Clinical trial NCT02059291: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Hereditary Periodic Fevers
Keywords: Canakinumab, interleukin-1, Hereditary Periodic Fevers, auto-inflammatory diseases
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2014-02-11
Enrollment: 203
Sex: ALL
Minimum age (years): 1
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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

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

Primary outcomes:
measure: Percentage of Participants With Resolution of Initial Flare and Absence of New Flares up to the End of the Randomized Treatment Epoch (16 Weeks)
timeFrame: 16 weeks
Secondary outcomes:
measure: Percentage of Participants Who Achieve Physician's Global Assessment (PGA) < 2
timeFrame: 16 weeks
measure: Percentage of Participants With the Serologic Remission
timeFrame: 16 weeks
measure: Percentage of Participants With Normalized Serum Amyloid A (SAA) Level
timeFrame: 16 weeks
measure: Percentage of Participants of Canakinumab Responders From Epoch 2 Who Maintained a Clinically Meaningful Response (Absence of New Flares) (40 Weeks)
timeFrame: 40 weeks
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Novartis Investigative Site
state: California
city: Ann Arbor
country: United States
facility: Novartis Investigative Site
state: Michigan
city: Cleveland
country: United States
facility: Novartis Investigative Site
state: Ohio
city: Edegem
country: Belgium
facility: Novartis Investigative Site
state: Antwerpen
city: Bruxelles
country: Belgium
facility: Novartis Investigative Site
city: Hasselt
country: Belgium
facility: Novartis Investigative Site
city: Leuven
country: Belgium
facility: Novartis Investigative Site
city: Liege
country: Belgium
facility: Novartis Investigative Site
city: Calgary
country: Canada
facility: Novartis Investigative Site
state: Alberta
city: Vancouver
country: Canada
facility: Novartis Investigative Site
state: British Columbia
city: Bron Cedex
country: France
facility: Novartis Investigative Site
city: Le Kremlin Bicetre
country: France
facility: Novartis Investigative Site
city: Nimes Cedex
country: France
facility: Novartis Investigative Site
city: Paris
country: France
facility: Novartis Investigative Site
city: Berlin
country: Germany
facility: Novartis Investigative Site
city: Berlin
country: Germany
facility: Novartis Investigative Site
city: Essen
country: Germany
facility: Novartis Investigative Site
city: Germering
country: Germany
facility: Novartis Investigative Site
city: Hamburg
country: Germany
facility: Novartis Investigative Site
city: Hamburg
country: Germany
facility: Novartis Investigative Site
city: Muenchen
country: Germany
facility: Novartis Investigative Site
city: Saint Augustin
country: Germany
facility: Novartis Investigative Site
city: Tübingen
country: Germany
facility: Novartis Investigative Site
city: Budapest
country: Hungary
facility: Novartis Investigative Site
city: Budapest
country: Hungary
facility: Novartis Investigative Site
city: Galway
country: Ireland
facility: Novartis Investigative Site
city: Haifa
country: Israel
facility: Novartis Investigative Site
city: Haifa
country: Israel
facility: Novartis Investigative Site
city: Jerusalem
country: Israel
facility: Novartis Investigative Site
city: Petach-Tikva
country: Israel
facility: Novartis Investigative Site
city: Ramat Gan
country: Israel
facility: Novartis Investigative Site
city: Sciacca
country: Italy
facility: Novartis Investigative Site
state: AG
city: Brescia
country: Italy
facility: Novartis Investigative Site
state: BS
city: Firenze
country: Italy
facility: Novartis Investigative Site
state: FI
city: Genova
country: Italy
facility: Novartis Investigative Site
state: GE
city: Messina
country: Italy
facility: Novartis Investigative Site
state: ME
city: Pavia
country: Italy
facility: Novartis Investigative Site
state: PV
city: Roma
country: Italy
facility: Novartis Investigative Site
state: RM
city: Trieste
country: Italy
facility: Novartis Investigative Site
state: TS
city: Napoli
country: Italy
facility: Novartis Investigative Site
city: Roma
country: Italy
facility: Novartis Investigative Site
city: Fukuoka city
country: Japan
facility: Novartis Investigative Site
state: Fukuoka
city: Yokohama-city
country: Japan
facility: Novartis Investigative Site
state: Kanagawa
city: Sakyo-ku
country: Japan
facility: Novartis Investigative Site
state: Kyoto
city: Niigata
country: Japan
facility: Novartis Investigative Site
city: Nijmegen
country: Netherlands
facility: Novartis Investigative Site
city: Utrecht
country: Netherlands
facility: Novartis Investigative Site
city: Moscow
country: Russian Federation
facility: Novartis Investigative Site
city: Moscow
country: Russian Federation
facility: Novartis Investigative Site
city: Moscow
country: Russian Federation
facility: Novartis Investigative Site
city: Rostov on Don
country: Russian Federation
facility: Novartis Investigative Site
city: Saint-Petersburg
country: Russian Federation
facility: Novartis Investigative Site
city: Esplugues de Llobregat
country: Spain
facility: Novartis Investigative Site
state: Barcelona
city: Barcelona
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Valencia
country: Spain
facility: Novartis Investigative Site
state: Comunidad Valenciana
city: El Palmar
country: Spain
facility: Novartis Investigative Site
state: Murcia
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Lausanne
country: Switzerland
facility: Novartis Investigative Site
city: Istanbul
country: Turkey
facility: Novartis Investigative Site
state: TUR
city: Ankara
country: Turkey
facility: Novartis Investigative Site
city: Istanbul
country: Turkey
facility: Novartis Investigative Site
city: Leeds
country: United Kingdom
facility: Novartis Investigative Site
city: London
country: United Kingdom
facility: Novartis Investigative Site
city: London
country: United Kingdom
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References:
citation: Jeyaratnam J, Simon A, Calvo I, Constantin T, Shcherbina A, Hofer M, Gattorno M, Martini A, Bader-Meunier B, Vastert B, Levy J, Dekker E, de Benedetti F, Frenkel J. Long-term efficacy and safety of canakinumab in patients with mevalonate kinase deficiency: results from the randomised Phase 3 CLUSTER trial. Rheumatology (Oxford). 2022 May 5;61(5):2088-2094. doi: 10.1093/rheumatology/keab696.
citation: De Benedetti F, Gattorno M, Anton J, Ben-Chetrit E, Frenkel J, Hoffman HM, Kone-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.