Muckle Wells Syndrome
Conditions
Keywords
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
Brief summary
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.
Interventions
DRUGACZ885
DRUGPlacebo
Sponsors
Novartis
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
4 Years to 75 Years
Healthy volunteers
No
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/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent of Participants With Disease Flare in Part II (After 24 Weeks of the Double-blind Part) | 32 weeks after study start | 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. |
| Number of Participants Who Experienced a Disease Flare in Part II | 32 weeks after study start | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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)) | 48 weeks after study start | Assessed serum clearance of ACZ885. |
| Number of Participants With Treatment Response in Part I (After 8 Weeks) | 8 weeks after study start | 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. |
| 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 | — |
| Pharmacodynamics Measured by Interleukin-1β (IL-1β) Concentrations at End of Part I. | until Week 8 | — |
| 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) | 32 weeks after study start | 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 |
Countries
France, Germany, India, Spain, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| ACZ885 ACZ885 150 mg subcutaneous injection or 2 mg/kg subcutaneous injection, depending on body weight, every 8 weeks. | 35 |
| Total | 35 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Part II - 1:1 ACZ885:Placebo | Unsatisfactory therapeutic effect | 0 | 12 |
| Part III - Open-label Treatment Period | Adverse Event | 1 | 0 |
| Part III - Open-label Treatment Period | Unsatisfactory therapeutic effect | 1 | 0 |
| Part I - Open-label Treatment Period | Unsatisfactory therapeutic effect | 4 | 0 |
Baseline characteristics
| Characteristic | ACZ885 |
|---|---|
| Age, Continuous | 34 years STANDARD_DEVIATION 14.89 |
| Sex: Female, Male Female | 25 Participants |
| Sex: Female, Male Male | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 27 / 35 | 15 / 15 | 14 / 16 | 24 / 31 | 35 / 35 |
| serious Total, serious adverse events | 0 / 35 | 0 / 15 | 0 / 16 | 2 / 31 | 2 / 35 |
Outcome results
Primary
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.
Time frame: 32 weeks after study start
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ACZ885 | Number of Participants Who Experienced a Disease Flare in Part II | 0 Participants |
| Placebo | Number of Participants Who Experienced a Disease Flare in Part II | 13 Participants |
Primary
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.
Time frame: 32 weeks after study start
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ACZ885 | Percent of Participants With Disease Flare in Part II (After 24 Weeks of the Double-blind Part) | 0 percent of participants |
| Placebo | Percent of Participants With Disease Flare in Part II (After 24 Weeks of the Double-blind Part) | 81.3 percent of participants |
Secondary
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.
Time frame: Week 8 and Week 32
Population: Intention to treat (ITT)population and LOCF.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| ACZ885 | 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. | C reactive protein (CRP (mg/L)) | 1.10 mg/L | Standard Deviation 3.086 |
| ACZ885 | 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. | Serum amyloid A (SAA (mg/L)) | 2.27 mg/L | Standard Deviation 8.604 |
| Placebo | 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. | C reactive protein (CRP (mg/L)) | 19.93 mg/L | Standard Deviation 24.175 |
| Placebo | 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. | Serum amyloid A (SAA (mg/L)) | 71.09 mg/L | Standard Deviation 136.637 |
Secondary
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
Time frame: 32 weeks after study start
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| ACZ885 | 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) | Minimal | 7 Participants |
| ACZ885 | 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) | Moderate | 0 Participants |
| ACZ885 | 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) | Mild | 0 Participants |
| ACZ885 | 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) | Severe | 0 Participants |
| ACZ885 | 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) | Absent | 8 Participants |
| Placebo | 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) | Severe | 0 Participants |
| Placebo | 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) | Absent | 0 Participants |
| Placebo | 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) | Minimal | 4 Participants |
| Placebo | 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) | Mild | 8 Participants |
| Placebo | 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) | Moderate | 4 Participants |
Secondary
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.
Time frame: 8 weeks after study start
| Arm | Measure | Group | Value (NUMBER) | Dispersion |
|---|---|---|---|---|
| ACZ885 | Number of Participants With Treatment Response in Part I (After 8 Weeks) | Complete response | 31 Participants | 25.2 |
| ACZ885 | Number of Participants With Treatment Response in Part I (After 8 Weeks) | Partial response | 2 Participants | — |
| ACZ885 | Number of Participants With Treatment Response in Part I (After 8 Weeks) | Disease flare | 1 Participants | — |
| ACZ885 | Number of Participants With Treatment Response in Part I (After 8 Weeks) | Non-responder (protocol violation) | 1 Participants | — |
Secondary
Pharmacodynamics Measured by Interleukin-1β (IL-1β) Concentrations at End of Part I.
Time frame: until Week 8
Population: Intention to treat (ITT) population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ACZ885 | Pharmacodynamics Measured by Interleukin-1β (IL-1β) Concentrations at End of Part I. | 19.047 pg/mL | Standard Deviation 17.6609 |
Secondary
Pharmacodynamics Measured by Interleukin-1β (IL-1β) Concentrations at End of Part II.
Time frame: 32 weeks after study start
Population: Intention to treat (ITT) population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ACZ885 | Pharmacodynamics Measured by Interleukin-1β (IL-1β) Concentrations at End of Part II. | 21.943 pg/mL | Standard Deviation 10.3698 |
| Placebo | Pharmacodynamics Measured by Interleukin-1β (IL-1β) Concentrations at End of Part II. | 0.596 pg/mL | Standard Deviation 0.7289 |
Secondary
Pharmacodynamics Measured by Interleukin-1β (IL-1β) Concentrations at End of Part III.
Time frame: 48 weeks after study start
Population: Intention to treat (ITT) population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ACZ885 | Pharmacodynamics Measured by Interleukin-1β (IL-1β) Concentrations at End of Part III. | 23.018 pg/mL | Standard Deviation 16.5193 |
Secondary
Pharmacokinetics (CLD (L/d))
Assessed serum clearance of ACZ885.
Time frame: 48 weeks after study start
Population: Patients in Part I and Part II who received at least one dose of ACZ885.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ACZ885 | Pharmacokinetics (CLD (L/d)) | 0.177 L/day | Standard Deviation 0.085 |