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),, MWS with overlapping symptoms of Neonatal Onset Multisystem Inflammatory Disease (NOMID) or Neonatal Onset Multisystem Inflammatory Disease (NOMID),, 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 will provided long-term safety and efficacy data for ACZ885 (a fully human anti-interleukin-1β \[anti-IL-1β\] monoclonal antibody) given as an injection subcutaneously in patients who participated in the CACZ885A2102 (NCT00487708), CACZ885D2201 (NCT00685373) or CACZ885D2304(NCT00465985) studies or newly identified patients with the following cryopyrin-associated periodic syndromes: Familial Cold Autoinflammatory Syndrome, Muckle-Wells Syndrome or Neonatal Onset Multisystem Inflammatory Disease. The duration of this study was 6 months with a maximum duration of 2 years
Interventions
6 mL glass vial containing 150 mg lyophilized Canakinumab reconstituted with water for a subcutaneous injection every 8 weeks. Dosage based on body weight.
Sponsors
Novartis
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
3 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Male and female patients at least 3 years of age 2. Diagnosis of Familial Cold Autoinflammatory Syndrome, Muckle-Wells Syndrome or Neonatal Onset Multisystem Inflammatory Disease. Prior agreement between the Investigator and Novartis for study eligibility is required for patients who do not have a molecular diagnosis of NALP3 mutations available (either testing not performed, or testing performed but negative)upon study entry. For those patients who have not been molecularly tested for NALP3 mutations, molecular testing should be performed during the course of the study 3. For patients under anakinra therapy or any other investigational IL-1 blocking therapy, these treatments should be discontinued prior to the baseline visit. 4. Patients from the CACZ885A2102 study may enter this study. However, dosing at Visit 2 (Baseline Visit) can only occur if either 1) the patient is experiencing disease flare or 2) at least two months have elapsed from their last injection even in the absence of flare, whichever is earlier. 5. Patients who completed the CACZ885D2304 study may enter this study 6. Patients who completed the CACZ885D2201 study may enter this study 7. Patients who discontinued from the CACZ885A2102, CACZ885D2201 or CACZ885D2304 studies and for whom in the Investigator's judgment (with prior agreement from Novartis) continued treatment with ACZ885 in this study is considered appropriate.
Exclusion criteria
1. Participation in any clinical investigation within 4 weeks prior to dosing or longer if required by local regulation with the exception of trials with anakinra, other investigational IL-1 blocking therapies, and/or ACZ885. 2. History of being immunocompromised, including a positive HIV at screening (ELISA and Western blot) test result. 3. A positive Hepatitis B surface antigen (HBsAg) or Hepatitis C antibody test result is not allowed. 4. 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. 5. History of recurrent and/or evidence of active bacterial, fungal, or viral infections. 6. Positive tuberculin skin test reaction (PPD 5 tuberculin units or as according to local standard practice) (\>= 5 mm induration) at 48 to 72 hours after administration at the screening visit or within 2 months prior to the screening visit. Patients who have a positive PPD skin test with a documentation of BCG vaccination, who are at low environmental risk for tuberculosis (TB) infection or reactivation, and have a negative chest X-ray can be included. Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Number of Participants With Adverse Events (AEs), Death, Serious Adverse Events (SAEs), Discontinuation of Study Drug Due to an AE, Infections and Infestations and Injection Site Reactions | 2 years depending on when the participant enters the study | The number of participants with Adverse Events and Infections & Infestations are regardless of study drug relationship by primary system organ class preferred term equal and/or greater than 2% in any group. The number of participants with mild injection site reactions= mild reactions observed on at least one occasion but no moderate or severe reactions. The number of participants with moderate injection site reactions= moderate reactions observed on at least one occasion but no severe reactions. |
Secondary
| 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 Inflammation Markers. | Every 8 weeks during the course of the trial for at least 6 months with a maximum duration of 2 years | 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. |
| Immunogenicity of Canakinumab (ACZ885) | Every 8 weeks during the course of the trial for at least 6 months with a maximum duration of 2 years | The number of participants who tested positive for anti-ACZ885 antibodies using the Biacore Assay at the end of the study. |
| Pharmacokinetics | Every 8 weeks during the course of the trial for at least 6 months with a maximum duration of 2 years | Mean Clearance from serum in Liter per Day (CLD) in adult participants \>=18, pediatric participants \<18 with body weight \>40 kg and pediatric participants \<18 with body weight \<=40 kg. |
Countries
Belgium, France, Germany, India, Italy, Spain, Turkey (Türkiye), United Kingdom, United States
Participant flow
Pre-assignment details
This study included participants previously enrolled in CACZ885A2102 (NCT00487708), CACZ885D2304 (NCT00465985) and ACZ885 naive patients.
Participants by arm
| Arm | Count |
|---|---|
| Canakinumab (ACZ885) Subcutaneous injection every 8 weeks based on participant's body weight. Body weight \>40 kilogram (kg): 150 milligrams (mg) per injection and body weight \<= 40 kg: 2 mg/kg per injection. For participants who did not experience sufficient symptomatic relief, an up-titration to the dose and/or more frequent doses were permitted as per protocol. | 166 |
| Total | 166 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 3 |
| Overall Study | Condition no longer requires study drug | 1 |
| Overall Study | Lack of Efficacy | 3 |
| Overall Study | Lost to Follow-up | 2 |
| Overall Study | Protocol Violation | 1 |
| Overall Study | Withdrawal by Subject | 5 |
Baseline characteristics
| Characteristic | Canakinumab (ACZ885) |
|---|---|
| Age, Customized >= 18 to < 41 years | 65 participants |
| Age, Customized >= 3 to < 18 years | 47 participants |
| Age, Customized >= 41 to < 75 years | 52 participants |
| Age, Customized >= 75 years | 2 participants |
| Disease Characteristics Familial Cold Autoinflammatory Syndrome | 30 participants |
| Disease Characteristics Information Missing | 1 participants |
| Disease Characteristics Muckle-Wells Syndrome | 103 participants |
| Disease Characteristics Neonatal Onset Multi-System Inflammatory Syndrome | 32 participants |
| Gender Female | 97 Participants |
| Gender Male | 69 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 124 / 166 |
| serious Total, serious adverse events | 18 / 166 |
Outcome results
Primary
The Number of Participants With Adverse Events (AEs), Death, Serious Adverse Events (SAEs), Discontinuation of Study Drug Due to an AE, Infections and Infestations and Injection Site Reactions
The number of participants with Adverse Events and Infections & Infestations are regardless of study drug relationship by primary system organ class preferred term equal and/or greater than 2% in any group. The number of participants with mild injection site reactions= mild reactions observed on at least one occasion but no moderate or severe reactions. The number of participants with moderate injection site reactions= moderate reactions observed on at least one occasion but no severe reactions.
Time frame: 2 years depending on when the participant enters the study
Population: Safety Population defined as all participants who received at least one dose of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Canakinumab (ACZ885) | The Number of Participants With Adverse Events (AEs), Death, Serious Adverse Events (SAEs), Discontinuation of Study Drug Due to an AE, Infections and Infestations and Injection Site Reactions | Adverse Event | 150 participants |
| Canakinumab (ACZ885) | The Number of Participants With Adverse Events (AEs), Death, Serious Adverse Events (SAEs), Discontinuation of Study Drug Due to an AE, Infections and Infestations and Injection Site Reactions | Death | 0 participants |
| Canakinumab (ACZ885) | The Number of Participants With Adverse Events (AEs), Death, Serious Adverse Events (SAEs), Discontinuation of Study Drug Due to an AE, Infections and Infestations and Injection Site Reactions | Serious Adverse Event | 18 participants |
| Canakinumab (ACZ885) | The Number of Participants With Adverse Events (AEs), Death, Serious Adverse Events (SAEs), Discontinuation of Study Drug Due to an AE, Infections and Infestations and Injection Site Reactions | Discontinuation of study drug due to an AE | 4 participants |
| Canakinumab (ACZ885) | The Number of Participants With Adverse Events (AEs), Death, Serious Adverse Events (SAEs), Discontinuation of Study Drug Due to an AE, Infections and Infestations and Injection Site Reactions | Infections and Infestations | 109 participants |
| Canakinumab (ACZ885) | The Number of Participants With Adverse Events (AEs), Death, Serious Adverse Events (SAEs), Discontinuation of Study Drug Due to an AE, Infections and Infestations and Injection Site Reactions | Any Injection Site Reactions | 13 participants |
| Canakinumab (ACZ885) | The Number of Participants With Adverse Events (AEs), Death, Serious Adverse Events (SAEs), Discontinuation of Study Drug Due to an AE, Infections and Infestations and Injection Site Reactions | Mild Injection Site Reactions | 11 participants |
| Canakinumab (ACZ885) | The Number of Participants With Adverse Events (AEs), Death, Serious Adverse Events (SAEs), Discontinuation of Study Drug Due to an AE, Infections and Infestations and Injection Site Reactions | Moderate Injection Site Reactions | 2 participants |
Secondary
Immunogenicity of Canakinumab (ACZ885)
The number of participants who tested positive for anti-ACZ885 antibodies using the Biacore Assay at the end of the study.
Time frame: Every 8 weeks during the course of the trial for at least 6 months with a maximum duration of 2 years
Population: Safety Population defined as all participants who received at least one dose of study drug and were tested for anti-ACZ885 antibodies at the end of the study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Canakinumab (ACZ885) | Immunogenicity of Canakinumab (ACZ885) | 0 participants |
Secondary
Pharmacokinetics
Mean Clearance from serum in Liter per Day (CLD) in adult participants \>=18, pediatric participants \<18 with body weight \>40 kg and pediatric participants \<18 with body weight \<=40 kg.
Time frame: Every 8 weeks during the course of the trial for at least 6 months with a maximum duration of 2 years
Population: Safety population defined as all participants who received at least 1 dose of study drug. 3 participants were excluded because dosing information was not available at the time of analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Canakinumab (ACZ885) | Pharmacokinetics | Adult Participants >= 18 years | 0.179 L/day | Standard Deviation 0.084 |
| Canakinumab (ACZ885) | Pharmacokinetics | Pediatric Participants <18 years and >40 kg | 0.180 L/day | Standard Deviation 0.145 |
| Canakinumab (ACZ885) | Pharmacokinetics | Pediatric Participants <18 years and <= 40 kg | 0.083 L/day | Standard Deviation 0.033 |
Secondary
The Percentage of Participants Without Disease Relapse as Determined by the Physician's Global Assessment of Autoinflammatory Disease Activity, Assessment of Skin Disease and 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: Every 8 weeks during the course of the trial for at least 6 months with a maximum duration of 2 years
Population: Safety Population defined as all participants who had at least one dose of study drug and were included in the Relapse Assessment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Canakinumab (ACZ885) | The Percentage of Participants Without Disease Relapse as Determined by the Physician's Global Assessment of Autoinflammatory Disease Activity, Assessment of Skin Disease and Inflammation Markers. | 90.1 Percentage of participants |