Efficacy and Safety Evaluation of Methyl-(1-{[6-{[(1S)-1-Cyclopropylethyl]amino}-2-(pyrazolo[5,1-b][1,3]thiazol-7-yl)-pyrimidin-4-yl]carbonyl}piperidin-4-yl)carbamate-Mono(4-methylbenzenesulfonate) Monohydrate in Eosinophilic Granulomatosis with Polyangiitis
- Trial ID
- 2023-504245-32-00
- Protocol
- NS229-P2-01
- Sponsor
- Ns Pharma Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **efficacy** and **safety** of NS-229 compared with placebo in the treatment of **Eosinophilic Granulomatosis with Polyangiitis (EGPA)**. This will be assessed by analyzing the number of EGPA subjects in remission and the number of adverse events. Understanding the efficacy and safety profile of NS-229 is clinically relevant as it may offer a new therapeutic option for patients with EGPA, a condition characterized by inflammation of small to medium-sized blood vessels, which can lead to significant morbidity.
The secondary objectives are to further investigate the efficacy and safety of NS-229 compared with placebo by analyzing the number of EGPA subjects in remission and the time to worsening or relapse of EGPA. These secondary endpoints will provide additional insights into the potential benefits and risks associated with NS-229, contributing to a comprehensive understanding of its therapeutic value in managing EGPA.
Participants
The clinical trial involves a total of **25 participants** diagnosed with **Eosinophilic granulomatosis with polyangiitis (EGPA)**. The study population includes both male and female subjects aged 18 years and older. Participants were selected based on their ability to provide written informed consent and a confirmed diagnosis of EGPA, characterized by eosinophilia and at least two additional features such as neuropathy, pulmonary infiltrates, or asthma. The trial population is not restricted by gender, and both male and female subjects are included. Participants are required to have a **BVAS** score of 3 or higher and must be on a specific dose of prednisone or prednisolone. The study does not specify any particular lifestyle considerations such as diet or physical activity. The selection criteria ensure that the participants are representative of the general population affected by EGPA, while also considering the need for effective contraception among participants of childbearing potential. The trial does not provide additional information regarding the general health status or specific lifestyle habits of the participants.
Plans and Procedures
The clinical trial is a **Phase 2**, double-blind, randomized, placebo-controlled study designed to evaluate the efficacy and safety of NS-229 in the treatment of **eosinophilic granulomatosis with polyangiitis (EGPA)**. The trial will involve the administration of NS-229, a Janus kinase (JAK) 1 inhibitor, in tablet form, compared to a placebo. The primary objective is to assess the proportion of subjects in remission and the number of adverse events over a 28-week treatment period. The study is expected to commence recruitment in April 2024 and conclude by December 2026.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, diagnosis of EGPA, and disease activity. Following successful screening, participants will be randomized to receive either NS-229 or placebo. The trial will include regular follow-up visits to monitor efficacy and safety endpoints, including the assessment of remission status and adverse events. The end-of-study visit will occur at the conclusion of the 28-week treatment period, where final evaluations will be conducted.
The expected duration of participant involvement is approximately 28 weeks, with conditions for early termination including significant adverse events or withdrawal of consent. Participants must adhere to study protocols, including the use of effective contraception for the duration of the study and for 90 days after the last dose of the study treatment. The trial's design ensures rigorous assessment of both primary and secondary endpoints, contributing valuable data on the potential benefits and risks of NS-229 in managing EGPA.
Treatment
The clinical trial involves the administration of **NS-229**, an experimental medication formulated as a tablet. The active substance in NS-229 is **methyl-(1-{[6-{[(1S)-1-cyclopropylethyl]amino}-2-(pyrazolo[5,1-b][1,3]thiazol-7-yl)-pyrimidin-4-yl]carbonyl}piperidin-4-yl)carbamate-mono(4-methylbenzenesulfonate) monohydrate**, which functions as a Janus kinase (JAK) 1 inhibitor. The medication is administered orally. The dosing schedule and specific dosage amounts are not detailed in the provided data, but the maximum treatment period is specified as 28 days. Participant compliance with the dosing regimen will be monitored throughout the study.
In addition to the experimental treatment, the study includes a **placebo** group. The placebo is designed as NS-229 matching tablets with no active treatment, ensuring that the appearance and administration route are identical to the active medication. This placebo control is essential for maintaining the double-blind nature of the trial, allowing for an unbiased comparison of the efficacy and safety of NS-229 in the treatment of **Eosinophilic Granulomatosis With Polyangiitis** (EGPA). The placebo tablets are also administered orally, with the same treatment period of up to 28 days.
Efficacy
The efficacy of NS-229 in the treatment of **Eosinophilic Granulomatosis With Polyangiitis (EGPA)** will be assessed through a series of primary and secondary endpoints. The primary efficacy endpoint is the proportion of subjects in remission, defined as oral glucocorticoid (OGC) 4.0, at Week 28 of the study treatment period. Secondary efficacy endpoints include the proportion of subjects in remission with OGC 7.5 at Week 28, the time to first relapse of EGPA, and the time to first worsening of EGPA. These endpoints will be measured at specified timepoints throughout the trial to evaluate the treatment's impact on disease activity and remission rates.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Ability to provide written informed consent prior to participation in the study. Subjects must be able to read, comprehend, and write at a level sufficient to complete study-related materials
- Male or female subjects aged ≥18 years at the time the informed consent form is signed
- Diagnosis of EGPA: Subjects who have been diagnosed with EGPA based on the history or presence of eosinophilia plus at least a history or presence of 2 of the following additional features of EGPA: a) A biopsy showing histopathological evidence of eosinophilic vasculitis, perivascular eosinophilic infiltration, or eosinophil-rich granulomatous inflammation b) Neuropathy, mono or poly c) Pulmonary infiltrates, non-fixed d) Sinonasal abnormality e) Cardiomyopathy f) Glomerulonephritis g) Alveolar hemorrhage h) Palpable purpura i) Positive test result for ANCA j) Asthma
- 4a: BVAS ≥3 on date of screening visit, using the standard 28-day look-back period and prednisone/prednisolone dose ≥7.5 mg/day. OR 4b: Disease activity of EGPA within 60 days of screening visit that is equivalent to BVAS ≥3 and prednisone/prednisolone dose ≥20 mg/day on day of screening.
- Female subjects of childbearing potential must commit to the consistent and correct use of highly effective methods of contraception from the time of informed consent until 90 days after the last dose of study treatment. Male subjects with pregnant partners or nonpregnant partners of childbearing potential must agree to use adequate and reliable contraception from informed consent (screening) until 90 days after the last dose of study treatment. (see Appendix 3 for additional guidance).
Exclusion Criteria
- Current diagnosis of either granulomatosis with polyangiitis or microscopic polyangiitis
- Parasitic infection: Subjects with a known parasitic infestation within 6 months prior to screening
- HIV-positive status
- Active hepatitis due to hepatitis B virus or hepatitis C virus
- History of hypersensitivity to the investigational product (IP) and prednisolone/prednisone, its excipients, or similar drugs (JAK inhibitors) and if used, to mepolizumab or benralizumab.
- Known history or presence of venous thromboembolism/venous thrombotic events
- Use of any of the following prohibited medications within the time points specified: a) Requirement of an OGC dose of prednisolone/prednisone >60 mg/day at baseline b) Previous receipt of a Janus kinase inhibitor c) Initiation of treatment with mepolizumab after screening d) Omalizumab within 130 days prior to baseline e) Rituximab within 180 days prior to baseline f) Dupilumab within 100 days prior to baseline g) Reslizumab within 120 days prior to baseline h) Initiation of treatment with Benralizumab after screening (Visit 1) i) Intravenous or subcutaneous immunoglobulin within 180 days prior to baseline j) Interferon-α within 180 days prior to baseline k) Antitumor necrosis factor therapy within 12 weeks prior to baseline l) Anti-CD52 within 180 days prior to baseline m) Cyclophosphamide (CYC): Subjects who received a CYC-based induction regimen may be randomized a minimum of 2 weeks after the last dose of daily oral CYC, or 3 weeks after the last dose of intravenous CYC, if their total WBC count is ≥4 × 109/L n) Any non-glucocorticoid immunosuppressive therapy (excluding CYC, mepolizumab or benralizumab) within 7 days prior to baseline o) The medications, as per the list of medications listed in Appendix 8 of the protocol, are prohibited within 7 days or 5 half-lives prior to baseline, whichever is longer.
- Receipt of any live vaccine within 4 weeks prior to the first dose of study treatment or expected need for live vaccination during study participation including at least 4 weeks after the last dose of study treatment
- Other laboratory parameter exclusions: a) Estimated glomerular filtration rate of <30 mL/min/1.73 m2 by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations (2021 CKD-EPI Creatinine) b) WBC count <4 × 109/L c) Absolute lymphocyte count <500 cells/mm3 d) Absolute neutrophil count <1000 cells/mm3 e) Platelet count <120,000/mm3 f) Hemoglobin <8 g/dL (<80 g/L)
- Subjects who are pregnant, breastfeeding, or planning to become pregnant during the time of study participation
- History of clinically significant drug or alcohol abuse within the last 6 months
- Imminently life-threatening EGPA defined as the presence of any of the following manifestations as active disease at the time of screening: a) Hospitalization in an intensive care unit b) Severe alveolar hemorrhage requiring transfusion or ventilation, or hemoglobin <8 g/dL (<80 g/L) or drop in hemoglobin of >2 g/dL (>20 g/L) over a 48-hour period due to alveolar hemorrhage c) Rapidly progressive glomerulonephritis over a 48-hour period d) Severe gastrointestinal involvement e) Severe central nervous system involvement f) Severe cardiac involvement
- Receipt of treatment with an IP within the past 30 days or 5 terminal phase half-lives of the IP, whichever is longer, prior to screening
- Current participation in any other interventional clinical study
- Unwilling or unable to comply with the protocol
- Suspected, probable, or confirmed diagnosis of active COVID-19
- Other concurrent disease and/or medical condition that may put the subject at risk or may influence the results of the study or the subject’s ability to complete the entire duration of the study
- History or presence of any form of cancer within 5 years prior to screening, with the exception of excised basal cell or squamous cell carcinoma of the skin, or carcinoma in situ such as cervical or breast carcinoma in situ that has been excised or resected completely and is without evidence of local recurrence or metastasis.
- Serious liver, renal, blood, or psychiatric disease a) Moderate and severe hepatic impairment by the Child-Pugh scoring system
- Severe or clinically significant cardiovascular disease uncontrolled with standard treatment
- Electrocardiogram measurement of corrected QT by Fridericia >450 ms
- Other concurrent medical conditions: Subjects who have known, preexisting, clinically significant endocrine, autoimmune, metabolic, neurologic, renal, gastrointestinal, hepatic, hematologic, respiratory, or any other system abnormalities that are not associated with EGPA and are uncontrolled with standard treatment and considered by the Investigator to be a contraindication for the subject to participate in the study
- Active tuberculosis (TB) or meets TB exclusionary parameters [German, Italy, Spain, and French subjects:] Active, previous, or latent tuberculosis (TB) or meets TB exclusionary parameters
- Active systemic infections
- French subjects: persons under court protection, persons not affiliated to a social security system, protected adults ((Art. L. 1121-5), Art. L. 1121-6, Art. L. 1121-8, Art. L. 1121-8-1).
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Recruiting | 01 Apr 2024 | 5 |
 Germany | Recruiting | 01 Apr 2024 | 1 |
 Italy | Recruiting | 01 Apr 2024 | 7 |
 Spain | Not Recruiting | 01 Apr 2024 | 7 |
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 |
|---|---|---|---|---|---|---|
NS-229 | Test | TABLET | ORAL USE | 0 | 28 | PRD10841483 |
NS-229 matching tablets with no active treatment | Placebo | N/A | — | — | — | N/A |