E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | SOC |
E.1.2 | Classification code | 10038738 |
E.1.2 | Term | Respiratory, thoracic and mediastinal disorders |
E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
• Evaluate the effects of rilzabrutinib compared to placebo on reducing the incidence of “loss of asthma control” (LOAC) events |
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E.2.2 | Secondary objectives of the trial |
• Evaluate the effects of rilzabrutinib compared to placebo on lung function as measured by FEV1 • Assess the effects of rilzabrutinib on other elements of spirometric lung function • Assess the effect of rilzabrutinib on patient reported outcomes • Assess the effects of rilzabrutinib on asthma symptoms • Assess the plasma pharmacokinetic (PK) of rilzabrutinib in participants with asthma • Assess the safety of rilzabrutinib in participants with asthma • Assess the effects of rilzabrutinib on use of bronchodilator therapy
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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 criteria 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. |
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E.4 | Principal 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 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. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Proportion of participants with an LOAC event during the treatment period ; Loss of Asthma Control (LOAC) event is defined as any of the following: - A 30% or greater reduction from baseline in morning 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
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
1 - Pre-bronchodilator FEV1 (Forced expiratory volume in one second) change from baseline to EOT (end of treatment) 2 - Post-bronchodilator FEV1 change from baseline to EOT 3 - The absolute change in the percent predicted FEV1 from baseline to EOT (pre- and post-bronchodilator) 4 - Change from baseline in pre- and post-bronchodilator FEV1 and other lung function measurements at each spirometry endpoint ; Other lung function measure includes peak expiratory flow [PEF], forced vital capacity [FVC], and forced expiratory flow [FEF] 25-75%) 5 - Asthma Control Questionnaire-5 (ACQ-5) score change from baseline at EOT and at each assessment time point ; 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. 6 - Asthma Quality of Life Questionnaire with Standardized Activities (AQLQ[S]) Self-administered score change from baseline at EOT and at each assessment time point ; 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. 7 - Change in Asthma Daytime Symptom Diary (ADSD) and Asthma Nighttime Symptom Diary (ANSD) scores from baseline to EOT and each week ; 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 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. 8 - Plasma PK concentrations of rilzabrutinib in participants with asthma 9 - Participants with Treatment Emergent Adverse Events 10 - Change in numbers of inhalations/day of albuterol or levalbuterol for symptom relief from baseline to EOT and each week |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1, 2, 3 - From baseline to Week 12 4 ,5, 6, 7 - From baseline until Week 12 8, 9 - Until Week 16 10 - From baseline until Week 12 |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 8 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 20 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Argentina |
Chile |
Ukraine |
Canada |
Korea, Republic of |
Mexico |
Russian Federation |
United Kingdom |
Bulgaria |
Hungary |
Poland |
Romania |
Spain |
Türkiye |
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E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | |
E.8.9.1 | In the Member State concerned months | 25 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial months | 25 |