Anti-IL-1β Therapy For Genetic Fever Syndromes Eliminates Flares in Nearly Half of Patients | NEJM


  • Clinical Trial: CLUSTER
  • Authors: Benedetti, Penades et al
  • Journal: New England Journal of Medicine
  • Date: May 17th, 2018


  • Subcutaneous canakinumab, an anti-IL-1β antibody, eliminated flares in 23-53% of patients with one of three autoinflammatory fever syndromes (FMF, MKD, TRAPS) for up to 40 weeks
  • IL-1β common mediator in FMF, MKD, TRAPS pathogenesis
  • Increased risk of infection w/ canakinumab use


  • 1º:  Complete response (resolution of the baseline flare + no new flare) until week 16:
    • 61% Tx vs. 6% PBO in colchicine-resistant FMF
    • 35% Tx vs. 6% PBO in MKD
    • 45% Tx vs. 8% PBO  in TRAPS
  • 2º: % Pts w/ complete 16w response and no flare up to 40w:
    • 100% in colchicine-resistant FMF
    • 82% in MKD
    • 83% in TRAPS
  • 2º: % Pts w/ no flare up to 40w:
    • 46% in colchicine-resistant FMF
    • 23% in  MKD
    • 53% in TRAPS


  • Tx:
    • 150 mg (or 2 mg/kg for pts ≤40 kg) SQ canakinumab Q4w x16w, then Q8w x26w, FMF pts continued colchicine
    • Increased to 300 mg in 10% colchicine-resistant FMF pts, 29% MKD, and 8% TRAP (if unresponsive to starting dose)
  • CTL: PBO injection Q4w x16w, then Q8w x26w

Adverse Events

  • Overall AE frequency: Mean total AE across treatment groups over 40w:
    • 403 tx
    • 114 PBO
  • Common AE: respiratory infections, abdominal pain, headaches, and injection-site reactions, arthralgia
  • Serious AE: 10 serious infections in tx groups, 2 in placebo
  • D/C due to AE: 3 in tx group, 1 in placebo


  • Disease: colchicine-resistant FMF, MKD, TRAPS
  • Phenotype: recurrent fever episodes lasting days to weeks, with skin, joint, and serosal involvement
  • Epidemiology: FMF most common, 400/100,000 in Eastern Mediterranean populations
  • Drug: canakinumab, monoclonal anti–interleukin-1β antibody
  • Previous Evidence:
    • FDA approved canakinumab in 2016 for treatment of FMF, MKD, TRAPS based on 16w (epoch 2) evidence from this trial
    • Also approved for Cryopyrin-Associated Periodic Syndromes (CAPS)
    • Also approved for Systemic Juvenile Idiopathic Arthritis (SJIA)


  • Study Design: Randomized Placebo-Controlled Phase III Clinical Trial
  • Study Size: 63 patients with colchicine-resistant familial Mediterranean fever, 72 with mevalonate kinase deficiency, and 46 with TRAPS, each randomized 1:1 with treatment and placebo
  • Timeline: treated for 16 weeks (epoch 2) after randomization, re-randomized and treated for 24 weeks (epoch 3) at increased dose interval
  • Demographics: age>2y, mean age 19y
  • Withdrawals: 10 canakinumab, 5 placebo
  • Funding: Novartis

*Abbreviations and Definitions

AE: Adverse events

CTL: Control

CRP: C-Reactive Protein – serum biomarker of inflammation

D/C: Discontinuation of treatment

Flare: PGA score of ≥2 and CRP level of ≥30 mg/L

FMF: familial Mediterranean fever

MKD: mevalonate kinase deficiency, aka hyperimmunoglobulinemia D syndrome

PBO: Placebo

PGA Score: Physician’s global assessment; physician score of disease severity, taking into account fever and clinical signs and symptoms associated with each disease on a 5-point scale, with scores of 0 (none), 1 (minimal), 2 (mild), 3 (moderate), and 4 (severe).

PTS: Patients

SQ: subcutaneous injection

TRAPS:  tumor necrosis factor receptor–associated periodic syndrome

Tx: Treatment