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

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01576367
• Collaborator: (none)
• Enrollment: 17
• Locations: 12
• Arm: 1
• Actual Duration (Months): 44.9
• Patients Per Site: 1.4
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

This trial will provide long-term safety, efficacy and tolerability of ACZ885 in CAPS patients that completed the CACZ885D2307 study

Condition or Disease	Intervention/Treatment	Phase
Cryopyrin-associated Periodic Syndromes; Familial Cold Autoinflammatory Syndrome; Muckle-Wells Syndrome; Neonatal Onset Multisystem Inflammatory Disease	Biological: ACZ885	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 17 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Primary Purpose: Treatment
• Official Title: An Open-label Extension Study to Assess Efficacy, Safety and Tolerability of Canakinumab and the Efficacy and Safety of Childhood Vaccinations in Patients With Cryopyrin Associated Periodic Syndromes (CAPS)
• Actual Study Start Date: Jan 16, 2012
• Actual Primary Completion Date: Oct 13, 2015
• Actual Study Completion Date: Oct 13, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 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)	Biological: ACZ885; Other Names: Canakinumab

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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.

2. 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.

3. 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

4. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 1 Year to 4 Years
• Sexes Eligible for Study: All
• Accepts 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/exclusion criteria may apply.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Bruxelles		Belgium	1200
2	Novartis Investigative Site	Laeken		Belgium	1020
3	Novartis Investigative Site	Toronto	Ontario	Canada	M5G 1X8
4	Novartis Investigative Site	Le Kremlin Bicetre		France	94275
5	Novartis Investigative Site	Berlin		Germany	13353
6	Novartis Investigative Site	Dresden		Germany	01307
7	Novartis Investigative Site	Saint Augustin		Germany	53757
8	Novartis Investigative Site	Tübingen		Germany	72076
9	Novartis Investigative Site	Granada	Andalucia	Spain	18012
10	Novartis Investigative Site	Valencia	Comunidad Valenciana	Spain	46026
11	Novartis Investigative Site	Lausanne		Switzerland	1011
12	Novartis Investigative Site	London		United Kingdom	WC1N 1EH

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT01576367
• Other Study ID Numbers: CACZ885D2307E1; 2011-005154-57
• First Posted: Apr 12, 2012
• Last Update Posted: Sep 11, 2018
• Last Verified: Aug 1, 2018

• Keywords provided by Novartis Pharmaceuticals: 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
• Additional relevant MeSH terms: Cellulitis; Eosinophilia; Cryopyrin-Associated Periodic Syndromes; Syndrome

Study Results

Participant Flow

Arm/Group Title	Canakinumab
Arm/Group Description	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)
Period Title: Overall Study
STARTED	17
COMPLETED	14
NOT COMPLETED	3

Baseline Characteristics

Arm/Group Title	Canakinumab
Arm/Group Description	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)
Overall Participants	17
Age (Years) [Mean (Standard Deviation) ]
Age at start of extension study (years)	3.1 (1.7)
Sex: Female, Male (Count of Participants)
Female	5 29.4%
Male	12 70.6%

Outcome Measures

1. Primary Outcome

Title	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.
Description	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)

Outcome Measure Data

Analysis Population Description

Extension Full analysis set (FAS) consisted of all patients who received at least one dose of study drug in the extension study

Arm/Group Title	Canakinumab
Arm/Group Description	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)
Measure Participants	17
Number [Percentage of participants]	94.1 553.5%

2. Secondary Outcome

Title	Immunogenicity of Canakinumab (ACZ885). Number of Participants With Anti-canakinumab Antibodies
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	minimum of 6 months and maximum of 24 months

Outcome Measure Data

Analysis Population Description

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/Group Title	Canakinumab
Arm/Group Description	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)
Measure Participants	15
Number [Participants]	0 0%

3. Secondary Outcome

Title	Change From Baseline (Core Study Baseline) in C--Reactive Protein (CRP) and Serum Amyloid A (SAA) Concentrations
Description	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

Outcome Measure Data

Analysis Population Description

Extension Full analysis set (FAS) consisted of all patients who received at least one dose of study drug in the extension study

Arm/Group Title	Canakinumab
Arm/Group Description	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)
Measure Participants	17
CRP at Core End of Study (last assessment) (n=14)	-5.4 (6.28)
CRP at week 80 (n=16)	-14.7 (35.8)
CRP at Week 104 (n=11)	-3.8 (14.4)
CRP at Week 128(n=12)	-4.1 (10.3)
CRP at Week 152 (n=12)	-4.3 (11)
CRP at End of Study (last assessment) (n=16)	-10.4 (30.3)
SAA at Core End of Study (last assessment) (n=16)	-54.4 (133.8)
SAA at Week 80 (n=12)	-79.1 (224.1)
SAA at week 104 (n=11)	15.8 (158.1)
SAA at week 128 (n=10)	-28.2 (47.4)
SAA at week 152 (n=11)	-6.4 (60.0)
SAA at End of Study (last assessment) (n=15)	-58.5 (183.6)

4. Secondary Outcome

Title	Frequency Counts of Physician's Global Assessment of Autoinflammatory Disease and Skin Disease
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	minimum of 6 months and maximum of 24 months

Outcome Measure Data

Analysis Population Description

Extension Full analysis set (FAS) consisted of all patients who received at least one dose of study drug in the extension study

Arm/Group Title	Canakinumab
Arm/Group Description	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)
Measure Participants	17
Assessment of autoinflammatory disease (Absent)	64.7 380.6%
Assessment of autoinflammatory disease (Minimal)	29.4 172.9%
Assessment of autoinflammatory disease (Mild)	5.9 34.7%
Assessment of autoinflammatory disease (Moderate)	0 0%
Assessment of autoinflammatory disease (Severe)	0 0%
Assessment of skin disease (Absent)	94.1 553.5%
Assessment of skin disease (Minimal)	0 0%
Assessment of skin disease (Mild)	5.9 34.7%
Assessment of skin disease (Moderate)	0 0%
Assessment of skin disease (Severe)	0 0%

5. Secondary Outcome

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	pre-vaccine dose, Day 28 post-vaccine

Outcome Measure Data

Analysis Population Description

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/Group Title	Canakinumab
Arm/Group Description	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)
Measure Participants	4
Measure patient-vaccination cases	17
Positive response for antibody levels	16
No pre-dose antibody levels	3

Adverse Events

Arm/Group Title	Canakinumab
Arm/Group Description	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)
All Cause Mortality
	Canakinumab
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Canakinumab
	Affected / at Risk (%)	# Events
Total	8/17 (47.1%)
Ear and labyrinth disorders
Conductive deafness	1/17 (5.9%)
Gastrointestinal disorders
Abdominal pain	1/17 (5.9%)
Vomiting	1/17 (5.9%)
General disorders
Papillitis	1/17 (5.9%)
Infections and infestations
Bronchitis	1/17 (5.9%)
Meningitis aseptic	1/17 (5.9%)
Pneumonia	2/17 (11.8%)
Injury, poisoning and procedural complications
Limb injury	1/17 (5.9%)
Vascular disorders
Haematoma	1/17 (5.9%)
Other (Not Including Serious) Adverse Events
	Canakinumab
	Affected / at Risk (%)	# Events
Total	16/17 (94.1%)
Blood and lymphatic system disorders
Eosinophilia	1/17 (5.9%)
Cardiac disorders
Angina pectoris	1/17 (5.9%)
Congenital, familial and genetic disorders
Cryopyrin associated periodic syndrome	1/17 (5.9%)
Ear and labyrinth disorders
Conductive deafness	1/17 (5.9%)
Ear pain	2/17 (11.8%)
Eye disorders
Eye pruritus	1/17 (5.9%)
Iridocyclitis	1/17 (5.9%)
Papilloedema	2/17 (11.8%)
Uveitis	1/17 (5.9%)
Gastrointestinal disorders
Abdominal pain	2/17 (11.8%)
Abdominal pain upper	2/17 (11.8%)
Aphthous stomatitis	2/17 (11.8%)
Diarrhoea	7/17 (41.2%)
Gingival hypertrophy	1/17 (5.9%)
Mouth ulceration	3/17 (17.6%)
Nausea	2/17 (11.8%)
Toothache	1/17 (5.9%)
Vomiting	6/17 (35.3%)
General disorders
Pyrexia	6/17 (35.3%)
Immune system disorders
Milk allergy	1/17 (5.9%)
Seasonal allergy	1/17 (5.9%)
Infections and infestations
Abscess limb	1/17 (5.9%)
Bronchitis	2/17 (11.8%)
Cellulitis	1/17 (5.9%)
Cystitis	1/17 (5.9%)
Ear infection	3/17 (17.6%)
Eczema infected	1/17 (5.9%)
Enterobiasis	1/17 (5.9%)
Gastroenteritis	4/17 (23.5%)
Hand-foot-and-mouth disease	1/17 (5.9%)
Impetigo	2/17 (11.8%)
Laryngitis	1/17 (5.9%)
Lice infestation	1/17 (5.9%)
Meningitis aseptic	1/17 (5.9%)
Molluscum contagiosum	2/17 (11.8%)
Nasopharyngitis	7/17 (41.2%)
Oral herpes	1/17 (5.9%)
Otitis media	1/17 (5.9%)
Paronychia	2/17 (11.8%)
Pharyngitis streptococcal	1/17 (5.9%)
Pneumonia	1/17 (5.9%)
Rhinitis	4/17 (23.5%)
Tonsillitis	3/17 (17.6%)
Upper respiratory tract infection	4/17 (23.5%)
Urinary tract infection	2/17 (11.8%)
Varicella	3/17 (17.6%)
Vulval abscess	1/17 (5.9%)
Injury, poisoning and procedural complications
Arthropod bite	1/17 (5.9%)
Craniocerebral injury	1/17 (5.9%)
Investigations
Body temperature increased	1/17 (5.9%)
C-reactive protein increased	1/17 (5.9%)
CSF white blood cell count increased	1/17 (5.9%)
Serum amyloid A protein increased	1/17 (5.9%)
Transaminases increased	1/17 (5.9%)
Tympanometry abnormal	2/17 (11.8%)
Metabolism and nutrition disorders
Decreased appetite	1/17 (5.9%)
Musculoskeletal and connective tissue disorders
Joint swelling	1/17 (5.9%)
Pain in extremity	1/17 (5.9%)
Nervous system disorders
Burning sensation	1/17 (5.9%)
Cerebral ventricle dilatation	1/17 (5.9%)
Headache	6/17 (35.3%)
Hemiplegia	1/17 (5.9%)
Lethargy	1/17 (5.9%)
Loss of consciousness	1/17 (5.9%)
Motor developmental delay	2/17 (11.8%)
Pyramidal tract syndrome	1/17 (5.9%)
Seizure	1/17 (5.9%)
Speech disorder developmental	3/17 (17.6%)
Renal and urinary disorders
Hypertonic bladder	1/17 (5.9%)
Reproductive system and breast disorders
Breast pain	1/17 (5.9%)
Vulvovaginal burning sensation	1/17 (5.9%)
Respiratory, thoracic and mediastinal disorders
Cough	5/17 (29.4%)
Epistaxis	1/17 (5.9%)
Oropharyngeal pain	3/17 (17.6%)
Productive cough	1/17 (5.9%)
Rhinorrhoea	1/17 (5.9%)
Skin and subcutaneous tissue disorders
Dermatitis	1/17 (5.9%)
Dermatitis diaper	1/17 (5.9%)
Dry skin	1/17 (5.9%)
Eczema	2/17 (11.8%)
Hypersensitivity vasculitis	1/17 (5.9%)
Prurigo	1/17 (5.9%)
Pruritus	1/17 (5.9%)
Pruritus generalised	1/17 (5.9%)
Rash	5/17 (29.4%)
Rash maculo-papular	1/17 (5.9%)
Skin lesion	1/17 (5.9%)
Urticaria	1/17 (5.9%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (i.e., data from all sites) in the clinical trial or disclosure of trial results in their entirety.