Asthma
Conditions
Brief 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 Background therapy of ICS/LABA will be withdrawn during the 12week randomized treatment period and resumed at the end of the IMP treatment period, as outlined below: * Screening period (4 weeks) * Randomized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)
Detailed description
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.
Interventions
DRUGRilzabrutinib
Pharmaceutical form: Tablet Route of administration: Oral
DRUGplacebo
Pharmaceutical form: Tablet Route of administration: Oral
Sponsors
Sanofi
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
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 \<1.25 or \>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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of participants with an LOAC event during the treatment period | Until Week 12 | Loss of Asthma Control (LOAC) event is defined as any of the following: * A 30% or greater reduction from baseline in morning peak expiratory flow (PEF) on 2 consecutive days * ≥6 additional reliever puffs of salbutamol/albuterol or levosalbutamol/levalbuterol in a 24-hour period (compared to baseline) on 2 consecutive days * Increase in ICS ≥4 times the last prescribed ICS dose (or ≥50% of the prescribed ICS dose at V2 if background therapy withdrawal completed) * Requiring use of systemic (oral and/or parenteral) steroid treatment * Requiring hospitalization or emergency room visit for asthma exacerbation |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Post-bronchodilator FEV1 change from baseline to EOT | From baseline to Week 12 | — |
| The absolute change in the percent predicted FEV1 from baseline to EOT (pre- and post-bronchodilator) | From baseline to Week 12 | — |
| Change from baseline in pre- and post-bronchodilator FEV1 and forced vital capacity [FVC] at each spirometry endpoint | From baseline until Week 12 | — |
| Change from baseline in peak expiratory flow [PEF] and forced expiratory flow [FEF] 25-75% at each spirometry endpoint | From baseline until Week 12 | — |
| Asthma Control Questionnaire-5 (ACQ-5) score change from baseline at EOT and at each assessment time point | From baseline until Week 12 | The ACQ-5 is a questionnaire that measures the adequacy of asthma control and any changes in asthma control that may occur spontaneously or as a result of treatment. The ACQ-5 has five questions on the asthma symptoms and patients are asked to recall how their asthma has been during the previous week and to respond on a 7-point scale for each question (0 = no impairment, 6 = maximum impairment). The ACQ-5 score is the mean of the 5 questions and, therefore, between 0 (totally controlled) and 6 (severely uncontrolled). A high score indicates low asthma control. |
| Pre-bronchodilator FEV1 (Forced expiratory volume in one second) change from baseline to EOT (end of treatment) | From baseline to Week 12 | — |
| Change in Asthma Daytime Symptom Diary (ADSD) and Asthma Nighttime Symptom Diary (ANSD) scores from baseline to EOT and each week | From baseline until Week 12 | ADSD and ANSD assess asthma severity based on patient self-report of asthma core symptoms, i.e., difficulty of breathing; wheezing; shortness of breath; chest tightness; chest pain; and cough. Both the ADSD and ANSD are composed of 6 items rated using an 11-point numerical rating scale (NRS) that ranges from 0 = None to 10 = As bad as you can imagine. The participants will record their daytime and nighttime asthma symptoms in an electronic diary, once in the evening and once in the morning, respectively. |
| Plasma pharmacokinetic (PK) concentrations of rilzabrutinib in participants with asthma | Until Week 16 | — |
| Participants with Treatment Emergent Adverse Events | Until Week 16 | — |
| Change in numbers of inhalations/day of albuterol or levalbuterol for symptom relief from baseline to EOT and each week | From baseline until Week 12 | — |
| Asthma Quality of Life Questionnaire with Standardized Activities (AQLQ[S]) Self-administered score change from baseline at EOT and at each assessment time point | From baseline until Week 12 | The AQLQ(S) was designed as a self-administered patient reported outcome to measure the functional impairments that are most troublesome to adolescents and adults ≥12 years of age as a result of their asthma. The instrument is comprised of 32 items, each rated on a 7-point Likert scales from 1 to 7. Higher scores indicate better quality of life. |
Countries
Argentina, Bulgaria, Canada, Chile, Germany, Hungary, Mexico, Poland, Romania, South Korea, Spain, Turkey (Türkiye), United Kingdom
Outcome results
None listed