Efficacy and Safety Study of ACZ885 in Patients With Active Recurrent or Chronic TNF-receptor Associated Periodic Syndrome (TRAPS).

Study Overview
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Brief Summary
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This trial will assess the safety and efficacy of ACZ885 in patients with active recurrent or chronic TNF-receptor associated periodic syndrome (TRAPS).

Official Title
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An Open-label, Multicenter, Efficacy and Safety Study of 4-month Canakinumab Treatment With 6-month Follow-up in Patients With Active Recurrent or Chronic TNF-receptor Associated Periodic Syndrome (TRAPS).

Conditions
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TNF-receptor Associated Periodic Syndromes (TRAPS)

Intervention / Treatment
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* Drug: ACZ885


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient's written informed consent for >or= 18 years of age before any assessment is performed. Parent or legal guardian's written informed consent and child's assent, if appropriate, are required before any assessment is performed for patients < 18 years of age. Male and female patients at least 4 years of age at the time of the screening visit. Patients with a clinical diagnosis of TRAPS and a mutation of TNFRSF1A gene. Patients with low penetrance mutations, such as R92Q or P46L, can be included with mutual agreement between the investigator and Novartis. Patients with a diagnosis of recurrent TRAPS must experience more than 6 episodes/year prior to receiving an effective biologic therapy and the duration of each episode lasted at least 8 days. For patients receiving biologic therapy, this criterion applies to prior to receiving the biologic therapy. Patients who have been treated with anakinra must have demonstrated a partial or complete clinical response with an associated decrease in their inflammation markers (CRP and SAA). Active TRAPS as evidenced by clinical signs and symptoms of active TRAPS (Physician's Global Assessment >or= 2) and an elevated CRP > 10mg/L (Normal CRP range <or= 10 mg/L) and/or SAA > 10 mg/L (Normal SAA range <or= 10 mg/L) at time of first canakinumab treatment. Exclusion Criteria: Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test (> 5 mIU/mL). Women of child-bearing potential, defined as pre-menarche females aged 8 years and above or all women physiologically capable of becoming pregnant, UNLESS they are women whose career, lifestyle, or sexual orientation precludes intercourse with a male partner women whose partners have been sterilized by vasectomy or other means using a highly effective method of birth control (i.e. one that results in a less than 1% per year failure rate when used consistently and correctly, such as implants, injectables, combined oral contraceptives, and some intrauterine devices [IUDs]; periodic abstinence [e.g. calendar, ovulation, symptothermal, post-ovulation methods] is not acceptable) or total abstinence at the discretion of the investigator in cases where the age, career, lifestyle, or sexual orientation of the patient ensures compliance. Women of child-bearing potential should be willing to use a reliable contraception throughout the study and for 3 months after study drug discontinuation. Women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms) or six months of spontaneous amenorrhea with serum FSH levels > 40 mIU/mL or have had surgical bilateral oophorectomy (with or without hysterectomy) at least six weeks ago. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child bearing potential. History of being immunocompromised, including a positive HIV at screening (ELISA and Western blot) test result. Positive QuantiFERON (QFT-TB G In-Tube) test or positive Purified Protein Derivative (PPD) test (>or= 5 mm induration) at screening or within 2 month prior to the screening visit, according to the national guidelines. Patients with a positive PPD test (>or= 5 mm induration) at screening may be enrolled only if they have either a negative chest x-ray or a negative QuantiFERON test. Live vaccinations within 3 months prior to the start of the trial, during the trial, and up to 3 months following the last dose. History of significant other medical conditions, which in the Investigator's opinion would exclude the patient from participating in this trial. History of recurrent and/or evidence of active bacterial, fungal, or viral infection(s). Use of prohibited therapies, any other investigational biologics within 8 weeks prior to the Baseline visit, any other investigational drugs, other than investigational biologic treatment, within 30 days (or 3 months for investigational monoclonal antibodies) or 5 half-lives prior to the Baseline visit, whichever is longer History of known hypersensitivity to canakinumab. History of malignancy of any organ system (other than localized basal cell carcinoma of the skin), treated or untreated, within the past 5 years, regardless of whether there is evidence of local recurrence or metastases Other protocol defined inclusion/exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 4 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Canakinumab<br>This was an open-label, single treatment arm, multicenter study of monthly canakinumab 150 mg (2 mg/kg for patient ≤ 40 kg) subcutaneous injections in patients with active recurrent or chronic TRAPS. | Drug: ACZ885<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Complete or Almost Complete Response at Day 15 | Complete response was defined as clinical remission and serological remission. Clinical remission was defined as Physician's Global Assessment of TRAPS activity absent or minimal and serological remission was defined as C reactive protein (CRP) and/or Serum amyloid A protein (SAA) to be less than (<) 10 milligram per liter (mg/L). Almost complete response was defined as clinical remission and a partial serological remission (equal to or more than [≥] 70% reduction of baseline CRP and/or SAA). | Day 15 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Complete or Almost Complete Response at Day 8 | Complete response was defined as clinical remission and serological remission. Clinical remission was defined as Physician's Global Assessment of TRAPS activity absent or minimal and serological remission was defined as CRP and/or SAA < 10 mg/L. Almost complete response was defined as clinical remission and a partial serological remission (≥70% reduction of baseline CRP and/or SAA). | Day 8 | 
| Percentage of Participants With Complete Clinical Remission at Day 8 and 15 | Complete clinical remission was defined as Physician's Global Assessment of TRAPS activity to be absent or minimal (1). TRAPS associated clinical signs and symptoms were assessed by the investigator at every visit on a 5-point scale: 0 = Absent; 1 = Minimal; 2 = Mild; 3 = Moderate; 4 = Severe. | Day 8 and Day 15 | 
| Percentage of Participant With Target Levels of C-reactive Protein (CRP) and Serum Amyloid A Protein (SAA) at Day 8 and 15 | The CRP and SAA were used as inflammatory markers. The target level concentration was ≤ 10 mg/L. | Day 8 and Day 15 | 
| Time to Physician's Assessed Clinical Remission | Time period for complete remission after initial canakinumab treatment as assessed by participants was defined as a Physician's Global Assessment of TRAPS symptoms of scale 1 or less. The physician's Global Assessment was based on a 5-point scale: 0 = None/absent ; 1 = Minimal; 2 = Mild; 3 = Moderate; 4 = Severe. | Baseline up to Day 15 | 
| Percentage of Participants With Complete or Almost Complete Response at Day 15 After Receiving Additional Dose at Day 8 | Participants who had not achieved a complete response at Day 8 were given an additional dose of canakinumab. Complete response was defined as clinical remission (Physician's Global Assessment of TRAPS activity absent or minimal) and serological remission (CRP and/or SAA < 10 mg/L). Almost complete response was defined as clinical remission and a partial serological remission (≥ 70% reduction of baseline CRP and/or SAA). | Day 15 | 
| Time to Participant's Assessed Clinical Remission | Time period for complete remission after initial canakinumab treatment as assessed by participants was defined as a participant's Global Assessment of TRAPS symptoms of scale 1 or less. The participant's Global Assessment was based on a 5-point scale: 0 = None/absent (no) ; 1 = Minimal; 2 = Mild; 3 = Moderate; 4 = Severe. | Baseline up to Day 15 | 
| Percentage Change From Baseline in C-reactive Protein (CRP) and Serum Amyloid A (SAA) Concentration to End of Study | The CRP and SAA were used as inflammatory markers. The target level concentration was ≤ 10 mg/L. Negative percent change in concentration of inflammatory markers indicated improvement. | Day 1 up to Day 953 (End of study) | 
| Percentage of Participants With Defined Grades for Skin Rash, Eye Manifestations, Extremity Pain and Abdominal Pain | TRAPS signs and symptoms were assessed in 4 key categories: skin disease (skin rash), eye manifestations, extremity pain (musculoskeletal), and abdominal pain. Participants were assessed for TRAPS associated signs and symptoms a 5-point Physician's global assessment scale: None/absent (no); 1 = Minimal; 2 = Mild; 3 = Moderate; 4 = Severe. | Day 113 (end of treatment period) up to Day 925 (End of study) | 
| Percentage of Participants With Defined Grades in Physician's Global Assessment Score | Participants were assessed based by physician on Physician's Global Assessment measured on a 5-point scale for TRAPS associated signs and symptoms as: 0 = None/absent; 1 = Minimal; 2 = Mild; 3 = Moderate; 4 = Severe. | Day 1 up to Day 953 (End of study) | 
| Percentage of Participants With Defined Grades in Participant's Global Assessment Score | Participants assessed the disease condition based on a 5-point participant's global assessment scale based on TRAPS associated signs and symptoms as: 0 = None/absent; 1 = Minimal; 2 = Mild; 3 = Moderate; 4 = Severe. | Day 1 up to Day 253 (End of follow-up period) | 
| Percentage of Relapsed Participants | Relapse was defined as a Physician's Global Assessment score of 2 (and an increase of at least 1 point compared to Day 15) and CRP and/or SAA ≥ 30 mg/L representing a 30% increase from Day 15. | Day 15, 29, 57, 85, 113, 141, 169, 197, 225, 253, 281, 309, 337, 365, 393, 421, 449,477,505, 533, 561, 589, 617, 645, 673,701, 729,757, 785, 813, 841,869, 897, 925 and 953 | 
| Time to Relapse After Last Dose of Canakinumab | Relapse was defined as a Physician's Global Assessment score of 2 (and an increase of at least 1 point compared to Day 15) and CRP and/or SAA ≥ 30 mg/L representing a 30% increase from Day 15. | Day 85 to Day 253 (End of treatment period to Follow-up period) | 
| Percentage of Participants Who Relapsed and Received Rescue Medication | Participants who relapsed after the last dose of canakinumab and received either corticosteroid treatment or NSAID or both corticosteroid treatment and NSAID as rescue medication. | Day 85 to Day 953 (End of treatment period to End of study) | 
| Serum Concentration of Canakinumab | Canakinumab concentrations in serum were assessed for evaluating pharmacokinetics of the drug. | Day 3, 8, 15, 29, 57, 85, 113, 141, 169, 197, 225, 253, 281, 309, 337, 365, 393, 421, 449, 533, 561, 589, 617, 645, 673, 729, 785, 841, 897, 925 and 953 | 
| Serum Concentration of Total Interleukin-1β Antibody (IL-1β) | Pharmacodynamics of canakinumab was assessed by total IL-1β (sum of free and bound canakinumab) concentration, determined in serum by means of competitive Enzyme-linked immunosorbent assay (ELISA) with limit of detection at 0.25 picogram/milliliter (pg/mL). | Day 3, 8, 15, 29, 57, 85, 113, 141, 169, 197, 225, 253, 281, 309, 337, 365, 393, 421, 449, 533, 561, 589, 617, 645, 673, 729, 785, 841, 897, 925 and 953 | 
| Number of Participants With Anti-canakinumab Antibodies at Any Visit | Immunogenicity assessment included determination of anti-canakinumab (ACZ885) antibodies in serum samples using BIAcore system. | Day 1 up to Day 953 (End of study) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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TNF-receptor associated periodic syndrome, fevers, rashes, musculoskeletal and abdominal pain, periorbital edema, TNFR1