7.3.9ANAKINRA (ANAKIN)

ReferenceStudy type
Evidence level
Number of patientsPatient characteristicsInterventionComparisonLength of follow-upOutcome measuresSource of funding
S. B. Cohen, J. M. Woolley, W. Chan, and Study Group. Interleukin 1 receptor antagonist anakinra improves functional status in patients with rheumatoid arthritis. Journal of Rheumatology 30 (2):225–231, 2003.

ID 98
RCT: 1++
Multicentre trial (36 centres in USA, Canada and Australia).
  • Randomised (method not mentioned)
  • Double blind
  • ITT analysis
Total N=419: N= 105 had 12 weeks treatment - randomised to placebo (N=27), anakinra 0.1 mg/kg (N=28), 0.4 mg/kg (N=23), 2.0 mg/kg (N=27); N=317 had 24 weeks treatment - randomised to placebo (N=47); anakinra 0.04 mg/kg (N=63); 0.1 mg/kg (N=46); 0.4 mg/kg (N=54); 1.0 mg/kg (N=59) and 2.0 mg/kg (N=45).

Drop-outs:
Not mentioned
Inclusion criteria: >6 months and <12 years symptoms of RA (ACR criteria); at least 6 swollen joints and at least 2 of the following: 9 tender/painful joints, morning stiffness lasting at least 45 mins, serum CRP level at least 1.5 mg/dl. Patients had received methotrexate (MTX) for at least 6 consecutive months, with the dosage stable for at least 4 weeks before study entry.

Exclusion criteria: Received IA or systemic CS injection within 4 weeks of study enrollment; received penicillamine, oral or parenteral gold, azathioprine or cyclosporine within 12 weeks before study start, received hydroxychloroquine or sulfasalazine within 8 weeks before study start.

1.7 Baseline characteristics:

Placebo group (N=74): mean age 53 years; Female 85%; Duration of RA 7.8 years; HAQ-DI score 1.4.

Anakinra 0.04 mg/kg group (N=63): mean age 53 years; Female 78%; Duration of RA 6.3 years; HAQ-DI 1.4.

Anakinra 0.1 mg/kg group (N=74): mean age 53 years; Female 80%; Duration of RA 8.8 years; HAQ-DI 1.5.

Anakinra 0.4 mg/kg group (N=77): mean age 53 years; Female 77%; Duration of RA 7.0 years; HAQ-DI 1.5.

Anakinra 1.0 mg/kg group (N=59): mean age 49 years; Female 85%; Duration of RA 6.5 years; HAQ-DI 1.3.

Anakinra 2.0 mg/kg group (N=72): mean age 54 years; Female 63%; Duration of RA 8.0 years; HAQ-DI 1.3.

The groups were similar for all baseline characteristics. All had moderate to severe RA (based on HAQ-DI scores).
Anakinra – doses of either 0.04, 0.1, 0.4 1.0 and 2.0 mg/kg (once daily)

Patients continued to receive their current treatment of MTX (15–25 mg) throughout the study.
Placebo (once daily)Assessments made every 4 weeks for a total period of 12 weeks (N=419 patients) or 24 weeks (N= 317 patients)HAQ (20 items on functioning and 4 items on aids and devices – scores from 0 without difficulty to 3 unable to do). HAQ-DI (weighted sum of the scale sores. Lower scores = better functional status.
MCID = decrease of 0.19 to 0.22 or 33% change.
Amgen Inc., USA.
Effect size

ANAKINRA 0.04 mg/kg vs PLACEBO
  • There was NS difference between Anakinra 0.04 mg/kg and placebo for:
    • HAQ-DI (change from baseline) at 12 weeks and 24 weeks (end of study)
    • Percentage of patients reporting no impairment of function (HAQ-DI = 0) at week 24, end of study (11.1% and 5.4% respectively)
ANAKINRA 0.1 mg/kg vs PLACEBO
  • There was NS difference between Anakinra 0.1 mg/kg and placebo for:
    • HAQ-DI (change from baseline) at 12 weeks and 24 weeks (end of study)
    • Percentage of patients reporting no impairment of function (HAQ-DI = 0) at week 24, end of study (9.5% and 5.4% respectively)
ANAKINRA 0.4 mg/kg vs PLACEBO
  • There was NS difference between Anakinra 0.4 mg/kg and placebo for:
    • HAQ-DI (change from baseline) at 12 weeks and 24 weeks (end of study)
    • Percentage of patients reporting no impairment of function (HAQ-DI = 0) at week 24, end of study (6.5% and 5.4% respectively)
ANAKINRA 1.0 mg/kg vs PLACEBO
  • Anakinra 1.0 mg/kg was significantly better than placebo for:
    • HAQ-DI (change from baseline) at 12 weeks (−0.35, p<0.05) and 24 weeks, end of study (−0.37, p<0.05)
    • Percentage of patients reporting no impairment of function (HAQ-DI = 0) at week 24, end of study (18.6% and 5.4% respectively, p<0.05; OR 4.76, 95% CI 1.1 to 20.0)
ANAKINRA 2.0 mg/kg vs PLACEBO
  • Anakinra 2.0 mg/kg was significantly better than placebo for:
    • HAQ-DI (change from baseline) at 12 weeks (−0.39, p<0.01) and 24 weeks, end of study (−0.51, p<0.01)
  • There was NS difference between Anakinra 2.0 mg/kg and placebo for:
    • Percentage of patients reporting no impairment of function (HAQ-DI = 0) at week 24, end of study (12.5% and 5.4% respectively)
ReferenceStudy type
Evidence level
Number of patientsPatient characteristicsInterventionComparisonLength of follow-upOutcome measuresSource of funding
M. C. Genovese, S. Cohen, L. Moreland, D. Lium, S. Robbins, R. Newmark, P. Bekker, and Study Group. Combination therapy with etanercept and anakinra in the treatment of patients with rheumatoid arthritis who have been treated unsuccessfully with methotrexate. Arthritis & Rheumatism 50 (5):1412–1419, 2004.
ID 71
RCT: 1+
USA
  • Randomised 1:1:1 ratio (method not mentioned)
  • Double blind
  • Not true ITT analysis
Total N=244 randomised (N=242 received medication).

N=80 etanercept, N=81 etancercept (once/week) + anakinra, etanercept (twice/week) + anakinra

Drop-outs:
N=5 (7%) etanercept 25mg BIW, N=18 (12%) etanercept 25mg QW + anakinra 100 mg QD, N=15 (20%) etanercept 25mg BIW + anakinra 100 mg QD
Inclusion criteria: Adults ≥18 years, > 6 month history of RA (ACR criteria); at least 6 swollen joints and 9 tender/painful joints and at least 2 of the following: morning stiffness lasting at least 45 mins, serum CRP level at least 1.5 mg/dl, ESR at least 28 mm/hour. Patients had received methotrexate (MTX) for at least 16 weeks, with the doseage stable at 10–25 mg/week for at least 8 weeks.

Exclusion criteria: Received any DMARD other than MTX within the past 4 weeks, had ever been treated with anakinra or any protein-based TNFα inhibitor, had received any IA or systemic corticosteroid injections within the past 4 weeks, recent history o significant infection or other important concurrent illness.

Baseline characteristics:
Etanercept group: mean age 54.4 years (SD 13.6); Female 83%; Weight, kg 75 kg (SD 18); Duration of RA 9.7 years (SD 9.4); HAQ score 1.5 (SD 0.6).

Etanercept once/week + anakinra group: mean age 53.8 years (SD 11.8); Female 72%; Weight, kg 82 kg (SD 21); Duration of RA 9.5 years (SD 10.3); HAQ score 1.5 (SD 0.6).

Etanercept twice/week + anakinra group: mean age 55.7 years (SD 13.0); Female 78%; Weight, kg 80 kg (SD 23); Duration of RA 10.6 years (SD 9.8); HAQ score 1.6 (SD 0.6).

The groups were similar for all baseline characteristics.
Etanercept 25mg BIW (twice a week)

Both drugs administered subcutaneously.

Patients continued to receive stable doses of MTX and other medications (e.g. corticosteroids) throughout the study.
Etanercept 25mg QW (once a week) + anakinra 100 mg QD (4 times a day)

Etanercept 25mg BIW (twice a week) + anakinra 100 mg QD (4 times a day)
24 weeks (end of treatment) and follow-up at 4 weeks post-treatment or time of early discontinuation.ACR core set of disease activity measures (ACR 20, 50 and 70 - ie. ACR 20%, 50% and 70% response); modified Disease Activity Score (DAS); European League Against Rheumatism (EULAR) response (a measure of change in disease activity and current disease activity; % of patients good, moderate or non-responders); duration of morning stiffness; SF-36 (QoL); AEs; withdrawals.

ACR50 responder = ≥50% reduction in number of tender and swollen joints and 3 of the following 5 measures: patient’s global assessment of disease activity (VAS), Patients assessment of pain (VAS), disability score (HAQ) and acute-phase reactants (CRP or ESR).
Amgen Inc., USA.
Effect size*

ETANERCEPT vs ETANERCEPT (ONCE A WEEK) + ANAKINRA
  • Etanercept was significantly better than etanercept (once a week) + anakinra for:
    • ACR20 (68% and 51% respectively; OR 1.98, 95% CI 1.05 to 3.78; p=0.037) at 24 weeks (end of treatment)
    • Number of withdrawals due to AEs (0% and 8.6% respectively, p value not given) at 24 weeks (end of treatment)
  • Etanercept was better than etanercept (once a week) + anakinra for:
    • EULAR response (79% and 66% patients respectively) at week 24 (end of treatment)
    • Number of withdrawals (7% and 12% respectively) at 24 weeks (end of treatment)
    • Number of SAEs (2.5% and 4.9% respectively) at 24 weeks (end of treatment)
    • Number of infections and number of serious infections over 24 weeks (end of treatment)
  • There was NS difference between Etanercept and etanercept (once a week) + anakinra for:
    • ACR50 (41% and 39% respectively) at 24 weeks (end of treatment)
    • ACR 70 (21% and 24% respectively) at 24 weeks (end of treatment)
  • Etanercept was similar to etanercept (once a week) + anakinra for:
    • DAS score, % reduction (39% and 40% respectively) at 24 weeks (end of treatment)
ETANERCEPT vs ETANERCEPT (TWICE A WEEK) + ANAKINRA
  • Etanercept was significantly better than etanercept (twice a week) + anakinra for:
    • Number of withdrawals due to AEs (0% and 7.4% respectively, p value not given) at 24 weeks (end of treatment)
  • Etanercept was better than etanercept (twice a week) + anakinra for:
    • EULAR response (79% and 73% patients respectively) at week 24 (end of treatment)
    • Number of withdrawals (7% and 20% respectively) at 24 weeks (end of treatment)
    • Number of SAEs (2.5% and 14.8% respectively) at 24 weeks (end of treatment)
    • Number of infections and number of serious infections over 24 weeks (end of treatment)
  • There was NS difference between Etanercept and etanercept (twice a week) + anakinra for:
    • ACR20 (68% and 62% respectively) at 24 weeks (end of treatment)
    • ACR50 (41% and 31% respectively) at 24 weeks (end of treatment)
    • ACR 70 (21% and 14% respectively) at 24 weeks (end of treatment)
  • Etanercept was similar to etanercept (twice a week) + anakinra for:
    • DAS score, % reduction (39% and 41% respectively) at 24 weeks (end of treatment)
ReferenceStudy type
Evidence level
Number of patientsPatient characteristicsInterventionComparisonLength of follow-upOutcome measuresSource of funding
G. Nuki, B. Bresnihan, M. B. Bear, D. McCabe. Long-term safety and maintenance of clinical improvement following treatment with Anakinra (Recombinant human interleukin-1 receptor antagonist) in patients with rheumatoid arthritis. Arthritis & Rheumatism; 46 (11): 2838–2846, 2002
ID 107
Extension of RCT (before and after study): 3

Placebo group from original randomisation was randomised into anakinra 30/75/150 mg/day groups
  • Randomised (method not mentioned)
  • Double blind in extension phase
  • Not true ITT analysis (only those with triplicate radiographs were analysed)
  • Multicentre trial (11 European countries)
N=472 in original study

N=309 (89.6%) enrolled into the extension phase; N=76 from the placebo group and N=233 from anakinra groups

Drop-outs: 91/309 (29.4%) at 52 weeks of extension phase

Anakinra to anakinra group 70/233 (30%)

Placebo to anakinra group 21/76 (28%)
Inclusion criteria: all patients met the ACR criteria for classification of RA, disease duration ≥12 months and< 8.5 years.

Exclusion criteria: previous receipt of other biological agents

Other study inclusion and exclusion criteria were not listed in this paper.

1.8 Baseline characteristics (of patients entering the extension phase):

Placebo to anakinra group (N=76):
mean age 53.1 ± 11.3 years; Female 69.7%; Duration of RA 3.7 ± 2.5 years; presence of erosive disease 73.7%.

Anakinra to anakinra group (N=233): mean age 52.7 ± 13.6 years; Female 76.8%; Duration of RA 4.1 ± 2.4 years; presence of erosive disease 74.2%.
Anakinra 30 mg/day by subcutaneous injection

Anakinra 75 mg/day by subcutaneous injection

Anakinra 150 mg/day by subcutaneous injection

Above patients remained in their treatment groups for 48 weeks
Patients treated with placebo in first 24 weeks then randomised to anakinra 30/75/150 mg/day during the extension phase.Original study 24 weeks

This study extension phase a further 52 weeks
Primary efficacy endpoint:
American College of Rheumatology (ACR) composite score.
ACR20 as assessed at week 48 (week 24 of extension phase)
Sustained ACR20 responders: at least 1 respnse at week 36 or 48
ACR50 (as assessed at week 48)
ACR70 (as assessed at week 48)

Secondary clinical efficacy endpoints:
Total Modified Sharp Score (TMSS) [derived from radiographic evaluation of the hands only]
Change form baseline in:
Number of swollen joints
Number of tender joints
Patients assessment of disease activity (0–4 scale)
Physicians assessment of disease activity (0–4 scale)
Health Assessment Questionnaire score (HAQ score)
Level of CRP
ESR
Amgen Inc
Effect size

Efficacy over 48 weeks

PLACEBO to ANAKINRA
ACR20
At week 48 there was a significantly higher proportion of patients who achieved an ACR20 response in the placebo to anakinra group (p=0.007) compared with the response at week 24. For the individual doses of Anakinra there were no significant differences between weeks 24 and 48.
At week 48 there was a significantly higher proportion of patients who achieved a sustained ACR20 response in the placebo to anakinra group (p<0.001) compared with the response at week 24. For the individual doses of Anakinra there were significant differences between weeks 24 and 48 for Anakinra 75mg (p=0.016) and Anakinra 150mg (p=0.022).

ACR50 and ACR70
ACR50 increased from 12% at week 24 to 20% at week 48 (p not given).
ACR70 was unchanged at 1% at weeks 24 and 48.

ACR component measures
Improvements in all ACR components were statistically significant for the combined cohort of patients that switched from placebo to anakinra (weeks 24 to 48): number of swollen joints (−4.1 ± 1.1, p<0.001), number of tender joints (−5.6 ± 1.3, p<0.001), patient global assessment (−0.3 ± 0.1, p<0.05), investigator assessment (−0.3 ± 0.1, p<0.05), pain assessment (−0.09 ± 0.03, p<0.005), HAQ (−0.26 ± 0.05, p<0.001), CRP (−1.0 ± 0.3, p<0.005), and ESR(−11.9 ± 2.2, p<0.001).
Improvements were also statistically significant for some of the parameters in the individual dose groups:
Anakinra 30mg: HAQ (−0.33 ± 0.1, p<0.005), CRP (−1.2 ± 0.5, p<0.05), and ESR(−11.9 ± 3.4, p<0.005)
Anakinra 75mg: number of swollen joints (−5.0 ± 1.1, p<0.05), number of tender joints (−6.1 ± 1.9, p<0.005), patient global assessment (−0.3 ± 0.1, p<0.05), and ESR(−15.0 ± 3.4, p<0.001)
Anakinra 150mg: number of swollen joints (4.4 ± 1.2, p<0.005), number of tender joints (−5.5 ± 1.8, p<0.05), and HAQ (−0.35 ± 0.1, p<0.005).

ANAKINRA to ANAKINRA
ACR20
There was no significant difference in the proportion of patients who achieved an ACR20 response in the anakinra to anakinra group between weeks 24 and 48. For the individual doses of anakinra there were no significant differences between weeks 24 and 48.
There was no significant difference in the proportion of patients who achieved a sustained ACR20 response in the anakinra to anakinra group between weeks 24 and 48.

ACR50 and ACR70
ACR50 decreased from 21% at week 24 to 18% at week 48 (p not given).
ACR70 was unchanged at 3% at weeks 24 and 48.

ACR component measures
For the combined cohort there was a small but statistically significant deterioration in the HAQ (+0.06 ± 0.03, p<0.05), and no difference in the other component measures.
In the group on anakinra 150 mg, there was deterioration of the patients global assessment (+0.2 ± 0.1, p<0.05), assessment of pain (+0.07 ± 0.03, p<0.05), and the HAQ (+0.1 ± 0.05, p<0.05).

Long term safety and tolerability/adverse events (evaluated over 72 weeks)
Rates of withdrawal during the extension phase were similar to those during the placebo-controlled phase; 29% overall in extension phase vs 25% in anakinra group (p not given).
Rates of withdrawal due to adverse vents were 18% in placebo/anakinra group vs. 14% in the anakinra/anakinra group vs. 17% in the anakinra group in the placebo controlled phase (p not given).

The most common adverse events were injection site reactions (ISR), the frequency and severity increased with increasing dose of anakinra. Frequency of ISR up to week 24 was: 0.82/patient year of exposure in placebo group, 1.01/patient year of exposure in anakinra 30 mg group, 2.43/patient year of exposure in anakinra 75 mg group, 3.73/patient year of exposure in anakinra 150 mg group, and 2.00/patient year of exposure in anakinra group overall.

Adverse events leading to withdrawal:
The most common adverse events leading to withdrawal were arthritis flare (placebo/anakinra group 5.2% vs. anakinra/anakinra group 6.0%, p not given).
1.3% of patients in each group withdrew due to infection, with an incidence of 1.40/patient year of exposure in placebo group, 0.91/patient year of exposure in anakinra 30 mg group, 1.0/patient year of exposure in anakinra 75 mg group, 1.1/patient year of exposure in anakinra 150 mg group (no p values given for comparisons).
ReferenceStudy type
Evidence level
Number of patientsPatient characteristicsInterventionComparisonLength of follow-upOutcome measuresSource of funding
B. Bresnihan, R. Newmark, S. Robbins, H. K. Genant. Effects of anakinra monotherapy on joint damage in patients with rheumatoid arthritis. Extension of a 24-week randomized, placebo-controlled trial. Journal of Rheumatology 31 (6):1103–11, 2004.
ID 67
RCT: 1+

Placebo group from original randomisation was randomised into anakinra 30/75/150 mg/day groups
  • Randomised (method not mentioned)
  • Double blind in extension phase
  • Not true ITT analysis (only those with triplicate radiographs were analysed)
N=472 in original study

N=309 (89.6%) enrolled into the extension phase; N=76 from the placebo group and N=233 from anakinra groups

Drop-outs: 91/309 (29.4%)
Anakinra 30 total drop out 19/101 (18.8%)
Anakinra 75 total drop out 33/103 (32%)
Anakinra 150 total drop out 29/95 (30.5%)
Inclusion criteria: aged between 18–75 years, active RA (defined as ≥10 swollen joints and at least 3 of the following: ≥10 tender or painful joints, disease activity graded as severe or very severe by the physician and a CRP > 1.5 mg/dl), had symptoms for > 6 months and < 8 years.

Exclusion criteria: previous receipt of other biological agents

Other study inclusion and exclusion criteria were not listed in this paper.

1.9 Baseline characteristics:

Placebo group (N=121): mean age 52.2 years; Female 70.2%; Duration of RA 3.7 years; HAQ 1.3, presence of erosive disease 74.4%.

Anakinra group (N=351): mean age 53.4 years; Female 76.6%; Duration of RA 4.1 years; HAQ 1.6, presence of erosive disease 73.2%.
Anakinra 30 mg/day by subcutaneous injection

Anakinra 75 mg/day by subcutaneous injection

Anakinra 150 mg/day by subcutaneous injection

Above patients remained in their treatment groups for 48 weeks
Patients treated with placebo in first 24 weeks then randomised to anakinra 30/75/150 mg/day for 24 weeksOriginal study 24 weeks

This study extension phase a further 24 weeks
Primary efficacy endpoint: American College of Rheumatology (ACR) composite score.

Secondary clinical efficacy endpoints: Total Modified Sharp Score (TMSS) [derived from radiographic evaluation of the hands only]
Amgen Inc
Effect size

ANAKINRA vs PLACEBO
Anakinra 30Anakinra 75Anakinra 150Placebo
ACR 20 response at 24 weeks (%)39 (NS vs placebo)34 (NS vs placebo)43 (p=0.014 vs placebo)27
ACR 20 response at 48 weeks (%)445349-
ACR 20 response at 48 weeks among placebo group randomised to receive anakinra in extension phase (%)50 (N=30)44 (N=24)71 (N=22)-
Radiographic evaluation of joint damage after 48 weeks (changes from baseline)
All AnakinraAnakinra 30Anakinra 75Anakinra 150Placebo1
TMSS mean change2.12 (p=0.015 vs placebo)2.43 (NS vs placebo)1.91 (p=0.025 vs placebo)1.90 (p=0.025 vs placebo)3.81
Erosion score mean change1.15 (p=0.006 vs placebo)0.88 (p=0.004 vs placebo)1.18 (p=0.035 vs placebo)1.21 (p=0.038 vs placebo)2.03
Joint space narrowing mean change0.89 (NS vs placebo)1.19 (NS vs placebo)0.66 (p=0.048 vs placebo)0.79 (NS vs placebo)1.53
1 Patients in the placebo group received anakinra between weeks 24 and 48.

Changes in radiographic progression in 2 consecutive 24 week treatment periods
  • Among both groups (placebo subjects randomised to anakinra in second 24 weeks and those treated with anakinra for 48 weeks) significantly less joint damage, as measured by the Modified Sharp Score, occurred in the second 24 week period than in the first 24 week period (p<0.001 for both groups)
  • In the placebo group there was a significant reduction in TMSS, modified Sharp erosion score and modified Sharp joint narrowing score for all anakinra doses in the extension (2nd 24 weeks) period. (p<0.001)
  • In patients treated with anakinra for 48 weeks, the TMSS and modified Sharp erosion score were significantly lower in the extension period (2nd 24 weeks) for the higher anakinra doses (75 and 150 mg/day), with no significant difference for the 30 mg/day dose and for the modified Sharp joint narrowing score at any dose.
Sensitivity analyses:
Comparison of patients who entered the extension phase with those who dropped out at 24 weeks showed that in the placebo group, those who dropped out had greater structural damage than those who continued into the extension phase. In the anakinra group, those who continued had greater joint damage than the dropouts.

From: Evidence Tables

Cover of Rheumatoid Arthritis
Rheumatoid Arthritis: National Clinical Guideline for Management and Treatment in Adults.
NICE Clinical Guidelines, No. 79.
National Collaborating Centre for Chronic Conditions (UK).
Copyright © 2009, Royal College of Physicians of London.

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