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 (seesupplementary 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 AUC0–2h and LAR AUC3–7h), maximum percentage decrease in FEV1 (EAR% and LAR%) and minimum FEV1 (EARmin and LARmin).
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 Pizzichini et al. [23 (link)].
Fractional exhaled nitric oxide (FENO) 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) FENO 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.
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
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 P
Fractional exhaled nitric oxide (FENO) 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) FENO 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.
