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Efficacy and Safety of Oral Dexpramipexole in Adolescents and Adults with Severe Eosinophilic Asthma: A Randomized, Double-Blind, Placebo-Controlled Study

Trial ID: 2023-503693-20-01
Protocol: AR-DEX-22-02
Sponsor: Areteia Therapeutics Inc.

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Diseases & Conditions

Asthma

Objectives

The primary objective of this study is to demonstrate the efficacy of **dexpramipexole** in reducing severe asthma exacerbations in patients 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, which is crucial for assessing the overall respiratory health and capacity of patients.
To demonstrate the efficacy of dexpramipexole on asthma control and quality of life, as improved asthma control can lead to better daily functioning and reduced symptom burden.
To evaluate the effect of dexpramipexole on blood eosinophils, which are key inflammatory markers in eosinophilic asthma and can provide insights into the drug's mechanism of action and potential anti-inflammatory effects.

Participants

The clinical trial investigating the efficacy of dexpramipexole in reducing severe asthma exacerbations involves a total of **745 participants**. The study population includes both **male and female** subjects, aged **12 years and older**, with participants in the EU required to be at least **18 years of age**. The trial specifically targets individuals diagnosed with **severe eosinophilic asthma**, characterized by an eosinophil count of at least 0.30x10⁹/L. Participants have a documented history of asthma for at least 12 months and have been on medium or high-dose inhaled corticosteroids for a minimum of 12 months prior to the screening. The trial includes individuals who have experienced at least two asthma exacerbations requiring systemic corticosteroid treatment in the past year. The study population was selected based on these criteria, ensuring a focus on those with significant asthma management needs. The trial includes a vulnerable population, indicating additional ethical considerations in the study design. Participants' lifestyle factors, such as diet and physical activity, are not specified in the available data.

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 a series of study visits, beginning with an inclusion (screening) visit, followed by multiple follow-up visits, and concluding with an end-of-study visit. The inclusion visit will assess eligibility based on criteria such as age, documented diagnosis of asthma, and specific eosinophil count levels. Participants will be required to have a documented history of asthma exacerbations and meet specific lung function criteria.

Throughout the trial, participants will be randomly assigned to receive either dexpramipexole or a placebo, with neither the participants nor the investigators aware of the group assignments, ensuring the double-blind nature of the study. The trial will span approximately 52 weeks, with participants expected to attend regular follow-up visits to monitor their health status, medication adherence, and any adverse events. The primary endpoint is the annualized rate of severe asthma exacerbations over the 52-week period, while secondary endpoints include changes in pre-bronchodilator FEV1 and scores on the Asthma Control Questionnaire-6 and the Asthma Quality of Life Questionnaire.

Participant involvement is expected to last for the entire 52-week duration unless specific conditions necessitate early termination. Such conditions may include significant adverse reactions, non-compliance with the study protocol, or withdrawal of consent. The study aims to provide comprehensive data on the potential benefits and risks associated with dexpramipexole in treating severe eosinophilic asthma, contributing valuable insights into its clinical application.

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 route of administration is oral. The maximum daily dose is 300 mg, with a total maximum dose of 105,000 mg over a treatment period of 52 weeks. The medication is provided by Areteia Therapeutics and is classified as a chemical substance.

Participants in the trial will also receive **Ventolin Evohaler**, a pressurised inhalation suspension containing **salbutamol sulfate** as the active substance. This medication is used as an auxiliary treatment and is administered via inhalation. The maximum daily dose is 1000 µg, with a total maximum dose of 425,000 µg over a treatment period of 425 days. The product is manufactured by GlaxoSmithKline Trading Services Limited and is classified as a chemical substance.

Another auxiliary treatment used in the study is **Novolizer Salbutamol Meda**, an inhalation powder containing **salbutamol sulfate**. This medication is also administered via inhalation, with a maximum daily dose of 1000 µg and a total maximum dose of 425,000 µg over 425 days. The product is provided by Mylan Österreich GmbH and is classified as a chemical substance.

The trial includes a **placebo** group, which serves as a comparator treatment. The placebo is not associated with any active substance and is used to maintain the double-blind nature of the study. The pharmaceutical form and route of administration for the placebo are not specified.

Additionally, **Budesonide/Formoterol Teva Pharma B.V.** is used as an auxiliary treatment. This inhalation powder contains a combination of **budesonide** and **formoterol fumarate dihydrate**. It is administered via inhalation, with a maximum daily dose of 2400 µg and a total maximum dose of 1,020,000 µg over 425 days. The product is manufactured by Teva Pharma B.V. and is classified as a mixture and chemical substance.

Participant compliance with the dosing schedule will be monitored throughout the study to ensure adherence to the treatment regimen. The trial aims to assess 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 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 (FEV1), averaged across visits at Weeks 36, 44, and 52, as well as changes from baseline in the Asthma Control Questionnaire-6 (ACQ-6) scores 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 multiple timepoints throughout the trial, specifically at Weeks 36, 44, and 52, to ensure comprehensive evaluation of the treatment's impact over time. The analysis will focus on comparing the changes from baseline in these parameters to determine the efficacy of dexpramipexole in reducing asthma exacerbations and improving lung function and quality of life in the study population.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Signed informed consent form and assent form, as appropriate.
Male or female ≥18 years of age at Screening Visit 1.
Documented physician diagnosis of asthma for ≥12 months prior to Screening Visit 1.
Eosinophil count of ≥0.30x10^9/L at Screening Visit 1. If the initial value is between0.250x10^9/L to 0.299x10^9/L, then this may be repeated once at an unscheduled visit (priorto 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 orhigh dose ICS (≥500 μg/day fluticasone propionate dry powder formulation dailyor clinically comparable, per GINA 2021) on a regular basis for at least12 months prior to Screening Visit 1. Equivalent medium and high dose ICSdoses are detailed in Appendix C. b.Documented treatment with a stable dose of either medium or high dose ICS forat least 3 months prior to Screening Visit 1. The ICS may be contained within anICS/LABA combination product. As noted in Section 5.2.2, daily oralcorticosteroids are an allowed concomitant medication; participants on daily oralcorticosteroids must be on a stable dose for 3 months before Screening Visit 1. c.Use of one or more additional daily maintenance asthma controller medicationsaccording to standard practice of care is required; eg, LABA, leukotrieneantagonist, theophylline, long-acting muscarinic antagonists. Use of a stable doseof any additional asthma controller medications must be documented for at least3 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 thebronchodilator reversibility inclusion criterion but have ≥10% and ≥160 mLreversibility may repeat the reversibility spirometry assessment once during theScreening 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) at the Screening and Baseline visits.
WOCBP (after menarche) must use either of the following methods of birth control, from Screening Visit 1 through the End of Study Visit (refer to Section 8.3.3.1 for details): 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 or more 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 (FSH) 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.

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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.
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-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. Monoclonal antibody therapies should not be delayed or excluded for the sole purpose of inclusion in this clinical trial.
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.
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 or positive serology at Screening Visit 2 (in EU countries).
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 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 (ANC) <2.000x10^9/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
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 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 breast feeding
Males who are unwilling to use an acceptable method of birth control during the entire study period (ie, condom with spermicide).
Allergy or hypersensitivity to dexpramipexole or any of its components.

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
Austria	Not Recruiting	03 Jan 2024	15
Croatia	Not Recruiting	03 Jan 2024	20
Czechia	Not Recruiting	03 Jan 2024	75
France	Not Recruiting	03 Jan 2024	69
Germany	Not Recruiting	03 Jan 2024	50
Hungary	Not Recruiting	03 Jan 2024	35
Italy	Not Recruiting	03 Jan 2024	171
Lithuania	Not Recruiting	03 Jan 2024	15
Spain	Not Recruiting	03 Jan 2024	40

Sites & Investigators

Research sites

Pneumologisches Studienzentrum MVZ dieLungenaerzte Pneumologie Odeonsplatz MUDr. Jaroslav Mares - ordinace pro TBC a respiracní nemoci Azienda Ospedaliera di Padova

Investigators

Gerald E.Gordana P.Robab B. K.Janos M.

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
Placebo	Placebo	N/A	—	—	—	N/A
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
Novolizer Salbutamol Meda 100 Mikrogramm/Dosis Pulver zur Inhalation	Other	PULVER ZUR INHALATION	INHALATION USE	1000	425	PRD537300
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
Ventolin 100 mikrogramų/išpurškime suslėgtoji įkvepiamoji suspensija	Other	SUSLĖGTOJI ĮKVEPIAMOJI SUSPENSIJA.	INHALATION USE	1000	425	PRD390130
DexpramipexoleKNS-760704	Test	FILM-COATED TABLET	ORAL USE	150	52	PRD10251346
Budesonide/Formoterol Teva Pharma B.V. 160 micrograms / 4.5 micrograms inhalation powder	Other	INHALATION POWDER	INHALATION USE	2400	425	PRD8003526
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

Also investigated for

Asthma 10 Chronic obstructive pulmonary disease 6 Conjunctivitis allergic 2 Crohn's disease 2