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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier:
NCT01242813
First received: November 16, 2010
Last updated: January 5, 2016
Last verified: January 2016
  Purpose
This trial will assess the safety and efficacy of ACZ885 in patients with active recurrent or chronic TNF-receptor associated periodic syndrome (TRAPS).

Condition Intervention Phase
TNF-receptor Associated Periodic Syndromes (TRAPS)
Drug: ACZ885
Phase 2

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: 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).

Resource links provided by NLM:


Further study details as provided by Novartis:

Primary Outcome Measures:
  • Percentage of Participants With Complete or Almost Complete Response at Day 15 [ Time Frame: Day 15 ] [ Designated as safety issue: No ]
    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).


Secondary Outcome Measures:
  • Percentage of Participants With Complete or Almost Complete Response at Day 8 [ Time Frame: Day 8 ] [ Designated as safety issue: No ]
    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).

  • Percentage of Participants With Complete Clinical Remission at Day 8 and 15 [ Time Frame: Day 8 and Day 15 ] [ Designated as safety issue: No ]
    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.

  • Percentage of Participant With Target Levels of C-reactive Protein (CRP) and Serum Amyloid A Protein (SAA) at Day 8 and 15 [ Time Frame: Day 8 and Day 15 ] [ Designated as safety issue: No ]
    The CRP and SAA were used as inflammatory markers. The target level concentration was ≤ 10 mg/L.

  • Time to Physician's Assessed Clinical Remission [ Time Frame: Baseline up to Day 15 ] [ Designated as safety issue: No ]
    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.

  • Percentage of Participants With Complete or Almost Complete Response at Day 15 After Receiving Additional Dose at Day 8 [ Time Frame: Day 15 ] [ Designated as safety issue: No ]
    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).

  • Time to Participant's Assessed Clinical Remission [ Time Frame: Baseline up to Day 15 ] [ Designated as safety issue: No ]
    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.

  • Percentage Change From Baseline in C-reactive Protein (CRP) and Serum Amyloid A (SAA) Concentration to End of Study [ Time Frame: Day 1 up to Day 953 (End of study) ] [ Designated as safety issue: No ]
    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.

  • Percentage of Participants With Defined Grades for Skin Rash, Eye Manifestations, Extremity Pain and Abdominal Pain [ Time Frame: Day 113 (end of treatment period) up to Day 925 (End of study) ] [ Designated as safety issue: No ]
    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.

  • Percentage of Participants With Defined Grades in Physician's Global Assessment Score [ Time Frame: Day 1 up to Day 953 (End of study) ] [ Designated as safety issue: No ]
    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.

  • Percentage of Participants With Defined Grades in Participant's Global Assessment Score [ Time Frame: Day 1 up to Day 253 (End of follow-up period) ] [ Designated as safety issue: No ]
    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.

  • Percentage of Relapsed Participants [ Time Frame: 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 ] [ Designated as safety issue: No ]
    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.

  • Time to Relapse After Last Dose of Canakinumab [ Time Frame: Day 85 to Day 253 (End of treatment period to Follow-up period) ] [ Designated as safety issue: No ]
    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.

  • Percentage of Participants Who Relapsed and Received Rescue Medication [ Time Frame: Day 85 to Day 953 (End of treatment period to End of study) ] [ Designated as safety issue: No ]
    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.

  • Serum Concentration of Canakinumab [ Time Frame: 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 ] [ Designated as safety issue: No ]
    Canakinumab concentrations in serum were assessed for evaluating pharmacokinetics of the drug.

  • Serum Concentration of Total Interleukin-1β Antibody (IL-1β) [ Time Frame: 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 ] [ Designated as safety issue: No ]
    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).

  • Number of Participants With Anti-canakinumab Antibodies at Any Visit [ Time Frame: Day 1 up to Day 953 (End of study) ] [ Designated as safety issue: Yes ]
    Immunogenicity assessment included determination of anti-canakinumab (ACZ885) antibodies in serum samples using BIAcore system.


Enrollment: 20
Study Start Date: October 2010
Study Completion Date: June 2014
Primary Completion Date: June 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Canakinumab
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

  Eligibility

Ages Eligible for Study:   4 Years and older   (Child, Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. 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.
  2. Male and female patients at least 4 years of age at the time of the screening visit.
  3. 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.
  4. 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.
  5. 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).
  6. 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:

  1. 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).
  2. 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.
  3. History of being immunocompromised, including a positive HIV at screening (ELISA and Western blot) test result.
  4. 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.
  5. Live vaccinations within 3 months prior to the start of the trial, during the trial, and up to 3 months following the last dose.
  6. History of significant other medical conditions, which in the Investigator's opinion would exclude the patient from participating in this trial.
  7. History of recurrent and/or evidence of active bacterial, fungal, or viral infection(s).
  8. 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
  9. History of known hypersensitivity to canakinumab.
  10. 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.

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01242813

Locations
Ireland
Novartis Investigative Site
Galway, Ireland
Italy
Novartis Investigative Site
Sciacca, AG, Italy, 92019
Novartis Investigative Site
Brescia, BS, Italy, 25123
Novartis Investigative Site
Genova, GE, Italy, 16147
Novartis Investigative Site
Pavia, PV, Italy, 27100
United Kingdom
Novartis Investigative Site
London, United Kingdom, NW3 2QG
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
  More Information

Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT01242813     History of Changes
Other Study ID Numbers: CACZ885D2203  2010-020061-24 
Study First Received: November 16, 2010
Results First Received: November 2, 2015
Last Updated: January 5, 2016
Health Authority: United States: Food and Drug Administration
Ireland: The Food Safety Authority of Ireland
United Kingdom: Medicines and Healthcare Products Regulatory Agency
Italy: AIFA-Italian Medicines Agency

Keywords provided by Novartis:
TNF-receptor associated periodic syndrome
fevers
rashes
musculoskeletal and abdominal pain
periorbital edema
TNFR1

Additional relevant MeSH terms:
Syndrome
Fever
Hereditary Autoinflammatory Diseases
Disease
Pathologic Processes
Body Temperature Changes
Signs and Symptoms
Genetic Diseases, Inborn
Skin Diseases, Genetic
Skin Diseases

ClinicalTrials.gov processed this record on August 25, 2016