjects completed an end-of-treatment period visit on day 85 and entered a 4-week follow-up period.

This was a longitudinal prospective pilot study including CF children aged
between 6 and 15 years and attending the pediatric CF center of the Brussels
Free University, Belgium. The patients were included during a period of 2 months
on the occasion of their follow-up visit. The patients with a medical
contraindication to practice a sport, including hypoxemia, post-pneumothorax
status severe, hemoptysis, or osteoarticular abnormalities, were excluded from
participation. The study was integrated into the regular patient follow-up,
scheduled to take place every 6 weeks, which included 3 follow-up visits. The
first consisted of a routine visit to explain the project. Following the signing
of patient or parental informed consent forms, the second visit was performed at
starting the practice of sport (T0), and the third took place
at month 6. The body mass index (BMI) and spirometric values, including forced
expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and 25% to
75% forced expiratory flow (FEF) were collected, along with the duration of
extracurricular PA (hours/week). Data were expressed as
z-scores based on GLI-2012 reference.^{10 (link)} An incremental shuttle
test (IST) was performed at T0 and month 6 in order to assess
maximum oxygen uptake (VO2max). A variety of tests was applied to evaluate the
children’s physical status. Cardiopulmonary exercise testing (CPET) is
considered the gold standard, yet it requires expensive equipment and
specialized personnel.^{3 (link),11 (link)} Therefore, IST may be a good alternative, given that it is
simple, inexpensive, and reliable.^{6 (link),12 (link)} In this study, we
performed a 15 m IST, conducted in an enclosed corridor on a flat 15 m-long
course. Patients were instructed to run around 2 cones following the rhythm
dictated by the audio signal. Subjects had to run at the prompting of a sound at
regular intervals, to reach the next pole before the next sound goes on. The
15 m IST has 17 levels. Each level includes an increasing number of shuttles and
the speed therefore increases as the level advances. The 15 m test begins with a
running speed above 7.71 km/hour at Level 1 and ends with a speed of 12 km/hour
at Level 17. The end of the test is determined by the patient, when he/she
becomes unable to maintain the required speed, or by the experimenter if the
patient fails to complete a shuttle during the time allowed. Different
parameters (oxygen saturation, heart rate, and respiratory rate) are documented
before, just after, and 3 minutes later the beginning of the test. This test
evaluates aerobic fitness in a maximal effort. A correlation between the test
performance and VO2max can be extrapolated and permits to evaluate the
cardiorespiratory status of the patients. We estimated the VO2max using the
Matsuzaka equation^{13 (link)}:

VO2max
(mL/minutes/kg) = (25.9 − 2.21 × G) − 0.0449 × A − 0.831 × Y + 4.12 × MS;
G = 0 for boys and G = 1 for girls; A = age in years; Y = BMI; and
MS = maximum speed.

To evaluate the project’s effects on nutritional and functional parameters, the
patients were classified into 2 groups depending on the PA increases: a first
group without change (PA−) and second group with a minimum increase of
1 hour/week (PA+).