Efficacy and Safety Evaluation of Dexpramipexole Dihydrochloride Monohydrate in Eosinophilic Asthma: A Randomized, Double-Blind, Placebo-Controlled Study
- Trial ID
- 2023-509739-22-00
- Protocol
- AR-DEX-22-03
- Sponsor
- Areteia Therapeutics Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **efficacy** of dexpramipexole on pulmonary function in participants with eosinophilic asthma. This is clinically relevant as improved pulmonary function can lead to better management of asthma symptoms and overall respiratory health in affected individuals.
Secondary objectives include:
- Evaluating the efficacy of dexpramipexole on asthma control, asthma symptoms, and quality of life. This is important for understanding the broader impact of the treatment on daily living and symptom management.
- Assessing the effect of dexpramipexole on blood eosinophils, which can provide insights into the drug's mechanism of action and its potential role in modulating inflammatory responses in eosinophilic asthma.
Participants
The clinical trial investigating the efficacy of dexpramipexole on pulmonary function in individuals with **eosinophilic asthma** includes a total of 525 participants. The study population comprises both male and female subjects aged 12 years and older, with specific age considerations for sites in Poland where participants must be at least 18 years old. Participants were selected based on a documented physician diagnosis of asthma for at least 12 months prior to the screening, and they must be on a stable regimen of daily inhaled corticosteroids and additional asthma controller medications. The trial includes individuals with a pre-bronchodilator FEV1 of less than 80% of the predicted value, or less than 90% for those aged 12 to 17 years, and requires evidence of bronchodilator reversibility. An eosinophil count of at least 0.30x10^9/L is also a criterion for inclusion. The study population is characterized by a requirement for stable medication doses and specific asthma control measures, ensuring a consistent baseline for evaluating the intervention's effects. The trial includes a vulnerable population, indicating additional ethical considerations in the study design.
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 24 weeks in participants with **eosinophilic asthma**. The trial involves the administration of **dexpramipexole** in the form of a film-coated tablet, with a maximum daily dose of 150 mg, and a placebo for comparison. The primary objective is to assess the efficacy of **dexpramipexole** on pulmonary function, specifically measuring the pre-bronchodilator forced expiratory volume in one second (FEV1), with changes from baseline averaged over weeks 20 and 24. Secondary endpoints include changes in the Asthma Control Questionnaire-6 (ACQ-6) and the Asthma Quality of Life Questionnaire for participants aged 12 years and older (AQLQ+12).
The trial is expected to last approximately 24 weeks, with participant involvement beginning at the screening visit and concluding at the end-of-study visit. The sequence of study visits includes an initial screening visit to confirm eligibility, followed by baseline assessments, regular follow-up visits to monitor safety and efficacy, and a final end-of-study visit to evaluate overall outcomes. Participants are required to meet specific inclusion criteria, such as a documented diagnosis of asthma for at least 12 months prior to the screening visit, and must be on stable doses of inhaled corticosteroids and other asthma controller medications. Exclusion criteria are not specified in the provided data.
Participants are expected to remain in the study for the full 24-week duration unless conditions arise that necessitate early termination, such as adverse events or non-compliance with study protocols. The trial is conducted in accordance with ethical guidelines, and informed consent is obtained from all participants. The study is categorized as a Phase III trial, aligning with regulatory standards for clinical development. The trial's estimated recruitment start date was January 4, 2023, with an anticipated end date of September 27, 2024.
Treatment
The clinical trial involves the administration of **Dexpramipexole (KNS-760704)**, a chemical compound formulated as a **film-coated tablet**. The active substance in this medication is **dexpramipexole dihydrochloride monohydrate**. The pharmaceutical form is designed for **oral** administration. Participants in the trial will receive a maximum daily dose of either 75 mg or 150 mg, depending on the specific study group they are assigned to. The treatment period is set for a duration of 24 weeks. The medication is produced by Areteia Therapeutics and is not a pediatric formulation. Compliance with the dosing schedule will be monitored throughout the study to ensure adherence to the protocol.
A **placebo** is also utilized in this study as a comparator treatment. The placebo is designed to mimic the appearance of the experimental medication but does not contain any active pharmaceutical ingredients. It serves as a control to assess the efficacy and safety of Dexpramipexole by providing a baseline for comparison. The placebo is administered in the same manner as the experimental drug, ensuring that the study remains double-blind and that neither the participants nor the investigators are aware of the treatment assignments.
Efficacy
The efficacy of dexpramipexole in the treatment of **eosinophilic asthma** will be assessed through a randomized, double-blind, placebo-controlled, parallel-group study. The primary endpoint for evaluating efficacy is the absolute change from baseline in pre-bronchodilator (pre-BD) forced expiratory volume in one second (FEV1), averaged over Weeks 20 and 24. Secondary endpoints include the change from baseline in the Asthma Control Questionnaire-6 (ACQ-6) scores, averaged across visits at Weeks 20 and 24, and the change from baseline to Week 24 in the standardized version of the Asthma Quality of Life Questionnaire for participants aged 12 years and older (AQLQ+12).
Measurements of these endpoints will be conducted at specified timepoints throughout the 24-week treatment period. The pre-BD FEV1 will be measured using spirometry, a standard laboratory test for assessing lung function. The ACQ-6 and AQLQ+12 are validated scales used to capture patient-reported outcomes related to asthma control and quality of life, respectively. Data collection will occur at baseline and at designated intervals, with analysis focusing on changes from baseline to the specified weeks. This structured approach ensures a comprehensive evaluation of the treatment's impact on pulmonary function and overall asthma management.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Signed informed consent form and assent form, as appropriate.
- Male or female ≥12 years of age at Screening Visit 1. Sites in Poland will only include participants aged ≥18 years.
- Documented physician diagnosis of asthma for ≥12 months prior to Screening Visit 1.
- 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. Note: Poland will include participants requiring a minimum daily medium dose ICS (≥500 μg/day fluticasone propionate dry powder formulation daily or clinically comparable, per GINA 2021). 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. The ICS may be contained within an ICS/ LABA combination product. As noted in Section 5.2.2, daily oral corticosteroids are an allowed concomitant medication.
- Pre-BD FEV1 <80% (<90% for participants 12 to 17 years of age) of predicted Screening Visit 2
- 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.
- ACQ-6 ≥1.5 at Screening Visit 2
- 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)
- 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 steroids) 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, or 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.
- 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-interleukin-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.
- 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 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.
- 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] 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.
- 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.
- Males who are unwilling to use an acceptable method of birth control during the entire study period (ie, condom with spermicide).
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Poland | Not Recruiting | 04 Jan 2023 | 14 |
 Romania | Not Recruiting | 04 Jan 2023 | 11 |
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 | 150 | 24 | PRD10251347 |
Placebo | Placebo | N/A | — | — | — | N/A |
DexpramipexoleKNS-760704 | Test | FILM-COATED TABLET | ORAL | 75 | 24 | PRD10251346 |