Canakinumab in Patients With Active Hyper-IgD Syndrome

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier:
NCT01303380
First received: February 23, 2011
Last updated: August 11, 2015
Last verified: August 2015
  Purpose

This pilot study is designed to evaluate the efficacy, the safety, and the pharmacokinetics (PK) / pharmacodynamics (PD) of canakinumab treatment in patients with HIDS.


Condition Intervention Phase
Mevalonate Kinase Deficiency
Drug: Canakinumab
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: An Open-label, Multicenter, Efficacy and Safety Pilot Study of 6-month Canakinumab Treatment With up to 6-month Follow-up in Patients With Active Hyper-IgD Syndrome (HIDS)

Resource links provided by NLM:


Further study details as provided by Novartis:

Primary Outcome Measures:
  • Number of Flares Per Participant During Historical Period and Treatment Period [ Time Frame: Historical period, Month 6 (End of treatment period) ] [ Designated as safety issue: No ]
    A flare was defined as Physician Global Assessment of HIDS flare severity score of ≥ 2 and a C-reactive protein (CRP) value > 10 mg/L. Flares during a historical period were defined as most recent 6-months in which the participant has not received treatment for their HIDS other than symptomatic treatment with NSAIDs and/or corticosteroids.


Secondary Outcome Measures:
  • Number of Flares Per Participant at During Treatment Period and 24 Month Extension Period [ Time Frame: Month 6 (End of treatment period), Month 36 (End of Long term treatment Period 2) ] [ Designated as safety issue: No ]
    A flare was defined as Physician Global Assessment of HIDS flare severity score of ≥ 2 and a CRP value > 10 mg/L.

  • Number of Participants Who Flared at Month 6, Month 24 and Month 36 [ Time Frame: Baseline, Month 6 (End of treatment period), Month 24 (End of Long term treatment period 1) and Month 36 (End of Long term treatment period 2) ] [ Designated as safety issue: No ]
    A flare was defined as Physician Global Assessment of HIDS flare severity score of ≥ 2 and a CRP value > 10 mg/L.

  • Number of Participants With Flare Events Based on Physician Assessed HIDS Flare Severity Score [ Time Frame: Any flare event [Baseline up to Month 36 (End of long term treatment period 2)] ] [ Designated as safety issue: No ]
    Physician global assessment of severity of HIDS after each flare was based on HIDS flare severity score, a 5- point scale: 0 = Absent signs/symptoms; 1 = Minimal signs/symptoms; 2 = Mild; 3= Moderate; 4 = Severe.

  • Number of Participants With Flare Events Based on Participant Assessed HIDS Flare Severity Score [ Time Frame: Baseline, Month 6 (End of treatment period), Month 12 (End of follow up period), Month 24 (End of Long term treatment period 1) and Month 36 (End of Long term treatment period 2) ] [ Designated as safety issue: No ]
    Participant's global assessment of severity of HIDS after each flare was based on HIDS flare severity score, a 5-point scale: 0 = Absent signs/symptoms; 1 = Minimal signs/symptoms; 2 = Mild; 3= Moderate; 4 = Severe. Same investigator assessed the same participant throughout the study to ensure consistency between assessments. Investigators reviewed every participant's diary at each visit after their own clinical assessment.

  • Percentage of Participants With Defined Grades of Participants Assessed Symptom Control [ Time Frame: Baseline, Month 6 (End of treatment period), Month 12 (End of follow up period), Month 24 (End of Long term treatment period 1) and Month 36 (End of Long term treatment period 2) ] [ Designated as safety issue: No ]
    Participants were assessed by participants/parent (participants aged 6-18 years) for control of signs and symptoms associated with HIDS based on 5-point scale: 0 = No control; 1 = Poor control; 2 = Somewhat control; 3 = Good control; and 4= Excellent control.

  • Percentage of Participants With Defined Grades of Physician Assessed Symptom Control [ Time Frame: Baseline, Month 6 (End of treatment period), Month 12 (End of follow up period), Month 24 (End of Long term treatment period 1) and Month 36 (End of Long term treatment period 2) ] [ Designated as safety issue: No ]
    Participants were assessed by physician for control of signs and symptoms associated with HIDS based on 5-point scale: 0 = No control; 1 = Poor control; 2 = Somewhat control; 3 = Good control; and 4= Excellent control.

  • Percentage of Participants Experiencing Fever as Assessed by Physician's Global Assessment [ Time Frame: Baseline, Month 6 (End of treatment period), Month 12 (End of follow up period), Month 24 (End of Long term treatment period 1) and Month 36 (End of Long term treatment period 2) ] [ Designated as safety issue: No ]
    Fever severity was assessed by physician after each flare using a 5-point scale: 0 =Absent signs/symptoms; 1 = Minimal signs/symptoms; 2 = Mild; 3 = Moderate; 4 = Severe.

  • Percentage of Participants Experiencing Apthus Ulcers as Assessed by Physician's Global Assessment [ Time Frame: Baseline, Month 6 (End of treatment period), Month 12 (End of follow up period), Month 24 (End of Long term treatment period 1) and Month 36 (End of Long term treatment period 2) ] [ Designated as safety issue: No ]
    Apthus ulcers were assessed by physician after each flare using a 5-point scale: 0 =Absent signs/symptoms; 1 = Minimal signs/symptoms; 2 = Mild; 3 = Moderate; 4 = Severe.

  • Percentage of Participants Experiencing Lymphadenopathy as Assessed by Physician's Global Assessment [ Time Frame: Baseline, Month 6 (End of treatment period), Month 12 (End of follow up period), Month 24 (End of Long term treatment period 1) and Month 36 (End of Long term treatment period 2) ] [ Designated as safety issue: No ]
    Lymphadenopathy severity was assessed by physician after each flare using a 5-point scale: 0 =Absent signs/symptoms; 1 = Minimal signs/symptoms; 2 = Mild; 3 = Moderate; 4 = Severe.

  • Percentage of Participants Experiencing Abdominal Pain as Assessed by Physician's Global Assessment [ Time Frame: Baseline, Month 6 (End of treatment period), Month 12 (End of follow up period), Month 24 (End of Long term treatment period 1) and Month 36 (End of Long term treatment period 2) ] [ Designated as safety issue: No ]
    Abdominal pain was assessed by physician after each flare using a 5-point scale: 0 =Absent signs/symptoms; 1 = Minimal signs/symptoms; 2 = Mild; 3 = Moderate; 4 = Severe.

  • Time to Resolution of the Initial Flare After First Canakinumab Treatment [ Time Frame: Day 1 (Baseline), Day 28 ] [ Designated as safety issue: No ]
    Time to resolution of the initial flare after first dose of canakinumab was determined.

  • Change From Baseline in Inflammation Markers Over Time up to Month 24 [ Time Frame: Baseline, Month 6 (End of treatment period), Month 12 (End of follow up period), Month 24 (End of Long term treatment period 1) and Month 36 (End of Long term treatment period 2) ] [ Designated as safety issue: No ]
    The C-reactive Protein (CRP) and/or Serum amyloid A protein (SAA) were used as inflammatory markers. The normal range of CRP was 0-10 mg/L.

  • Health Assessment Questionnaire (HAQ) Global Score in Adults Over Time [ Time Frame: Baseline, Month 6 (End of treatment period), Month 12 (End of follow up period), Month 24 (End of Long term treatment period 1) and Month 36 (End of Long term treatment period 2) ] [ Designated as safety issue: No ]
    Participants were assessed for health-related quality of life (HRQoL) based on Health Assessment Questionnaire (HAQ). HAQ was an eight 8 categories questionnaire representing all activities related to physical function. Each category has various sub-categories, which were rated by the participants on a 4- point difficulty scale: 0 = any difficulty; 1 = some difficulty; 2 = much difficulty; 3 = unable to do. The total score was the mean of the 8 scores, and ranged from 0 (no disability) to 3 (completely disabled).

  • Childhood Health Assessment Questionnaire (CHAQ) Global Score in Children Over Time [ Time Frame: Baseline, Month 6 (End of treatment period), Month 12 (End of follow up period), Month 24 (End of Long term treatment period 1) and Month 36 (End of Long term treatment period 2) ] [ Designated as safety issue: No ]
    Participants or their parents (participants aged 6 to 17 years) were assessed for HRQoL based on Childhood Health Assessment Questionnaire (CHAQ). CHAQ was an eight domain questionnaire representing functional capacity and independence, evaluated for previous week. Each domain was rated on a 4-point difficulty scale: 0 = any difficulty; 1 = some difficulty; 2 = much difficulty; 3 = unable to do.The total score is the mean from the 8 scores, and ranges from 0 (no disability) to 3 (completely disabled).

  • Percentage of Participants Who Received Dose Up-titration During 6-month Treatment Period [ Time Frame: Day 1 up to Month 6 (End of follow up) ] [ Designated as safety issue: No ]
    Participants who experienced a new HIDS flare between baseline and Week 4 and received an escalated dose of 450 mg of canakinumab every 6 weeks thereafter starting at Week 6 were determined.

  • Duration of Flares Experienced During the Study [ Time Frame: Baseline, Month 6 (End of treatment period), Month 12 (End of follow up period), Month 24 (End of Long term treatment period 1) and Month 36 (End of Long term treatment period 2) ] [ Designated as safety issue: No ]
    Flare was defined as Physician Global Assessment of HIDS flare severity score of ≥ 2 and a CRP value > 10 mg/L. The change in post canakinumab treatment flare duration during the study were assessed as compared to historical period.

  • Time to Flare After the Last Dose of Canakinumab During the Follow-up Period [ Time Frame: Last dose of canakinumab treatment in follow-up period to end of follow-up period (Day 337) ] [ Designated as safety issue: No ]
    The median time to flare by the participants after administration of the last dose of canakinumab during the follow-up period was analysed using Kaplan-Meier method.

  • Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: Day 1 (Start of study treatment) up to Month 36 (End of study) ] [ Designated as safety issue: Yes ]
    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) hospitalisation, 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.

  • Participants Who Received Rescue Treatment [ Time Frame: Baseline up to Month 36 (End of study) ] [ Designated as safety issue: No ]
    Participants who experienced flares were treated with corticosteroids and NSAIDs as rescue medication.

  • Serum Concentration-time Profile of Canakinumab [ Time Frame: Day 1 (Pre-dose), Day 4, Day 15, Day 43, Day 85, Day 127, Day 169 (End of treatment period), Day 197, Day 225, Day 253, Day 281, Day 309, and Day 337 (End of follow-up period) (Post-dose) ] [ Designated as safety issue: No ]
    Canakinumab concentrations in serum were assessed for evaluating pharmacokinetics (PK) of the drug.

  • Serum Concentration of Total Interleukin-1β Antibody (IL-1β) [ Time Frame: Day 1 (Pre-dose), Day 4, Day 15, Day 43, Day 85, Day 127, Day 169 (End of treatment period), Day 197, Day 225, Day 253, Day 281, Day 309, and Day 337 (End of follow-up period) (Post-dose) ] [ 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 sandwich ELISA assay with limit of detection at 0.1 picogram/millilitre.

  • Number of Participants Exhibiting Anti-canakinumab Antibodies at Any Visit [ Time Frame: Baseline up to Month 36 (End of study) ] [ Designated as safety issue: No ]
    Immunogenicity assessment included determination of anti-canakinumab (ACZ885) antibodies in serum samples using bridging ECLIA assay.


Enrollment: 9
Study Start Date: March 2011
Study Completion Date: July 2014
Primary Completion Date: July 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Canakinumab
Participants received body weight stratified dosage of canakinumab (4 mg/kg for participants less than or equal to (≤) 40 kg or 300 mg for participants more than (>) 40 kg) as starting dose s.c. injection every 6 weeks during 6 months of treatment. The dose was escalated to additional 150 mg (2 mg/kg for participants ≤40 kg) dose at the moment of flare, and 450 mg (6 mg/kg for participants ≤40 kg) every 6 weeks, thereafter starting at Week 6 in participants who experienced a new HIDS flare between baseline and Week 4 as per investigator's discretion. If the flare occurred between Weeks 5-6, the participants received rescue medication and waited up to Week 6 to receive a total of 450 mg of canakinumab.
Drug: Canakinumab

Detailed Description:

The main objective of the study was to assess reduction of the flare frequency after administration of canakinumab in individuals with active Hyper-IgD Syndrome (HIDS) during the 6-month treatment period compared to historical period (defined as the most recent 6 months in which the individuals had not received drugs other than symptomatic treatment with Nonsteroidal anti-inflammatory drugs (NSAIDs) and/or steroids).

  Eligibility

Ages Eligible for Study:   2 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Patients with a diagnosis of HIDS proven by DNA analysis and/or enzymatic studies.
  2. At time of start of drug treatment: active HIDS as evidenced by a physician global assessment of HIDS flare severity ≥ 2 and CRP values >10 mg/L (normal CRP < or = 10 mg/L).
  3. Patients who have a history of > or = 3 febrile acute HIDS flares in a 6-month period when not receiving prophylaxis treatment (e.g. anakinra daily treatment) with a duration of each flare lasting > or = 4 days and limiting the normal daily activities.

Exclusion Criteria:

  1. Pregnant or nursing (lactating) women.
  2. History of being immunocompromised, including a positive HIV at screening (ELISA and Western blot) test result.
  3. Positive Hepatitis B or Hepatitis C.
  4. Live vaccinations within 3 months prior to the start of the trial
  5. Positive tuberculosis screening test.

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: NCT01303380

Locations
Spain
Novartis Investigative site
Barcelona, Spain
Novartis Investigative site
Valencia, Spain
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
  More Information

No publications provided

Responsible Party: Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier: NCT01303380     History of Changes
Other Study ID Numbers: CACZ885D2402, 2010-020904-31
Study First Received: February 23, 2011
Results First Received: July 15, 2015
Last Updated: August 11, 2015
Health Authority: Spain: Agencia Española de Medicamentos y Productos Sanitarios

Keywords provided by Novartis:
Hyper IgD syndrome
canakinumab
HIDS
mevalonate kinase deficiency
MKD

Additional relevant MeSH terms:
Mevalonate Kinase Deficiency
Blood Protein Disorders
Brain Diseases
Brain Diseases, Metabolic
Brain Diseases, Metabolic, Inborn
Central Nervous System Diseases
Genetic Diseases, Inborn
Hematologic Diseases
Hereditary Autoinflammatory Diseases
Hypergammaglobulinemia
Immune System Diseases
Immunoproliferative Disorders
Metabolic Diseases
Metabolism, Inborn Errors
Nervous System Diseases
Peroxisomal Disorders
Antibodies, Monoclonal
Immunologic Factors
Pharmacologic Actions
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on August 27, 2015