Study of Efficacy and Safety of Canakinumab in Patients With Hereditary Periodic Fevers

• ClinicalTrials.gov Identifier: NCT02059291
• Recruitment Status: Completed
• First Posted: February 11, 2014
• Results First Posted: March 17, 2017
• Last Update Posted: May 17, 2018
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Tracking Information

• First Submitted Date: February 7, 2014
• First Posted Date: February 11, 2014
• Results First Submitted Date: November 21, 2016
• Results First Posted Date: March 17, 2017
• Last Update Posted Date: May 17, 2018
• Actual Study Start Date: June 27, 2014
• Actual Primary Completion Date: July 4, 2017 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 6, 2018)

Percentage of Participants With Resolution of Initial Flare and Absence of New Flares up to the End of the Randomized Treatment Epoch (16 Weeks) [ Time Frame: 16 weeks ]

Resolution of the initial disease flare is defined as: Physician's Global Assessment of Disease activity (PGA) <2 and C-reactive protein (CRP) within normal range (<= 10 mg/L) or reduction by at least 70% from baseline. The PGA was evaluated by the investigator based on a 5-point scale: 0 = None (no) disease associated with clinical signs and symptoms; 1 = minimal disease associated signs and symptoms; 2 = mild disease associated signs and symptoms; 3 = moderate disease associated signs and symptoms; and 5 = severe disease associated signs and symptoms.

Original Primary Outcome Measures (submitted: February 7, 2014)

Proportion of participants with resolution of initial flare at time of the randomization and absence of new flares [ Time Frame: 16 weeks ]

To demonstrate significant reduction of disease activity with canakinumab versus placebo

Current Secondary Outcome Measures (submitted: April 6, 2018)

• Percentage of Participants Who Achieve Physician's Global Assessment (PGA) < 2 [ Time Frame: 16 weeks ]
  The PGA was evaluated by the investigator based on a 5-point scale: 0 = None (no) disease associated with clinical signs and symptoms; 1 = minimal disease associated signs and symptoms; 2 = mild disease associated signs and symptoms; 3 = moderate disease associated signs and symptoms; and 5 = severe disease associated signs and symptoms.
• Percentage of Participants With the Serologic Remission [ Time Frame: 16 weeks ]
  Serologic remission was defined as C-reactive protein <= 10 mg/L.
• Percentage of Participants With Normalized Serum Amyloid A (SAA) Level [ Time Frame: 16 weeks ]
  Normalized SAA was defined as SAA <= 10 mg/L.
• Percentage of Participants of Canakinumab Responders From Epoch 2 Who Maintained a Clinically Meaningful Response (Absence of New Flares) (40 Weeks) [ Time Frame: 40 weeks ]
  A responder was defined as a participant who had no flare between week 16 and week 40.

Original Secondary Outcome Measures (submitted: February 7, 2014)

• Percentage of participants who achieve Physician's global assessment < 2 [ Time Frame: 16 weeks ]
  Assessment of Physician's global assessment
• Percentage of participantswith the serologic remission [ Time Frame: 16 weeks ]
  Normalization of C-reactive protein, Serum Amyloid A

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Study of Efficacy and Safety of Canakinumab in Patients With Hereditary Periodic Fevers
• Official Title: A Randomized, Double-blind, Placebo Controlled Study of Canakinumab in Patients With Hereditary Periodic Fevers (TRAPS, HIDS, or crFMF), With Subsequent Randomized Withdrawal/Dosing Frequency Reduction and Open-label Long-term Treatment Epochs
• Brief Summary: This study is to determine whether canakinumab is able to induce and maintain a clinically meaningful reduction of disease activity in participants with Hereditary Periodic Fevers (HPF) compared to placebo.

Detailed Description

This study consists of 3 randomized cohorts (one per condition of colchicine resistant/intolerant Familial Mediterranean Fever (crFMF), Hyper Immunoglobulin D Syndrome (also known as mevalonate kinase deficiency (HIDS/MKD), and Tumor Necrosis Factor Receptor Associated Periodic Syndrome (TRAPS), and 4 study epochs:

1. Epoch 1: a screening epoch to assess participant's eligibility;

2. Epoch 2: a randomized treatment epoch of 16 weeks where participants are randomized to canakinumab 150 mg every 4 weeks (q4w) or to placebo to obtain efficacy and safety data in a double-blind placebo controlled parallel-arm setting. This epoch contained 2 possible escape options :

   1. early blinded escape option for non responders from Day 8 to Day 28 with here an add-on dose of 150mg canakinumab followed by blinded uptitration at the next scheduled visit (Day 29)
   2. late unblinded escape option for non responders from Day 29 to Day 112; with open-label uptitration
3. Epoch 3: a randomized withdrawal epoch of 24 weeks where canakinumab responders from the randomized treatment epoch were re-randomized to canakinumab 150mg q8w or placebo to assess the potential for canakinumab to maintain clinical efficacy at a reduced dosing frequency;
4. Epoch 4: an open-label treatment epoch of 72 weeks to collect long-term

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Hereditary Periodic Fevers

Intervention

• Drug: Canakinumab
  Canakinumab solution for subcutaneous injection in vial which contained 150mg/mL canakinumab in 1 mL solution.
  Other Name: ACZ885
• Drug: Placebo
  Matching placebo to canakinumab solution for subcutaneous injection

Study Arms

• Experimental: crFMF: 150 mg
  During Epoch 2, participants received canakinumab 150mg (or 2mg/kg for participants weighing <= 40kg) q4w for 16 weeks. If participants were eligible for blinded escape, they received a single add-on dose of canakinumab (150 mg or 2mg/kg for participants weighing <= 40kg) between day 8 and day 28, and then received blinded uptitration to canakinumab 300 mg q4w from day 29 through day 112. If patients on the highest allowed canakinumab dose of 300 mg (or 4 mg/kg for patients weighing ≤ 40 kg) q4w and re-flared (PGA ≥ 2 and CRP ≥ 30 mg/L) were not eligible for further up-titration.
  Intervention: Drug: Canakinumab
• Placebo Comparator: crCMF: placebo

  During epoch 2, participants received matching placebo to canakinumab 150 mg Participants who required blinded escape,they received a single add-on dose of canakinumab (150 mg or 2mg/kg for participants weighing <= 40kg) between day 8 and day 28, and then received blinded one dose of placebo and one dose of canakinumab q4w from day 29 through day 112. If flare or re-flare still occurred after receipt of canakinumab.

  150mg, participants were uptitrated to open-label canakinumab 300 mg.

  Intervention: Drug: Placebo
• Experimental: HIDS/MKD: 150 mg
  During Epoch 2, participants received canakinumab 150mg (or 2mg/kg for participants weighing <= 40kg) q4w for 16 weeks. If participants were eligible for blinded escape, they received a single add-on dose of canakinumab (150 mg or 2mg/kg for participants weighing <= 40kg) between day 8 and day 28, and then received blinded uptitration to canakinumab 300 mg q4w from day 29 through day 112. If patients on the highest allowed canakinumab dose of 300 mg (or 4 mg/kg for patients weighing ≤ 40 kg) q4w and re-flared (PGA ≥ 2 and CRP ≥ 30 mg/L) were not eligible for further up-titration.
  Intervention: Drug: Canakinumab
• Placebo Comparator: HIDS/MKD: placebo
  During epoch 2, participants received matching placebo to canakinumab 150 mg qw4. Participants who required blinded escape, they received a single add-on dose of canakinumab (150 mg or 2mg/kg for participants weighing <= 40kg) between day 8 and day 28 and then received blinded one dose of placebo and one dose of canakinumab q4w from day 29 through day 112. If flare or re-flare still occurred after receipt of canakinumab 150mg, participants were uptitrated to open-label canakinumab 300 mg.
  Intervention: Drug: Placebo
• Experimental: TRAPS: 150 mg
  During Epoch 2, participants received canakinumab 150mg (or 2mg/kg for participants weighing <= 40kg) q4w for 16 weeks. If participants were eligible for blinded escape, they received a single add-on dose of canakinumab (150 mg or 2mg/kg for participants weighing <= 40kg) between day 8 and day 28, and then received blinded uptitration to canakinumab 300 mg q4w from day 29 through day 112. If patients on the highest allowed canakinumab dose of 300 mg (or 4 mg/kg for patients weighing ≤ 40 kg) q4w and re-flared (PGA ≥ 2 and CRP ≥ 30 mg/L) were not eligible for further up-titration
  Intervention: Drug: Canakinumab
• Placebo Comparator: TRAPS: placebo
  During epoch 2, participants received matching placebo to canakinumab 150 mg qw4. Participants who required blinded escape,they received a single add-on dose of canakinumab (150 mg or 2mg/kg for participants weighing <= 40kg) between Day 8 and 28 and then received blinded one dose of placebo and one dose of canakinumab q4w from day 29 through day 112. If flare or re-flare still occurred after receipt of canakinumab 150mg, participants were uptitrated to open-label canakinumab 300 mg.
  Intervention: Drug: Placebo

• Publications *: De Benedetti F, Gattorno M, Anton J, Ben-Chetrit E, Frenkel J, Hoffman HM, Koné-Paut I, Lachmann HJ, Ozen S, Simon A, Zeft A, Calvo Penades I, Moutschen M, Quartier P, Kasapcopur O, Shcherbina A, Hofer M, Hashkes PJ, Van der Hilst J, Hara R, Bujan-Rivas S, Constantin T, Gul A, Livneh A, Brogan P, Cattalini M, Obici L, Lheritier K, Speziale A, Junge G. Canakinumab for the Treatment of Autoinflammatory Recurrent Fever Syndromes. N Engl J Med. 2018 May 17;378(20):1908-1919. doi: 10.1056/NEJMoa1706314.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: April 6, 2018): 203
• Original Estimated Enrollment (submitted: February 7, 2014): 180
• Actual Study Completion Date: July 4, 2017
• Actual Primary Completion Date: July 4, 2017 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria: - Patient's written informed consent (or parent's written informed consent in case of pediatric patient) at screening - Male and female patients at least 2 years of age at the time of the screening visit. Male and female patients >28 days but <2 years eligible for open label treatment only. - Confirmed diagnosis and active flare at randomization - CRP >10mg/L at randomization

Exclusion Criteria: - Use of the following therapies (within varying protocol defined timeframes): Corticosteroids, anakinra, canakinumab, rilonacept, tocilizumab, TNF inhibitors, abatacept, tofacitinib, rituximab, leflunomide, thalidomide, cyclosporine, intravenous immunoglobulin, 6-Merceptopurine, azathioprine, cyclophosphamide, or chlorambucil, any other investigational biologics - History of malignancy of any organ system (other than localized basal cell carcinoma of the skin or in - situ cervical cancer), treated or untreated - Significant medical diseases, including but not limited to the following: a. History of organ transplantation b. Elevated liver enzymes ≥3x ULN d. Increase in total bilirubin e. Serious hepatic disorder (Child-Pugh scores B or C) f. Chronic Kidney Disease g. Thyroid disease h. Diagnosis of active peptic ulcer disease i. Coagulopathy j. Significant CNS effects including vertigo and dizziness - Any conditions or significant medical problems which immunecompromise the patient and/or places the patient at unacceptable risk for immunomodulatory therapy - Live vaccinations within 3 months prior to the start of the trial, during the trial, and up to 3 months following the last dose

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 1 Month and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Belgium, Canada, France, Germany, Hungary, Ireland, Israel, Italy, Japan, Netherlands, Russian Federation, Spain, Switzerland, Turkey, United Kingdom, United States
• Removed Location Countries: Greece

Administrative Information

• NCT Number: NCT02059291
• Other Study ID Numbers: CACZ885N2301
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: Novartis ( Novartis Pharmaceuticals )
• Study Sponsor: Novartis Pharmaceuticals
• Collaborators: Not Provided

Investigators

• Study Director: Novartis Pharmaceuticals; Novartis Pharmaceuticals

• PRS Account: Novartis
• Verification Date: April 2018