| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated | | Severe Eosinophilic Asthma | |
| E.1.1.1 | Medical condition in easily understood language | |
| E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 | | E.1.2 | Level | LLT | | E.1.2 | Classification code | 10068462 | | E.1.2 | Term | Eosinophilic asthma | | E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders | |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial | | • To demonstrate the efficacy of dexpramipexole in reducing severe asthma exacerbations. | |
| E.2.2 | Secondary objectives of the trial | • 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. | |
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria | 1.Signed informed consent form and assent form, as appropriate.
2.Male or female ≥12 years of age at Screening Visit 1.
Asthma-related criteria
3.Documented physician diagnosis of asthma for ≥12 months prior to Screening Visit 1.
4.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.
5.Pre-BD FEV1 ≥40% and <80% (<90% for participants 12 to 17 years of age) of predicted at Screening Visit 2.
6.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.
7.ACQ-6 ≥1.5 at Screening Visit 2.
8.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.
General medical history
9.Negative urine pregnancy test for women of childbearing potential (WOCBP; after menarche) at the Screening Visit 2 and Baseline Visit.
10.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.
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 would 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 would be considered postmenopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatment.
| |
| E.4 | Principal exclusion criteria | 1.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.
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,hypereosinophilic syndrome,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 Visit 1.
4.For participants aged 12 to 17 years old,AEC of <0.15x10ˆ9/L at Screening Visit 1.
Prohibited medications/procedures
5.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.
6.Treatment with any of the following monoclonal antibody therapies within 120 days prior to Baseline Visit:benralizumab,dupilumab,mepolizumab,resizumab,omalizumab,tezepelumab,or tralokinumab.
7.Treatment with pramipexole(Mirapex®) within 30 days of Baseline Visit.
8.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).
9.Bronchial thermoplasty procedure in the past 12 months prior to Screening Visit 1 or planned during the coming year.
10.Weight <40 kg at Screening Visit 2.
11.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.
12.Known or suspected alcohol or drug abuse
13.Uncontrolled severe hypertension:systolic blood pressure >180 mmHg or diastolic blood pressure >110 mmHg prior to the Baseline Visit despite anti-hypertensive therapy.
14.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
15.History of human immunodeficiency virus(HIV) infection or chronic infection with hepatitis B or C.
16.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.
17.Medical or other condition likely to interfere with participant’s ability to undergo study procedures,adhere to visit schedule,or comply with study requirements.
18.Known or suspected noncompliance with medication.
19.Unwillingness or inability to follow the procedures outlined in the protocol.
20.Absolute neutrophil count <2.000x10ˆ9/L at Scrn Visit 1 or Scrn Visit 2.
21.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).
22.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.
Cardiac safety
23.History of New York Heart Association class IV heart failure or last known left ventricular ejection fraction <25%.
24.History of major adverse cardiovascular event (MACE) within 3 months prior to the Baseline Visit.
25.History of cardiac arrhythmia within 3 months prior to the Baseline Visit that is not controlled by medication or via ablation.
26.History of long QT syndrome.
27.Corrected QT interval by Fridericia(QTcF) interval >450 ms for males and >470ms for females at Screening Visit 2 or QTcF ≥480ms for participants with bundle branch block.
28.Clinically important abnormalities in resting ECG that may interfere with the interpretation of QTcF interval changes at Screening Visit 2,including heart rate <45 beats per minute (bpm) or >100 bpm.
29.Pregnant women or women breastfeeding.
30.Males who are unwilling to use an acceptable method of birth control during the entire study period(ie,condom with spermicide). | |
| E.5 End points |
| E.5.1 | Primary end point(s) | | •Annualized rate of severe asthma exacerbations (AAER) over 52 weeks. | |
| E.5.1.1 | Timepoint(s) of evaluation of this end point | |
| E.5.2 | Secondary end point(s) | •Pre-BD FEV1, absolute change from baseline, averaged across visits at Weeks 36, 44, and 52.
•Asthma Control Questionnaire-6 (ACQ-6), change from baseline, averaged across visits at Weeks 36, 44, and 52.
•Standardized version of the Asthma Quality of Life Questionnaire for 12 years and older (AQLQ+12) change from baseline to Week 52.
| |
| E.5.2.1 | Timepoint(s) of evaluation of this end point | | Please refer to the clinical study Protocol | |
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 | The trial involves single site in the Member State concerned | No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 10 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 4 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned | | Argentina | | Colombia | | North Macedonia | | Brazil | | Georgia | | Korea, Republic of | | Mexico | | Serbia | | United Kingdom | | United States | | Bulgaria | | Hungary | | Poland | | Romania | |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 | Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial | |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
