Randomized, Double‑Blind, Placebo‑Controlled Trial of Oral Dexpramipexole (KNS‑760704) as Add‑On to Standard Inhaled Therapy in Adolescents and Adults with Severe Eosinophilic Asthma
- Trial ID
- 2023-503693-20-00
- Protocol
- AR-DEX-22-02
- 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 severe asthma exacerbations significantly impact patient morbidity and healthcare utilization, and effective management can improve patient outcomes and quality of life.
Secondary objectives include:
- To demonstrate the efficacy of dexpramipexole on pulmonary function.
- To demonstrate the efficacy of dexpramipexole on asthma control and quality of life.
- To evaluate the effect of dexpramipexole on blood eosinophils.
Participants
The clinical trial investigating the efficacy of dexpramipexole in reducing severe asthma exacerbations involves a total of **834 participants**. The study population includes both **male and female** subjects aged **12 years and older**, with a documented physician diagnosis of **asthma** for at least 12 months prior to the screening. Participants were selected based on specific criteria, including an eosinophil count of at least 0.30x109/L and a history of asthma exacerbations requiring systemic corticosteroids within the past year. The trial includes individuals who have been on a stable regimen of medium or high-dose inhaled corticosteroids, possibly in combination with other asthma controller medications, for at least three months prior to the screening. The study population is characterized by variable airflow obstruction and a pre-bronchodilator FEV1 between 40% and 80% of the predicted value. Both genders are represented, and the trial includes a vulnerable population, ensuring a comprehensive assessment of the treatment's efficacy across a diverse group of individuals with severe eosinophilic asthma.
Plans and Procedures
The clinical trial is designed as a **randomized, double-blind, placebo-controlled, parallel-group study** to evaluate the efficacy, safety, and tolerability of **dexpramipexole** administered orally over a period of 52 weeks in participants with severe eosinophilic asthma. The primary objective is to demonstrate the efficacy of dexpramipexole in reducing severe asthma exacerbations. The trial will include several key phases, beginning with a screening visit to confirm eligibility based on specific inclusion criteria, such as a documented diagnosis of asthma for at least 12 months and an eosinophil count of ≥0.30x109/L. Participants will be required to have a history of asthma exacerbations and be on a stable dose of asthma controller medication.
Following the screening, eligible participants will be randomized to receive either dexpramipexole or a placebo. The trial will involve multiple study visits, including baseline, periodic follow-up visits at weeks 36, 44, and 52, and an end-of-study visit. These visits are designed to monitor the participants' health, assess the primary endpoint of the annualized rate of severe asthma exacerbations, and evaluate secondary endpoints such as changes in pre-bronchodilator FEV1 and asthma control questionnaire scores. The expected length of participant involvement is 52 weeks, with conditions for early termination including significant adverse events or withdrawal of consent.
Throughout the trial, participants will be monitored for safety and efficacy outcomes, with data collected on the annualized rate of severe asthma exacerbations and other secondary endpoints. The trial is expected to conclude by August 2025, with recruitment starting in September 2023. The study is categorized as a phase III therapeutic confirmatory trial, aligning with EMA guidance on clinical trial disclosure rules. Participants will be required to adhere to the study protocol, including the use of effective birth control methods for women of childbearing potential, and maintain stable asthma treatment regimens as outlined in the inclusion criteria.
Treatment
The clinical trial involves the administration of **Dexpramipexole (KNS-760704)**, an experimental medication, in the form of a film-coated tablet. The active substance is **dexpramipexole dihydrochloride monohydrate**. The pharmaceutical form is a film-coated tablet, and the medication is administered orally. The maximum daily dose is 150 mg, with a total maximum dose of 54,600 mg over a treatment period of 52 weeks. Participant compliance is monitored through regular assessments to ensure adherence to the dosing schedule.
In addition to the experimental treatment, the study includes the use of **Budesonide/Formoterol Teva Pharma B.V.**, which is an inhalation powder containing the active substances **budesonide** and **formoterol fumarate dihydrate**. This medication is administered via inhalation, with a maximum daily dose of 2400 micrograms. It serves as a standard-of-care therapy for participants with severe eosinophilic asthma.
The trial also incorporates the use of **Ventolin**, a pressurised inhalation suspension containing **salbutamol sulfate**. This medication is administered via inhalation, with a maximum daily dose of 1000 micrograms. It is used as a comparator treatment to evaluate the efficacy of the experimental medication.
A **placebo** is also utilized in the study to maintain the double-blind nature of the trial. The placebo is administered in a manner consistent with the experimental treatment to ensure blinding is maintained. The placebo does not contain any active substances and is used to assess the true efficacy of the experimental medication by comparison.
Efficacy
The efficacy of dexpramipexole in the clinical trial will be assessed primarily by measuring the **annualized rate of severe asthma exacerbations (AAER)** over a 52-week period. This primary endpoint is designed to evaluate the reduction in severe asthma exacerbations in participants with severe eosinophilic asthma. 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, as well as changes from baseline in the Asthma Control Questionnaire-6 (ACQ-6) and the standardized version of the Asthma Quality of Life Questionnaire for participants aged 12 years and older (AQLQ+12), with assessments at Weeks 36, 44, and 52.
Data collection will involve validated scales and questionnaires, such as the ACQ-6 and AQLQ+12, to capture patient-reported outcomes related to asthma control and quality of life. The schedule for efficacy assessments includes specific timepoints throughout the trial, ensuring comprehensive data collection for analysis. The trial is structured as a randomized, double-blind, placebo-controlled, parallel-group study, which supports the objective evaluation of dexpramipexole's efficacy in reducing severe asthma exacerbations.
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.
- 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): 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 or 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% (<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: 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 (≥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. b. Bronchodilator reversibility, using the criteria above, documented in the past 24 months prior to Screening Visit 1. c. Peak flow variation of ≥20% over a 2-week period, documented in the past 24 months prior to Screening Visit 1. d. Airflow variability in clinic FEV1 ≥20% between two consecutive clinic visits, documented in the past 24 months prior to Screening Visit 1. e. 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.
- Negative urine pregnancy test for women of childbearing potential (WOCBP; after menarche) at Screening and Baseline.
- WOCBP (after menarche) 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 IUS, or oral contraceptive. 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 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.
- 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 [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 (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 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 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.
- 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 |
|---|---|---|---|
 Czechia | Not Yet Recruiting | 30 Sept 2023 | 20 |
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 |
|---|---|---|---|---|---|---|
Budesonide/Formoterol Teva Pharma B.V. 160 micrograms / 4.5 micrograms inhalation powder | Other | INHALATION POWDER | INHALATION USE | 2400 | 425 | PRD8003526 |
Ventolin 100 microgramos/inhalación suspensión para inhalación en envase a presión* (*) sin CFC | Other | SUSPENSIÓN PARA INHALACIÓN EN ENVASE A PRESIÓN. | INHALATION USE | 1000 | 425 | PRD391605 |
Placebo | Placebo | N/A | — | — | — | N/A |
DexpramipexoleKNS-760704 | Test | FILM-COATED TABLET | ORAL USE | 150 | 52 | PRD10251346 |
Ventolin 100 mikrogramų/išpurškime suslėgtoji įkvepiamoji suspensija | Other | SUSLĖGTOJI ĮKVEPIAMOJI SUSPENSIJA. | INHALATION USE | 1000 | 425 | PRD390130 |
Ventolin Inhaler N Suspenze k inhalaci v tlakovém obalu | Other | SUSPENZE K INHALACI V TLAKOVÉM OBALU | INHALATION USE | 1000 | 425 | PRD418497 |
Sultanol Dosier-Aerosol
100 Mikrogramm/Dosis Druckgasinhalation, Suspension | Other | DRUCKGASINHALATION, SUSPENSION | INHALATION USE | 1000 | 425 | PRD378061 |
DexpramipexoleKNS-760704 | Test | FILM-COATED TABLET | ORAL USE | 300 | 52 | PRD10251347 |
Ventolin Evohaler túlnyomásos inhalációs szuszpenzió | Other | TÚLNYOMÁSOS INHALÁCIÓS SZUSZPENZIÓ | INHALATION USE | 1000 | 425 | PRD401111 |
Novolizer Salbutamol Meda 100 Mikrogramm/Dosis Pulver zur Inhalation | Other | PULVER ZUR INHALATION | INHALATION USE | 1000 | 425 | PRD537300 |