Efficacy and Safety of Dexpramipexole in Severe Eosinophilic Asthma: A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study
- Trial ID
- 2023-507665-25-00
- Protocol
- AR-DEX-22-01
- Sponsor
- Areteia Therapeutics Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to demonstrate the efficacy of **dexpramipexole** in reducing severe asthma exacerbations in participants with severe eosinophilic asthma. This is clinically relevant as it addresses a critical need for effective management strategies in patients with this condition, potentially improving patient outcomes and reducing healthcare burdens associated with frequent exacerbations.
Secondary objectives include:
- To demonstrate the efficacy of dexpramipexole on pulmonary function, which is essential for assessing the overall respiratory health and capacity of patients.
- To demonstrate the efficacy of dexpramipexole on asthma control and quality of life, providing insights into the broader impact of treatment on daily living and symptom management.
- To evaluate the effect of dexpramipexole on blood eosinophils, which may offer additional understanding of the drug's mechanism of action and its potential role in modulating inflammatory responses in asthma.
Participants
The clinical trial investigating the efficacy of dexpramipexole in reducing severe asthma exacerbations involves a total of **965 participants**. The study population includes both **male and female subjects** aged 12 years and older, with a specific requirement for participants in Poland to be at least 18 years old. Participants have a documented physician diagnosis of **asthma** for at least 12 months prior to the screening. The trial includes individuals who have been on a stable regimen of medium or high-dose inhaled corticosteroids, with or without additional asthma controller medications, for a minimum of three months before the screening. The study population is characterized by a history of at least two asthma exacerbations requiring systemic corticosteroid treatment within the past year. Participants exhibit variable airflow obstruction and meet specific lung function criteria, such as a pre-bronchodilator FEV1 between 40% and 80% of the predicted value. The trial includes a vulnerable population, and lifestyle factors such as diet and physical activity are not specified. The selection process ensures that participants meet the inclusion criteria, including a negative pregnancy test for women of childbearing potential and the use of effective birth control methods. The trial does not provide additional information on lifestyle considerations or specific exclusion criteria beyond those mentioned.
Plans and Procedures
The clinical trial is a **randomized, double-blind, placebo-controlled, parallel-group** study designed to evaluate the efficacy, safety, and tolerability of **dexpramipexole** administered orally over a period of 52 weeks in participants with severe eosinophilic asthma. The trial involves the administration of **dexpramipexole** in the form of film-coated tablets, with a maximum daily dose of 75 mg or 150 mg, depending on the treatment group. The study also includes a placebo group for comparison. The primary objective is to demonstrate the efficacy of **dexpramipexole** in reducing severe asthma exacerbations, with the primary endpoint being the annualized rate of severe asthma exacerbations over the 52-week period. Secondary endpoints include changes in pre-bronchodilator FEV1, the Asthma Control Questionnaire-6, and the Asthma Quality of Life Questionnaire for participants aged 12 years and older.
The trial is structured to include several key visits: an initial screening visit, baseline visit, multiple follow-up visits, and an end-of-study visit. The screening visit is designed to confirm eligibility based on inclusion criteria such as age, documented asthma diagnosis, and treatment history. Participants must have a documented history of asthma exacerbations and meet specific lung function criteria. The baseline visit marks the start of the treatment period, where participants are randomized to receive either **dexpramipexole** or placebo. Follow-up visits are scheduled at regular intervals to monitor safety, efficacy, and adherence to the study protocol. The end-of-study visit concludes the participant's involvement, with final assessments conducted to evaluate the overall impact of the treatment.
Participant involvement is expected to last for the entire 52-week duration of the trial, with conditions for early termination including adverse events, withdrawal of consent, or non-compliance with the study protocol. The trial is not classified as a low-intervention study and is conducted in accordance with regulatory guidelines to ensure the integrity and reliability of the data collected. The study aims to provide valuable insights into the potential benefits of **dexpramipexole** for individuals with severe eosinophilic asthma, contributing to the advancement of therapeutic options for this condition.
Treatment
The clinical trial involves the administration of **Dexpramipexole (KNS-760704)**, a chemical compound provided in the form of a **film-coated tablet**. The active substance in this medication is **dexpramipexole dihydrochloride monohydrate**. The trial includes two dosing regimens for this experimental medication. The first regimen involves a maximum daily dose of 75 mg, while the second regimen allows for a maximum daily dose of 150 mg. Both regimens are administered orally. The treatment period for each regimen is set at 52 weeks. The medication is manufactured by Areteia Therapeutics and is not a paediatric formulation. Participant compliance with the dosing schedule will be monitored throughout the study.
In addition to the experimental medication, a **placebo** is used as a comparator treatment in this study. The placebo is designed to mimic the appearance of the film-coated tablet but does not contain any active pharmaceutical ingredients. The placebo is administered orally, following the same schedule as the experimental medication, to maintain the double-blind nature of the trial. The use of a placebo allows for the assessment of the efficacy, safety, and tolerability of dexpramipexole in reducing severe asthma exacerbations in participants with severe eosinophilic asthma.
Efficacy
The efficacy of dexpramipexole in the treatment of severe eosinophilic asthma will be assessed in a randomized, double-blind, placebo-controlled, parallel-group clinical trial over a period of 52 weeks. The primary endpoint for evaluating efficacy is the **Annualized Rate of Severe Asthma Exacerbations (AAER)** over the 52-week treatment period. This endpoint will provide a quantitative measure of the frequency of severe asthma exacerbations experienced by participants during the trial.
Secondary endpoints include the absolute change from baseline in pre-bronchodilator forced expiratory volume in one second (Pre-BD FEV1), averaged across visits at Weeks 36, 44, and 52. Additionally, changes from baseline in the Asthma Control Questionnaire-6 (ACQ-6) scores, averaged across the same timepoints, will be evaluated. The standardized version of the Asthma Quality of Life Questionnaire for participants aged 12 years and older (AQLQ+12) will also be used to assess changes from baseline to Week 52.
These efficacy parameters will be measured using validated scales and laboratory tests at specified timepoints throughout the study. The data collected will be analyzed to determine the impact of dexpramipexole on the management of severe eosinophilic asthma, with the aim of demonstrating a reduction in severe asthma exacerbations and improvements in lung function and quality of life.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Signed informed consent form and assent form, as appropriate.
- Male or female ≥18 years of age at Screening Visit 1. a. Participants in Poland must be ≥18 years of age at Screening Visit 1.
- Documented physician diagnosis of asthma for ≥12 months prior to Screening Visit 1.
- Treatment of asthma, participants must satisfy all the below (items a to c): a. 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. Equivalent medium and high dose ICS doses are detailed in Appendix C b. Documented treatment with a stable dose of either medium or high dose ICS for at least 3 months prior to Screening Visit 1. The ICS may be contained within an ICS/long-acting β2 agonist (LABA) combination product. As noted in Section 5.2.2, 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. c. Use of one of more additional daily maintenance asthma controller medications according to standard practice of care is required; eg, LABA, leukotriene antagonist, theophylline, long-acting muscarinic antagonists, cromolyn/nedocromil. 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% of predicted at Screening Visit 2.
- Variable airflow obstruction documented with at least one of the following criteria: a. 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. 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. b. Bronchodilator reversibility, using the criteria above, documented in the past 24 months prior to Screening Visit 1 or during screening. c. Peak flow variation of ≥20% over a 2-week period, documented in the past 24 months prior to Screening Visit 1 or during screening. d. Airflow variability in clinic FEV1 ≥20% between two consecutive clinic visits, documented in the past 24 months prior to Screening Visit 1 or during screening. e. Airway hyperresponsiveness (provocative concentration causing a 20% fall in FEV1 of methacholine <8 mg/mL, or other clinically relevant bronchoprovocation testing) 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.
- 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. 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. b. Or b. 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: c. 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 d. 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
- 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. 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.
- Weight <40 kg at Screening Visit 2.
- 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 the 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 the 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 to 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.
- 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).
- Absolute neutrophil count <2.000x109/L 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]
- 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.
- 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 the 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 resting heart rate <45 beats per minute (bpm) or >100 bpm.
- Pregnant women or women breastfeeding.
- Respiratory infection: Upper or lower respiratory tract, sinus, or middle ear infection within the 4 weeks before Screening Visit 1.
- Males who are unwilling to use an acceptable method of birth control during the entire study period (ie, condom with spermicide).
- For participants aged 12 to 17 years old, AEC of <0.15x109/L at Screening Visit 1. Not applicable in Poland where all participants are at least 18 years of age. Note: enrollment of participants of 12-17 years of age is closed.
- 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-ILn-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 (see Appendix A).
- Bronchial thermoplasty procedure in the past 12 months prior to Screening Visit 1 or planned during the coming year.
- Allergy or hypersensitivity to dexpramipexole or any of its components
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Bulgaria | Not Recruiting | 23 Feb 2023 | 240 |
 Poland | Not Recruiting | 23 Feb 2023 | 95 |
 Romania | Not Recruiting | 23 Feb 2023 | 95 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
DexpramipexoleKNS-760704 | Test | FILM-COATED TABLET | ORAL USE | 75 | 52 | PRD10251346 |
Placebo | Placebo | N/A | — | — | — | N/A |
DexpramipexoleKNS-760704 | Test | FILM-COATED TABLET | ORAL USE | 150 | 52 | PRD10251347 |