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Efficacy, Safety and Tolerability of ACZ885 in Pediatric Patients With the Following Cryopyrin-associated Periodic Syndromes: Familial Cold Autoinflammatory Syndrome, Muckle-Wells Syndrome, or Neonatal Onset Multisystem Inflammatory Disease

Primary Purpose

Cryopyrin-associated Periodic Syndromes, Familial Cold Autoinflammatory Syndrome, Muckle-Wells Syndrome

Status
Completed
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
ACZ885
Sponsored by
Novartis Pharmaceuticals
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Cryopyrin-associated Periodic Syndromes focused on measuring Cryopyrin-associated periodic syndromes (CAPS), Familial Cold Autoinflammatory Syndrome (FCAS), Muckle-Wells Syndrome (MWS) or Neonatal Onset Multisystem Inflammatory Disease (NOMID), children, systemic autoinflammatory disease, CIAS-1 gene, NALP-3, NLRP3, ACZ885, Ilaris, human monoclonal anti-human interleukin-1 beta (IL-beta), antibody, autosomal dominant, familial autoinflammatory syndrome

Eligibility Criteria

1 Month - 60 Months (Child)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Male and female patients that are 28 days up to 60 months of age at the time of the screening visit.
  2. Body weight > or = 2.5 kg.
  3. Parent or legal guardian's written informed consent is required before any assessment is performed for patients.
  4. At study entry, patients should have a clinical diagnosis of FCAS, MWS, or NOMID and symptoms requiring pharmacological intervention. 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.
  5. For patients treated with an IL-1 blocking agent (i.e. anakinra, rilonacept), these treatments should be discontinued prior to the baseline visit and patients must demonstrate active disease prior to treatment.
  6. Patients who are scheduled to receive an immunization, according to their local vaccination guidelines, with an inactivated vaccine must be willing to participate in the assessment schedule for vaccinated patients.

Exclusion Criteria:

  1. Preterm neonates for whom, in the Investigator's judgment, participation in the study is not deemed appropriate.
  2. History of recurrent and/or evidence of active bacterial, fungal, or viral infections (including HIV).
  3. Patients with immunodeficiency or treatment with immunosuppressive drugs.
  4. Live vaccinations within < or = 3 months prior to screening. No live vaccinations will be allowed throughout the course of this study and up to 3 months following the last dose.
  5. Patients with an increased risk of tuberculosis (TB) infection according to following risk factors:

    • Patients with recent close contact with persons known to have active pulmonary TB disease
    • Foreign-born patients from countries with a high prevalence of tuberculosis
    • Patients with recent tuberculosis infection (including children > 6 months with a positive PPD test [defined as an induration of at least 10mm])
    • Patients with end-stage renal disease
    • Patients with diabetes mellitus
    • Patients receiving immunosuppressive therapy
    • Patients with hematologic cancers.
  6. Participation in another trial within the last 30 days or 5 half-lives of the investigational compound (whichever is longer).
  7. Familial and social conditions rendering regular medical assessment not possible.
  8. Pediatric patients with neutropenia (absolute neutrophil count [ANC] < 1.5 x 10 to the 9th/l)

Other protocol defined inclusion/exclusion criteria may apply

Sites / Locations

  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Canakinumab

Arm Description

Canakinumab s.c. injection (2 mg/kg) was administered every 8 weeks.

Outcomes

Primary Outcome Measures

Percentage of Participants Aged 4 Years or Younger With at Least One Complete Response at Week 56
Complete response was defined as clinical remission and serological remission. Clinical remission was defined as Physician global assessment of auto-inflammatory disease activity as absent or minimal (using a 5-point scale ranging from absent to severe) and assessment of skin disease as absent or minimal (using a 5-point scale ranging from absent to severe). Serological remission was defined as C reactive protein (CRP) or Serum amyloid A protein (SAA) to be less than (<) 15 milligram per liter (mg/L) and <10 mg/L respectively.

Secondary Outcome Measures

Percentage of Participants Aged 2 Years or Younger With at Least One Complete Response at Week 56
Complete response was defined as clinical remission and serological remission. Clinical remission was defined as Physician global assessment of auto-inflammatory disease activity as absent or minimal (using a 5-point scale ranging from absent to severe) and assessment of skin disease as absent or minimal (using a 5-point scale ranging from absent to severe). Serological remission was defined as CRP or SAA to be <15 mg/L and <10 mg/L respectively.
Percentage of Participants With Defined Grades in Physician's Global Assessment Score at Week 56
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.
Percentage of Participants With Defined Grades in Physician Assessment of Skin Disease at Week 56
Participants were assessed by physician for skin disease (urticarial skin rash) measured on a 5--point scale as: 0 = None/absent; 1 = Minimal; 2 = Mild; 3 = Moderate; 4 = Severe.
Change From Baseline in C--Reactive Protein (CRP) and Serum Amyloid A (SAA) Concentrations at Week 56
The CRP and SAA were used as 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.
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
Adverse events (AEs) were defined as any unfavorable and unintended diagnosis, symptom, sign (including an abnormal laboratory finding), syndrome or disease which either occurs during study, having been absent at baseline, or, if present at baseline, appears to worsen. Serious adverse events (SAEs) were defined as any untoward medical occurrences that result in death, are life threatening, require (or prolong) hospitalization, cause persistent or significant disability/incapacity, result in congenital anomalies or birth defects, or are other conditions which in judgement of investigators represent significant hazards.
Percentage of Participants Receiving a Concomitant Vaccination During the Study
Participants received any one of the following inactivated vaccines as per the immunization program: Corynebacterium diphtheria, Bordetella pertussis, Neisseria meningitidis, Clostridium tetani, Influenza type A, Influenza type B, Haemophilus influenza B, Streptococcus pneumoniae, or Hepatitis B were determined.
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.
Number of Participants With Anti-canakinumab Antibodies at Week 56
Immunogenicity assessment included determination of anti-canakinumab (ACZ885) antibodies in serum samples using BIAcore system, with detection based on surface plasmon resonance technique.

Full Information

First Posted
February 22, 2011
Last Updated
February 28, 2017
Sponsor
Novartis Pharmaceuticals
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1. Study Identification

Unique Protocol Identification Number
NCT01302860
Brief Title
Efficacy, Safety and Tolerability of ACZ885 in Pediatric Patients With the Following Cryopyrin-associated Periodic Syndromes: Familial Cold Autoinflammatory Syndrome, Muckle-Wells Syndrome, or Neonatal Onset Multisystem Inflammatory Disease
Official Title
A One-year Open-label, Multicenter Trial to Assess Efficacy, Safety and Tolerability of Canakinumab (ACZ885) and the Efficacy and Safety of Childhood Vaccinations in Patients Aged 4 Years or Younger With Cryopyrin Associated Periodic Syndromes (CAPS)
Study Type
Interventional

2. Study Status

Record Verification Date
February 2017
Overall Recruitment Status
Completed
Study Start Date
November 2010 (undefined)
Primary Completion Date
November 2014 (Actual)
Study Completion Date
November 2014 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Novartis Pharmaceuticals

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This trial will assess the safety, efficacy and tolerability of ACZ885 in patients aged 4 years and younger with cryopyrin associated periodic syndromes (CAPS)

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Cryopyrin-associated Periodic Syndromes, Familial Cold Autoinflammatory Syndrome, Muckle-Wells Syndrome, Neonatal Onset Multisystem Inflammatory Disease
Keywords
Cryopyrin-associated periodic syndromes (CAPS), Familial Cold Autoinflammatory Syndrome (FCAS), Muckle-Wells Syndrome (MWS) or Neonatal Onset Multisystem Inflammatory Disease (NOMID), children, systemic autoinflammatory disease, CIAS-1 gene, NALP-3, NLRP3, ACZ885, Ilaris, human monoclonal anti-human interleukin-1 beta (IL-beta), antibody, autosomal dominant, familial autoinflammatory syndrome

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
17 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Canakinumab
Arm Type
Experimental
Arm Description
Canakinumab s.c. injection (2 mg/kg) was administered every 8 weeks.
Intervention Type
Drug
Intervention Name(s)
ACZ885
Primary Outcome Measure Information:
Title
Percentage of Participants Aged 4 Years or Younger With at Least One Complete Response at Week 56
Description
Complete response was defined as clinical remission and serological remission. Clinical remission was defined as Physician global assessment of auto-inflammatory disease activity as absent or minimal (using a 5-point scale ranging from absent to severe) and assessment of skin disease as absent or minimal (using a 5-point scale ranging from absent to severe). Serological remission was defined as C reactive protein (CRP) or Serum amyloid A protein (SAA) to be less than (<) 15 milligram per liter (mg/L) and <10 mg/L respectively.
Time Frame
Week 56
Secondary Outcome Measure Information:
Title
Percentage of Participants Aged 2 Years or Younger With at Least One Complete Response at Week 56
Description
Complete response was defined as clinical remission and serological remission. Clinical remission was defined as Physician global assessment of auto-inflammatory disease activity as absent or minimal (using a 5-point scale ranging from absent to severe) and assessment of skin disease as absent or minimal (using a 5-point scale ranging from absent to severe). Serological remission was defined as CRP or SAA to be <15 mg/L and <10 mg/L respectively.
Time Frame
Week 56
Title
Percentage of Participants With Defined Grades in Physician's Global Assessment Score at Week 56
Description
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
Week 56
Title
Percentage of Participants With Defined Grades in Physician Assessment of Skin Disease at Week 56
Description
Participants were assessed by physician for skin disease (urticarial skin rash) measured on a 5--point scale as: 0 = None/absent; 1 = Minimal; 2 = Mild; 3 = Moderate; 4 = Severe.
Time Frame
Week 56
Title
Change From Baseline in C--Reactive Protein (CRP) and Serum Amyloid A (SAA) Concentrations at Week 56
Description
The CRP and SAA were used as 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
Baseline, Week 56
Title
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
Description
Adverse events (AEs) were defined as any unfavorable and unintended diagnosis, symptom, sign (including an abnormal laboratory finding), syndrome or disease which either occurs during study, having been absent at baseline, or, if present at baseline, appears to worsen. Serious adverse events (SAEs) were defined as any untoward medical occurrences that result in death, are life threatening, require (or prolong) hospitalization, cause persistent or significant disability/incapacity, result in congenital anomalies or birth defects, or are other conditions which in judgement of investigators represent significant hazards.
Time Frame
Day 1 (start of study treatment) up to Week 56 (end of study)
Title
Percentage of Participants Receiving a Concomitant Vaccination During the Study
Description
Participants received any one of the following inactivated vaccines as per the immunization program: Corynebacterium diphtheria, Bordetella pertussis, Neisseria meningitidis, Clostridium tetani, Influenza type A, Influenza type B, Haemophilus influenza B, Streptococcus pneumoniae, or Hepatitis B were determined.
Time Frame
Day 1 (start of study treatment) to Week 56 (end of study)
Title
Number of Vaccination Cases With Protective Antibody Levels Following Immunization With Inactivated Vaccines
Description
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
Day -14 (prior-vaccination), Day 0 (vaccination), Day 28, Day 57 (post-vaccination)
Title
Number of Participants With Anti-canakinumab Antibodies at Week 56
Description
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
Week 56 (End of study)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
1 Month
Maximum Age & Unit of Time
60 Months
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Male and female patients that are 28 days up to 60 months of age at the time of the screening visit. Body weight > or = 2.5 kg. Parent or legal guardian's written informed consent is required before any assessment is performed for patients. At study entry, patients should have a clinical diagnosis of FCAS, MWS, or NOMID and symptoms requiring pharmacological intervention. 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. For patients treated with an IL-1 blocking agent (i.e. anakinra, rilonacept), these treatments should be discontinued prior to the baseline visit and patients must demonstrate active disease prior to treatment. Patients who are scheduled to receive an immunization, according to their local vaccination guidelines, with an inactivated vaccine must be willing to participate in the assessment schedule for vaccinated patients. Exclusion Criteria: Preterm neonates for whom, in the Investigator's judgment, participation in the study is not deemed appropriate. History of recurrent and/or evidence of active bacterial, fungal, or viral infections (including HIV). Patients with immunodeficiency or treatment with immunosuppressive drugs. Live vaccinations within < or = 3 months prior to screening. No live vaccinations will be allowed throughout the course of this study and up to 3 months following the last dose. Patients with an increased risk of tuberculosis (TB) infection according to following risk factors: Patients with recent close contact with persons known to have active pulmonary TB disease Foreign-born patients from countries with a high prevalence of tuberculosis Patients with recent tuberculosis infection (including children > 6 months with a positive PPD test [defined as an induration of at least 10mm]) Patients with end-stage renal disease Patients with diabetes mellitus Patients receiving immunosuppressive therapy Patients with hematologic cancers. Participation in another trial within the last 30 days or 5 half-lives of the investigational compound (whichever is longer). Familial and social conditions rendering regular medical assessment not possible. Pediatric patients with neutropenia (absolute neutrophil count [ANC] < 1.5 x 10 to the 9th/l) Other protocol defined inclusion/exclusion criteria may apply
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Novartis Pharmaceuticals
Organizational Affiliation
Novartis Pharmaceuticals
Official's Role
Study Director
Facility Information:
Facility Name
Novartis Investigative Site
City
Bruxelles
ZIP/Postal Code
1200
Country
Belgium
Facility Name
Novartis Investigative Site
City
Laeken
ZIP/Postal Code
1020
Country
Belgium
Facility Name
Novartis Investigative Site
City
Toronto
State/Province
Ontario
ZIP/Postal Code
M5G 1X8
Country
Canada
Facility Name
Novartis Investigative Site
City
Le Kremlin Bicetre
ZIP/Postal Code
94275
Country
France
Facility Name
Novartis Investigative Site
City
Berlin
ZIP/Postal Code
13353
Country
Germany
Facility Name
Novartis Investigative Site
City
Dresden
ZIP/Postal Code
01307
Country
Germany
Facility Name
Novartis Investigative Site
City
St. Augustin
ZIP/Postal Code
53757
Country
Germany
Facility Name
Novartis Investigative Site
City
Tübingen
ZIP/Postal Code
72076
Country
Germany
Facility Name
Novartis Investigative Site
City
Granada
State/Province
Andalucia
ZIP/Postal Code
18012
Country
Spain
Facility Name
Novartis Investigative Site
City
Valencia
State/Province
Comunidad Valenciana
ZIP/Postal Code
46026
Country
Spain
Facility Name
Novartis Investigative Site
City
Lausanne
ZIP/Postal Code
1011
Country
Switzerland
Facility Name
Novartis Investigative Site
City
London
ZIP/Postal Code
WC1N 1EH
Country
United Kingdom

12. IPD Sharing Statement

Citations:
PubMed Identifier
31161734
Citation
Brogan PA, Hofer M, Kuemmerle-Deschner JB, Kone-Paut I, Roesler J, Kallinich T, Horneff G, Calvo Penades I, Sevilla-Perez B, Goffin L, Lauwerys BR, Lachmann HJ, Uziel Y, Wei X, Laxer RM. Rapid and Sustained Long-Term Efficacy and Safety of Canakinumab in Patients With Cryopyrin-Associated Periodic Syndrome Ages Five Years and Younger. Arthritis Rheumatol. 2019 Nov;71(11):1955-1963. doi: 10.1002/art.41004. Epub 2019 Sep 9.
Results Reference
derived

Learn more about this trial

Efficacy, Safety and Tolerability of ACZ885 in Pediatric Patients With the Following Cryopyrin-associated Periodic Syndromes: Familial Cold Autoinflammatory Syndrome, Muckle-Wells Syndrome, or Neonatal Onset Multisystem Inflammatory Disease

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