Trial Outcomes & Findings for 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 (NCT NCT01576367)

Last Updated: 2018-09-11

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

17 participants

Primary outcome timeframe

Week /80, 104, 128, and 152 (A minimum of 6 months and maximum of 24 months)

Results posted on

2018-09-11

Participant Flow

Participant milestones

Participant milestones
Measure	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)
Overall Study STARTED	17
Overall Study COMPLETED	14
Overall Study NOT COMPLETED	3

Reasons for withdrawal

Reasons for withdrawal
Measure	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)
Overall Study Unsatisfactory therapeutic effect	2
Overall Study Moved to commercial use after 6 months	1

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Canakinumab n=17 Participants 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)
Age, Continuous Age at start of extension study (years)	3.1 Years STANDARD_DEVIATION 1.7 • n=5 Participants
Sex: Female, Male Female	5 Participants n=5 Participants
Sex: Female, Male Male	12 Participants n=5 Participants

PRIMARY outcome

Timeframe: 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

Outcome measures

Outcome measures
Measure	Canakinumab n=17 Participants 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)
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 outcome

Timeframe: 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.

Immunogenicity assessment included determination of anti-canakinumab (ACZ885) antibodies in serum samples using BIAcore system, with detection based on surface plasmon resonance technique.

Outcome measures

Outcome measures
Measure	Canakinumab n=15 Participants 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)
Immunogenicity of Canakinumab (ACZ885). Number of Participants With Anti-canakinumab Antibodies	0 Participants

SECONDARY outcome

Timeframe: 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

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.

Outcome measures

Outcome measures
Measure	Canakinumab n=17 Participants 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)
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
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
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
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
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
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
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
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
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
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
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 60.0
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

SECONDARY outcome

Timeframe: 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

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

Outcome measures

Outcome measures
Measure	Canakinumab n=17 Participants 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)
Frequency Counts of Physician's Global Assessment of Autoinflammatory Disease and Skin Disease Assessment of autoinflammatory disease (Absent)	64.7 Percentage of participants
Frequency Counts of Physician's Global Assessment of Autoinflammatory Disease and Skin Disease Assessment of autoinflammatory disease (Minimal)	29.4 Percentage of participants
Frequency Counts of Physician's Global Assessment of Autoinflammatory Disease and Skin Disease Assessment of autoinflammatory disease (Mild)	5.9 Percentage of participants
Frequency Counts of Physician's Global Assessment of Autoinflammatory Disease and Skin Disease Assessment of autoinflammatory disease (Moderate)	0 Percentage of participants
Frequency Counts of Physician's Global Assessment of Autoinflammatory Disease and Skin Disease Assessment of autoinflammatory disease (Severe)	0 Percentage of participants
Frequency Counts of Physician's Global Assessment of Autoinflammatory Disease and Skin Disease Assessment of skin disease (Absent)	94.1 Percentage of participants
Frequency Counts of Physician's Global Assessment of Autoinflammatory Disease and Skin Disease Assessment of skin disease (Minimal)	0 Percentage of participants
Frequency Counts of Physician's Global Assessment of Autoinflammatory Disease and Skin Disease Assessment of skin disease (Mild)	5.9 Percentage of participants
Frequency Counts of Physician's Global Assessment of Autoinflammatory Disease and Skin Disease Assessment of skin disease (Moderate)	0 Percentage of participants
Frequency Counts of Physician's Global Assessment of Autoinflammatory Disease and Skin Disease Assessment of skin disease (Severe)	0 Percentage of participants

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Canakinumab n=17 patient-vaccination cases 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)
Number of Vaccination Cases With Protective Antibody Levels Following Immunization With Inactivated Vaccines Positive response for antibody levels	16 vaccination cases
Number of Vaccination Cases With Protective Antibody Levels Following Immunization With Inactivated Vaccines No pre-dose antibody levels	3 vaccination cases

Adverse Events

Canakinumab

Serious events: 8 serious events

Other events: 16 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Canakinumab n=17 participants at risk 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)
Infections and infestations Meningitis aseptic	5.9% 1/17
Infections and infestations Pneumonia	11.8% 2/17
Injury, poisoning and procedural complications Limb injury	5.9% 1/17
Ear and labyrinth disorders Conductive deafness	5.9% 1/17
Gastrointestinal disorders Abdominal pain	5.9% 1/17
Gastrointestinal disorders Vomiting	5.9% 1/17
General disorders Papillitis	5.9% 1/17
Infections and infestations Bronchitis	5.9% 1/17
Vascular disorders Haematoma	5.9% 1/17

Other adverse events

Other adverse events
Measure	Canakinumab n=17 participants at risk 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)
Blood and lymphatic system disorders Eosinophilia	5.9% 1/17
Cardiac disorders Angina pectoris	5.9% 1/17
Congenital, familial and genetic disorders Cryopyrin associated periodic syndrome	5.9% 1/17
Ear and labyrinth disorders Conductive deafness	5.9% 1/17
Ear and labyrinth disorders Ear pain	11.8% 2/17
Eye disorders Eye pruritus	5.9% 1/17
Eye disorders Iridocyclitis	5.9% 1/17
Eye disorders Papilloedema	11.8% 2/17
Eye disorders Uveitis	5.9% 1/17
Gastrointestinal disorders Abdominal pain	11.8% 2/17
Gastrointestinal disorders Abdominal pain upper	11.8% 2/17
Gastrointestinal disorders Aphthous stomatitis	11.8% 2/17
Gastrointestinal disorders Diarrhoea	41.2% 7/17
Gastrointestinal disorders Gingival hypertrophy	5.9% 1/17
Gastrointestinal disorders Mouth ulceration	17.6% 3/17
Gastrointestinal disorders Nausea	11.8% 2/17
Gastrointestinal disorders Toothache	5.9% 1/17
Gastrointestinal disorders Vomiting	35.3% 6/17
General disorders Pyrexia	35.3% 6/17
Immune system disorders Milk allergy	5.9% 1/17
Immune system disorders Seasonal allergy	5.9% 1/17
Infections and infestations Abscess limb	5.9% 1/17
Infections and infestations Bronchitis	11.8% 2/17
Infections and infestations Cellulitis	5.9% 1/17
Infections and infestations Cystitis	5.9% 1/17
Infections and infestations Ear infection	17.6% 3/17
Infections and infestations Eczema infected	5.9% 1/17
Infections and infestations Enterobiasis	5.9% 1/17
Infections and infestations Gastroenteritis	23.5% 4/17
Infections and infestations Hand-foot-and-mouth disease	5.9% 1/17
Infections and infestations Impetigo	11.8% 2/17
Infections and infestations Laryngitis	5.9% 1/17
Infections and infestations Lice infestation	5.9% 1/17
Infections and infestations Meningitis aseptic	5.9% 1/17
Infections and infestations Molluscum contagiosum	11.8% 2/17
Infections and infestations Nasopharyngitis	41.2% 7/17
Infections and infestations Oral herpes	5.9% 1/17
Infections and infestations Otitis media	5.9% 1/17
Infections and infestations Paronychia	11.8% 2/17
Infections and infestations Pharyngitis streptococcal	5.9% 1/17
Infections and infestations Pneumonia	5.9% 1/17
Infections and infestations Rhinitis	23.5% 4/17
Infections and infestations Tonsillitis	17.6% 3/17
Infections and infestations Upper respiratory tract infection	23.5% 4/17
Infections and infestations Urinary tract infection	11.8% 2/17
Infections and infestations Varicella	17.6% 3/17
Infections and infestations Vulval abscess	5.9% 1/17
Injury, poisoning and procedural complications Arthropod bite	5.9% 1/17
Injury, poisoning and procedural complications Craniocerebral injury	5.9% 1/17
Investigations Body temperature increased	5.9% 1/17
Investigations C-reactive protein increased	5.9% 1/17
Investigations CSF white blood cell count increased	5.9% 1/17
Investigations Serum amyloid A protein increased	5.9% 1/17
Investigations Transaminases increased	5.9% 1/17
Investigations Tympanometry abnormal	11.8% 2/17
Metabolism and nutrition disorders Decreased appetite	5.9% 1/17
Musculoskeletal and connective tissue disorders Joint swelling	5.9% 1/17
Musculoskeletal and connective tissue disorders Pain in extremity	5.9% 1/17
Nervous system disorders Burning sensation	5.9% 1/17
Nervous system disorders Cerebral ventricle dilatation	5.9% 1/17
Nervous system disorders Headache	35.3% 6/17
Nervous system disorders Hemiplegia	5.9% 1/17
Nervous system disorders Lethargy	5.9% 1/17
Nervous system disorders Loss of consciousness	5.9% 1/17
Nervous system disorders Motor developmental delay	11.8% 2/17
Nervous system disorders Pyramidal tract syndrome	5.9% 1/17
Nervous system disorders Seizure	5.9% 1/17
Nervous system disorders Speech disorder developmental	17.6% 3/17
Renal and urinary disorders Hypertonic bladder	5.9% 1/17
Reproductive system and breast disorders Breast pain	5.9% 1/17
Reproductive system and breast disorders Vulvovaginal burning sensation	5.9% 1/17
Respiratory, thoracic and mediastinal disorders Cough	29.4% 5/17
Respiratory, thoracic and mediastinal disorders Epistaxis	5.9% 1/17
Respiratory, thoracic and mediastinal disorders Oropharyngeal pain	17.6% 3/17
Respiratory, thoracic and mediastinal disorders Productive cough	5.9% 1/17
Respiratory, thoracic and mediastinal disorders Rhinorrhoea	5.9% 1/17
Skin and subcutaneous tissue disorders Dermatitis	5.9% 1/17
Skin and subcutaneous tissue disorders Dermatitis diaper	5.9% 1/17
Skin and subcutaneous tissue disorders Dry skin	5.9% 1/17
Skin and subcutaneous tissue disorders Eczema	11.8% 2/17
Skin and subcutaneous tissue disorders Hypersensitivity vasculitis	5.9% 1/17
Skin and subcutaneous tissue disorders Prurigo	5.9% 1/17
Skin and subcutaneous tissue disorders Pruritus	5.9% 1/17
Skin and subcutaneous tissue disorders Pruritus generalised	5.9% 1/17
Skin and subcutaneous tissue disorders Rash	29.4% 5/17
Skin and subcutaneous tissue disorders Rash maculo-papular	5.9% 1/17
Skin and subcutaneous tissue disorders Skin lesion	5.9% 1/17
Skin and subcutaneous tissue disorders Urticaria	5.9% 1/17

Additional Information

Study Director

Novartis Pharmaceuticals

Phone: 862-778-8300

Results disclosure agreements

Principal investigator is a sponsor employee 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.
Publication restrictions are in place

Restriction type: OTHER