proof of concept study of rilzabrutinib in adult participants with moderate-to-severe asthma

Conditions: Asthma

Summary: this is a parallel, treatment, phase 2, double-blind, 2 arm, 12-week proof of concept (poc) study with 2 staggered cohorts (2 arms in each cohort) that is designed to assess the efficacy, safety, and tolerability of rilzabrutinib in adult participants (aged 18-70 years) with moderate-to-severe asthma who are not well controlled on ics/laba therapy. study treatment includes investigational medicinal product (imp) (rilzabrutinib or placebo) added-on to a background therapy of ics/laba (fluticasone/salmeterol \[non-investigational medicinal product\], standardized at screening). background therapy of ics/laba will be withdrawn during the 12week randomized treatment period and resumed at the end of the imp treatment period, as outlined below: * screening period (4 weeks) * randomized imp treatment period (12 weeks ± 3 days) * background therapy stabilization phase (4 weeks) * background therapy withdrawal phase (4-5 weeks) * no background therapy phase (3-4 weeks) * post imp treatment safety follow-up period (4 weeks ± 3 days)

the total study duration per participant is expected to be up to 20 weeks: up to 4 weeks screening, 12 weeks on-treatment double-blind period, and 4-week post-imp treatment follow up.

Eligibility criteria:
inclusion criteria: * a physician diagnosis of asthma for at least 12 months based on the global initiative for asthma (gina) 2018,2019, 2020 guidelines. * participants with existing treatment with at least moderate to high doses of ics therapy in combination with a laba as second controller for at least 3 months with a stable dose ≥1 month prior to visit 1. * participants with prebronchodilator fev1 \>40% of predicted normal at visit 1/screening. prebronchodilator fev1 ≥50% of predicted normal at visit 2/baseline. * participants with reversibility of at least 12% and 200 ml in fev1 15 to 30 minutes after administration of 2 to 4 puffs (200-400 mcg) of albuterol/salbutamol or levalbuterol/levosalbutamol during screening or documented history of a reversibility test that meets this criterion within 5 years prior to visit 1 or documented positive response to methacholine challenge (a decrease in fev by 20% \[pc20\] of \<8mg/ml) within 5 years prior to visit 1/screening is considered acceptable to meet this inclusion criterion. * participants must have experienced, within 2 years prior to visit 1, any of the following asthma exacerbation events at least once: treatment with a systemic steroid (oral or parenteral) for worsening asthma or hospitalization or emergency medical care visit for worsening asthma. * body mass index (bmi) ≥17.5 and ≤40 kg/m2 * all contraceptive use by men and women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. * participants must have completed covid-19 vaccination per current regional health authority recommendations prior to screening. exclusion criteria: * history of serious infections requiring intravenous therapy with the potential for recurrence (as judged by site investigator), with less than 4 weeks interval between resolution of serious infection and first dose of study drug, or currently active moderate-to-severe infection at screening (grade 2 or higher). * chronic lung disease (for example, chronic obstructive pulmonary disease \[copd\], or idiopathic pulmonary fibrosis \[ipf\]) which may impair lung function, or another diagnosed pulmonary or systemic disease associated with elevated peripheral eosinophil counts, for e.g. eosinophilic granulomatosis with polyangiitis. * history of life-threatening asthma (i.e., severe exacerbation that requires intubation). * participants with any of the following events within the 4 weeks prior to their screening visit 1 or during the screening period: treatment with 1 or more systemic (oral and/or parenteral) steroid bursts for worsening asthma or hospitalization or emergency medical care visit for worsening asthma * asthma control questionnaire 5-question version (acq-5) score \ 3.0 at v2/randomization. during the screening period an acq-5 of up to ≤4 is acceptable. * current smoker or cessation of smoking within the 6 months prior to visit 1. * previous smoker with a smoking history \>10 pack-years. * current or chronic history of liver disease. * known hepatic or biliary abnormalities, e.g. moderate or severe hepatic impairment, such as child pugh b or c * symptomatic herpes zoster within 3 months prior to screening. * refractory nausea and vomiting, malabsorption, external biliary shunt, or significant bowel resection that would preclude adequate rilzabrutinib/placebo absorption. * conditions that may predispose the participant to excessive bleeding * history of solid organ transplant. * a history of malignancy of any type within 5 years before day 1, other than surgically excised non-melanoma skin cancers or in situ cervical cancer. * is not up-to-date with recommended vaccinations per local guidelines. * anti-immunoglobulin e (ige) therapy (e.g., omalizumab \[xolair®\]) within 130 days prior to visit 1 or any other biologic therapy (including anti-il4/4r or il-5/5r monoclonal antibodies \[mab\]) or systemic immunosuppressant (e.g., methotrexate) to treat inflammatory disease or autoimmune disease (e.g., rheumatoid arthritis, inflammatory bowel disease, primary biliary cirrhosis, systemic lupus erythematosus, multiple sclerosis) and other diseases, within 2 months or 5 half-lives prior to visit 1, whichever is longer. * use of inhalers other than icss, labas, and short-acting beta agonists (no long-acting muscarinic antagonists (lamas) or mucolytics) and leukotriene receptor antagonists (montelukast, zafirkulast) during the study period. * participants who have received bronchial thermoplasty within 2 years prior to visit 1 or plan to begin therapy during the screening period or the randomized treatment period. * use of proton pump inhibitor drugs such as omeprazole and esomeprazole within 3 days of day 1. * use of known systemic strong-to-moderate inducers or inhibitors of cyp3a within 14 days or 5 half-lives (whichever is longer) of study day 1 and until the end of the active treatment period. * live vaccine except bacille calmette guerinn-vaccination within 28 days prior to day 1 or plans to receive one during the trial; calmette guerin-vaccination within 12 months prior to screening. * covid-19 vaccine within 14 days prior to study day 1. * previous use of a bruton tyrosine kinase (btk) inhibitor. * has received any investigational drug (or is currently using an investigational device) within the 30 days before day 1, or at least 5 times the respective elimination half-life time (whichever is longer). * electrocardiogram (ecg) findings of qt corrected for heart rate (qtc) \>450 msec (males) or \>470 msec (females), poorly controlled atrial fibrillation (i.e., symptomatic patients or a ventricular rate above 100 beats/min on ecg), or other clinically significant cardiovascular abnormalities. * active covid-19 infection as documented by a positive covid-19 molecular test. the above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.