Evidence of efficacy and safety from RCTs and non-RCTs of CAPS, HIDS/MKD and TRAPS
| Study, year, country | Study design | Population | Treatment(s) | N | Follow-up | Key findings | |
|---|---|---|---|---|---|---|---|
| Efficacy | Safety | ||||||
| RCTs | |||||||
| Lachmann et al 2009,13 14 International | Phase III, DB, 3-parts (OL 8 W, DB 16 W, 24 OL Ext) | CAPS | Canakinumab, Placebo | 35 | 48 W | 8 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) | CAPS | Rilonacept, Placebo | 101 | 96 W | Rilonacept 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 International | Phase III, DB, 4 epoch (E1, 12 W screening; E2, 16 W DB; E3, 24 W WDL; E4, OL Ext 72 W | HIDS/MKD | Canakinumab, Placebo | 72 | 112 W | 16 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). |
| TRAPS | Canakinumab, Placebo | 46 | 112 W | 16 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 Netherlands | DB, crossover (two TPs each 24 W and 4 W washout) | HIDS/MKD | Simvastatin, Placebo | 6 | 52 W | Simvastatin 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. |
| Non-RCTs | |||||||
| †Brogan et al 2015,‡6 9‡ International | Phase III, OL, MC (core study, 56 W; extension, 152 W) | CAPS (12 MWS, 4 CINCA/ NOMID, 1 FCAS) | Canakinumab | 17 | 152 W | 56 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 Japan | Phase III, OL (core, 24 W; Ext 22 M) | CAPS (7 MWS, CINCA/ NOMID 12) | Canakinumab | 19 | 48 W | 24 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, OL | CAPS (CINCA/ NOMID) | Canakinumab | 6 | 24 M | 6 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 International | Phase III, OL, MC | CAPS | Canakinumab | 166 | 2 Y | CR‡ (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 International | Phase II, OL | CAPS (MWS, CINCA/ NOMID) | Canakinumab | 7 | _ | 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 Spain | Phase II, 3-part OL (6 M TP, 6 M WDL, 24 M TP) | HIDS/MKD | Canakinumab | 9 | 36 M | 6 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 Europe | Phase II, 3-part OL (6 M TP, 5 M WDL, 24 M TP) | Recurrent or chronic TRAPS | Canakinumab | 20 | ~2.5Y | D 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-escalation | TRAPS | Etanercept | 15 | 10 Y | Etanercept 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 treatment | Etanercept 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 study | CAPS (FCAS) | Rilonacept | 5 | 24 M | Cold-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 arm | CAPS | Anakinra | 43 | 5 Y | 6 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.