Proof of Concept Study of Rilzabrutinib in Adult Participants With Moderate-to-severe Asthma
Study Details
Study Description
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 inhaled 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 Background therapy of ICS/LABA will be withdrawn during the 12week randomized treatment period and resumed at the end of the IMP treatment period, as outlined below:
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Screening period (4 weeks)
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Randomized IMP treatment period (12 weeks ± 3 days)
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Background therapy stabilization phase (4 weeks)
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Background therapy withdrawal phase (4-5 weeks)
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No background therapy phase (3-4 weeks)
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Post IMP treatment safety follow-up period (4 weeks ± 3 days)
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2 |
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.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Rilzabrutinib Rilzabrutinib BID or TID and ICS/LABA |
Drug: Rilzabrutinib
Pharmaceutical form: Tablet Route of administration: Oral
Other Names:
|
| Placebo Comparator: Placebo Placebo and ICS/LABA |
Drug: placebo
Pharmaceutical form: Tablet Route of administration: Oral
|
Outcome Measures
Primary Outcome Measures
- 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 Outcome Measures
- Pre-bronchodilator FEV1 (Forced expiratory volume in one second) change from baseline to EOT (end of treatment) [From baseline to Week 12]
- 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.
- 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.
- 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]
Eligibility Criteria
Criteria
Inclusion Criteria:
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A physician diagnosis of asthma for at least 12 months based on the Global Initiative for Asthma (GINA) 2018,2019, 2020 Guidelines.
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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.
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Participants with prebronchodilator FEV1 >40% of predicted normal at Visit 1/Screening. Prebronchodilator FEV1 ≥50% but ≤85% of predicted normal at Visit 2/Baseline.
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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 12 months prior to Visit 1 or documented positive response to methacholine challenge (a decrease in FEV by 20% [PC20] of <8mg/mL) within 12 months prior to Visit 1/Screening is considered acceptable to meet this inclusion criterion.
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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.
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Body mass index (BMI) ≥17.5 and ≤40 kg/m2
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All Contraceptive use by men and women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
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Participants must have completed COVID-19 vaccination per current regional health authority recommendations prior to screening.
Exclusion Criteria:
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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).
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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.
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History of life-threatening asthma (i.e., severe exacerbation that requires intubation).
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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
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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.
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Current smoker or cessation of smoking within the 6 months prior to Visit 1.
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Previous smoker with a smoking history >10 pack-years.
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Current or chronic history of liver disease.
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Known hepatic or biliary abnormalities.
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Symptomatic herpes zoster within 3 months prior to screening.
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Refractory nausea and vomiting, malabsorption, external biliary shunt, or significant bowel resection that would preclude adequate rilzabrutinib/placebo absorption.
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Conditions that may predispose the participant to excessive bleeding
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History of solid organ transplant.
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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.
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Is not up-to-date with recommended vaccinations per local guidelines.
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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.
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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.
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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.
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Use of proton pump inhibitor drugs such as omeprazole and esomeprazole within 3 days of Day 1.
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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.
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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.
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COVID-19 vaccine within 14 days prior to Study Day 1.
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Previous use of a Bruton tyrosine kinase (BTK) inhibitor.
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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).
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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.
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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.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Investigational Site Number :0320004 | Berazategui | Buenos Aires | Argentina | CP 1884 |
| 2 | Investigational Site Number :0320006 | Caba | Buenos Aires | Argentina | C1122AAK |
| 3 | Investigational Site Number :0320003 | Caba | Buenos Aires | Argentina | C1425FVH |
| 4 | Investigational Site Number :0320001 | Buenos Aires | Argentina | C1121ABE | |
| 5 | Investigational Site Number :0320005 | Ciudad Autonoma Buenos Aires | Argentina | C1414AIF | |
| 6 | Investigational Site Number :0320002 | Ciudad Autonoma Buenos Aires | Argentina | C1425BEN | |
| 7 | Investigational Site Number :1240001 | Kingston | Ontario | Canada | K7L2V7 |
| 8 | Investigational Site Number :1240003 | Toronto | Ontario | Canada | M5G 1E2 |
| 9 | Investigational Site Number :1240005 | Waterloo | Ontario | Canada | N2J 1C4 |
| 10 | Investigational Site Number :4100004 | Seoul | Seoul-teukbyeolsi | Korea, Republic of | 03312 |
| 11 | Investigational Site Number :4100005 | Seoul | Seoul-teukbyeolsi | Korea, Republic of | 05030 |
| 12 | Investigational Site Number :4100001 | Seoul | Korea, Republic of | 06591 | |
| 13 | Investigational Site Number :4840001 | Guadalajara | Jalisco | Mexico | 44100 |
| 14 | Investigational Site Number :4840003 | Durango | Mexico | 34000 | |
| 15 | Investigational Site Number :4840004 | Veracruz | Mexico | 91910 | |
| 16 | Investigational Site Number :6160003 | Bialystok | Podlaskie | Poland | 15-044 |
| 17 | Investigational Site Number :6160005 | Bialystok | Poland | 15010 | |
| 18 | Investigational Site Number :6160002 | Krakow | Poland | 30-033 | |
| 19 | Investigational Site Number :6160001 | Lodz | Poland | 90141 | |
| 20 | Investigational Site Number :8040004 | Chernivtsi | Ukraine | 58001 | |
| 21 | Investigational Site Number :8040001 | Ivano-Frankivsk | Ukraine | 76018 | |
| 22 | Investigational Site Number :8260002 | Cambridge | Cambridgeshire | United Kingdom | CB2 OQQ |
| 23 | Investigational Site Number :8260001 | Bradford | United Kingdom | BD9 6RJ |
Sponsors and Collaborators
- Sanofi
Investigators
- Study Director: Clinical Sciences & Operations, Sanofi
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- ACT17208
- U1111-1262-2956
- 2021-002490-26