Evidence Table 7. Targeted Immune Modulators – Plaque Psoriasis STUDY: Authors: Asahina et al. 106 Year: 2010 Study name: The Adalimumab M04-688 Study Group Country: Japan Quality rating: Fair FUNDING: Sponsored by Abbott Japan, Tokyo, Japan, and Eisai, Tokyo, Japan; Abbot Laboratories provided medical writing support. RESEARCH OBJECTIVE: To evaluate the efficacy and safety of three different dosing regimens of adalimumab in Japanese patients with moderate to severe chronic plaque psoriasis. DESIGN & SIZE: Study design: Phase II/III RCT Setting: multicenter (42 sites in Japan) Number screened: Not Reported Number eligible: 235 consented Number enrolled: 169 Run-in/Wash-out period: 14 days for topical therapies and phototherapy, 28 days for systemic therapy and PUVA. INTERVENTION: Dose: Duration: Sample size: Drug 1 Adalimumab 40mg every other week 24 weeks 38 Drug 2 Adalimumab 40mg every other wk starting wk 2, after loading dose of 80mg at wk 0 24 weeks 43 Drug 3 Adalimumab 80mg every other week 24 weeks 42 Drug 4 Placebo every other week 24 weeks 46 INCLUSION CRITERIA: ≥20 years of age, a clinical diagnosis of moderate to severe chronic plaque psoriasis, defined by a score of 12 or greater on the Psoriasis Area and Severity Index (PASI) and body surface area (BSA) involvement
Year: 2010Study name: The Adalimumab M04-688 Study GroupCountry: JapanQuality rating: Fair
FUNDING: Sponsored by Abbott Japan, Tokyo, Japan, and Eisai, Tokyo, Japan; Abbot Laboratories provided medical writing support.
RESEARCH OBJECTIVE: To evaluate the efficacy and safety of three different dosing regimens of adalimumab in Japanese patients with moderate to severe chronic plaque psoriasis.
DESIGN & SIZE: Study design: Phase II/III RCTSetting: multicenter (42 sites in Japan)Number screened: Not ReportedNumber eligible: 235 consentedNumber enrolled: 169Run-in/Wash-out period: 14 days for topical therapies and phototherapy, 28 days for systemic therapy and PUVA.
INTERVENTION: Dose:
Duration: Sample size:
Drug 1Adalimumab 40mg every other week
24 weeks38
Drug 2Adalimumab 40mg every
other wk starting wk 2, after loading dose of 80mg at wk 0
24 weeks43
Drug 3Adalimumab 80mg every other week
24 weeks42
Drug 4Placebo every other
week
24 weeks46
INCLUSION CRITERIA: ≥20 years of age, a clinical diagnosis of moderate to severe chronic plaque psoriasis, defined by a score of 12 or greater on the Psoriasis Area and Severity Index (PASI) and body surface area (BSA) involvement of 10% or greater, for at least 6 months, during which time plaque psoriasis was stable for at least the recent two months
EXCLUSION CRITERIA: previous exposure to anti-TNF therapy, other active skin diseases or skin infections, diagnosis of systemic lupus erythematosus, scleroderma, or rheumatoid arthritis, history of central nervous system demyelinating disease, cancer, lymphoma, leukemia, tuberculosis, or lymphoproliferative disease, positive serology for anti-HIV antibody, hepatitis B surface antigen, anti-hepatitis C antibody, active infectious disease, immunosuppressive disease, or abnormal hematological, hepatic, or renal values
OTHER MEDICATIONS/ INTERVENTIONS ALLOWED:
weak or medium-potency topical corticosteroids to palms, soles, face, scalp, and groin
Authors: Asahina et al.Year: 2010POPULATION CHARACTERISTICS:
Adalimumab 40mg Adalimumab 40mgwith 80mg loading
dose
Adalimumab 80mg Placebo
Mean age (years): 47.8±12.81 44.2±14.32 43.5±12.40 43.9±10.75Sex (% female): 6 (15.8%) 8 (18.6%) 7 (16.7%) 5 (10.9%)Ethnicity: Japanese Japanese Japanese JapaneseClass naïve: 100% 100% 100% 100%Other germane population qualities:
Mean PASI Mean body surface area
involvement
25.44±8.97743.3%
30.24±10.94648.3%
28.27±11.02946.1%
29.10±11.76746.7%
Mean duration of psoriasis 14.2 yrs ±9.29 yrs 14.0 yrs ±7.36 yrs 11.6 yrs ±7.45 yrs 15.5 yrs ±8.83 yrs Received prior systemic
therapy of nonbiologics within 6 mo prior to screening (%)
47.4% 41.9% 42.9% 37.0%
Phototherapy received within 6 months prior to screening (%)
18.4% 23.3% 16.7% 41.3%
RESULTS: Primary Outcome Measures: %of patients achieving a 75% or greater improvement in Psoriasis Area and Severity Index (PASI 75) score at week 16: Drug 1: 57.9%; Drug 2: 62.8%; Drug 3: 81.0%; Placebo 4.3% (p<0.001).Secondary Outcome Measures: % of patients achieving PASI 50, PASI 90 and Physicians Global Assessment of “clear” or “minimal”, changes in health-related QOL were assessed by the Dermatology Life Quality Index (DLQI) and Short Form 36 (SF-36) Health Survey at week 16; PASI 50: Drug 1: 73.7%; Drug 2: 81.4%; Drug 3: 90.5%; Placebo 19.6%; PASI 90: Drug 1: 36.8%; Drug 2: 39.5%; Drug 3: 61.9%; Placebo: 0%; PGA “Clear” or “Minimal”: Drug 1: 44.7%; Drug 2: 60.5%; Drug 3: 78.6%; Placebo: 4: 8.7%; DLQI change from baseline to week 16: Drug 1: -3.9; Drug 2: -5.1; Drug 3: -6.8; Placebo:+1.0 (p<0.001 for PASI, PGA, and DLQI); SF-36change from baseline to week 16: Drug 1: 3.7 (p<0.05); Drug 2: 4.6 (p<0.01); Drug 3: 4.9 (p<0.001); Placebo: -0.4(p>0.05).
Authors: Asahina et al.Year: 2010METHOD OF ADVERSE EVENTS REPORTING:
Adverse events were assessed at each, every other week, visit. Laboratory evaluations and vital signs were conducted at baseline and at weeks 2, 4, 8, 12, 16, 20, and 24.
ADVERSE EVENTS (%): Drug 1 Drug 2 Drug 3 Drug 4Overall adverse effects reported: 37 (97.4%) 39 (90.7%) 38 (90.5%) 41 (89.1)
Infections 55.3% 41.9% 50.0% 50.0% URTI abnormal LFT see below see below see below see below herpes simplex pneumonia tb 0% 0% 0% not stated: assume 0% ISR 15.8% 18.6% 14.3% 6.5% ALT 15.8% 16.3% 4.8% 6.5% AST 7.9% 9.3% 2.4% 4.3% GGT Hepatic event Hepatobiliary disorders
13.2%39.5%7.9%
2.3%30.2%7.0%
2.4%23.8%11.9%
0%8.7%0%
ATTRITION (overall):
ATTRITION (treatment specific):Attrition overall: Attrition due to adverse events:
Overall attrition: 22 (13.0%)Attrition differential high: Possibly, for comparisons of Drug 1 and 3 vs Drug 2
Drug 14 (10.5%)2 (5.3%)
Drug 28 (18.6%)5 (11.6%)
Drug 34 (9.5%)3 (7.1%)
Drug 46 (13.0%)5 (10.9%)
URTI: upper respiratory tract infection; LFT: liver function test; ISR: injection site reaction; tb: tuberculosis
DESIGN: Study design: Systematic reviewNumber of patients: 7,931
AIMS OF REVIEW: To evaluate and compare the efficacy and safety of biological agents in the treatment of plaque psoriasisSTUDIES INCLUDED IN META-ANALYSIS
TIME PERIOD COVERED: MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov. were searched from inception to June 2005; an updating search was conducted in July 2006 to capture reports from the interim period
STUDY: Authors: Gordon et al.108and Shikiar et al.109
Year: 2006Country: US and Canada
FUNDING: Abbott Labs
RESEARCH OBJECTIVE: Efficacy and safety of ADA in patients with moderate to severe plaque psoriasis. After 12 week all patients were switched to active arms.
DESIGN:
Study design: RCTSetting: MulticenterSample size: 147
INTERVENTION: Dose: Duration: Sample size:
PlaceboN/A
12 weeks52
ADA EOW80 mg at week 0 and 40 mg EOW
12 weeks45
ADA Weekly80 mg at week 0 and 40 mg weekly
12 weeks50
INCLUSION CRITERIA: Men and women age 18 years and older with plaque psoriasis of at least 1-year duration and involving 5% or more of their body surface area.
EXCLUSION CRITERIA: History of neurologic symptoms suggestive of central nervous system demyelinating disease, or with a history of cancer or lymphoproliferative disease (other than successfully treated non-melanoma skin cancer or localized carcinoma in situ of the cervix)
OTHER MEDICATIONS/ INTERVENTIONS ALLOWED:
Low to mid dose topical corticosteroids
Authors: Gordon et al. and Shikiar et al.Year: 2006POPULATION CHARACTERISTICS: Mean age (years):Sex (% female):Ethnicity (% Caucasian): Other germane population qualities:
Mean PASI Mean body surface area
involvement Mean duration of psoriasis -yrs Received prior systemic
therapy (%)
Groups similar at baseline: Placebo
433592
16.028
19NR
ADA EOW462989
16.729
21NR
ADA Weekly443490
14.525
18NR
OUTCOME ASSESSMENT: Primary Outcome Measures: PASI 75% and DLQI at 12 weeksSecondary Outcome Measures: PASI 75 at 24 weeks and PGA, SF-36 Health Survey, and Euro QoL-5D (EQ-5D)Timing of assessments: weeks 0, 1, 2, and 4, and then every 4 or 8 weeks thereafter.
RESULTS: Health Outcome Measures: PASI 75% at 12 weeks Placebo 4% ADA EOW 53% ADA WK 80% PASI 100% at 12 weeks Placebo 0% ADA EOW 11% ADA WK 26% DLQI change at 12 weeks Placebo 1.3% (3.3, 0.7) ADA EOW 10.8 (13.1, 8.5) ADA WK 11.5
(13.6, 9.4) ADA(both) vs. placebo P < 0.001 EQ-5D Index score change at 12 weeks Placebo 0.01 (0.07, 0.1) ADA EOW 0.21 (0.11, 0.31)
ADA WK 0.19 (0.09, 0.28) ADA(both) vs. placebo P < 0.001 EQ-5D VAS change at 12 weeks Placebo 0.5 (5.7, 6.8) ADA EOW 17.9 (10.5, 25.2) ADA WK
10.7 (4.1, 17.4) ADA EOW vs. placebo P < 0.001 and ADA WK vs. placebo P = 0.013 SF-36 PCS change at 12 weeks Placebo 0.5 (2.4, 3.5) ADA EOW 3.6 (0.2, 7.0) ADA WK 5.5
(2.4, 8.6) ADA EOW vs. placebo P = 0.118 and ADA WK vs. placebo P = 0.010 SF-36 MCS change at 12 weeks Placebo 0.1 (3.5, 3.3) ADA EOW 7.8 (3.9, 11.8) ADA WK 5.2
(1.6, 8.9) ADA EOW vs. placebo P < 0.001 and ADA WK vs. placebo P = 0.017
Authors: Gordon et al. and Shikiar et al.Year: 2006ADVERSE EVENTS: Overall adverse effects reported:
FUNDING: Centocor Research and Development (pharmaceutical industry)RESEARCH OBJECTIVE: To compare two biologic agents, ustekinumab and etanercept, for the treatment of psoriasisDESIGN & SIZE: Study design: head-to-head RCT
Setting: multi-centerNumber screened: 1,175Number eligible: not reportedNumber enrolled: 903Run-in/Wash-out period: no
INTERVENTION: Dose: Duration: Sample size:
ETA50 mg twice weekly
12 weeks347
UST45 mg at weeks 0 and 4
12 weeks209
UST90 mg at weeks 0 and 4
12 weeks347
INCLUSION CRITERIA: ≥18 years of age, diagnosis of plaque psoriasis at least 6 months earlier, candidates for phototherapy or systemic treatment, score ≥12 on PASI, score ≥3 on physician’s global assessment; involvement of ≥10% of body-surface area; inadequate response, intolerance or contraindication to ≥1 conventional systemic agent (i.e., methotrexate, cyclosporine, or psoralen plus UVA), and no previous treatment with UST or ETA.
EXCLUSION CRITERIA: Nonplaque or drug-induced forms of psoriasis, recent serious infection, history of chronic or recurrent infectious disease, known malignant condition (other than treated basal- or squamous-cell skin cancer or cervical cancer in situ with no evidence of recurrence for ≥5 years), receipt of conventional systemic therapy or phototherapy within 4 weeks before enrollment, topical psoriasis agents within 2 weeks, investigational drugs within 4 weeks or 5 half-lives, biologic agents within 3 months or 5 half-lives.
OTHER MEDICATIONS/ INTERVENTIONS ALLOWED:
None reported
Authors: Griffiths et al.Year: 2010POPULATION CHARACTERISTICS:
ETA UST 45 mg UST 90 mg
Mean age (years): 45.7 45.1 44.8Sex (% female): 29.1% 36.4% 32.6%Ethnicity: 91.1% white 92.3% white 89.0% whiteClass naïve: 88.2% 87.6% 89.6%Other germane population qualities:
Mean PASI 18.6 20.5 19.9 Mean body surface area
involvement23.8% 26.7% 26.1%
Mean duration of psoriasis 18.8 years 18.9 years 18.7 years Received prior systemic
therapy (%)57.3% 61.7% 52.4%
RESULTS: Primary Outcome Measures: 56.8% of ETA group had ≥75% improvement in PASI score compared with 67.5% of UST 45 mg group (P=0.01 vs. ETA)and 73.8% of UST 90 mg group (P<0.001 vs. ETA).Secondary Outcome Measures: 23.1% of ETA group had ≥90% improvement in PASI score compared with 36.4% of UST 45 mg group (P<0.001 vs. ETA) and 44.7% of UST 90 mg group (P<0.001 vs. ETA).49.0% of ETA group had cleared or minimal disease (physician’s global assessment score=0 or 1) compared with 65.1% of UST 45 mg group (P<0.001 vs. ETA) and 70.6% of UST 90 mg group (P<0.001 vs. ETA).8.6% of ETA group had cleared disease (physician’s global assessment score=0) compared with 16.3% of UST 45 mg group (P=0.006 vs. ETA) and 26.2% of UST 90 mg group (P<0.001 vs. ETA).
Authors: Griffiths et al.Year: 2010METHOD OF ADVERSE EVENTS REPORTING:
Safety was evaluated by assessing adverse events and routine hematologic and laboratory values. Possible major cardiovascular events were adjudicated by an independent panel of academic cardiologists. Serum samples were evaluated for antibodies to UST.
Infections 29.1% 30.6% 29.7% URTI 5.8% 6.2% 6.3% abnormal LFT NR NR NR herpes simplex NR NR NR pneumonia NR NR NR tb NR NR NR ISR 24.8% 4.3% 3.7% nonmelanoma skin cancer 0.0% 1.0% 0.3% back pain 2.0% 6.7% 4.3% ≥ serious adverse event 1.2% 1.9% 1.2%
ATTRITION (overall):
ATTRITION (treatment specific):Attrition overall: Attrition due to adverse events:
Overall attrition: 2.7%Attrition differential high: No
ETA3.2%2.3%
UST 45 mg3.8%1.9%
UST 90 mg1.4%1.2%
URTI: upper respiratory tract infection; LFT: liver function test; ISR: injection site reaction; tb: tuberculosis
INCLUSION CRITERIA: Men and women (age, ≥18 years); a diagnosis of plaque psoriasis for at least 6 months, candidates for phototherapy or systemic therapy, a baseline score on the psoriasis area-and-severity index of 12 or higher (on a scale of 0 to 72, with higher scores indicating more severe disease), and involvement of at least 10% body-surface area
EXCLUSION CRITERIA: Nonplaque forms of psoriasis; recent serious systemic or local infection; active or latent tuberculosis, asthma, or a known malignancy within the previous 5 years (except treated basal-cell skin cancer); previous treatment with any agent specifically targeting interleukin-12 or interleukin-23; biologic or investigational agents within the previous month or five drug half-lives; conventional systemic psoriasis therapy or phototherapy within the previous 4 weeks; or topical psoriasis treatment within the previous 2 weeks.
INCLUSION CRITERIA: 18 years or older; a diagnosis of plaque psoriasis for 6 months or longer, a baseline psoriasis area and severity index (PASI) score of 12 or higher, at least 10% body surface area involvement, and candidates for phototherapy or systemic therapy.
EXCLUSION CRITERIA: History or symptoms of active tuberculosis; non-plaque forms of psoriasis, recent serious systemic or local infection, known malignancy (except treated basal cell skin cancer or squamous cell skin cancer of at least5 years’ duration), treatment with any agent that specifically targeted interleukins 12 or 23, received biological or investigational agents within the previous 3 months or five drug half-lives, conventional systemic psoriasis treatment or phototherapy within the previous 4 weeks, or topical psoriasis treatment within 2 weeks.
OTHER MEDICATIONS/ INTERVENTIONS ALLOWED:
See above
Authors: Leonardi et al. and Lebwohl et al.Year: 2008 and 2009POPULATION CHARACTERISTICS:
Ustekinumab 45 Ustekinumab 90 Placebo
Mean age (years): 44.8 46.2 44.8Sex (% female): 31.4 32.4 28.2Ethnicity: NR NR NRClass naïve: NR NR NROther germane population qualities:
Mean PASI 20.5 19.7 20.4 Mean body surface area
involvement27.2 25.2 27.7
Mean duration of psoriasis 19.7 19.6 20.4 Received prior systemic
therapy (%)55.3 55.2 55.7
RESULTS: Primary Outcome Measures: PASI 75Secondary outcomes: PGA, DLQI
Year: 2011Study name: Randomized Controlled Evaluation of Adalimumab in Treatment of Chronic Plaque Psoriasis of the Hands and Feet (REACH) Country: US and CanadaQuality rating: FAIR
FUNDING: Abbott Laboratories (pharmaceutical industry)RESEARCH OBJECTIVE: To evaluate the efficacy and safety of adalimumab in psoriasis of the hands and/or feetDESIGN & SIZE: Study design: placebo-controlled RCT
Setting: multicenterNumber screened: NRNumber eligible: NRNumber enrolled: 81Run-in/Wash-out period: Washout periods of 30 days or 5 half-lives (whichever was longer) were required for biological, systemic, and investigational agents prior to baseline.
INTERVENTION: Dose: Duration: Sample size:
Adalimumab (ADA)40mg every other week
16 weeks49
PlaceboNA
16 weeks23
INCLUSION CRITERIA: Adults 18 years and older diagnosed as having moderate to severe chronic plaque psoriasis of the hands and/or feet for at least 6 months with a Physician’s Global Assessment of the hands and/or feet (hfPGA) score of 3 or higher at baseline and with evidence of psoriatic disease on at least 1 other area of skin outside the hands and/or feet.
EXCLUSION CRITERIA: Receipt of prior treatment with adalimumab, diagnosis of palmoplantar pustulosisOTHER MEDICATIONS/ INTERVENTIONS ALLOWED:
Psoralen and UV-A phototherapy was not allowed within 4 weeks of baseline; topical therapies on the hands and/or feet (except low- to mid-potency corticosteroids [classes VI and VII]), UV-B phototherapy, and excessive sun exposure or tanning bed use were not allowed within 2 weeks of baseline.
Authors: Leonardi, et al.Year: 2011POPULATION CHARACTERISTICS:
ADA Placebo
Mean age (years): 49.0 54.8Sex (% female): 57% 65%Ethnicity: 92% white 87% whiteClass naïve: NR NROther germane population qualities:
Mean PASI 8.8 5.7 Mean body surface area
involvement8.9% 5.1%
Mean duration of psoriasis 14.9 years 11.5 years Received prior systemic
therapy (%)NR NR
RESULTS: Primary Outcome Measure: 31% of ADA patients achieved hfPGA score of clear (0) or almost clear (1) compared with 4% of placebo (p=0.01).Secondary Outcome Measures: 51% of ADA patients achieved hfPGA score of clear (0), almost clear (1), or mild (2) compared with 26% of placebo (p=NR).29% of ADA patients achieved >75% improvement in ESIF (ESIF 75) relative to baseline compared with 4% of placebo (p=0.03).43% of ADA patients achieved >50% improvement in ESIF (ESIF 50) relative to baseline compared with 17% of placebo (p=0.04).Mean % improvement in total ESIF score relative to baseline was 41% for ADA patients, compared with 21% for placebo (p=NR).In patients with palmar involvement, mean % improvement in total ESIF score relative to baseline was 47% for ADA patients, compared with 20% for placebo (p=0.01).In patients with plantar involvement, mean % improvement in total ESIF score relative to baseline was 41% for ADA patients, compared with 35% for placebo (p=0.67).In patients with psoriatic nail disease, mean % improvement in total NAPSI relative to baselime was 50% for ADA patients, compared with 8% for placebo (p=0.02)Mean pain score was 26.6 for ADA patients, compared with 43.4 for placebo (p=0.048).In patients with pain score >0 at baseline, mean % improvement in pain score was 31% for ADA patients, compared with 9% for placebo (p=0.39).
Authors: Leonardi, et al.Year: 2011METHOD OF ADVERSE EVENTS REPORTING:
ADVERSE EVENTS (%): ADA PlaceboOverall adverse effects reported: 63% reported any AE
0% reported a serious AE35% reported an infectious AE
70% reported any AE4% reported a serious AE
44% reported an infectious AE Infections Opportunistic only: 2%
(oral candidiasis)Opportunistic only: 0%
URTI NR NR abnormal LFT NR NR herpes simplex NR NR pneumonia NR NR tb NR NR ISR NR NR malignant diseases 0% 4% (N=1, breast cancer) serious hepatic events 2% 0% psoriasis 4% 9%
ATTRITION (overall):
ATTRITION (treatment specific):Attrition overall: Attrition due to adverse events:
STUDY: Authors: Menter et al.115 and Revicki et al.116,117
Year: 2008 and 2007Country: United States and Canada
FUNDING: Abbott Labs
RESEARCH OBJECTIVE: Clinical efficacy and safety of adalimumab for moderate to severe psoriasis and investigate continuous versus interrupted therapy
DESIGN:
Study design: RCTSetting: MulticenterSample size: 1212
INTERVENTION: Dose: Duration: Sample size:
PlaceboNA
16 weeks398
Adalimumab80 mg at wk 0 then 40 mg eow
16 weeks814
drug 3
INCLUSION CRITERIA: 18 years or older, clinical diagnosis of psoriasis for at least 6 months, stable plaque psoriasis for at least 2 months before screening, moderate to severe plaque psoriasis defined as 10% or more of body surface area affected, a PASI score of 12 or greater, and PGA of at least moderate severity at the baseline.
EXCLUSION CRITERIA: history of neurologic symptoms suggestive of central nervous system demyelinating disease or with a history of cancer or lymphoproliferative disease (other than successfully treated nonmelanoma skin cancer or localized carcinoma in situ of the cervix)
OTHER MEDICATIONS/ INTERVENTIONS ALLOWED:
Low- to mid-potency topical corticosteroids applied to the palms, soles, face, and intertriginous areas
Authors: Menter et al. and Revicki et al.Year: 2008, 2007 POPULATION CHARACTERISTICS:
Mean age (years):Sex (% female):Ethnicity (% Caucasian): Other germane population qualities:
Mean PASI Mean body surface area
involvement Mean duration of psoriasis Prior Systemic therapy: Non-
biologic/Biologic (%)
Groups similar at baseline: YesPlacebo
45.435.490.2
18.825.6
18.4 yrs22.1/13.3
Adalimumab
44.132.991.2
19.025.8
18.1 yrs23.1/11.9
OUTCOME ASSESSMENT: Primary Outcome Measures: PASI 75 at 16 weeks, % of patients losing an adequate response after week 33 to week 52 and DLQISecondary Outcome Measures: PGA, SF-36Timing of assessments: Baseline and weeks 4,8,12,16,24,33,36,40,44,48,and 52
RESULTS: Health Outcome Measures: PASI 75 at 16 weeks Placebo 7% vs. ADA 71% P < 0.001 PASI 90 and 100 at 16 weeks Placebo 2% and 1% vs. ADA 45% and 20% P < 0.001 PGA, clear or minimal at week 12, Placebo 4% vs. ADA 60% P < 0.001 From weeks 33 to 52, patients rerandomized to placebo (28%; 68 of 240) compared with patients
rerandomized to adalimumab (5%; 12 of 250) P < 0.001.
Measure Placebo change from baseline at 16 weeks
ADA change from baseline at 16 weeks
DLQI 1.9 (2.6, 1.3) 8.4 (8.8, 7.9) P < 0.001SF 36 PCS 0.4 (0.5, 1.2) 3.7 (3.1, 4.3) P < 0.001SF 36 MCS 0.3 (0.7, 1.4) 3.8 (3.1, 4.5) P < 0.001Patients global assessment
0.4 (0.5, 0.3) 1.7 (1.8, 1.6) P < 0.001
Authors: Menter et al. and Revicki et al.Year: 2008 and 2007ADVERSE EVENTS %: Overall adverse effects reported:
STUDY: Authors: Paller et al.118 and Siegfried et al.119 and Langley et al.120
Year: 2008, 2010, 2011Country: US and CanadaQuality rating: Fair
FUNDING: Immunex, a wholly owned subsidiary of Amgen, and by Wyeth Pharmaceuticals. RESEARCH OBJECTIVE: Assess the efficacy and safety of etanercept in children and adolescents with moderate-to-severe plaque
psoriasis.DESIGN & SIZE: Study design: RCT
Setting: Multicenter Sample size: 211; 138 in withdrawal-retreatment phase
INCLUSION CRITERIA: 4 to 17 years; stable, moderate-to-severe plaque psoriasis at screening, defined as a psoriasis area-andseverity index (PASI) score of at least 12), a static physician’s global assessment of at least 3 (where 0 indicates clear and 5 severe psoriasis), and psoriasis involvement of at least 10% of the BSA; a history of psoriasis for at least 6 months; and previous or current treatment with phototherapy or systemic psoriasis therapy (e.g., methotrexate, cyclosporine, or retinoids) or psoriasis considered by the investigator as poorly controlled with topical therapy.
EXCLUSION CRITERIA: Pregnancy or lactation (sexually active patients were required to use contraception); guttate, erythrodermic, or pustular psoriasis; other skin conditions that would interfere with study evaluations; previous treatment with anti-TNF agents; major concurrent medical conditions; treatment with psoralen and ultraviolet A (PUVA), ultraviolet A, ultraviolet B, systemic psoriasis medications, oral or parenteral corticosteroids, topical corticosteroids, topical vitamin A or D analogue preparations, anthralin, or calcineurin
inhibitor within a 14-day washout period before the study; and treatment with biologic agents within a 30-day washout period
OTHER MEDICATIONS/ INTERVENTIONS ALLOWED:
Low-to-moderate-potency topical steroids on the scalp, axillae, or groin.
Authors: Paller et al. and Siegfried et al. and Langley et al.Year: 2008, 2010, 2011POPULATION CHARACTERISTICS:
Groups similar at baselineEtanercept Placebo Withdrawal-Retreatment
PeriodMean age (years): 14 13 13 (median)Sex (% female): 48 50 51Ethnicity: 78% white 71% white 78% whiteOther germane population qualities:
Mean PASI 16.7 16.4 16.7 (median) Mean body surface area
involvement21.0 20.0 20.5 (median)
Mean duration of psoriasis 6.8 years 5.8 years 5.8 years (median) Received prior systemic
therapy (%)55 59 57
OUTCOME ASSESSMENT: Primary Outcome Measures: PASI 75 at week 12Secondary Outcome Measures: PASI 50 and 90, physicians global assessment of clear or almost clear, Children’s Dermatology Life Quality IndexTiming of assessments: Baseline weeks 2 ,4, 6, 8, 12, 16 and every 4 weeks
Following the 12 week double-blind period, all patients received open-label etanercept for 24 weeks. At the end of this period, patients who received 75% improvement in PASI response from baseline (PASI 75) were re-randomized to a 12-week, double-blind withdrawal-treatment period. During this phase, patients received either placebo or etanercept as long as they maintained a clinical response, defined as PASI 75. Patients whose response fell below PASI 75 were retreated with etanercept in an open-label fashion until study completion. PASI 75 was assessed every 4 weeks during the 12-week, double-blind withdrawal-retreatment period.
RESULTS: Health Outcome Measures at 12 weeks:
• PASI 75: etanercept 57% vs. placebo 11%, p<0.001• PASI 50: etanercept 75% vs. placebo 23%, p<0.001• PASI 90: etanercept 27% vs. placebo 7%, p<0.001• Physicians global assessment of clear or almost clear: etanercept 53% vs. placebo 13%, p<0.001• CDLQI mean improvement: etanercept 52% vs. placebo 18%
Withdrawal-Retreatment period: Etanercept (received etanercept throughout withdrawal-retreatment) vs. Placebo (received placebo in withdrawal phase) vs. Placebo (received etanercept in retreatment phase)• Percentage of patients who achieved PASI 75 at:
Week 40: 81% vs. 75% vs. N/AWeek 44: 82% vs. 76% vs. 27%Week 48: 80% vs. 85% vs. 36%
• Percentage of patients who achieved PGA clear/almost clear at:Week 40: 69% vs. 60% vs N/AWeek 44: 65% vs. 57% vs 33%Week 48: 58% vs. 68% vs 29%
• In the group treated with blinded or open-label etanercept, 80% patients maintained or regained PASI 75 at the end of the 12-week period. In all, 70% patients on blinded etanercept maintained PASI 75 at every study visit during the 12-week period, compared with 54% patients who did so on blinded placebo.• At the time the 29 patients on placebo began receiving etanercept retreatment, their mean improvementfrom baseline in the PASI response had decreased to 47.4%. After 4 to 8 weeks of retreatment, their mean improvement from baseline in the PASI response was 64.4%.• Of the 137 patients who completed the 12-week period, 95 (69%) remained on blinded placebo or blinded etanercept for the 12-week period. In the placebo group, 40/69 (58%) patients remained on blinded placebo throughout the period, and 29/69 (42%) received etanercept retreatment. In the etanercept group, 55/68 (81%) patients remained on blinded etanercept. The remaining 13 (19%) patients on etanercept entered the open-label retreatment phase, although one patient entered without losing PASI 75.
Authors: Paller et al. and Siegfried et al. and Langley et al.Year: 2008, 2010, 2011ADVERSE EVENTS: Etanercept PlaceboOverall adverse effects reported (event rates per 100 pt/yrs:
Overall adverse effects 52.9% 46.4% 42.9% At least 1 serious AE 0% 0% 0% Headache 8.8% 2.9% NR Nasophyrantgitis 10.3% 2.9% NR URTI NR NR 14.3% Sinitius NR NR 7.1% Injection site reaction 1.5% 1.4% 2.4%
ATTRITION (overall):
ATTRITION (treatment specific):Attrition overall: Attrition due to adverse events:
Overall attrition: 3 (plus 1 in withdrawal-retreatment phase)Attrition differential high: No
Year: 2008Study name: PHOENIX 2Country: MultinationalQuality rating: Good
FUNDING: CentocorRESEARCH OBJECTIVE: Assess the efficacy and safety of ustekinumab in patients with moderate-to-severe psoriasis with
up to 52 weeks of treatment.DESIGN & SIZE: Study design: RCT
Setting: MulticenterNumber screened: 1568Number eligible: NRNumber enrolled: 1230Run-in/Wash-out period: No
INTERVENTION: Dose:
Duration: Sample size:
Ustekinumab 4545 mg weeks 0 and 4, then
every 12 weeks12 weeks
409
Ustekinumab 9090 mg weeks 0 and 4, then
every 12 weeks12 weeks
411
PlaceboNA
12 weeks410
INCLUSION CRITERIA: 18 years or older; a diagnosis of plaque psoriasis for 6 months or longer, a baseline psoriasis area and severity index (PASI) score of 12 or higher, at least 10% body surface area involvement, and candidates for phototherapy or systemic therapy.
EXCLUSION CRITERIA: History or symptoms of active tuberculosis; non-plaque forms of psoriasis, recent serious systemic or local infection, known malignancy (except treated basal cell skin cancer or squamous cell skin cancer of at least5 years’ duration), treatment with any agent that specifically targeted interleukins 12 or 23, received biological or investigational agents within the previous 3 months or fi ve drug half-lives, conventional systemic psoriasis treatment or phototherapy within the previous 4 weeks, or topical psoriasis treatment within 2 weeks
OTHER MEDICATIONS/ INTERVENTIONS ALLOWED:
See above
Authors: Papp et al.Year: 2008POPULATION CHARACTERISTICS:
Ustekinumab 45 Ustekinumab 90 Placebo
Mean age (years): 45.1 46.6 47.0Sex (% female): 30.8 32.3 31.0Ethnicity: NR NR NRClass naïve: 61.6 63.5 61.2Other germane population qualities:
Mean PASI 19.4 20.1 19.4 Mean body surface area
involvement25.9 27.1 26.1
Mean duration of psoriasis 19.3 20.3 20.8 Received prior systemic
therapy (%)54.5 54.5 58.8
RESULTS: Primary Outcome Measures: PASI 75Secondary outcomes: PGA, DLQI
At 12 weeks Ustekinumab 45 Ustekinumab 90 PlaceboPASI 50 n (%) 342 (83.6%)* 367 (89.3%)* 41 (10.0%)PASI 75 n (%) 273 (66.7%)* 311 (75.7%)* 15 (3.7%)PASI 90 n (%) 173 (42.3%)* 209 (50.9%)* 3 (0.7%)PASI 100 n (%) 74 (18.1%)* 75 (18.2%)* 0Physicians assessmentCleared 93 (22.7%)* 115 (28.0%)* 0Cleared or Minimal 278 (68.0%)* 302 (73.5%)* 20 (4.9%)Change in DLQI -9.3 (7.12)* -10.0 (6.67)* -0.5 (5.66)
* vs placebo P < 0.001
Authors: Papp et al. Year: 2008METHOD OF ADVERSE EVENTS REPORTING: at visitsADVERSE EVENTS (%): Ustekinumab 45 Ustekinumab 90 Placebo
RESEARCH OBJECTIVE: To present the results of a phase III study, addressing the long-term safety, efficacy and productivity of infliximab for the treatment of skin and nail lesions in patients with psoriasis
DESIGN:
Study design: RCT Setting: MulticenterSample size: 378
INTERVENTION: Dose: Duration: Sample size:
Placebo / INFN/A, then 5 mg/kg (wk 0,2,6,14,22)22 weeks, then 24 weeks (total 46)
77
INF5 mg/kg (wk 0,2,6, then every 8 wks)
46 weeks301
INCLUSION CRITERIA: Patients diagnosed with moderate to severe plaque psoriasis for > 6 months; candidates for phototherapy or systemic therapy; PASI of > 12 and > 10% of their total body surface area affected by psoriasis.
EXCLUSION CRITERIA: History or risk of serious infection, lymphoproliferative disease, or active TB; previous treatment with INF or any other TNF-antagonist was allowed.
OTHER MEDICATIONS/ INTERVENTIONS ALLOWED:
2.5% hydrocortisone, or equivalent, applied topically to face, groin, or both, after week 10.
Authors: Reich et al.Year: 2005 and 2006 and 2007POPULATION CHARACTERISTICS:
Mean age (years):Sex (% female):Ethnicity: Other germane population qualities:
Psoriasis duration (yrs) Body surface area (%) PASI Patients with nail psoriasis (%) MTX use (%)
Groups similar at baseline: YesDisease severity: Moderate-to-severe
Placebo43.821NR
17.318
22.88646
INF42.631NR
19.119
22.98142
OUTCOME ASSESSMENT: Primary Outcome Measures: PASI 75 (> 75% improvement in baseline PASI) at week 10 and Quality of life DLQI and SF-36, 10-cm productivity visual analog scale (VAS), role-physical and role-emotional domain scores of the Short Form 36-Item questionnaire (SF-36).Secondary Outcome Measures: PASI 75 at week 24; PGA of cleared or minimal at week 10, 24, and 50; PASI 50; PASI 90; NAPSI at weeks 10, 24, and 50.Timing of assessments: NR
RESULTS: Health Outcome Measures: At week 24, PASI 75 achieved by 82% (INF) vs. 4% (placebo) (P < 0.0001) The % improvement in the NAPSI was significantly greater in INF-treated patients than placebo at
weeks 10 and 24.Improvement from baseline At week 24, DLQI INF 10.0 vs. placebo 0.2 (P < 0.001) At week 24, SF-36 PCS INF 4.9 vs. placebo -1.4 (P < 0.001) At week 24, SF-MCS INF 5.3 vs. placebo -0.5 (P < 0.001) At week 24, Productivity VAS, INF – 0.2 ± 3.2 vs. placebo 2.5 ± 3.5 (P < 0.001) At week 24, PGA response INF 74 vs. placebo 3%, (P < 0.0001)
Intermediate Outcome Measures: 6% and 2% of patients in INF group had asymptomatic increases in alanine aminotransferase and
aspartate aminotransferase, respectively. Fewer antibody-positive patients achieved PASI 75.
Authors: Reich et al.Year: 2005 and 2006 and 2007ADVERSE EVENTS: Overall adverse effects reported (%)
URTI Headache Pain Psoriasis Severe adverse event Infections Neoplasms
Placebo/INF
16125
133
400
INF
1514636
421
Significant differences in adverse events:
No
ANALYSIS: ITT: YesPost randomization exclusions: NR
ADEQUATE RANDOMIZATION: Yes
ADEQUATE ALLOCATION CONCEALMENT:
Yes
BLINDING OF OUTCOME ASSESSORS:
Yes
ATTRITION %(overall):
ATTRITION (treatment specific):Loss to follow-up: Withdrawals due to adverse events:
Overall loss to follow-up: 17.5% (24 weeks)Loss to follow-up differential high: No
FUNDING: Wyeth Research (pharmaceutical industry)RESEARCH OBJECTIVE: To assess baseline patient-reported outcomes (PROs) and PRO improvement in patients with psoriasis
administered 50 mg once weekly.DESIGN & SIZE: Study design: placebo-controlled RCT
INCLUSION CRITERIA: Clinically stable plaque psoriasis involving ≥10% of body surface area; minimum PASI score of 10 (moderate-to-severe); failed to respond to, had a contradiction for or were intolerant of ≥1 systemic treatment or phototherapy at an adequate dose of sufficient duration.
EXCLUSION CRITERIA: Patients with active guttate, erythrodermic or pustular psoriasis at the time of screening, or other active skin conditions that would interfere with study evaluations, were excluded. Patients were also ineligible if they had a serious infection within 1 month of study screening or the baseline visit or a body mass index (BMI) greater than 38 kg m2. Patients were not to have received etanercept, an antibody to TNF, or other TNF inhibitors at any time; alefacept, efalizumab, anti-CD4 agents, or diphtheria interleukin-2 fusion protein within the previous 6 months; ultraviolet A or B phototherapy, psoralen and ultraviolet A phototherapy, systemic psoriasis therapy (methotrexate, ciclosporin, acitretin or fumarates), or oral or parenteral corticosteroids within the previous month; or topical corticosteroids in high strengths, topical vitamin A or D analogue preparations, dithranol or topical calcineurin inhibitors (pimecrolimus or tacrolimus) within the previous 2 weeks.
OTHER MEDICATIONS/ INTERVENTIONS ALLOWED:
Patients were permitted to use only topical corticosteroids of low to moderate strength on the scalp, axillae and groin during the study. Topical corticosteroids were not allowed on other areas, including the hands and feet. Doses of topical corticosteroids were to remain stable for at least 2 weeks before the baseline visit until the end of the double-blind period.
Authors: Reich et al. and van de Kerkhof et al.Year: 2009, 2008POPULATION CHARACTERISTICS:
ETA Placebo Full Sample
Mean age (years): 45.9 43.6 44.7Sex (% female): 38.5% 45.6% 42%Ethnicity: NR NR NRClass naïve: 100% 100% 100%Other germane population qualities:
Mean PASI 21.4 21.0 21.2 Mean body surface area
involvement26.5% 30.3% 28.4
Mean duration of psoriasis 19.3 years 17.3 years 18.3 years Received prior systemic
therapy (%)49.0% (failed ≥1) 47.8% (failed ≥1) NR
RESULTS: Primary Outcome Measures: 37.5% of ETA patients had ≥75% improvement on the PASI, compared with 2.2% of placebo (p<0.0001);ETA patients had a mean decrease in DLQI of 7.4 compared with placebo (-1.2); P<0.0001;ETA patients had a mean increase in EQ-5D utility score of 0.12 compared with placebo (+0.02); P<0.05;ETA patients had a mean change in EQ-5D VAS score of +6.8 compared with placebo (-4.9); P<0.01;Secondary Outcome Measures: 19.8% of ETA patients and 50.0% of placebo patients had DLQI ≥11;29.2% of ETA patients and 15.2% of placebo patients achieved DLQI of 0 or 1;74.7% of ETA patients and 28.6% of placebo patients achieved improvement of ≥5 points on DLQI; P<0.0001;Mean DLQI score: ETA = 5.8 vs. placebo = 12.3; P<0.0001;Mean EQ-5D utility score: ETA = 0.81 vs. placebo = 0.69;Mean FACIT-F score (change from baseline): ETA = 40.7 (+1.3) vs. placebo = 39.5 (+0.3); no significant difference;9.4% fewer ETA patients reported mobility problems, compared with no fewer placebo patients (P<0.05);10.4% fewer ETA patients reported anxiety/depression, compared with 4.4% fewer placebo patients (P<0.05);
26% fewer ETA patients reported pain discomfort, compared with 13% fewer placebo patients (P<0.05);14.5% fewer ETA patients reported problems with usual activities, compared with 2.1% more placebo patients, NSD;7.2% fewer ETA patients reported problems with self-care, compared with 4.4% fewer placebo patients, NSD.
Authors: Reich et al. and van de Kerkhof et al.Year: 2009, 2008METHOD OF ADVERSE EVENTS REPORTING:
NR
ADVERSE EVENTS (%): ETA PlaceboOverall adverse effects reported: NR NR
Infections NR NR URTI NR NR abnormal LFT NR NR herpes simplex NR NR pneumonia NR NR tb NR NR ISR NR NR
ATTRITION (overall):
ATTRITION (treatment specific):Attrition overall: Attrition due to adverse events:
STUDY: Authors: Saurat et al.127 and Revicki et al.128
Year: 2007, 2008Country: Multinational
FUNDING: Abbott Labs
RESEARCH OBJECTIVE: Compare a biologic agent ADA with MTX, a traditional systemic agent, to define clearly the role of biologics in psoriasis
DESIGN:
Study design: RCTSetting: MulticenterSample size: 271
INTERVENTION: Dose: Duration: Sample size:
PlaceboNA
16 weeks53
Methotrexate7.5 to 25 mg weekly
16 weeks110
Adalimumab80 mg load then 40 mg eow
16 weeks108
INCLUSION CRITERIA: >18 years of age with moderate to severe psoriasis, plaque psoriasis for at least 1 year and stable plaque psoriasis for at least 2 months, candidates for systemic therapy or phototherapy and to have had active psoriasis despite treatment with topical agents, naive to both TNF-antagonist therapy and methotrexate.
EXCLUSION CRITERIA: History of clinically significant haematological, renal or liver disease ⁄abnormal laboratory values; with a history of demyelinating disease, cancer, or other lymphoproliferative disease (other than successfully treated nonmetastatic cutaneous squamous cell or basal cell carcinoma and ⁄or localized carcinoma in situ of the cervix); or who were immunocompromised.
OTHER MEDICATIONS/ INTERVENTIONS ALLOWED:
Shampoos free of corticosteroids; bland emollients; and low-potency topical corticosteroids for the palms, soles, face, inframammary areas and groin only, not used within 24 h of a study visit
Authors: Saurat et al. and Revicki et al.Year: 2007, 2007POPULATION CHARACTERISTICS:
Mean age (years):Sex (% female):Ethnicity (% Caucasian): Other germane population qualities:
Mean PASI Mean body surface area
involvement Mean duration of psoriasis Received prior systemic
therapy and/or phototherapy (%)
Groups similar at baseline: YesPlacebo
40.734
92.5
19.228.4
18.890.4
Methotrexate
41.633.695.5
19.432.4
18.987.2
Adalimumab
42.935.295.4
20.233.6
17.982.2
OUTCOME ASSESSMENT: Primary Outcome Measures: PASI 75 at week 16 and DLQI
Secondary Outcome Measures: PASI 50, 90 and 100, and PGA and EuroQOL5D
Timing of assessments: baseline and at weeks 1, 2, 4, 8, 12 and 16.
RESULTS: Health Outcome Measures at 16 weeks:PASI 75 ADA 79.6% vs. 35.5% MTX vs. Placebo 18.9% PASI 100 ADA 16.7% vs. MTX 7.3% vs. placebo 1.9 P = .004DLQI change from baseline (95% CI) ADA 9.1 (-10.4 to -7.8) vs. MTX-5.7 (-6.8 to -4.5) vs. placebo -3.4 (-5.2 to -1.6) ADA vs. placebo P < 0.001EQ 5D Index Score change from baseline (95% CI) ADA 0.2 (0.2 to 0.3) vs. MTX 0.1 (0.1 to 0.2) vs. placebo 0.1 (0.0 to 0.2) EQ-5D VAS change from baseline (95% CI) ADA 21.4 (16.6 to 26.3) vs. MTX 11.5 (6.5 to 16.5) vs5.7 (-1.4 to 12.8)PGA ADA -1.6 vs. placebo -0.5 P < 0.001
Authors: Saurat et al. and Revicki et al.Year: 2007, 2008ADVERSE EVENTS %: Overall adverse effects reported:
