Efficacy, Safety, and Tolerability of ACZ885 in Patients With Muckle-Wells Syndrome

Study Overview
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Brief Summary
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This study is designed to provide efficacy and safety data for ACZ885 (a fully human anti-interleukin-1beta (anti-IL-1beta) monoclonal antibody) administered as an injection subcutaneously (s.c.) in patients with Muckle-Wells Syndrome. Part I is an 8-week open-label, active treatment period to identify ACZ885 responders. Part II is a double-blind, placebo-controlled period to assess primarily the efficacy of ACZ885 compared to placebo. Part III is an open-label, active treatment period where patients will receive ACZ885 every 8 weeks after withdrawal or completion of Part II.

Official Title
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A Three-part,Multicenter Study,With a Randomized,Double-blind,Placebo Controlled,Withdrawal Design in Part II to Assess Efficacy,Safety,and Tolerability of ACZ885(Anti-interleukin-1beta Monoclonal Antibody)in Patients With Muckle-Wells Syndrome

Conditions
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Muckle Wells Syndrome

Intervention / Treatment
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* Drug: ACZ885
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Molecular diagnosis of NALP3 mutations and clinical picture resembling Muckle-Wells Syndrome. Muckle-Wells Syndrome patients who participated in the CACZ885A2102 study, will have the option to participate in this study upon disease flare Muckle-Wells Syndrome patients requiring medical intervention either untreated or treated (i.e. under ACZ885, anakinra, or any other investigational IL-1 blocking therapy). Exclusion Criteria: History of being immunocompromised, including a positive HIV at screening test result. No live vaccinations within 3 months prior to the start of the trial, during the trial, and up to 3 months following the last dose. History of significant medical conditions, which in the Investigator's opinion would exclude the patient from participating in this trial. History of recurrent and/or evidence of active bacterial, fungal, or viral infections. Positive tuberculin skin test at 48 to 72 hours after administration at the screening visit or within 2 months prior to the screening visit, according to national guidelines. Other protocol-defined inclusion/exclusion criteria may apply

Ages Eligible for Study
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Minimum Age: 4 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part I, Part II-arm1, & Part III<br> | Drug: ACZ885<br> <br> |
| Placebo Comparator: Part II - arm 2<br> | Drug: Placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent of Participants With Disease Flare in Part II (After 24 Weeks of the Double-blind Part) | Determined by the Physician's global assessment of autoinflammatory disease activity, assessment of skin disease and inflammation markers. Data expressed as a percent of participants who had experienced a flare by the end of Part II. | 32 weeks after study start | 
| Number of Participants Who Experienced a Disease Flare in Part II | Disease flare is determined by the Physician's global assessment of autoinflammatory disease activity, assessment of skin disease and inflammation markers. Disease Flare = the C-reactive protein and/or serum amyloid A (SAA) > 30 mg/L and either a PGA > minimal, or PGA equal to minimal and > minimal SD. | 32 weeks after study start | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment Response in Part I (After 8 Weeks) | Treatment response was based on Physician's global assessment(PGA) of autoinflammatory disease activity, assessment of skin disease(SD) and serum values of C-reactive protein(CRP) and/or serum amyloid A(SAA). Complete Response (CR):PGA and SD ≤ minimal and normal CRP and/or SAA. Partial Response (PR): a reduction of CRP and/or SAA from baseline (BL) by >30% but not reaching normal values and PGA improvement from BL by at least one category. Disease flare: a CRP and/or SAA > 30 mg/L and either PGA > minimal or PGA = minimal and SD > minimal. Non-responders = no PR by Day 8 or no CR by Day 15. | 8 weeks after study start | 
| Investigator's Clinical Assessment of Autoinflammatory Disease Activity & Participant's Assessment of Symptoms at End of Part II (After 24 Weeks of the Double-blind Part) | A 5-point scale was used for the Physician's global assessment on autoinflammatory disease activity (absent, minimal, mild, moderate and severe) and for the assessment of the following items: skin disease (urticarial skin rash) arthralgia myalgia headache/migraine conjunctivitis fatigue/malaise other symptoms related to autoinflammatory syndrome other symptoms not related to autoinflammatory syndrome | 32 weeks after study start | 
| Change in Inflammation Markers at the End of Part II (C-reactive Protein and/or Serum Amyloid A) (After 24 Weeks of the Double-blind Part) From Week 8. |  | Week 8 and Week 32 | 
| Pharmacokinetics (CLD (L/d)) | Assessed serum clearance of ACZ885. | 48 weeks after study start | 
| Pharmacodynamics Measured by Interleukin-1β (IL-1β) Concentrations at End of Part I. |  | until Week 8 | 
| Pharmacodynamics Measured by Interleukin-1β (IL-1β) Concentrations at End of Part II. |  | 32 weeks after study start | 
| Pharmacodynamics Measured by Interleukin-1β (IL-1β) Concentrations at End of Part III. |  | 48 weeks after study start | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Muckle-Wells Syndrome, children, systemic autoinflammatory disease, CIAS-1 gene, NALP-3, ACZ885, human monoclonal anti-human interleukin-1beta (IL-1beta), antibody, autosomal dominant, familial autoinflammatory syndrome