A Clinical Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of ZYIL1 in Subjects With Cryopyrin Associated Periodic Syndromes (CAPS)

Study Overview
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Brief Summary
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ZYIL1 is expected to show benefit in patients with CAPS. The present study aims to determine the safety, tolerability, pharmacokinetics, and pharmacodynamics of ZYIL1 when administered to subjects with CAPS.

Detailed Description
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This is a phase 2a, prospective, open-label study. Primary objective of the study is to determine safety and tolerability profile of twice daily oral administration of ZYIL1 administered for 7 days. The study will be conducted in 3 subjects having CAPS as per eligibility criteria. The study will be divided in three periods: Screening Period; Run-in Period and Study Period.

Official Title
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A Phase 2a, Prospective, Open-Label Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of ZYIL1 in Subjects With Cryopyrin Associated Periodic Syndromes (CAPS)

Conditions
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Cryopyrin Associated Periodic Syndrome

Intervention / Treatment
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* Drug: ZYIL1 capsule


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects with a confirmed diagnosis of CAPS (FCAS, NOMID, or MWS) aged 18 to 75 years inclusive at screening A confirmed diagnosis of CAPS comprises the following: Subject has previously experienced at least 2 typical clinical symptoms of CAPS (may include urticarial skin rash, myalgia, arthralgia, recurrent fever, fatigue/malaise, headache, conjunctivitis, and any other autoinflammatory symptom); and Documented verification of a genetic mutation in NLRP3. Positive response of ZYIL1 in inhibiting secreted IL-1β from peripheral blood mononuclear cells isolated from the subject's blood treated with LPS ex vivo showing half maximal inhibitory concentration below 500 nM. Subject must be willing to discontinue current anti-IL-1 treatment prior to study drug dosing if applicable. Subject must demonstrate flaring of CAPS de novo or after discontinuation of anti-IL-1 inhibitor treatment. Flaring is defined as worsening of disease activity as per physician global assessment of disease activity with elevation of CRP (>2 x upper limit of normal [ULN]). Subject must have a body mass index (BMI) between ≥18.0 and ≤38.0 kg/m2 at Screening. Female subject of reproductive age must be non-pregnant and non-lactating, and must use an acceptable, highly effective contraception from screening until 1 month after the last dose of study drug. Male subject must be willing to use contraception and must not donate sperm for at least 90 days after the last dose of study drug. Exclusion Criteria: Any severe, progressive, or uncontrolled medical condition within the past 3 months that might have impact on the clinical trial as per the investigator's discretion. Use of any investigational drug or investigational medical device or participation in other clinical study within 4 weeks prior to Screening or 5 half- lives of the product (whichever is longer). Any clinically significant laboratory or ECG findings during the screening in the opinion of the Investigator. Estimated glomerular filtration rate (eGFR) < 90 mL/min/1.73m2, as measured by the Cockcroft-Gault equation at screening Total bilirubin above upper limit of normal (ULN) or AST(SGOT)/ALT(SGPT) > 1.5 times of ULN at screening QT interval corrected for heart rate using Fridericia's method (QTcF) > 450 msec at screening History of clinically significant hypersensitivity, intolerance, or allergies, as determined by the investigator. History of fever, cough or any other active systemic infections within 2 weeks prior to receiving study drug. History or presence of alcohol abuse (alcohol consumption more than 40 g/4 units/4standard drinks per day), or drug habituation, or any prior intravenous usage of an illicit substance Surgery within last 3 months or planned major surgery within next 3 months from the date of screening (other than minor cosmetic surgery and minor dental surgery). Subjects who have donated one unit (490 mL) of blood in the past 3 months. Use or intend to use any medications/products known to alter drug absorption, metabolism, or elimination processes including St John's Wort within 4 weeks prior to receiving study drug and up to end of study. Use of such medication will be considered on a case-by-case basis as per the opinion of the investigator and/or independent medical monitor, or use of grapefruit or similar substances (Seville oranges or marmalade, grapefruit juice, grapefruit hybrids, pomelos, exotic citrus fruits or fruit juices) within 7 days prior to the Run-in period. Use or intend to use any over-the-counter (vitamins, minerals, and phytotherapeutic/herbal/plant-derived preparations) or prescription medications within 7 days or 5 half-lives (whichever is longer) prior to receiving study drug, with the exception of hormone replacement therapy and therapies for chronic stable diseases that have been stable for at least 30 days prior to screening and until Day 1, unless deemed acceptable by the investigator History of or positive screening test for hepatitis C infection (defined as positive for hepatitis C virus antibody), hepatitis B infection (defined as positive for hepatitis B surface antigen), or human immunodeficiency virus I or II. Female subjects who are pregnant, currently breastfeeding, or attempting to conceive. Any disorder that, in the Investigator's opinion, may interfere with study compliance, such as significant mental, nervous disorder or other illness. In making this assessment, the Investigator must refer to the study information provided including the Investigator's Brochure. Inability to be venipuncture or tolerate venous puncture. Any condition or abnormal baseline findings that in investigator's judgment might increase the risk to the subject or decrease the chance of obtaining satisfactory data needed to obtain the objective of the study. Other unspecified reasons that, in the opinion of the investigator make the subject unsuitable for the study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ZYIL1 Capsule<br>subject will receive 50 mg twice daily (BD) dose for 7 days | Drug: ZYIL1 capsule<br>* NLRP3 inflammasome inhibitor<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence and Severity of Adverse event of ZYIL1 | The Common Terminology Criteria for Adverse Event (CTCAE) (Version 5.0 or higher) system will be used for reporting and grading | Baseline to Day 7 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum concentration (Cmax) | Blood samples will be withdrawn on Day 1 and Day 7 to evaluate maximum concentration | Pre-dose to Day 7 | 
| To evaluate disease activity scores based on 5 point physician and patient global assessment over 7 days treatment of ZYIL1 | Physician global assessment on 5 point scale score will be taken | Baseline to Day 10 | 
| Time to reach maximum concentration (Tmax) | Blood samples will be withdrawn on Day 1 and Day 7 to evaluate Time to reach maximum concentration | Pre-dose to Day 7 | 
| Area under the curve for dosing interval(12 hours) AUCtau | Blood samples will be withdrawn on Day 1 and Day 7 to evaluate AUCtau | Pre-dose to Day 7 | 
| Change in WBC count | Blood samples will be collected from pre-dose till Day 10 to evaluate the change | Baseline to Day 10 | 
| Change in IL-1β | Blood samples will be collected from pre-dose till Day 10 to evaluate the change | Baseline to Day 10 | 
| Change in Serum amyloid protein A | Blood samples will be collected from pre-dose till Day 10 to evaluate the change | Baseline to Day 10 | 
| Change in IL-6 | Blood samples will be collected from pre-dose till Day 10 to evaluate the change | Baseline to Day 10 | 
| Change in CRP | Blood samples will be collected from pre-dose till Day 10 to evaluate the change | Baseline to Day 10 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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NLRP3, NLPR3 Inflammasone inhibitor