Clinical trial NCT05104892: Proof of Concept Study of Rilzabrutinib in Adult Participants With Moderate-to-severe Asthma
Official title: A Randomized, Double-blind, Placebo-controlled, Parallel-group, 12 Week Proof-of-Concept (PoC) Study to Assess the Efficacy, Safety, and Tolerability of Rilzabrutinib in Participants With Moderate-to-severe Asthma Who Are Not Well Controlled on Inhaled Corticosteroid (ICS) Plus Long-acting β2 Adrenergic Agonist (LABA) Therapy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Asthma
Lead sponsor: Sanofi
Sponsor class: INDUSTRY
First posted: 2021-11-03
Enrollment: 196
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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 Background therapy of ICS/LABA will be withdrawn during the 12week randomized treatment period and resumed at the end of the IMP treatment period, as outlined below: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.

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 \<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.

Primary outcomes:
measure: Proportion of participants with an LOAC event during the treatment period
timeFrame: Until Week 12
Secondary outcomes:
measure: Pre-bronchodilator FEV1 (Forced expiratory volume in one second) change from baseline to EOT (end of treatment)
timeFrame: From baseline to Week 12
measure: Post-bronchodilator FEV1 change from baseline to EOT
timeFrame: From baseline to Week 12
measure: The absolute change in the percent predicted FEV1 from baseline to EOT (pre- and post-bronchodilator)
timeFrame: From baseline to Week 12
measure: Change from baseline in pre- and post-bronchodilator FEV1 and forced vital capacity [FVC] at each spirometry endpoint
timeFrame: From baseline until Week 12
measure: Change from baseline in peak expiratory flow [PEF] and forced expiratory flow [FEF] 25-75% at each spirometry endpoint
timeFrame: From baseline until Week 12
measure: Asthma Control Questionnaire-5 (ACQ-5) score change from baseline at EOT and at each assessment time point
timeFrame: From baseline until Week 12
measure: Asthma Quality of Life Questionnaire with Standardized Activities (AQLQ[S]) Self-administered score change from baseline at EOT and at each assessment time point
timeFrame: From baseline until Week 12
measure: Change in Asthma Daytime Symptom Diary (ADSD) and Asthma Nighttime Symptom Diary (ANSD) scores from baseline to EOT and each week
timeFrame: From baseline until Week 12
measure: Plasma pharmacokinetic (PK) concentrations of rilzabrutinib in participants with asthma
timeFrame: Until Week 16
measure: Participants with Treatment Emergent Adverse Events
timeFrame: Until Week 16
measure: Change in numbers of inhalations/day of albuterol or levalbuterol for symptom relief from baseline to EOT and each week
timeFrame: From baseline until Week 12
Other outcomes:
Locations:
city: Berazategui
country: Argentina
facility: Investigational Site Number : 0320004
state: Buenos Aires
city: Caba
country: Argentina
facility: Investigational Site Number : 0320006
state: Buenos Aires
city: Caba
country: Argentina
facility: Investigational Site Number : 0320003
state: Buenos Aires
city: Buenos Aires
country: Argentina
facility: Investigational Site Number : 0320001
city: Ciudad Autonoma Buenos Aires
country: Argentina
facility: Investigational Site Number : 0320005
city: Ciudad Autonoma Buenos Aires
country: Argentina
facility: Investigational Site Number : 0320002
city: Kozloduy
country: Bulgaria
facility: Investigational Site Number : 1000004
city: Ruse
country: Bulgaria
facility: Investigational Site Number : 1000001
city: Sevlievo
country: Bulgaria
facility: Investigational Site Number : 1000003
city: Sofia
country: Bulgaria
facility: Investigational Site Number : 1000002
city: Vancouver
country: Canada
facility: Investigational Site Number : 1240006
state: British Columbia
city: Waterloo
country: Canada
facility: Investigational Site Number : 1240005
state: Ontario
city: Curicó
country: Chile
facility: Investigational Site Number : 1520005
state: Maule
city: Talca
country: Chile
facility: Investigational Site Number : 1520002
state: Maule
city: Santaigo
country: Chile
facility: Investigational Site Number : 1520007
state: Reg Metropolitana De Santiago
city: Santiago
country: Chile
facility: Investigational Site Number : 1520001
state: Reg Metropolitana De Santiago
city: Santiago
country: Chile
facility: Investigational Site Number : 1520004
state: Reg Metropolitana De Santiago
city: Santiago
country: Chile
facility: Investigational Site Number : 1520003
state: Reg Metropolitana De Santiago
city: Quillota
country: Chile
facility: Investigational Site Number : 1520006
state: Valparaíso
city: Dusseldorf
country: Germany
facility: Investigational Site Number : 6420001
city: Edelény
country: Hungary
facility: Investigational Site Number : 3480001
city: Hajdunánás
country: Hungary
facility: Investigational Site Number : 3480004
city: Pécs
country: Hungary
facility: Investigational Site Number : 3480003
city: Daegu
country: Korea, Republic of
facility: Investigational Site Number : 4100007
state: Daegu-gwangyeoksi
city: Seoul
country: Korea, Republic of
facility: Investigational Site Number : 4100004
state: Seoul-teukbyeolsi
city: Seoul
country: Korea, Republic of
facility: Investigational Site Number : 4100005
state: Seoul-teukbyeolsi
city: Seoul
country: Korea, Republic of
facility: Investigational Site Number : 4100002
state: Seoul-teukbyeolsi
city: Seoul
country: Korea, Republic of
facility: Investigational Site Number : 4100006
state: Seoul-teukbyeolsi
city: Seoul
country: Korea, Republic of
facility: Investigational Site Number : 4100001
city: Guadalajara
country: Mexico
facility: Investigational Site Number : 4840001
state: Jalisco
city: Monterrey
country: Mexico
facility: Investigational Site Number : 4840002
state: Nuevo León
city: San Juan del Rio
country: Mexico
facility: Investigational Site Number : 4840005
state: Querétaro
city: Durango
country: Mexico
facility: Investigational Site Number : 4840003
city: Veracruz
country: Mexico
facility: Investigational Site Number : 4840004
city: Lublin
country: Poland
facility: Investigational Site Number : 6160007
state: Lubuskie
city: Bialystok
country: Poland
facility: Investigational Site Number : 6160003
state: Podlaskie
city: Gdansk
country: Poland
facility: Investigational Site Number : 6160006
state: Pomorskie
city: Ostrowiec Swietokrzyski
country: Poland
facility: Investigational Site Number : 6160008
state: Swietokrzyskie
city: Poznan
country: Poland
facility: Investigational Site Number : 6160009
state: Wielkopolskie
city: Bialystok
country: Poland
facility: Investigational Site Number : 6160005
city: Krakow
country: Poland
facility: Investigational Site Number : 6160002
city: Lodz
country: Poland
facility: Investigational Site Number : 6160010
city: Lodz
country: Poland
facility: Investigational Site Number : 6160001
city: Cluj-Napoca
country: Romania
facility: Investigational Site Number : 6420002
city: Santander
country: Spain
facility: Investigational Site Number : 7240004
state: Cantabria
city: Madrid / Madrid
country: Spain
facility: Investigational Site Number : 7240003
state: Madrid, Comunidad De
city: Málaga
country: Spain
facility: Investigational Site Number : 7240001
city: Istanbul
country: Turkey
facility: Investigational Site Number : 7920002
city: Mersin
country: Turkey
facility: Investigational Site Number : 7920001
city: Cambridge
country: United Kingdom
facility: Investigational Site Number : 8260002
state: Cambridgeshire
city: Bradford
country: United Kingdom
facility: Investigational Site Number : 8260001
Study officials:
affiliation: Sanofi
name: Clinical Sciences & Operations
role: STUDY_DIRECTOR
References: