Table 2

Evidence of efficacy and safety from RCTs and non-RCTs of CAPS, HIDS/MKD and TRAPS

Study, year, countryStudy designPopulationTreatment(s)NFollow-upKey findings
Lachmann et al 2009,13 14 InternationalPhase III, DB, 3-parts (OL 8 W, DB 16 W, 24 OL Ext)CAPSCanakinumab, Placebo3548 W8 W: CR‡, 34 (97%).
16 W DB: 15 (100%) Canakinumab-treated pts remained in remission, while 13/16 of placebo-treated pts (81%) had relapse.
24 W OL Ext: 30/31 (97%) had no or minimal disease activity by physician assessment.
Canakinumab was well-tolerated up to 48 W. SAEs (2 patients; urosepsis in one patient, and vertigo in another). One patient discontinued because of an AE (vertigo). No deaths/life-threatening AE.
>91% of patients reported no injection-site reactions; 4 patients had mild reactions, but no severe reactions.
Hoffman et al 2008,15 16 U.S.Two DB, Phase III sequential studies (24 W), followed by OL Ext (72 W)CAPSRilonacept, Placebo10196 WRilonacept vs Placebo: Study 1, n=47 (6 W): reduction in mean composite symptom score, 84% vs 13% (p<0.001); PhGA, PtGA, hsCRP and SAA reduced significantly with rilonacept vs placebo.
Study 2, n=45 (24 W): Treatment effect continued.
OL Ext, n=101 (44 from study 2 and 57 directly in OL) (72 W): Mean key symptom score reduced from 2.6 to 0. hsCRP and SAA normalised
24 W: study 1 (rilonacept vs placebo), any AEs (74% vs 54%); injection-site reaction (48% vs 13%), upper RTI (26% vs 4%).
Study 2 (rilonacept vs placebo), any AEs (68% vs 57%); injection-site reaction (36% vs 13%). One SAE (worsening sciatica).
72 W: Rilonacept, any AE (89%); erythema (32%), pruritus (13%), bruising (12%), swelling (11%), influenza, sinusitis (10% each). Nine SAEs reported by 7 patients: sinusitis and pneumococcal meningitis, coronary atherosclerosis, sciatica and arthritis, gastro-oesophageal reflux disease, cholelithiasis, and renal colic.
†De Benedetti et al 2016,17 20 InternationalPhase III, DB, 4 epoch (E1, 12 W screening; E2, 16 W DB; E3, 24 W WDL; E4, OL Ext 72 WHIDS/MKDCanakinumab, Placebo72112 W16 W (E2): Canakinumab vs Placebo: clinical response2, 13/37 (35%) vs 2/35 (6%) (p=0.0020); inactive disease, 40%.
40 W (E3): 3/6 (50%) vs 1/7 (14%) (p=0.2168)
16 W: AEs (canakinumab, 14 patients; placebo, 4 patients). Infections and infestations (canakinumab, 10 patients; placebo, 2 patients). SAEs (canakinumab, 0; placebo, 2 patients).
40 W: AE rate/100 PY (canakinumab, 1 121; placebo, 816.7). SAE rate/100 PY (canakinumab, 34.0; placebo, 42.7).
TRAPSCanakinumab, Placebo46112 W16 W (E2): Canakinumab vs Placebo: clinical response2, 10/22 (45%) vs 2/24 (8%) (p=0.0050); inactive disease, 46%.
40 W (E3): 3/4 (75%) vs 2/5 (40%) (p=0.3571)
16 W: AEs (canakinumab, 9 pts; placebo, 3 patients). Infections and infestations (canakinumab, 2 patients; placebo, 2 patients). SAEs (canakinumab, 0; placebo, 0).
40 W: AE rate/100 PY (canakinumab, 747.1; placebo, 816.7). SAE rate/100 PY (canakinumab, 19.0; placebo, 42.7).
Simon et al 2004,8‡ The NetherlandsDB, crossover
(two TPs each 24 W and 4 W washout)
HIDS/MKDSimvastatin, Placebo652 WSimvastatin vs Placebo: mean no. of febrile days per pts per 6 M, 16.7 vs 24.3 days; mean no. of fever attacks, 3.0 vs 3.8; mevalonic acid levels, 1.9 vs 4.9 mg/g creatinine (p<0.001)No AEs in five patients. One patient reported flatulence, nightmares, tiredness and myalgias.
†Brogan et al 2015,‡6 9‡ InternationalPhase III, OL, MC (core study, 56 W; extension, 152 W)CAPS (12 MWS, 4 CINCA/
Canakinumab17152 W56 W: CR3: 16 (94%); 4 pts subsequently relapsed, but all regained CR
152 W: CR3: 17 (100%); pts with no disease activity improved (24% to 65%)
10 patients (59%) were suspected to have study-drug related AEs, with most common of diarrhoea, pneumonia, rhinitis and cough (3 patients each). SAEs, 8 patients (47.1%), with pneumonia as the most frequent SAE (12%). No deaths.
Imagawa et al 2013,21 22 JapanPhase III, OL (core, 24 W; Ext 22 M)CAPS (7 MWS, CINCA/
Canakinumab1948 W24 W: CR4: 18 (95%); remission (relapse free): 14/18 (78%); pts with no disease activity improved (11% to 32%).
48 W: CR4: 19 (100%); remission: 18 (95%); pts with no disease activity, 11 (58%).
48 W: Any AEs (100%). Most common AEs: upper RTI (73.7%), nasopharyngitis (52.6%), gastroenteritis (36.8%), sinusitis and stomatitis (each 26.3%). SAEs, 5 patients (26%): parvovirus infection and Epstein-Barr virus infection (n=1), pneumonia (n=1), sinoatrial block and headache (n=1), asthma (n=1) and appendicitis (n=1). No deaths. One patient discontinued (withdrew consent).
Sibley et al 2015,23 U.S.Phase I/II, OLCAPS (CINCA/
Canakinumab624 M6 M: inflammatory remission5: 4/6 (67%)
24 M: inflammatory remission5: 5/6 (83%)
Infections (6 patients). One serious AE (abscess due to a methicillin-resistant Staphylococcus aureus infection).
Kuemmerle-Deschner et al 2011,24 InternationalPhase III, OL, MCCAPSCanakinumab1662 YCR‡ (Canakinumab-naïve pts): 85/109 (78%) (79 within D 8, and 5 within days 10 and 21). Of 141 pts with relapse assessment available, 90% did not relapse, their CRP/SAA levels normalised (<10 mg/L)Any AEs (90.4%). Most common AEs were infections (65.7%) (mostly mild-to-moderate severity). SAEs, 18 patients (10.8%; mainly infections and were responsive to standard therapy). 92% of patients had no injection-site reactions and 8% had mild-to-moderate reactions.
Kuemmerle-Deschner et al 2011,25 InternationalPhase II, OLCAPS (MWS, CINCA/
Canakinumab7_D 7: CR6, 100%; CRP and SAA normalised.
Relapse, 6 (86%); median time to relapse, 49 days. CR6 on retreatment, 4/6 (67%).
Canakinumab was well-tolerated. Common AEs were upper RTI (71%), rash (57%), pharyngitis, nasopharyngitis, vomiting (43% each), diarrhoea, rhinitis, sleep disorder, cough and acne (29% each). SAE, 1 patient (vertigo).
Arostegui et al 2017,26 SpainPhase II, 3-part OL (6 M TP, 6 M WDL, 24 M TP)HIDS/MKDCanakinumab936 M6 M TP: CR7, 100%; median time to resolution, 3 days. Median no. of attacks decreased from 5 to 0 (p=0.009). 6 M WDL: relapse, 7 (78%); median time to relapse, 110 days. 24 M TP: No. of attacks/pts decreased significantly (p=0.008).AEs, 9 patients (100%) (infections, 44% is most common). 14 SAEs occurred in 4 patients (8 SAEs occurred in same patient who had a complicated medical history; other SAEs were cellulitis in one patient, and hidradenitis suppurativa requiring hospitalisation in one patient).
Gattorno et al 2017,27 EuropePhase II, 3-part OL (6 M TP, 5 M WDL, 24 M TP)Recurrent or chronic TRAPSCanakinumab20~2.5YD 15: CR8, 19 (95%); median time to clinical remission, 4 days. 5 M WD: relapse, 100%; median time to relapse, 91.5 days.
Ext TP: all pts regained CR. CPS/SAA levels normalised by D15 and remained normal during TP
Canakinumab was well tolerated. AEs, 20 pts (100%), with nasopharyngitis (60%), abdominal pain, headache, oropharyngeal pain (55% each) and fever (50%) as most common. SAEs reported in 7 patients: pericarditis, abdominal pain, diarrhoea, intestinal obstruction, vomiting, upper RTI, meniscus injury, hypertriglyceridaemia, hyperkalaemia, foot deformity and condition aggravated.
Bulua et al 2012,6‡ U.S.OL, single arm, dose-escalationTRAPSEtanercept1510 YEtanercept two times per week (period 2) and 3 times weekly (period 3) was significantly associated with a dose-related attenuation in the total symptom score, decreasing by 36% (p=0.02) in period 2 and 66% (p<0.0001) in period 3. CRP, ESR and SAA levels were significantly lower during etanercept treatmentEtanercept was well-tolerated, with most AEs being local injection-site reactions. No SAEs reported.
Goldbach-Mansky et al 2008,28 U.S.Phase II, OL, pilot studyCAPS (FCAS)Rilonacept524 MCold-induced clinical symptoms improved within days of RIL dose. ESR, hsCRP and SAA reduced statistically at doses of 100 mg.Rilonacept was well-tolerated. No injection-site reactions reported. Infections occurred but resolved. No SAEs reported.
Goldbach-Mansky et al 2006,29 31 U.S.Phase I/II, OL, single armCAPSAnakinra435 Y6 M: all 18 pts had rapid response with disappearance of rash. Global diary scores and ESR, CRP and SAA reduced significantly (p<0.001).
3 and 5 Y: improvements sustained in diary scores, PtGA, PhGA, PtGA pain scores and inflammatory markers.
6 M: No discontinuations. Injection-site reactions, 8 patients (44%). AEs included upper RTI (15 patients), UTI (2 patients), and a hospital admission for dehydration from non-bacterial diarrhoea (1 patient).
3 and 5 Y: AE rate was 7.7 AEs per patient per year. Anakinra had similar safety profiles in adults and children. Most common AEs were headache and arthralgia. 14 patients reported 24 SAEs: pneumonia, gastroenteritis, wound infection, post-lumbar puncture syndrome and macrophage activation syndrome.
  • †Studies published as conference abstracts only.

  • ‡CR: PhGA (no or minimal disease activity), no or minimal rash (skin disease) and CRP and SAA both <10 mg/L;2 Clinical response: resolution of index flare at Day 15 and no new disease flare over 16 weeks of treatment;3 CR: clinical response and normal CRP;4 CR: PhGA (no or minimal), no or minimal skin disease, and serological remission (CRP and/or SAA <10 mg/L);5 Inflammatory remission (global daily diary score (mean/week) ≤2 and normal CRP (≤10 mg/L));6 CR: PhGA (no or minimal disease activity), no or minimal rash, and normal CRP and/or SAA (<10 mg/L);7 CR: PhGA (0 (no) or 1 (minimal) disease activity) and plasma CRP <10 mg/L;8 CR: clinical remission (PhGA ≤1) and full serological remission (CRP and/or SAA <10 mg/L).

  • AE, adverse event; CAPS, cryopyrin-associated periodic syndromes; CINCA, chronic infantile neurological cutaneous and articular syndrome; CRP, C reactive protein; D, days; ESR, erythrocyte sedimentation rate; FCAS, familial cold autoinflammatory syndrome; HIDS, hyperimmunoglobulin D syndrome; hsCRP, high-sensitivity CRP; M, months; MC, multicentre; MKD, mevalonate kinase deficiency; MWS, Muckle–Wells syndrome; N, number of patients; NOMID, neonatal-onset multisystem inflammatory disease; OL, open-label; PhGA, physician assessed global assessment of the disease; PtGA, patient/parent assessed global assessment of the disease; PY, patient-years; RTI, respiratory tract infection; SAA, serum amyloid A; SAE, serious AE; TP, treatment period; TRAPS, tumour necrosis factor receptor-associated periodic syndrome; UTI, urinary tract infection; W, weeks; WDL, withdrawal; Y, years.