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Long-term efficacy and safety of canakinumab in patients with colchicine-resistant familial Mediterranean fever: results from the randomised phase III CLUSTER trial
  1. Seza Ozen1,
  2. Eldad Ben-Cherit2,
  3. Ivan Foeldvari3,
  4. Gil Amarilyo4,5,
  5. Huri Ozdogan6,
  6. Steven Vanderschueren7,
  7. Katherine Marzan8,
  8. J Michelle Kahlenberg9,
  9. Elise Dekker10,
  10. Fabrizio De Benedetti11,
  11. Isabelle Koné-Paut12,13
  1. 1 Department of Pediatric Rheumatology, Hacettepe University, Ankara, Turkey
  2. 2 Rheumatology Unit, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
  3. 3 Pediatric Rheumatology, Hamburg Centre for Pediatric and Adolescent Rheumatology, Hamburg, Germany
  4. 4 Pediatric Rheumatology Unit, Schneider Children's Medical Center of Israel, Petah Tikva, Israel
  5. 5 Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
  6. 6 Department of Internal Medicine, Division of Rheumatology, University of Istanbul-Cerrahpaşa, Istanbul, Turkey
  7. 7 Clinical Department of General Internal Medicine, Research Department of Immunology, Microbiology and Transplantation, Laboratory for Clinical Infectious and Inflammatory Disorders, University Hospitals, Leuven, Belgium
  8. 8 Pediatrics Keck School of Medicine of USC, Children's Hospital Los Angeles, Los Angeles, California, USA
  9. 9 Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
  10. 10 Immunology, Hepatology & Dermatology Franchise, Novartis Pharma AG, Basel, Switzerland
  11. 11 Division of Rheumatology, Ospedale Pediatrico Bambino Gesù, Roma, Italy
  12. 12 Université de Paris Sud-Saclay, Le Kremlin Bicêtre, France
  13. 13 Pediatric Rheumatology and CEREMAIA, Centre Hospitalier Universitaire (CHU) de Le Kremlin Bicêtre, Le Kremlin Bicêtre, France
  1. Correspondence to Dr Seza Ozen, Department of Pediatric Rheumatology, Hacettepe University, Ankara 06800, Turkey; sezaozen{at}


Objectives To evaluate the long-term efficacy and safety of canakinumab to treat patients with colchicine-resistant familial Mediterranean fever (crFMF) during Epoch 4 (weeks 41 to 113) of the CLUSTER study.

Methods Patients received open-label canakinumab 150 or 300 mg, every 4 or 8 weeks during a 72-week period. We evaluated disease activity every 8 weeks using the physician global assessment (PGA) of disease activity, counting the number of flares, and measuring concentrations of C reactive protein (CRP) and serum amyloid A (SAA). Safety was studied by determination and classification of observed adverse events (AEs). We analysed safety and efficacy separately in two subgroups of patients receiving a cumulative dose of less than 2700 mg, or equal or more than 2700 mg.

Results Of the 61 patients that started the CLUSTER study, 60 entered Epoch 4 and 57 completed it. During the 72-week period, 35/60 (58.3%) patients experienced no flares, and 23/60 (38.3%) had one flare, as compared with a median of 17.5 flares per year reported at baseline. PGA scores indicated no disease activity for the majority of patients throughout the study. Median CRP concentrations were always lower than 10 mg/L, while median SAA concentrations remained over the limit of normal (10 mg/L) but under the 30 mg/L threshold. No new or unexpected AEs were reported.

Conclusion crFMF patients treated with canakinumab during 72 weeks experienced a minimal incidence of flares and good control of clinical disease activity, with no new safety concerns reported.

  • familial mediterranean fever
  • autoimmune diseases
  • cytokines
  • treatment

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  • Handling editor Josef S Smolen

  • Twitter @drsezaozen, @Kahlenberglab

  • Contributors The study was designed by academic authors and Novartis. All authors attest to the completeness and veracity of data and data analyses. All authors had full access to study data, reviewed and revised the manuscript. Authors have approved the final version of the manuscript to be published. All authors were involved in the decision to submit the manuscript for publication.

  • Funding This study was funded by Novartis Pharma.

  • Competing interests SO has been a consultant for Novartis and Speaker’s Bureau for Sobi; EB-C has been a consultant for Novartis; IF has been an Advisor for Novartis; GA has received research grants from Novartis; HO has no potential conflict of interest; SV has no potential conflict of interest; KM has received research grant from Novartis; JMK has been an Advisor for AstraZeneca, Bristol Myers Squibb, Boehringer Ingleheim and Eli Lilly; JMK has received research grants from Bristol Myers Squibb; ED is an employee of Novartis; FDB has received research grants from Novartis, Sobi, Novimmune, Abbvie, Roche and Sanofi; IK-P has been a consultant for Novartis, LBF, Sobi, CHUGAI, Pfizer and Abbvie; IK-P has received research grant (non-financial) from Sobi.

  • Patient consent for publication Not required.

  • Ethics approval The study was conducted according to the ethical principles of the Declaration of Helsinki. The study protocol was approved by the Independent Ethics Committee or Institutional Review Board at each site.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information. Additional data are available on reasonable request.

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