A Study to Assess the Effect of Dexpramipexole in Adolescents and Adults With Severe Eosinophilic Asthma. (EXHALE-2)

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

This study will assess the efficacy and safety of dexpramipexole as an adjunctive oral therapy in participants with inadequately controlled asthma with an eosinophilic phenotype and a history of asthma exacerbations.

Study Overview

• Status: Recruiting
• Conditions: Asthma; Eosinophilic Asthma; Asthma; Eosinophilic
• Intervention / Treatment: Drug: Dexpramipexole Dihydrochloride; Drug: Placebo

Detailed Description

This is a multicenter, randomized, double-blind, placebo controlled, parallel group study designed to evaluate the efficacy and safety of dexpramipexole in adults and adolescents with severe, inadequately controlled asthma with eosinophilic phenotype on medium to high-dose inhaled corticosteroids (ICS )and at least one additional asthma controller medication with or without oral corticosteroids (OCS). Approximately 1400 participants will be randomized globally. Participants will receive dexpramipexole, or placebo, administered orally, over a 52-week treatment period. The study also includes a post-treatment follow-up period of 4 weeks.

• Study Type: Interventional
• Enrollment (Anticipated): 1395
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: EXHALE Recruiting; Phone Number: 888-584-9281; Email: [email protected]

Study Locations

• United Kingdom
  • Altrincham, United Kingdom, WA14 1PF
    • Recruiting
    • Research Site 20044-010
  • Bellshill, United Kingdom, ML4 3NJ
    • Recruiting
    • Research Site 20044-018
  • Birmingham, United Kingdom, B15 2SQ
    • Recruiting
    • Research Site 20044-021
  • Chorley, United Kingdom, PR7 7NA
    • Recruiting
    • Research Site 20044-017
  • Enfield Town, United Kingdom, EN3 4GS
    • Recruiting
    • Research Site 20044-022
  • Liverpool, United Kingdom, L22 0LG
    • Recruiting
    • Research Site 20044-019
  • Manchester, United Kingdom, M15 6SE
    • Recruiting
    • Research Site 20044-020
  • Manchester, United Kingdom, M20 6BA
    • Recruiting
    • Research Site 20044-031
  • Manchester, United Kingdom, M23 2SY
    • Recruiting
    • Research Site 20044-032
  • Manchester, United Kingdom, M24 4DZ
    • Recruiting
    • Research Site 20044-009
  • Manchester, United Kingdom, M27 8HP
    • Recruiting
    • Research Site 20044-005
  • Manchester, United Kingdom, M41 8AA
    • Recruiting
    • Research Site 20044-030
  • Manchester, United Kingdom, M42 7WJ
    • Recruiting
    • Research Site 20044-012
  • Manchester, United Kingdom, OL6 6HD
    • Recruiting
    • Research Site 20044-004
  • Preston, United Kingdom, PR2 9RB
    • Recruiting
    • Research Site 20044-024
  • Rochdale, United Kingdom, OL11 4AU
    • Recruiting
    • Research Site 20044-026
  • Stockport, United Kingdom, SK3 9NX
    • Recruiting
    • Research Site 20044-029
  • Stockport, United Kingdom, SK8 5LL
    • Recruiting
    • Research Site 20044-034
• United States
  • California
    • Newport Beach, California, United States, 92660
      • Recruiting
      • Research Site 20001-062
    • West Covina, California, United States, 91790
      • Recruiting
      • Research Site 20001-003
  • Florida
    • Aventura, Florida, United States, 33180
      • Recruiting
      • Research Site 20001-048
    • Brandon, Florida, United States, 33511
      • Recruiting
      • Research Site 20001-051
    • Greenacres City, Florida, United States, 33467
      • Recruiting
      • Research Site 20001-014
    • Hialeah, Florida, United States, 33016
      • Recruiting
      • Research Site 20001-067
    • Homestead, Florida, United States, 33030
      • Recruiting
      • Research Site 20001-020
    • Kissimmee, Florida, United States, 34744
      • Recruiting
      • Research Site 20001-015
    • Loxahatchee Groves, Florida, United States, 33470
      • Recruiting
      • Research Site 20001-086
    • Miami, Florida, United States, 33126
      • Recruiting
      • Research Site 20001-066
    • Miami, Florida, United States, 33135
      • Recruiting
      • Research Site 20001-001
    • Miami, Florida, United States, 33155
      • Recruiting
      • Research Site 20001-026
    • Miami, Florida, United States, 33173
      • Recruiting
      • Research Site 20001-065
    • Tampa, Florida, United States, 33607
      • Recruiting
      • Research Site 20001-004
  • Illinois
    • Berwyn, Illinois, United States, 60402
      • Recruiting
      • Research Site 20001-090
  • Kentucky
    • Owensboro, Kentucky, United States, 42301
      • Recruiting
      • Research Site 20001-019
  • Michigan
    • Flint, Michigan, United States, 48504
      • Recruiting
      • Research Site 20001-006
  • Missouri
    • Saint Charles, Missouri, United States, 63301
      • Recruiting
      • Research Site 20001-074
  • New York
    • E. Amherst, New York, United States, 14051
      • Recruiting
      • Research Site 20001-050
  • North Carolina
    • Gastonia, North Carolina, United States, 28054
      • Recruiting
      • Research Site 20001-039
  • Ohio
    • Cincinnati, Ohio, United States, 45215
      • Recruiting
      • Research Site 20001-034
    • Dayton, Ohio, United States, 45424
      • Recruiting
      • Research Site 20001-017
  • Oklahoma
    • Edmond, Oklahoma, United States, 73034
      • Recruiting
      • Research Site 20001-038
    • Oklahoma City, Oklahoma, United States, 73120
      • Recruiting
      • Research Site 20001-079
  • South Carolina
    • Greenville, South Carolina, United States, 29615
      • Recruiting
      • Research Site 20001-025
    • Spartanburg, South Carolina, United States, 29303
      • Recruiting
      • Research Site 20001-073
  • Texas
    • Dallas, Texas, United States, 75235
      • Recruiting
      • Research Site 20001-028

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years to 99 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Signed informed consent form and assent form, as appropriate

2. Male or female ≥12 years of age at randomization

   Asthma-related criteria

3. Documented physician diagnosis of asthma for ≥12 months.

4. Treatment of asthma, participants must satisfy all the below (items a to c):

   1. 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 Global Initiative for Asthma (GINA) 2021) on a regular basis for at least 12 months prior to screening.
   2. 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/LABA (long-acting β2 agonist) 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.
   3. 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.
5. Pre-bronchodilator forced expiratory volume (Pre-BD FEV₁) ≥40% and <80% of predicted at Screening

6. Variable airflow obstruction documented with at least one of the following criteria:

   1. Bronchodilator reversibility during screening, 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.
   2. Bronchodilator reversibility, using the criteria above, documented in the past 12 months.
   3. Peak flow variation of ≥20% over a 2-week period, documented in the past 12 months.
   4. Airflow variability in clinic FEV₁ ≥20% between two consecutive clinic visits, documented in the past 12 months.
   5. Airway hyperresponsiveness (provocative concentration causing a 20% fall in FEV₁ of methacholine <8 mg/mL) documented in the past 12 months.
7. ACQ-6 ≥1.5 at Screening.

8. Documented history of at least two asthma exacerbations requiring treatment with systemic corticosteroids (intramuscular, intravenous, or oral) within the past 12-month period.

   General medical history

9. Negative urine pregnancy test for women of childbearing potential (WOCBP; after menarche) at Screening and Baseline.

10. WOCBP must use either of the following methods of birth control, from Screening through the End of Study Visit:

    1. 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

    2. 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 randomization without an alternative medical cause. The following age specific requirements apply:

    3. Women <50 years old would 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.
    4. Women ≥50 years old would 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

1. 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 the Screening Visit 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.

2. 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, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis.
3. Respiratory infection: Upper or lower respiratory tract, sinus, or middle ear infection within the 4 weeks before Screening.

4. For participants aged 12 to 17 years old, AEC of <0.15x10⁹/L at Screening.

   Prohibited medications/procedures

5. Treatment with a biologic investigational drug in the last 5 months. Treatment with non-biologic investigational drugs in the previous 30 days or five-half-lives, whichever is longer. Treatment with GSK3511294 (long-acting anti-IL-5) in the past 12 months.
6. Treatment with any of the following monoclonal antibody therapies within 120 days prior to Baseline: benralizumab, dupilumab, mepolizumab, reslizumab, omalizumab, tezepelumab, or tralokinumab.
7. Treatment with pramipexole (Mirapex®) within 30 days of Baseline.
8. Treatment with selected drugs known to have a substantial risk of neutropenia in the past 30 days.

9. Bronchial thermoplasty procedure in the past 12 months or planned during the coming year.

   General medical history

10. Weight <40 kg.
11. Current smoking within the past year or a smoking history of >10 pack-years. Smoking includes tobacco, vaping, and/or marijuana use.
12. Known or suspected alcohol or drug abuse
13. Uncontrolled severe hypertension: systolic blood pressure >180 mmHg or diastolic blood pressure >110 mmHg prior to randomization despite antihypertensive therapy.
14. History of malignancy that required surgery (excluding local and wide-local excision), radiation therapy and/or systemic therapy during the 5 years prior to randomization.
15. History of human immunodeficiency virus (HIV) infection or chronic infection with hepatitis B or C.
16. A helminth parasitic infection diagnosed within 24 weeks prior to the date informed consent, and assent when applicable, that has not been treated with or has failed to respond to standard of care (SoC) therapy.
17. Medical or other condition likely to interfere with participant's ability to undergo study procedures, adhere to visit schedule, or comply with study requirements.
18. Known or suspected noncompliance with medication.

19. Unwillingness or inability to follow the procedures outlined in the protocol.

    Clinical safety labs

20. Absolute neutrophil count (ANC) <2.000x10⁹/L at screening.
21. Renal dysfunction, defined as an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73m² at Screening (using the Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] formula for age ≥18 years at screening; using the Bedside Schwartz eGFR formula for age <18).

22. 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 confirmed by a repeat abnormal measurement of the relevant value(s), at least 1 week apart.

    Cardiac safety

23. History of New York Heart Association class IV heart failure or last known left ventricular ejection fraction <25%.
24. History of major adverse cardiovascular event (MACE) within 3 months prior to randomization.
25. History of cardiac arrhythmia within 3 months prior baseline that is not controlled by medication or via ablation.
26. History of long QT syndrome.
27. Corrected QT interval by Fridericia (QTcF) interval >450 ms for males and >470 ms for females at Screening QTcF ≥480 ms for participants with bundle branch block.

28. Clinically important abnormalities in resting ECG that may interfere with the interpretation of QTcF interval changes at Screening, including heart rate <45 beats per minute (bpm) or >100 bpm.

    Pregnancy/Lactation

29. Pregnant women or women breastfeeding
30. Males who are unwilling to use an acceptable method of birth control during the entire study period (ie, condom with spermicide).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 150 mg BID; Dexpramipexole 150 mg oral tablet taken twice a day	Drug: Dexpramipexole Dihydrochloride; oral administration of dexpramipexole tablet
Experimental: 75 mg BID; Dexpramipexole 75 mg oral tablet taken twice a day	Drug: Dexpramipexole Dihydrochloride; oral administration of dexpramipexole tablet
Placebo Comparator: Placebo; Placebo oral tablet taken twice a day	Drug: Placebo; oral administration of placebo tablet

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 FEV)₁ 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
Change From Baseline in Asthma Control Questionnaire-6 (ACQ-6)	Asthma Control Questionnaire-6 (ACQ-6), change from baseline, averaged across visits at Weeks 36, 44, and 52.	Day 1 (baseline, pre-dose), Weeks 36, 44, 52
Annualized Rate of severe exacerbations from Week 4 to Week 52		Week 4 through Week 52
Change in absolute eosinophil count (AEC)		Day 1 (baseline, pre-dose) through Week 52
Average change from baseline in forced vital capacity (FVC)		Day 1 (baseline, pre-dose), Weeks 36, 44, 52
Change from baseline in forced vital capacity (FVC)		Day 1 (baseline, pre-dose), Weeks 4, 12, 20,28 36, 44, 52
Change from baseline in Post-bronchodilator FEV₁		Day 1 (baseline, pre-dose) through Week 52
Change from baseline in peak expiratory flow (PEF)		Day 1 (baseline, pre-dose) through Week 52
Time to first severe asthma exacerbation		Up to Week 52
Change from baseline in total asthma symptom score		Day 1 (baseline, pre-dose) through Week 52
Change from baseline in the EuroQol five-dimensional questionnaire (EQ-5D-5L)		Day 1 (baseline, pre-dose) through Week 52
Change in Standardized version of the Asthma Quality of Life Questionnaire for 12 years and older (AQLQ+12) from baseline to Week 52.		Day 1 (baseline, pre-dose) through Week 52
Annualized rate of severe exacerbations requiring an emergency department visit or hospitalization over 52 weeks.		Day 1 (baseline, pre-dose) through Week 52

Collaborators and Investigators

• Sponsor: Areteia Therapeutics
• Investigators: Principal Investigator: Salman Siddiqui, MD, Imperial College Healthcare NHS Trust (via Imperial Consultants)

Study record dates

Study Major Dates

• Study Start (Actual): January 30, 2023
• Primary Completion (Anticipated): November 1, 2025
• Study Completion (Anticipated): December 1, 2025

Study Registration Dates

• First Submitted: February 20, 2023
• First Submitted That Met QC Criteria: March 1, 2023
• First Posted (Actual): March 10, 2023

Study Record Updates

• Last Update Posted (Estimate): May 4, 2023
• Last Update Submitted That Met QC Criteria: May 2, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Keywords: Severe Asthma; Uncontrolled Asthma; Exacerbations; Asthma Attack; Dexpramipexole; EXHALE; Areteia; EXHALE-2
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Immune System Diseases; Lung Diseases; Hypersensitivity, Immediate; Hematologic Diseases; Bronchial Diseases; Lung Diseases, Obstructive; Respiratory Hypersensitivity; Hypersensitivity; Leukocyte Disorders; Eosinophilia; Hypereosinophilic Syndrome; Asthma; Pulmonary Eosinophilia; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Protective Agents; Dopamine Agonists; Dopamine Agents; Antioxidants; Antiparkinson Agents; Anti-Dyskinesia Agents; Pramipexole
• Other Study ID Numbers: AR-DEX-22-01; 2022-003004-33 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No