Cryopyrin-associated Periodic Syndromes, Familial Cold Autoinflammatory Syndrome, Muckle-Wells Syndrome, Neonatal Onset Multisystem Inflammatory Disease
Conditions
Keywords
Cryopyrin-associated periodic syndromes (CAPS), Familial Cold Autoinflammatory Syndrome (FCAS), Muckle-Wells Syndrome (MWS), Neonatal Onset Multisystem Inflammatory Disease (NOMID), children, systemic autoinflammatory disease, CIAS-1 gene, NALP-3, NLRP3, ACZ885, canakinumab, human monoclonal anti-human interleukin-1 antibody, autosomal dominant, familial autoinflammatory syndrome, childhood immunizations vaccinations
Brief summary
This trial will provide long-term safety, efficacy and tolerability of ACZ885 in CAPS patients that completed the CACZ885D2307 study
Interventions
BIOLOGICALACZ885
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Eligibility
Sex/Gender
ALL
Age
1 Years to 4 Years
Healthy volunteers
No
Inclusion criteria
1. Patients who completed the core CACZ885D2307 study (a patient is defined as having completed the core study if they completed the study up to and including the EOS visit with no major protocol deviations in the core). 2. Male and female patients that are ≥ 1 year of age at the time of the roll-over visit. 3. Parent or legal guardian written informed consent must be obtained before any assessment in the extension CACZ885D2307E1 study is performed.
Exclusion criteria
1. Patients for who continued treatment in the CACZ885D2307E1 extension study is not considered appropriate by the treating physician. 2. Patients who discontinued from the core CACZ885D2307 study Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Percentage of Participants Without Disease Relapse as Determined by the Physician's Global Assessment of Autoinflammatory Disease Activity, Assessment of Skin Disease and Serological Inflammation Markers. | Week /80, 104, 128, and 152 (A minimum of 6 months and maximum of 24 months) | Disease relapse following complete response is defined as inflammation markers: C-Reactive Protein (CRP) and/or Serum Amyloid A (SAA) result \> 30 mg/L AND Physician's Global Assessment of Autoinflammatory Disease Activity \> minimal or Physician's Global Assessment \>= minimal AND Skin Disease Assessment \> minimal. Physician's Global Assessment of Autoinflammatory Disease Activity and Skin Disease Assessment (urticarial skin rash) are completed by the investigator using a 5 point rating scale: absent, minimal, mild, moderate and severe. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Immunogenicity of Canakinumab (ACZ885). Number of Participants With Anti-canakinumab Antibodies | minimum of 6 months and maximum of 24 months | Immunogenicity assessment included determination of anti-canakinumab (ACZ885) antibodies in serum samples using BIAcore system, with detection based on surface plasmon resonance technique. |
| Change From Baseline (Core Study Baseline) in C--Reactive Protein (CRP) and Serum Amyloid A (SAA) Concentrations | Week 0, 80, 104, 128 and 152, last assessment | CRP and SAA were used as serologic inflammatory markers. The target level concentrations for CRP and SAA was ≤15 mg/L and ≤10 mg/L, respectively. Negative change in concentration of inflammatory markers indicated improvement. |
| Frequency Counts of Physician's Global Assessment of Autoinflammatory Disease and Skin Disease | minimum of 6 months and maximum of 24 months | Participants were assessed based by physician on Physician's Global Assessment measured on a 5--point scale for auto inflammatory disease activity as: 0 = None/absent; 1 = Minimal; 2 = Mild; 3 = Moderate; 4 = Severe |
| Number of Vaccination Cases With Protective Antibody Levels Following Immunization With Inactivated Vaccines | pre-vaccine dose, Day 28 post-vaccine | Participants who received any inactivated vaccines during the study were assessed for their ability to attain protective antibody levels against the vaccine (antigen) post immunization. Participants vaccinations were not assessed for a response if the antibody titre was already sufficient at pre-dose and maintained during the study. |
Countries
Belgium, Canada, France, Germany, Spain, Switzerland, United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Canakinumab Patients will receive a standard dose at an equivalent of 2 mg/kg s.c. of canakinumab (ACZ885) every 8 weeks. Possible dose and/or dosing regimen adjustments that can be administered include: 4 mg/kg s.c. (every 4 to 8 weeks) 6 mg/kg s.c. (every 4 to 8 weeks) 8 mg/kg s.c. (every 4 to 8 weeks) | 17 |
| Total | 17 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Moved to commercial use after 6 months | 1 |
| Overall Study | Unsatisfactory therapeutic effect | 2 |
Baseline characteristics
| Characteristic | Canakinumab |
|---|---|
| Age, Continuous Age at start of extension study (years) | 3.1 Years STANDARD_DEVIATION 1.7 |
| Sex: Female, Male Female | 5 Participants |
| Sex: Female, Male Male | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 16 / 17 |
| serious Total, serious adverse events | 8 / 17 |
Outcome results
Primary
The Percentage of Participants Without Disease Relapse as Determined by the Physician's Global Assessment of Autoinflammatory Disease Activity, Assessment of Skin Disease and Serological Inflammation Markers.
Disease relapse following complete response is defined as inflammation markers: C-Reactive Protein (CRP) and/or Serum Amyloid A (SAA) result \> 30 mg/L AND Physician's Global Assessment of Autoinflammatory Disease Activity \> minimal or Physician's Global Assessment \>= minimal AND Skin Disease Assessment \> minimal. Physician's Global Assessment of Autoinflammatory Disease Activity and Skin Disease Assessment (urticarial skin rash) are completed by the investigator using a 5 point rating scale: absent, minimal, mild, moderate and severe.
Time frame: Week /80, 104, 128, and 152 (A minimum of 6 months and maximum of 24 months)
Population: Extension Full analysis set (FAS) consisted of all patients who received at least one dose of study drug in the extension study
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Canakinumab | The Percentage of Participants Without Disease Relapse as Determined by the Physician's Global Assessment of Autoinflammatory Disease Activity, Assessment of Skin Disease and Serological Inflammation Markers. | 94.1 Percentage of participants |
Secondary
Change From Baseline (Core Study Baseline) in C--Reactive Protein (CRP) and Serum Amyloid A (SAA) Concentrations
CRP and SAA were used as serologic inflammatory markers. The target level concentrations for CRP and SAA was ≤15 mg/L and ≤10 mg/L, respectively. Negative change in concentration of inflammatory markers indicated improvement.
Time frame: Week 0, 80, 104, 128 and 152, last assessment
Population: Extension Full analysis set (FAS) consisted of all patients who received at least one dose of study drug in the extension study
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Canakinumab | Change From Baseline (Core Study Baseline) in C--Reactive Protein (CRP) and Serum Amyloid A (SAA) Concentrations | CRP at Core End of Study (last assessment) (n=14) | -5.4 (mg/L) | Standard Deviation 6.28 |
| Canakinumab | Change From Baseline (Core Study Baseline) in C--Reactive Protein (CRP) and Serum Amyloid A (SAA) Concentrations | CRP at week 80 (n=16) | -14.7 (mg/L) | Standard Deviation 35.8 |
| Canakinumab | Change From Baseline (Core Study Baseline) in C--Reactive Protein (CRP) and Serum Amyloid A (SAA) Concentrations | CRP at Week 104 (n=11) | -3.8 (mg/L) | Standard Deviation 14.4 |
| Canakinumab | Change From Baseline (Core Study Baseline) in C--Reactive Protein (CRP) and Serum Amyloid A (SAA) Concentrations | CRP at Week 128(n=12) | -4.1 (mg/L) | Standard Deviation 10.3 |
| Canakinumab | Change From Baseline (Core Study Baseline) in C--Reactive Protein (CRP) and Serum Amyloid A (SAA) Concentrations | SAA at End of Study (last assessment) (n=15) | -58.5 (mg/L) | Standard Deviation 183.6 |
| Canakinumab | Change From Baseline (Core Study Baseline) in C--Reactive Protein (CRP) and Serum Amyloid A (SAA) Concentrations | CRP at Week 152 (n=12) | -4.3 (mg/L) | Standard Deviation 11 |
| Canakinumab | Change From Baseline (Core Study Baseline) in C--Reactive Protein (CRP) and Serum Amyloid A (SAA) Concentrations | CRP at End of Study (last assessment) (n=16) | -10.4 (mg/L) | Standard Deviation 30.3 |
| Canakinumab | Change From Baseline (Core Study Baseline) in C--Reactive Protein (CRP) and Serum Amyloid A (SAA) Concentrations | SAA at Core End of Study (last assessment) (n=16) | -54.4 (mg/L) | Standard Deviation 133.8 |
| Canakinumab | Change From Baseline (Core Study Baseline) in C--Reactive Protein (CRP) and Serum Amyloid A (SAA) Concentrations | SAA at Week 80 (n=12) | -79.1 (mg/L) | Standard Deviation 224.1 |
| Canakinumab | Change From Baseline (Core Study Baseline) in C--Reactive Protein (CRP) and Serum Amyloid A (SAA) Concentrations | SAA at week 104 (n=11) | 15.8 (mg/L) | Standard Deviation 158.1 |
| Canakinumab | Change From Baseline (Core Study Baseline) in C--Reactive Protein (CRP) and Serum Amyloid A (SAA) Concentrations | SAA at week 128 (n=10) | -28.2 (mg/L) | Standard Deviation 47.4 |
| Canakinumab | Change From Baseline (Core Study Baseline) in C--Reactive Protein (CRP) and Serum Amyloid A (SAA) Concentrations | SAA at week 152 (n=11) | -6.4 (mg/L) | Standard Deviation 60 |
Secondary
Frequency Counts of Physician's Global Assessment of Autoinflammatory Disease and Skin Disease
Participants were assessed based by physician on Physician's Global Assessment measured on a 5--point scale for auto inflammatory disease activity as: 0 = None/absent; 1 = Minimal; 2 = Mild; 3 = Moderate; 4 = Severe
Time frame: minimum of 6 months and maximum of 24 months
Population: Extension Full analysis set (FAS) consisted of all patients who received at least one dose of study drug in the extension study
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Canakinumab | Frequency Counts of Physician's Global Assessment of Autoinflammatory Disease and Skin Disease | Assessment of autoinflammatory disease (Absent) | 64.7 Percentage of participants |
| Canakinumab | Frequency Counts of Physician's Global Assessment of Autoinflammatory Disease and Skin Disease | Assessment of skin disease (Minimal) | 0 Percentage of participants |
| Canakinumab | Frequency Counts of Physician's Global Assessment of Autoinflammatory Disease and Skin Disease | Assessment of skin disease (Mild) | 5.9 Percentage of participants |
| Canakinumab | Frequency Counts of Physician's Global Assessment of Autoinflammatory Disease and Skin Disease | Assessment of skin disease (Moderate) | 0 Percentage of participants |
| Canakinumab | Frequency Counts of Physician's Global Assessment of Autoinflammatory Disease and Skin Disease | Assessment of skin disease (Severe) | 0 Percentage of participants |
| Canakinumab | Frequency Counts of Physician's Global Assessment of Autoinflammatory Disease and Skin Disease | Assessment of autoinflammatory disease (Minimal) | 29.4 Percentage of participants |
| Canakinumab | Frequency Counts of Physician's Global Assessment of Autoinflammatory Disease and Skin Disease | Assessment of autoinflammatory disease (Mild) | 5.9 Percentage of participants |
| Canakinumab | Frequency Counts of Physician's Global Assessment of Autoinflammatory Disease and Skin Disease | Assessment of autoinflammatory disease (Moderate) | 0 Percentage of participants |
| Canakinumab | Frequency Counts of Physician's Global Assessment of Autoinflammatory Disease and Skin Disease | Assessment of autoinflammatory disease (Severe) | 0 Percentage of participants |
| Canakinumab | Frequency Counts of Physician's Global Assessment of Autoinflammatory Disease and Skin Disease | Assessment of skin disease (Absent) | 94.1 Percentage of participants |
Secondary
Immunogenicity of Canakinumab (ACZ885). Number of Participants With Anti-canakinumab Antibodies
Immunogenicity assessment included determination of anti-canakinumab (ACZ885) antibodies in serum samples using BIAcore system, with detection based on surface plasmon resonance technique.
Time frame: minimum of 6 months and maximum of 24 months
Population: Extension Safety set consisted of all patients from the core study who received at least one dose of study drug in the extension study and had at least one post-treatment safety assessment. Of note, the statement that a patient had no AE also constituted a safety assessment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Canakinumab | Immunogenicity of Canakinumab (ACZ885). Number of Participants With Anti-canakinumab Antibodies | 0 Participants |
Secondary
Number of Vaccination Cases With Protective Antibody Levels Following Immunization With Inactivated Vaccines
Participants who received any inactivated vaccines during the study were assessed for their ability to attain protective antibody levels against the vaccine (antigen) post immunization. Participants vaccinations were not assessed for a response if the antibody titre was already sufficient at pre-dose and maintained during the study.
Time frame: pre-vaccine dose, Day 28 post-vaccine
Population: Extension Full analysis set (FAS) consisted of all patients who received at least one dose of study drug in the extension study. Out of 20 unique patient-vaccination cases, 17 cases were assessable for a vaccination response due to availability of pre dose antibody titer.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Canakinumab | Number of Vaccination Cases With Protective Antibody Levels Following Immunization With Inactivated Vaccines | Positive response for antibody levels | 16 vaccination cases |
| Canakinumab | Number of Vaccination Cases With Protective Antibody Levels Following Immunization With Inactivated Vaccines | No pre-dose antibody levels | 3 vaccination cases |