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

NCT ID: NCT02059291

Last Updated: 2018-05-17

Study Results

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Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE3

Total Enrollment

203 participants

Study Classification

INTERVENTIONAL

Study Start Date

2014-06-27

Study Completion Date

2017-07-04

Brief Summary

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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

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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

Conditions

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Hereditary Periodic Fevers

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

TREATMENT

Blinding Strategy

QUADRUPLE

Participants Caregivers Investigators Outcome Assessors

Study Groups

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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.

Group Type EXPERIMENTAL

Canakinumab

Intervention Type DRUG

Canakinumab solution for subcutaneous injection in vial which contained 150mg/mL canakinumab in 1 mL solution.

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.

Group Type PLACEBO_COMPARATOR

Placebo

Intervention Type DRUG

Matching placebo to canakinumab solution for subcutaneous injection

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.

Group Type EXPERIMENTAL

Canakinumab

Intervention Type DRUG

Canakinumab solution for subcutaneous injection in vial which contained 150mg/mL canakinumab in 1 mL solution.

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.

Group Type PLACEBO_COMPARATOR

Placebo

Intervention Type DRUG

Matching placebo to canakinumab solution for subcutaneous injection

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

Group Type EXPERIMENTAL

Canakinumab

Intervention Type DRUG

Canakinumab solution for subcutaneous injection in vial which contained 150mg/mL canakinumab in 1 mL solution.

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.

Group Type PLACEBO_COMPARATOR

Placebo

Intervention Type DRUG

Matching placebo to canakinumab solution for subcutaneous injection

Interventions

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Canakinumab

Canakinumab solution for subcutaneous injection in vial which contained 150mg/mL canakinumab in 1 mL solution.

Intervention Type DRUG

Placebo

Matching placebo to canakinumab solution for subcutaneous injection

Intervention Type DRUG

Other Intervention Names

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ACZ885

Eligibility Criteria

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Inclusion 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
Minimum Eligible Age

1 Month

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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Novartis Pharmaceuticals

INDUSTRY

Sponsor Role lead

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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Novartis Pharmaceuticals

Role: STUDY_DIRECTOR

Novartis Pharmaceuticals

Locations

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Novartis Investigative Site

Los Angeles, California, United States

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Ann Arbor, Michigan, United States

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Cleveland, Ohio, United States

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Edegem, Antwerpen, Belgium

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Brussels, , Belgium

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Hasselt, , Belgium

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Leuven, , Belgium

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Liège, , Belgium

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Calgary, Alberta, Canada

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Vancouver, British Columbia, Canada

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Bron, , France

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Le Kremlin-Bicêtre, , France

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Nîmes, , France

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Paris, , France

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Berlin, , Germany

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Berlin, , Germany

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Essen, , Germany

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Germering, , Germany

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Hamburg, , Germany

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Hamburg, , Germany

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München, , Germany

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Saint Augustin, , Germany

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Tübingen, , Germany

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Budapest, , Hungary

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Budapest, , Hungary

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Galway, , Ireland

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Haifa, , Israel

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Haifa, , Israel

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Jerusalem, , Israel

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Petah Tikva, , Israel

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Ramat Gan, , Israel

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Sciacca, AG, Italy

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Brescia, BS, Italy

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Florence, FI, Italy

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Genova, GE, Italy

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Messina, ME, Italy

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Pavia, PV, Italy

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Roma, RM, Italy

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Trieste, TS, Italy

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Napoli, , Italy

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Roma, , Italy

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Fukuoka, Fukuoka, Japan

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Yokohama, Kanagawa, Japan

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Sakyo-ku, Kyoto, Japan

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Niigata, , Japan

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Nijmegen, , Netherlands

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Utrecht, , Netherlands

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Moscow, , Russia

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Moscow, , Russia

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Moscow, , Russia

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Rostov-on-Don, , Russia

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Saint Petersburg, , Russia

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Esplugues de Llobregat, Barcelona, Spain

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Barcelona, Catalonia, Spain

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El Palmar, Murcia, Spain

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Valencia, Valencia, Spain

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Madrid, , Spain

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Madrid, , Spain

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Lausanne, , Switzerland

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Istanbul, TUR, Turkey (Türkiye)

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Ankara, , Turkey (Türkiye)

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Istanbul, , Turkey (Türkiye)

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Leeds, , United Kingdom

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Novartis Investigative Site

London, , United Kingdom

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Novartis Investigative Site

London, , United Kingdom

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Countries

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United States Belgium Canada France Germany Hungary Ireland Israel Italy Japan Netherlands Russia Spain Switzerland Turkey (Türkiye) United Kingdom

References

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Gattorno M, Obici L, Penades IC, Kallinich T, Benseler S, Dekker E, Levy J, De Benedetti F, Lachmann H. Long-Term Efficacy and Safety of Canakinumab in Patients With Tumor Necrosis Factor Receptor-Associated Periodic Syndrome: Results From a Phase III Trial. Arthritis Rheumatol. 2024 Feb;76(2):304-312. doi: 10.1002/art.42695. Epub 2023 Dec 8.

Reference Type DERIVED
PMID: 37668289 (View on PubMed)

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.

Reference Type DERIVED
PMID: 34554243 (View on PubMed)

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.

Reference Type DERIVED
PMID: 29768139 (View on PubMed)

Provided Documents

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Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

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CACZ885N2301

Identifier Type: -

Identifier Source: org_study_id

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