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Articles Efficacy and safety of ustekinumab, a human ... - Huidarts.com

Articles Efficacy and safety of ustekinumab, a human ... - Huidarts.com

Articles Ustekinumab 45 mg (n=255) Ustekinumab 90 mg (n=256) Placebo (n=255) Age (years) 44·8 (12·5) 46·2 (11·3) 44·8 (11·3) Sex (male) 175 (68·6%) 173 (67·6%) 183 (71·8%) Weight (kg) 93·7 (23·8) 93·8 (23·9) 94·2 (23·5) Duration of psoriasis (years) 19·7 (11·7) 19·6 (11·1) 20·4 (11·7) Involved body surface area 27·2% (17·5) 25·2% (15·0) 27·7% (17·4) Physician’s global assessment—marked or severe* 114 (44·7%) 109 (42·6%) 112 (43·9%) Psoriasis area and severity index 20·5 (8·6) 19·7 (7·6) 20·4 (8·6) Dermatology life quality index 11·1 (7·1) 11·6 (6·9) 11·8 (7·4) Patients with psoriatic arthritis 74 (29·0%) 94 (36·7%) 90 (35·3%) Treated previously with Topical agent† 245 (96·1%) 239 (93·4%) 242 (94·9%) Phototherapy‡ 173 (67·8%) 169 (66·0%) 150 (58·8%) Conventional systemics§ 141 (55·3%) 141 (55·1%) 142 (55·7%) Biologicals 134 (52·5%) 130 (50·8%) 128 (50·2%) Patients with latent tuberculosis|| 8 (3·1%) 7 (2·7%) 10 (3·9%) Data are mean (SD) or n (%). *Rated as cleared (0), minimal (1), mild (2), moderate (3), marked (4), or severe (5). †Patients had to have discontinued topical therapies (except moisturisers and shampoos) 2 weeks, conventional systemic therapies 4 weeks, and biological agents at least 3 months before randomisation. ‡Includes ultraviolet B light and psoralen plus ultraviolet A. §Includes psoralen plus ultraviolet A, methotrexate, acitretin, and ciclosporin. Includes etanercept, alefacept, efalizumab, infliximab, or adalimumab. ||Latent tuberculosis was identified by a positive purified protein derivative test without evidence of active tuberculosis. Table 1: Demographic and clinical characteristics at baseline system (ClinPhone; East Windsor, NJ, USA). Baseline randomisation was stratified by investigational site, weight (≤90 kg or >90 kg), and the number of conventional systemic therapies to which patients had an inadequate response, intolerance, or contraindication (90 kg). Key efficacy parameters, including PASI, physician’s global assessment, and dermatology life quality index, were assessed until week 76. PASI response indicates the extent and severity of psoriasis, yielding an overall scale of 0 (no psoriasis) to 72 (severe). 15 With the physician’s global assessment, a patient’s psoriasis is assessed as cleared (0), minimal (1), mild (2), moderate (3), marked (4), or severe (5). The dermatology life quality index is a 10-item questionnaire that determines whether psoriasis affects patient-reported quality of life, with overall scores ranging from 0 (not at all) to 30 (very much). 16 Adverse events and routine haematology and chemistry laboratory tests and haemoglobin A₁ c levels were monitored until week 76, and serum samples collected up to week 76 were tested for antibodies to ustekinumab with a bridging immunoassay. 17 Fasting glucose, C-reactive protein (CRP), and D-dimer levels were monitored during the placebo-controlled phase. The primary efficacy endpoint was the proportion of patients achieving PASI 75 at week 12. Major secondary endpoints included: the proportion of patients with a physician’s global assessment score of cleared or minimal at week 12; the change in dermatology life quality index from baseline at week 12; and, in the randomised withdrawal phase, time to loss of PASI 75 response in the group receiving maintenance ustekinumab compared with the group withdrawn from treatment at week 40. Statistical analysis The study was designed to enrol 750 patients to assess both the primary and major secondary endpoints and to characterise the efficacy and safety of long-term treatment. The sample size calculations took into account the results of the phase II trial 11 and assumed PASI 75 response rates of 50% (≤90 kg) and 40% (>90 kg) in each ustekinumab group and 10% for the placebo group. On the basis of simulation studies in SAS (version 8.02) using Cochran-Mantel-Haenszel χ² tests stratified by weight, the trial with 250 patients per group provided more than 99% power to detect at least one pairwise treatment effect in the primary endpoint based on Holm’s procedure at an overall 5% level of significance. To maintain an overall type I error rate of 0·05, the primary and major secondary analyses were done sequentially with each endpoint tested at an alpha level of 0·05. All other statistical tests were two-sided. Efficacy data from all randomised patients were analysed according to the assigned treatment group, whereas safety analyses were based on actual treatment in patients receiving at least one administration of study agent. For patients randomly assigned to placebo at baseline, only those who crossed over to active treatment at week 12 were included in subsequent efficacy summaries. Patients who discontinued study treatment due to unsatisfactory therapeutic effect or who started a protocol-prohibited therapy that could improve psoriasis were deemed to be treatment failures. For analyses in such cases, baseline values were assigned for continuous endpoints and patients were deemed to be non-responders for dichotomous endpoints. In the primary efficacy and week 12 binary PASI and physician’s global assessment analyses, patients with missing data were deemed to be non-responders. For analyses of time to loss of PASI 75 response, intermittent missing values were imputed by linear interpolation. For other efficacy analyses, missing data were not imputed and were treated as missing. Dichotomous endpoints were analysed with the Cochran-Mantel-Haenszel χ² test stratified by site (pooled) and weight, and continuous variables were compared with an analysis of variance (ANOVA) on the van der Waerden normal scores with weight as a binary covariate. Time to loss of PASI 75 response was analysed with the log-rank test stratified by weight. This trial is registered with ClinicalTrials.gov, number NCT00267969. All analyses were done with SAS version 8.02. Role of the funding source Employees of the study sponsor were involved in the design of this study together with members of the 1668 www.thelancet.com Vol 371 May 17, 2008

Articles steering committee, with input from study investigators. The steering committee reviewed study progress. Study investigators collected data, which were maintained in a database by the study sponsor. Statisticians and programmers at the study sponsor did the data analyses. An independent safety monitoring committee reviewed safety data during the study. All authors had full access to the data, and the steering committee had final responsibility for the decision to submit for publication. Results The trial profile is shown in figure 2. Baseline demographic and clinical characteristics were much the same across treatment groups (table 1) and among patients re-randomised at week 40 (data not shown). About two-thirds of patients in each group were men. On average, patients had a 20-year history of psoriasis and about a quarter of their body surface area affected by psoriasis. Over 90% of patients had used topical treatments previously, and at least 50% each had previously used conventional systemic or biological therapies. 25 patients diagnosed with latent tuberculosis infection before or at screening received isoniazid during the study (table 1). Significantly more patients in both the 45 and 90 mg ustekinumab groups achieved the primary endpoint— PASI 75 at week 12—than did those in the placebo group (table 2; difference in response rate 63·9%, 95% CI 57·8–70·1, p

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