A Study to Assess the Effect of Dexpramipexole in Adolescents and Adults With Severe Eosinophilic Asthma (EXHALE-3)

Study Overview
=================
Brief Summary
-----------------
The objective of this clinical study is to investigate the safety, tolerability, and efficacy of dexpramipexole in participants with inadequately controlled severe eosinophilic asthma.

Official Title
-----------------
A Randomized, Double-blind, Placebo-controlled, Parallel-group Study to Assess the Efficacy, Safety, and Tolerability of Dexpramipexole Administered Orally for 52 Weeks in Participants With Severe Eosinophilic Asthma

Conditions
-----------------
Eosinophilic Asthma, Asthma; Eosinophilic, Asthma

Intervention / Treatment
-----------------
* Drug: Dexpramipexole Dihydrochloride
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Signed informed consent form and assent form, as appropriate. Male or female ≥12 years of age at Screening Visit 1. Asthma-related criteria Documented physician diagnosis of asthma for ≥12 months prior to Screening Visit 1. Eosinophil count of ≥0.30x10⁹/L at Screening Visit 1. If the initial value is between 0.250x10⁹/L to 0.299x10⁹/L, then this may be repeated once at an unscheduled visit (prior to Screening Visit 2). Treatment of asthma, participants must satisfy all the below (items a to c): Participants who have received asthma controller medication with medium or high dose inhaled corticosteroids (ICS ≥500 μg/day fluticasone propionate dry powder formulation daily or clinically comparable, per GINA 2021) on a regular basis for at least 12 months prior to Screening Visit 1. Documented treatment with a stable dose of either medium or high dose ICS for at least 3 months prior to Visit 1. The ICS may be contained within an ICS/long-acting β2 agonist (LABA) combination product. Daily oral corticosteroids are an allowed concomitant medication; participants on daily oral corticosteroids must be on a stable dose for 3 months before Screening Visit 1. Use of one of more additional daily maintenance asthma controller medications according to standard practice of care is required. Use of a stable dose of any additional asthma controller medications must be documented for at least 3 months prior to Screening Visit 1. Pre-BD FEV₁ ≥40% and <80% (<90% for participants 12 to 17 years of age) of predicted at Screening Visit 2. Variable airflow obstruction documented with at least one of the following criteria: Bronchodilator reversibility at Screening Visit 2, as evidenced by ≥12% and ≥200 mL improvement in FEV₁, 15 to 30 minutes following inhalation of 400 µg (four puffs) of albuterol/salbutamol (≥12% and ≥160 mL for ages 12 to 17). Participants who do not meet the bronchodilator reversibility inclusion criterion but have ≥10% and ≥160 mL reversibility, may repeat the reversibility spirometry assessment once during the Screening period, at an unscheduled visit at least 7 days prior to baseline. Bronchodilator reversibility, using the criteria above, documented in the past 24 months prior to Screening Visit 1. Peak flow variation of ≥20% over a 2-week period, documented in the past 24 months prior to Screening Visit 1. Airflow variability in clinic FEV₁ ≥20% between two consecutive clinic visits, documented in the past 24 months prior to Screening Visit 1. Airway hyperresponsiveness (provocative concentration causing a 20% fall in FEV₁ of methacholine <8 mg/mL) documented in the past 24 months prior to Screening Visit 1. ACQ-6 ≥1.5 at Screening Visit 2. Documented history of at least two asthma exacerbations requiring treatment with systemic corticosteroids (intramuscular, intravenous, or oral) within the past 12-month period prior to Screening Visit 1. General medical history Negative urine pregnancy test for women of childbearing potential (WOCBP; after menarche) at the Screening and Baseline visits. WOCBP must use either of the following methods of birth control, from Screening Visit 1 through the End of Study Visit: A highly effective form of birth control (confirmed by the investigator). Highly effective forms of birth control include: true sexual abstinence, a vasectomized sexual partner, Implanon, female sterilization by tubal occlusion, any effective Intrauterine device (IUD), IUD/intrauterine system (IUS), Levonorgestrel Intrauterine system, or oral contraceptive. Or Two protocol acceptable methods of contraception in tandem. Women not of childbearing potential are defined as women who are either permanently sterilized (hysterectomy, bilateral oophorectomy, or bilateral salpingectomy), or who are postmenopausal. Women will be considered postmenopausal if they have been amenorrheic for ≥12 months prior to the planned date of the Baseline Visit without an alternative medical cause. The following age specific requirements apply: Women <50 years old will be considered postmenopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatment and follicle stimulating hormone levels in the postmenopausal range. Women ≥50 years old will be considered postmenopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatment. Exclusion Criteria: Asthma-related criteria A participant who experiences a severe asthma exacerbation (defined as a deterioration of asthma that results in emergency treatment, hospitalization due to asthma, or treatment with systemic corticosteroids) at any time from 4 weeks prior to Screening Visit 1 up to and including the Baseline Visit. Participants who experience an asthma exacerbation during the Screening/Run-in Period may remain in screening and proceed with study visits 14 days after they have completed their course of oral steroids or returned to their pre-Screening Visit maintenance dose of oral steroids and the investigator considers participant has returned to baseline status. Current diagnosis of diseases which may confound interpretation of this study's findings such as allergic bronchopulmonary aspergillosis, eosinophilic granulomatosis with polyangiitis, eosinophilic gastrointestinal diseases, hypereosinophilic syndrome, or lung diseases (eg, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis). Respiratory infection: Upper or lower respiratory tract, sinus, or middle ear infection within the 4 weeks before Screening Visit 1. Prohibited medications/procedures Treatment with a biologic investigational drug in the last 5 months prior to Screening Visit 1. Treatment with non-biologic investigational drugs in the previous 30 days or five-half-lives prior to Screening Visit 1, whichever is longer. Treatment with GSK3511294 (long-acting anti-IL-5) in the past 12 months. Treatment with any of the following monoclonal antibody therapies within 120 days prior to Baseline: benralizumab, dupilumab, mepolizumab, reslizumab, omalizumab, tezepelumab, or tralokinumab. Treatment with pramipexole (Mirapex®) within 30 days of Baseline. Treatment with selected drugs known to have a substantial risk of neutropenia in the past 30 days prior to Screening Visit 1. Bronchial thermoplasty procedure in the past 12 months prior to Screening Visit 1 or planned during the coming year. General medical history Weight <40 kg at Screening Visit 1. Current smoking within 12 months prior to Screening Visit 1 or a smoking history of >10 pack-years. Smoking includes tobacco, vaping, and/or marijuana use. Known or suspected alcohol or drug abuse Uncontrolled severe hypertension: systolic blood pressure >180 mmHg or diastolic blood pressure >110 mmHg prior to Baseline Visit despite anti-hypertensive therapy. History of malignancy that required surgery (excluding local and wide-local excision), radiation therapy and/or systemic therapy during the 5 years prior to Baseline Visit. History of human immunodeficiency virus (HIV) infection or chronic infection with hepatitis B or C. A helminth parasitic infection diagnosed within 24 weeks prior Screening Visit 1 that has not been treated with or has failed to respond to standard of care (SoC) therapy. Medical or other condition likely to interfere with participant's ability to undergo study procedures, adhere to visit schedule, or comply with study requirements. Known or suspected noncompliance with medication. Unwillingness or inability to follow the procedures outlined in the protocol. Clinical safety labs Absolute neutrophil count <2.000x10⁹/L at screening at Screening Visit 1 or Screening Visit 2. Renal dysfunction, defined as an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73m² at Screening Visit 2 (using the Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] formula [Levey et al, 2009] for age ≥18 years at screening; using the Bedside Schwartz [Schwartz and Work, 2009] eGFR formula for age <18). Active liver disease defined as any known current infectious, neoplastic, or metabolic pathology of the liver or unexplained elevations in alanine aminotransferase (ALT), aspartate aminotransferase (AST), >3x the upper limit of normal (ULN), or total bilirubin >2x ULN at Screening Visit 2 confirmed by a repeat abnormal measurement of the relevant value(s), at least 1 week apart. Cardiac safety History of New York Heart Association class IV heart failure or last known left ventricular ejection fraction <25%. History of major adverse cardiovascular event (MACE) within 3 months prior to the Baseline Visit. History of cardiac arrhythmia within 3 months prior to Baseline Visit that is not controlled by medication or via ablation. History of long QT syndrome. Corrected QT interval by Fridericia (QTcF) interval >450 ms for males and >470 ms for females at Screening Visit 2 or QTcF ≥480 ms for participants with bundle branch block. Clinically important abnormalities in resting ECG that may interfere with the interpretation of QTcF interval changes at Screening Visit 2, including heart rate <45 beats per minute (bpm) or >100 bpm. Pregnancy/Lactation Pregnant women or women breastfeeding. Males who are unwilling to use an acceptable method of birth control during the entire study period (ie, condom with spermicide).

Ages Eligible for Study
-----------------
Minimum Age: 12 Years
Maximum Age: 99 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 150 mg BID<br>Dexpramipexole 150 mg oral tablet taken twice a day | Drug: Dexpramipexole Dihydrochloride<br>* Oral administration of dexpramipexole tablet<br>|
| Experimental: 75 mg BID<br>Dexpramipexole 75 mg oral tablet taken twice a day | Drug: Dexpramipexole Dihydrochloride<br>* Oral administration of dexpramipexole tablet<br>|
| Placebo Comparator: Placebo<br>Placebo oral tablet taken twice a day | Drug: Placebo<br>* Oral administration of placebo tablet<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Annualized rate of severe asthma exacerbations over 52 weeks. | A severe exacerbation was defined as a deterioration of asthma requiring: use of systemic corticosteroids for >=3 days; or hospitalization or emergency room visit because of asthma, requiring systemic corticosteroids; or death due to asthma. | Day 1 (baseline, pre-dose) through Week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Absolute Change in pre-bronchodilator forced expiratory volume (Pre-BD FEV₁) from Baseline | The absolute change from baseline in pre-bronchodilator forced expiratory volume, averaged across visits at Weeks 36, 44, and 52. | Day 1 (baseline, pre-dose), Weeks 36, 44, 52 | 
| Mean Change From Baseline at Week 52 in Asthma Control Questionnaire-6 (ACQ-6) (Key Secondary Endpoint) | Change from baseline in ACQ-6 as compared to placebo at Week 52. The ACQ-6 captures asthma symptoms and short-acting β2-agonist use via subject-report. Questions are weighted equally and scored from 0 (totally controlled) to 6 (severely uncontrolled). The ACQ-6 score is the mean of the responses | From randomization to Study Week 52 | 
| Mean Change From Baseline at Week 52 in Standardized Asthma Quality of Life Questionnaire for 12 Years and Older (AQLQ+12) Total Score (Key Secondary Endpoint) | Mean change from baseline in AQLQ+12 as compared to placebo at Week 52. The AQLQ+12 is a questionnaire that measures the health-related quality of life experienced by asthma subjects. The total score is defined as the average of all 32 questions in the AQLQ+12 questionnaire. AQLQ+12 is a 7-point scale questionnaire, ranging from 7 (no impairment) to 1 (severe impairment). | From randomization to Study Week 52 | 
| Annualized rate of severe exacerbations requiring an emergency over 52 weeks department visit or hospitalization |  | Day 1 (baseline, pre-dose), Week 52 | 
| Annualized rate of severe exacerbations (AAER) from Week 4 to Week 52. |  | Week 4 through Week 52 | 
| Change in absolute eosinophil count (AEC) |  | Day 1 (baseline, pre-dose), Week 52 | 
| Average change from baseline in forced vital capacity (FVC) |  | Day 1(baseline, pre-dose), Weeks 36, 44, and 52 | 
| FVC, change from baseline at Weeks 4, 12, 20, 28, 36, 44, and 52. |  | Day 1(baseline, pre-dose), Weeks 4, 12, 20, 28, 36, 44, and 52. | 
| Post-bronchodilator FEV₁, change from baseline to Week 52 |  | Day 1 (baseline, pre-dose) through Week 52 | 
| Time to first severe asthma exacerbation |  | Up to Week 52 | 
| Mean Change From Baseline at Week 52 in Asthma Symptom Diary (ASD) | The Asthma Symptom Diary comprises of 10 items (5 items in the morning; 5 items in the evening). Asthma symptoms during night time and daytime are recorded by the patient each morning and evening in the daily diary. A daily ASD score is the mean of the 10 items. Responses for all 10 items are required to calculate the daily ASD score; otherwise, it is treated as missing. For the 7-day average asthma symptom score, scoring is done with no imputation using the mean of at least 4 of the 7 daily ASD scores as a mean weekly item score. The 7-day average ASD score ranges from 0 to 4, where 0 indicates no asthma symptoms. | From randomization to Study Week 52 | 
| Mean Change From Baseline at Week 52 in EQ-5D-5L | EQ-5D-5L allows subjects to rate current health status on a scale of 0-100, with 0 being the worst imaginable health state. | At Study Week 52 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Uncontrolled Asthma, Asthma Attack, Exacerbations, Severe Asthma, Dexpramipexole, EXHALE, Areteia, EXHALE-3