A Study to Assess the Effect of Dexpramipexole in Adolescents and Adults With Eosinophilic Asthma (EXHALE-4)

• ClinicalTrials.gov Identifier: NCT05748600
• Recruitment Status: Recruiting
• First Posted: February 28, 2023
• Last Update Posted: March 3, 2023
• Sponsor: Areteia Therapeutics
• Information provided by (Responsible Party): Areteia Therapeutics

Study Description

Brief Summary:

The purpose of this study is to evaluate dexpramipexole as an add-on oral therapy in participants with inadequately controlled eosinophilic asthma to evaluate improvements in lung function, asthma control, and quality of life. In addition, the study will further evaluate the safety and tolerability of dexpramipexole in participants with eosinophilic asthma.

Condition or disease	Intervention/treatment	Phase
Eosinophilic Asthma; Asthma; Eosinophilic; Asthma Attack	Drug: Dexpramipexole Dihydrochloride; Drug: Placebo	Phase 3

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 750 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-blind, Placebo-controlled, Parallel-group Study to Assess the Efficacy, Safety, and Tolerability of Dexpramipexole Administered Orally for 24 Weeks in Participants With Eosinophilic Asthma
• Actual Study Start Date: January 30, 2023
• Estimated Primary Completion Date: June 2024
• Estimated Study Completion Date: July 2024

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. Change in pre-BD FEV₁ from baseline [ Time Frame: Day 1 (baseline, pre-dose), Weeks 20, 24 ]
   Pre-bronchodilator forced expiratory volume (pre-BD) FEV₁, absolute change from baseline, averaged over Weeks 20 and 24.

Secondary Outcome Measures :

1. Change from baseline in Asthma Control Questionnaire-6 (ACQ-6) [ Time Frame: Day 1 (baseline, pre-dose), Weeks 20, 24 ]
   Change from baseline in Asthma Control Questionnaire-6 (ACQ-6) averaged over visits at Weeks 20 and 24.
2. Change from baseline in the Asthma Quality of Life Questionnaire for 12 years and older (AQLQ+12) [ Time Frame: Day 1 (baseline, pre-dose) through Week 24 ]
   Standardized version of the Asthma Quality of Life Questionnaire for 12 years and older (AQLQ+12) change from baseline to Week 24.
3. Change from baseline absolute eosinophil count (AEC) to Week 24. [ Time Frame: Day 1 (baseline, pre-dose) through Week 24 ]
4. Change from baseline forced vital capacity (FVC) averaged over Weeks 20 and 24. [ Time Frame: Day 1 (baseline, pre-dose), Weeks 20, 24 ]
5. Change from baseline forced vital capacity (FVC) at Weeks 4, 8, 12, 16, 20, and 24. [ Time Frame: Day 1 (baseline, pre-dose), Weeks 4, 8, 12, 16, 20, and 24 ]
6. Change from baseline post-bronchodilator (post-BD) forced expiratory volume (FEV₁) at Week 24. [ Time Frame: Day 1 (baseline, pre-dose) through Week 24 ]
7. The EuroQol 5-dimensional questionnaire (EQ-5D-5L) change from baseline to Week 24 [ Time Frame: Day 1 (baseline, pre-dose) through Week 24 ]

Eligibility Criteria

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

Criteria

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. Participants requiring at a minimum daily low dose inhaled corticosteroids (ICS; ≥100 μg/day fluticasone propionate dry powder formulation daily or clinically comparable, per GINA 2021), plus one or more additional daily maintenance asthma controller medications, eg, long-acting β2 agonist (LABA), leukotriene antagonist, theophylline, long-acting muscarinic antagonists, cromolyn/nedocromil. Use of daily ICS must be for at least 12 weeks prior to Screening Visit 1 and the doses of all controller medications must be stable for at least 4 weeks prior to Screening Visit 1.
5. Pre-BD FEV1 ≥40% and <80% of predicted at Screening.
6. Bronchodilator reversibility, 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.
7. ACQ-6 ≥1.5 at Screening.

8. 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).

   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 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.
    4. 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. least 7 days prior to baseline.

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 priorr 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, or hypereosinophilic syndrome, or lung diseases (eg, 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.

   Prohibited medications/procedures

4. 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 (longacting anti-interleukin-5) in the past 12 months.
5. Treatment with any of the following monoclonal antibody therapies within 120 days prior to Baseline: benralizumab, dupilumab, mepolizumab, reslizumab, omalizumab, tezepelumab, or tralokinumab.
6. Treatment with pramipexole (Mirapex®) within 30 days of Baseline.
7. Treatment with selected drugs known to have a substantial risk of neutropenia in the past 30 days.

8. Bronchial thermoplasty procedure in the past 12 months or planned during the study period.

   General medical history

9. Weight <40 kg.
10. Current smoking within the past year or a smoking history of >10 packyears. Smoking includes tobacco, vaping, and/or marijuana use.
11. Known or suspected alcohol or drug abuse.
12. Uncontrolled severe hypertension: systolic blood pressure >180 mmHg or diastolic blood pressure >110 mmHg prior to randomization despite antihypertensive therapy.
13. 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.
14. History of human immunodeficiency virus (HIV) infection or chronic infection with hepatitis B or C.
15. 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 therapy.
16. Medical or other condition likely to interfere with participant's ability to undergo study procedures, adhere to visit schedule, or comply with study requirements.
17. Known or suspected noncompliance with medication.

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

    Clinical safety labs

19. Absolute neutrophil count <2.000x10⁹/L at Screening.
20. 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 [Levey et al, 2009] for age ≥18 years at screening; using the Bedside Schwartz [Schwartz and Work, 2009] eGFR formula for age <18).

21. 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

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

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

    Pregnancy/Lactation

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

For this study, rescreening may only be permitted under specific circumstances and only after contact with a Sponsor Clinical representative.

Contacts and Locations

Contacts

Contact: EXHALE Recruiting; 888-584-9281; clinicaltrials@areteiatx.com

Locations

United States, California

Research Site 20001-003; Recruiting

West Covina, California, United States, 91790

United States, Florida

Research Site 20001-048; Recruiting

Aventura, Florida, United States, 33180

Research Site 20001-051; Not yet recruiting

Brandon, Florida, United States, 33511

Research Site 20001-067; Not yet recruiting

Hialeah, Florida, United States, 33016

Research Site US-40001-015; Recruiting

Kissimmee, Florida, United States, 34744

Research Site 20001-004; Recruiting

Tampa, Florida, United States, 33607

United States, Missouri

Research Site 20001-074; Recruiting

Saint Charles, Missouri, United States, 63301

United States, Oklahoma

Research Site US-40001-038; Recruiting

Edmond, Oklahoma, United States, 73034

Sponsors and Collaborators

Areteia Therapeutics

Investigators

• Principal Investigator: Mona Bafadhel, MD; Guy's and St Thomas' NHS Foundation Trust

More Information

• Responsible Party: Areteia Therapeutics
• ClinicalTrials.gov Identifier: NCT05748600
• Other Study ID Numbers: AR-DEX-22-03; 2022-003005-30 ( EudraCT Number )
• First Posted: February 28, 2023
• Last Update Posted: March 3, 2023
• Last Verified: March 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Areteia Therapeutics:

FEV1; Asthma; Dexpramipexole; EXHALE; EXHALE-4; Areteia; Uncontrolled Asthma; Asthma Attack; forced expiratory volume

Additional relevant MeSH terms:

Asthma; Pulmonary Eosinophilia; Bronchial Diseases; Respiratory Tract Diseases; Lung Diseases, Obstructive; Lung Diseases; Respiratory Hypersensitivity; Hypersensitivity, Immediate; Hypersensitivity; Immune System Diseases; Hypereosinophilic Syndrome; Eosinophilia; Leukocyte Disorders; Hematologic Diseases; Pramipexole; Antioxidants; Molecular Mechanisms of Pharmacological Action; Protective Agents; Physiological Effects of Drugs; Antiparkinson Agents; Anti-Dyskinesia Agents; Dopamine Agonists; Dopamine Agents; Neurotransmitter Agents