Efalizumab for Patients with Moderate to Severe Plaque Psoriasis a Randomized Controlled Trial

ORIGINAL CONTRIBUTION

Efalizumab for Patients With Moderate to Severe Plaque Psoriasis A Randomized Controlled Trial

Kenneth B. Gordon, MD Context Because T-cell interactions are involved in the pathophysiology of psoria- Kim A. Papp, MD sis, therapy with a T-cell modulator may have beneficial effects on psoriasis severity Tiffani K. Hamilton, MD and health-related quality of life (HRQL). Objective To assess the efficacy and safety of efalizumab, a T-cell modulator, in pa- Patricia A. Walicke, MD tients with plaque psoriasis. Wolfgang Dummer, MD Design, Setting, and Patients Phase 3 randomized, double-blind, parallel- Nicole Li, PhD group, placebo-controlled trial involving 556 adult patients with stable, moderate to severe plaque psoriasis and conducted at 30 study centers in the United States and Brian W. Bresnahan, PhD Canada between January and July 2002. Alan Menter, MD Interventions Patients were randomly assigned in a 2:1 ratio to receive 12 weekly for the Efalizumab Study Group doses of subcutaneous efalizumab, 1 mg/kg (n=369), or placebo equivalent (n=187). Main Outcome Measures At least 75% improvement on the Psoriasis Area and SORIASIS, A DISEASE AFFECTING Severity Index (PASI-75); improvement on the overall Dermatology Life Quality In- millions of persons world- dex (DLQI), Itching Visual Analog Scale (VAS), and Psoriasis Symptom Assessment wide, is a chronic inflamma- (PSA) at week 12 vs baseline. tory disease that has a pro- Results Efalizumab-treated patients experienced significantly greater improvement Pfound adverse effect on patients’ on all end points than placebo-treated patients. Twenty-seven percent of efalizumab- physical, social, and mental well- treated patients achieved PASI-75 vs 4% of the placebo group ( PϽ.001). Efalizumab- being.1-6 In the National Psoriasis Foun- treated patients exhibited significantly greater mean percentage improvement than dation survey of more than 17000 re- placebo-treated patients on the overall DLQI (47% vs 14%; PϽ.001), Itching VAS spondents, 79% of patients with severe (38% vs −0.2%; PϽ.001), and PSA frequency and severity subscales (48% vs 18% disease reported that psoriasis ad- and 47% vs 17%, respectively; PϽ.001 for both) at the first assessment point. Efali- versely affected their lives and limited zumab was safe and well tolerated, with primarily mild to moderate adverse events. activities of daily living (eg, work and Conclusion In this 12-week study, efalizumab resulted in significant improvements school participation).3 in clinical end points, including physician-assessed and dermatology-specific patient- The physical symptoms of psoriasis reported HRQL measures, in patients with moderate to severe plaque psoriasis. adversely affect daily functioning, with JAMA. 2003;290:3073-3080 www.jama.com the most frequently reported symptoms including scaling, itching, and barrassment6,10 and have adverse ef- Author Affiliations: Loyola University Medical Cen- 3,7,8 ter, Maywood, Ill (Dr Gordon); Probity Medical Re- burning. With inadequate control of fects on emotional aspects and normal search, Waterloo, Ontario (Dr Papp); Atlanta Derma- these symptoms, physical, social, and functioning.11 Up to 10% of psoriasis tology, Vein and Research Center LLC, Atlanta, Ga (Dr Hamilton); Genentech Inc, South San Francisco, Calif mental functioning and overall health- patients, especially younger patients, (Drs Walicke, Dummer, Li, and Bresnahan); and Bay- related quality of life (HRQL) are com- harbor suicidal thoughts compared with lor University Medical Center, Dallas, Tex (Dr Menter). promised.8,9 For example, the physi- Members of the Efalizumab Study Group are listed approximately 3% of general medical at the end of this article. cal appearance of lesions can cause patients, indicating a significant un- Financial Disclosures: Dr Gordon has received re- patients to experience stress and em- 3,12 search funding from Genentech Inc and Dr Papp has met medical need. served as a consultant to Genentech Inc. Efalizumab is a humanized mono- Corresponding Author and Reprints: Kenneth B. Gor- clonal IgG1 antibody that targets T- don, MD, Loyola University Medical Center, 2160 S See also p 3133 and Patient Page. First Ave, Bldg 112, Room 342, Maywood, IL 60153 cell interactions central to the patho- (e-mail: [email protected]).

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physiology of psoriasis.13-23 In this study, ate to severe plaque psoriasis was ex- tiating the study, and all patients pro- the effect of efalizumab on dermatology- amined using a broad set of outcome vided written informed consent. related HRQL in patients with moder- measures including physicians’ assess- Patients were randomly assigned to re- ments and patients’ perceptions. ceive 12 weekly doses of either subcutaneous efalizumab, 1 mg/kg, or pla- Figure 1. Flow of Study Participants METHODS cebo equivalent, as per the original study Protocol protocol (FIGURE 1). Allocation se- 556 Patients Enrolled and Randomized quences were generated by an un- This phase 3 randomized, double- blinded statistician at Genentech Inc, the blind, parallel-group, placebo- 187 Assigned to Receive 369 Assigned to Receive study sponsor, who then passed them to controlled multicenter trial evaluated the Placebo for 12 wk Efalizumab for 12 wk the interactive voice response system efficacy and safety of efalizumab (anti- vendor. The sites enrolled and random- 7 Discontinued Treatment 20 Discontinued Treatment CD11a; Raptiva, Genentech Inc) in (<10 Doses Received) (<10 Doses Received) ized patients by calling the interactive adults with moderate to severe psoria- 3 Patient Decision 7 Patient Decision voice response system, which assigned 2 Adverse Events 7 Adverse Events sis. Eligible patients were 18 to 75 years 2 Investigator Decision 5 Use of Excluded patients to either efalizumab or placebo Medication of age, diagnosed as having plaque pso- 5 Lost to Follow-up using a random permuted-block design 1 Investigator Decision riasis for at least 6 months with at least 4 Lost to Follow-up to obtain approximately a 2:1 ratio within 10% of total body surface area (BSA) af- categories defined by the stratification fected, had a minimum Psoriasis Area 175 Completed Treatment 345 Completed Treatment variables: baseline PASI score (Յ16.0 vs 29 Received 10 or 74 Received 10 or and Severity Index (PASI) score of 12.0 11 Doses 11 Doses Ն16.1), prior treatment for psoriasis (yes 146 Received 12 271 Received 12 at screening, and were candidates for sys- Doses Doses vs no), and study center. temic therapy. Patients could with- Each patient received an initial con- draw or be withdrawn from the study 187 Included in Primary 369 Included in Primary ditioning dose of 0.7 mg/kg followed by Analysis Analysis at any time. All sites received institu- 11 weekly doses of 1 mg/kg of study tional review board approval prior to ini- drug (efalizumab or placebo equivalent). After 12 weeks of placebo- Box. Efficacy Outcomes Assessed During the Study controlled treatment, all patients were enrolled in a separate long-term open- Physician-Assessed Outcomes label extension study. Psoriasis Area and Severity Index (PASI): Assesses the extent of psoriasis on 4 Patients received efalizumab mono- body surface areas (head, trunk, and upper and lower limbs) and the degree of plaque erythema, scaling, and thickness. The PASI scores account for both the ex- therapy, with all phototherapy and sys- tent of body surface area affected by the erythema, scaling, and thickness and the temic therapy excluded. Patients were severity of these measures. The score ranges from 0 (no disease) to 72 (maximal permitted to use emollients. Tar and disease). salicylic acid preparations were per- Overall Lesion Severity Scale (OLS): Static global assessment with 6 categories mitted for the scalp, and low-potency (clear, minimal, mild, moderate, severe, and very severe) based on the character- topical corticosteroids were allowed for istics of plaque elevation, scaling, and erythema. the face, hands, feet, groin, and axil- Physician’s Global Assessment (PGA): Captures and categorizes the global re- lae. Patients, investigators, sponsor, and sponse to therapy of all clinical signs and symptoms of disease relative to baseline. the contract research organization were Physicians use all available information for the assessment, including subjective blinded regarding treatment assign- information gathered from the patient and photographs taken at baseline. The cat- ment or active study drug until the egories are worse, unchanged, slight, fair, good, excellent, and cleared. analyses of all data were complete. Patient-Reported Outcomes Dermatology Life Quality Index (DLQI): The DLQI is a 10-item questionnaire Assessments that incorporates patients’ assessments of itch, pain, feelings of embarrassment and The primary efficacy outcome mea- self-consciousness, problems with their psoriasis treatment, and interference of sure was the proportion of patients with their psoriasis with daily activities, relationships, and sexual activity. The DLQI at least 75% improvement in PASI scores range from 0 (no impairment) to 30 (maximal impairment). Itching Visual Analog Scale (VAS): The 10-point Itching VAS is a modified VAS (PASI-75) at week 12 relative to base- with scores ranging from 0 (no itching) to 10 (severe itching). line (BOX). The PASI is a physician- Psoriasis Symptom Assessment (PSA): The PSA is a 16-item measure of 8 psoriasis- assessed score, recognized by the US related cutaneous symptoms (hurt, burning or stinging, itched, bothered by wa- Food and Drug Administration24 to as- ter, irritated, sensitive, skin condition bled, scaling). The PSA contains 2 sub- sess efficacy of psoriasis therapies in scales, one measuring the frequency of the 8 symptoms and the other assessing clinical trials, that takes into account how troublesome or bothersome psoriasis symptoms are. the extent of involved skin surface area and severity of erythema, desquama-

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tion, and plaque induration.25 The com- tion of the first dose of study drug. The Table 1. Baseline Characteristics of Study posite score ranges from 0 to 72, with PASI was assessed at baseline and ev- Participants* higher numbers indicating more se- ery 2 weeks thereafter. The patient- Placebo Efalizumab vere disease and a reduction in score reported outcomes (DLQI, Itching VAS, Characteristics (n = 187) (n = 369) representing improvement. The PASI and PSA) were performed prior to ob- Sex, No. (%) components of lesion thickness, ery- taining physician assessments for mea- Male 132 (71) 251 (68) thema, and scaling were examined sepa- sures (eg, PASI) at baseline and at weeks Female 55 (29) 118 (32) Race/ethnicity, rately. The PASI-75 is the currently rec- 4, 8, and 12. No. (%) ognized benchmark of end points used The safety and tolerability of efali- White 167 (89) 331 (90) in psoriasis clinical trials.26 For each zumab were monitored by adverse Hispanic 7 (4) 17 (5) study site, PASI assessments were per- events, vital signs, physical examina- Other† 13 (7) 21 (6) formed by a single investigator who was tion, clinical laboratory evaluation, and Age, y 45 (20-75) 45 (18-75) blinded to randomization. serum human antihuman antibody Duration of 19 (1-53) 19 (1-62) Secondary efficacy measures in- measurement. Adverse events were as- psoriasis, y Prior systemic cluded 2 global physician assess- sessed weekly. Standard methods to as- psoriasis ments: a static measure designated the sess safety were used. therapy, No. (%) Overall Lesion Severity Scale (OLS) and Yes 139 (74) 283 (77) a dynamic measure designated the Phy- Statistical Analyses No 48 (26) 86 (23) sician’s Global Assessment (PGA). Ad- The sample size was based primarily on PASI score 19 (11-50) 19 (10-59) BSA affected 27 (10-90) 28 (10-95) ditional secondary outcome measures safety considerations. With a planned by psoriasis, % were the proportion of patients with at sample size of 333 patients in the efali- DLQI score 12 (0-30) 12 (0-30) least 50% improvement on the PASI zumab group and 167 patients in the Itching VAS score 6 (0-10) 6 (0-10) (PASI-50) relative to baseline, the per- placebo group, using a 2-sided Fisher PSA frequency score 14 (2-24) 14 (2-24) centage of PASI improvement over time, exact test, the study had 99% power to PSA severity score 15 (2-24) 15 (0-24) PASI thickness component, and the per- detect a difference between the as- Abbreviations: BSA, body surface area; DLQI, Dermatol- centage of BSA affected by psoriasis. sumed placebo response rate of 5% and ogy Life Quality Index; PASI, Psoriasis Area and Sever- ity Index; PSA, Psoriasis Symptom Assessment; VAS, Patient-reported outcomes were the assumed efalizumab response rate Visual Analog Scale. ␣ *Data are presented as mean (range) unless otherwise evaluated using prospectively defined of 25% at an =.05 significance level. noted. Mean values have been rounded. mean improvement in the overall Der- Analyses were conducted with nQuery †Other includes persons who described their race/ ethnicity as Asian or Pacific Islander, black, American matology Life Quality Index (DLQI), Advisor software, version 4.0 (Statisti- Indian or Alaskan Native, or other. Itching Visual Analog Scale (VAS), and cal Solutions, Saugus, Mass). Psoriasis Symptom Assessment (PSA) The main analysis population for pri- Figure 2. Mean PASI Percentage Change frequency and severity subscales. The mary and secondary end points was the Relative to Baseline Over the Study Period overall improvement for all patient- intention-to-treat population, consist- 60 reported outcomes was assessed at week ing of all patients who were random- Efalizumab ∗ Placebo ∗ 12 relative to baseline. ized whether or not they received any 50 The DLQI measures the impact of skin study drug or completed the full course ∗ disorders and treatment on patient func- of treatment. Patients were analyzed ac- 40 ∗ tioning and well-being using a 7-day re- cording to their randomized treat- 30 call period.27 The psychometric charac- ment group. Safety analyses were per- ∗

teristics relating to the validity and formed on an as-treated population. to Baseline, % 20 reliability of the DLQI are well estab- The primary end point was evalu- lished.27,28 The Itching VAS used in pre- ated by comparing the proportion of Change Relative Mean PASI 10

vious trials of efalizumab has been shown those in the efalizumab group and those 0 to be a valid and reliable measure.28 The in the placebo group who achieved 2 4 6 8 10 12 PSA is an adaptation of a validated skin PASI-75 at week 12 relative to base- Study Week 29,30 disorder instrument, the Skindex, line using a 2-sided Fisher exact test for PASI indicates Psoriasis Area and Severity Index. Er- with 2 additional questions related to the binomial outcome at the .05 level of sig- ror bars indicate SEMs. Asterisks indicate PϽ.001 for frequency and severity of skin scaling us- nificance; the exact 95% confidence in- efalizumab vs placebo. ing a 2-week recall period. The PSA, also terval for response rates within each used in prior efalizumab studies, has been treatment group and the difference in score was missing were classified as established to be a valid, reliable, and re- response rates between the efali- nonresponders. sponsive measure.28 zumab and placebo group were calcu- The following secondary end points Baseline measurements were those lated. Patients who discontinued early were compared between treatment made closest but prior to administra- from the study or whose week 12 PASI groups using a 2-sided Fisher exact test

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for binomial outcome performed at the 12. Using the 2-sided t test at the .05 baseline were summarized by time .05 level of significance: the propor- significance level, mean improvement point. At each point, the mean percent- tion of patients who achieved an OLS from baseline in the PASI thickness age improvement from baseline was rating of minimal or clear at week 12, score at week 12 and mean improve- compared between the treatment the proportion of patients with PASI-50 ment from baseline in the percentage groups using the t test. A hierarchical at week 12 relative to day 0, and the pro- of BSA affected by psoriasis at week 12 testing procedure determined the ear- portion of patients who achieved a PGA were compared. The PASI score and liest point at which a statistically sig- rating of excellent or cleared at week percentage of PASI improvement from nificant difference (at the .05 level) be-

Table 2. Improvement From Baseline in DLQI and PSA Severity Components* Baseline Week 12 Improvement

No. Mean (SD) Median (IQR) Mean (SD) Median (IQR) Mean (SD) Median (IQR) DLQI Components Symptoms and feelings Placebo 175 3.8 (1.6) 4 (3 to 5) 3.1 (1.6) 3 (2 to 4) 0.7 (1.6) 1 (0 to 2) Efalizumab 346 4.0 (1.5) 4 (3 to 5) 2.0 (1.6) 2 (1 to 3) 1.9 (1.9) 2 (1 to 3) Daily activities Placebo 172 2.5 (1.7) 2.5 (1 to 4) 2.2 (1.7) 2 (1 to 3) 0.3 (1.6) 0 (−1 to 1) Efalizumab 347 2.5 (1.6) 2 (1 to 4) 1.4 (1.6) 1 (0 to 2) 1.1 (1.8) 1 (0 to 2) Leisure Placebo 174 1.8 (1.8) 1 (0 to 3) 1.5 (1.6) 1 (0 to 2) 0.3 (1.6) 0 (0 to 1) Efalizumab 345 1.8 (1.8) 1 (0 to 3) 0.8 (1.3) 0 (0 to 1) 1.0 (1.7) 0 (0 to 2) Work and school Placebo 171 0.7 (0.9) 0 (0 to 1) 0.5 (0.8) 0 (0 to 1) 0.2 (0.8) 0 (0 to 0) Efalizumab 335 0.8 (0.9) 1 (0 to 1) 0.3 (0.7) 0 (0 to 1) 0.4 (0.9) 0 (0 to 1) Personal relationships Placebo 175 1.5 (1.7) 1 (0 to 2) 1.2 (1.6) 1 (0 to 2) 0.3 (1.3) 0 (0 to 1) Efalizumab 346 1.4 (1.7) 1 (0 to 2) 0.7 (1.3) 0 (0 to 1) 0.7 (1.6) 0 (0 to 2) Treatment Placebo 175 1.2 (1.1) 1 (0 to 2) 1.3 (1.0) 1 (1 to 2) 0 (1.0) 0 (−1 to 0) Efalizumab 346 1.3 (1.0) 1 (0 to 2) 0.7 (0.8) 1 (0 to 1) 0.6 (1.1) 1 (0 to 1) PSA Severity Subscales† Hurt Placebo 176 1.8 (1.0) 2 (1 to 3) 1.4 (1.0) 1 (1 to 2) 0.4 (1.0) 0 (0 to 1) Efalizumab 343 1.8 (1.0) 2 (1 to 3) 0.8 (0.9) 1 (0 to 1) 0.9 (1.2) 1 (0 to 2) Burning or stinging Placebo 176 1.7 (1.0) 2 (1 to 2) 1.4 (1.0) 1 (1 to 2) 0.3 (1.0) 0 (0 to 1) Efalizumab 343 1.7 (1.0) 2 (1 to 3) 0.8 (0.9) 1 (0 to 1) 0.9 (1.2) 1 (0 to 2) Itched Placebo 175 2.4 (0.8) 3 (2 to 3) 2.1 (0.9) 2 (1 to 3) 0.3 (0.8) 0 (0 to 1) Efalizumab 338 2.4 (0.8) 3 (2 to 3) 1.3 (0.9) 1 (1 to 2) 1.1 (1.0) 1 (0 to 2) Bothered by water Placebo 176 1.1 (1.1) 1 (0 to 2) 0.9 (1.0) 1 (0 to 2) 0.2 (1.0) 0 (0 to 1) Efalizumab 342 1.1 (1.1) 1 (0 to 2) 0.6 (0.9) 0 (0 to 1) 0.5 (1.1) 0 (0 to 1) Irritated Placebo 175 2.1 (0.9) 2 (2 to 3) 1.6 (0.9) 2 (1 to 2) 0.5 (0.9) 0 (0 to 1) Efalizumab 343 2.0 (0.9) 2 (1 to 3) 1.0 (0.9) 1 (0 to 2) 1.0 (1.1) 1 (0 to 2) Sensitive Placebo 175 1.9 (0.9) 2 (1 to 3) 1.6 (1.0) 1 (1 to 2) 0.3 (1.0) 0 (0 to 1) Efalizumab 343 1.9 (1.0) 2 (1 to 3) 1.0 (1.0) 1 (0 to 1) 0.9 (1.1) 1 (0 to 2) Skin condition bled Placebo 175 1.3 (0.9) 1 (1 to 2) 1.2 (0.9) 1 (0 to 2) 0.1 (0.9) 0 (0 to 1) Efalizumab 343 1.3 (0.9) 1 (1 to 2) 0.6 (0.8) 0 (0 to 1) 0.7 (1.0) 1 (0 to 1) Scaling Placebo 176 2.6 (0.6) 3 (2 to 3) 2.1 (0.9) 2 (1 to 3) 0.5 (0.9) 0 (0 to 1) Efalizumab 344 2.5 (0.8) 3 (2 to 3) 1.2 (1.0) 1 (1 to 2) 1.3 (1.1) 1 (0 to 2) Abbreviations: DLQI, Dermatology Life Quality Index; IQR, interquartile range; PSA, Psoriasis Symptom Assessment. *P values calculated by 2-sample Wilcoxon rank sum test for between-group comparisons of improvement were Ͻ.001 for all comparisons. †For this measure patients were asked to indicate how troubling/bothersome each listed symptom was during the previous 2 weeks.

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tween the treatment groups was Table 3. DLQI Improvement Stratified by PASI Response at Week 12 observed. No multiple-comparison ad- PASI Improvement, % justment for the type I error was made in the hierarchical testing procedure, Ն75 51-74 Յ50 since there was no inflation of the type Placebo I error. To ensure an overall type I er- No. (%) of patients 8 (4) 18 (10) 157 (86) ror rate of ␣=.05 (2-sided) for all sec- Mean (SD) improvement 8.8 (5.5) 6.8 (5.7) 2.5 (6.5) ondary efficacy analyses, the Hochberg- Median (IQR) improvement 8 (5 to 12) 5 (2 to 11) 2 (−1 to 6) Bonferroni31 multiple-comparisons Efalizumab procedure was used to adjust for mul- No. (%) of patients 98 (27) 118 (32) 153 (41) tiple comparisons of secondary end Mean (SD) improvement 8.8 (5.5) 6.8 (5.7) 2.5 (6.5) points; all secondary end points re- Median (IQR) improvement 8 (5 to 12) 5 (2 to 11) 2 (−1 to 6) tained statistical significance after mul- Abbreviations: DLQI, Dermatology Life Quality Index; IQR, interquartile range; PASI, Psoriasis Area and Severity Index. tiplicity adjustments. Mean improvements from baseline to verse event (n=9), use of an excluded Figure 3. Median Change in PSA Severity week 12 on the overall DLQI and each medication (n=5), and investigator de- Relative to Baseline Over the Study Period of the 2 PSA scales were compared be- cision (n=3) (Figure 1). Four hundred tween treatment groups using the Wil- seventeen patients (75%) received all 12 12 Efalizumab 11 coxon rank sum test. The mean im- doses of assigned study drug. Placebo provement from baseline in the Itching 10 9 Treatment Efficacy VAS at week 12 was compared be- 8 tween treatment groups using the t test. Physician-Assessed Outcomes. At the 7 The overall scores and improvements end of the 12-week treatment course, 6 from baseline for all patient-reported 27% of patients treated with efali- 5 outcome scales were summarized by zumab (98/369) achieved PASI-75 com- 4 3 time point. At each point, the mean per- pared with 4% of patients who re- 2 centage improvement from baseline was ceived placebo (8/187; PϽ.001). The 1 compared between the treatment treatment effect, defined as the differ- 0 groups using the Wilcoxon rank sum ence in the proportion of patients who Median Change in PSA Severity Scores –1 –2 test (DLQI and PSA) or t test (Itching achieved PASI-75 between the efali- 4 8 12 VAS). A hierarchical testing proce- zumab and placebo groups, was 22.3% Study Week dure was used, as for efficacy. (95% confidence interval, 15.8%-29.5%). PSA indicates Psoriasis Symptom Assessment. Error bars Fifty-nine percent of efalizumab- indicate interquartile ranges. RESULTS treated patients (216/369) achieved Patient Characteristics PASI-50 compared with 14% of pa- Between January and July 2002, 556 patients receiving placebo (26/187; greater in the efalizumab-treated group tients were enrolled at 30 study centers PϽ.001). The mean PASI improve- than in the placebo group (47% vs 14%; and randomized into the study, 369 pa- ment at week 12 in the efalizumab- PϽ.001). Patients in the efalizumab- tients into the 1-mg/kg-per-week efali- treated patients relative to baseline was treated group showed improvement in zumab group and 187 patients into the about 52% compared with 19% in the mean DLQI scores compared with the placebo group (Figure 1). There were no patients who received placebo (PϽ.001) placebo-treated group at 28 days statistically significant differences be- (FIGURE 2). (PϽ.001). Given the 1-week recall pe- tween the 2 treatment groups with re- The proportion of patients with an riod associated with the DLQI, this dif- spect to demographics, baseline char- OLS rating of minimal or clear at week ference in score between the 2 groups acteristics, and disease severity 12 in the efalizumab group was signifi- indicates that reduced dermatology- (TABLE 1). The mean PASI score at base- cantly higher than that in the placebo related limitations and improved func- line for the entire study cohort was 19, group (26% vs 3%; PϽ.001). Simi- tioning occurred fairly soon after initi- and mean BSA with psoriasis was 28% larly, the proportion of patients with a ating efalizumab therapy. There was a for the efalizumab-treated group and PGA rating of excellent or cleared at statistically significant trend toward a 27% for the placebo-treated group. The week 12 was significantly greater in the positive efalizumab treatment effect proportion of patients who did not com- efalizumab group compared with the across all DLQI components (TABLE 2), plete treatment was similar in both placebo group (33% vs 5%; PϽ.001). with the greatest difference between the groups (6.5% vs 6.4%); the most com- Patient-Reported Outcomes. At week treatment groups at week 12 observed mon reasons were patient decision 12, the mean percentage improvement in the “symptoms and feelings” do- (n=10), loss to follow-up (n=9), ad- from baseline in DLQI overall score was main (48% vs 18%). Additional analy-

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treated patients (9/368) and 1% of pla- Table 4. Adverse Events Occurring in at Least 5% of All Patients cebo-treated patients (1/187). No deaths No. (%) of Patients were reported for patients during the Placebo Efalizumab study. Fourteen patients (3%) (12 [3%] Adverse Events (n = 187) (n = 368)* P Value† in the efalizumab group and 2 [1%] in Total‡ 133 (71) 296 (80) .02 the placebo group) experienced ad- Headache 39 (21) 123 (33) .002 verse events that resulted in with- Infection, not otherwise specified 23 (12) 46 (13) Ͼ.99 drawal of study drug. Chills 10 (5) 44 (12) .01 No clinically significant laboratory Nausea 13 (7) 39 (11) .22 abnormalities or pattern of changes in Myalgia 8 (4) 38 (10) .01 vital signs were observed during efali- Pain 9 (5) 37 (10) .03 zumab treatment. Eight patients (2%) Pharyngitis 10 (5) 27 (7) .47 Flulike syndrome 7 (4) 27 (7) .13 developed positive antibodies to efali- Fever 3 (2) 25 (7) .007 zumab after exposure to the drug. None Rhinitis 11 (6) 23 (6) Ͼ.99 of these patients experienced serious ad- Asthenia 9 (5) 22 (6) .70 verse events or discontinued treat- Diarrhea 10 (5) 20 (5) Ͼ.99 ment. No patients in the placebo group Unintentional injury 19 (10) 17 (5) .02 developed anti-efalizumab antibodies. *Excludes 1 patient who was randomized but discontinued before receiving any study drug. The rate of diagnosed infections was †P values were calculated using a 2-sided Fisher exact test for binomial distributions. 27% for the efalizumab group and 23% ‡Patients with at least 1 adverse event. for the placebo group. Infections that occurred at least 1% more frequently ses showed the summary statistics on was a trend toward improvement across in the efalizumab-treated patients than DLQI improvement stratified by PASI re- all symptoms in both frequency and se- in the placebo-treated patients in- sponse at week 12 in the 369 patients verity in the efalizumab group, as evi- cluded mild to moderate viral infec- who were randomized to receive efali- denced by the mean improvement in tion (primarily mild to moderate viral zumab, with the greatest improvement PSA scores (Table 2). With respect to upper respiratory tract infections), bac- observed in the patients who achieved the frequency of symptoms, differ- terial infection (eg, impetigo, strepto- PASI-50 (TABLE 3). ences between absolute improve- coccal pharyngitis), cellulitis, and fun- When patients with a baseline Itch- ments were similar for most symp- gal (yeast) infection. Infections graded ing VAS score of 0 (9 patients in the efali- toms (itching, irritation, sensitivity, as severe occurred in 0.5% of patients zumab group and 3 in the placebo group) bleeding, and scaling). With respect to in both the efalizumab and placebo were excluded from the analysis, efali- severity, or how bothersome the symp- groups. Efalizumab-treated patients did zumab treatment was shown to pro- toms were, the largest absolute im- not exhibit increased susceptibility to duce a 38% improvement in Itching VAS provements occurred in both the itch- any one type of pathogen, nor was there score, compared with a slight worsen- ing (mean improvement of 1.1 for evidence of infection characteristic of ing in score (−0.2%) in the placebo group efalizumab vs 0.3 for placebo; PϽ.001) opportunistic infections observed in im- at 12 weeks (PϽ.001). A significant im- and scaling (1.2 for efalizumab vs 0.4 munocompromised hosts. provement in the mean Itching VAS in for placebo; PϽ.001) components. No cases of anaphylaxis were ob- the efalizumab group relative to the pla- served during efalizumab therapy. Dur- cebo group was observed at the first time Safety Evaluation ing the study, 2 cases of malignancy point measured (PϽ.001). Efalizumab therapy was generally well were diagnosed (1 case each of squa- Comparisons of the mean percent- tolerated. All adverse events that oc- mous cell cancer at day 2 and basal cell age improvement from baseline in the curred in at least 5% of all patients are cancer at day 77) in efalizumab- efalizumab group vs the placebo group shown in TABLE 4. Five types of ad- treated patients, although neither was were statistically significant for both fre- verse events (headache, chills, fever, judged as being related to efalizumab quency of symptoms (48% vs 18%; myalgia, and pain) occurred at least 5% by investigators. PϽ.001) and severity of symptoms (eg, more frequently in the efalizumab troubling or bothersome) (47% vs 17%; group than in the placebo group. These COMMENT PϽ.001). Improvement in both mean events tended to be a portion of the Limitations of currently available pso- PSA frequency and mean PSA severity complex of mild to moderate flulike riasis therapies highlight the need for ef- subscale scores was evident in the efali- symptoms that occur following the first fective and safe treatment options. Tra- zumab group vs the placebo group at 1 to 2 injections of efalizumab. ditional systemic therapies are associated the first time point at which PSA was Serious adverse events were infre- with cumulative toxic effects, poten- measured (PϽ.001) (FIGURE 3). There quent, occurring in 2% of efalizumab- tially increasing the risk of end-organ

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damage or malignancy.32,33 In this phase ing leisure and work), and their per- did not compare efalizumab directly 3 randomized, placebo-controlled trial, sonal relationships, and they reported with any of the currently used thera- efalizumab therapy resulted in signifi- fewer treatment-related problems com- pies for psoriasis. Additional random- cant improvement in the primary end pared with placebo. ized studies would be needed to com- point and other prespecified efficacy end Efalizumab exhibited a favorable pare this profile with other currently points. The efficacy, accompanied by the safety profile and was generally well tol- available therapies. safety profile and the HRQL outcomes, erated. The most commonly occur- Efalizumab was recently approved for provides evidence of potential benefit for ring adverse events during the initia- treatment of patients with chronic mod- efalizumab in patients with psoriasis. By tion of efalizumab treatment were mild erate to severe plaque psoriasis.38 The week 12, 27% of efalizumab-treated pa- to moderate flulike symptoms follow- benefit across physician-assessed end tients achieved a PASI-75 response com- ing the first 1 to 2 injections. Serious points and multiple patient-reported pared with 4% of placebo-treated pa- adverse events were infrequent and oc- measures of HRQL observed in this tients. These results are consistent with curred at only a slightly greater fre- study along with the favorable safety the physician-reported outcomes from quency in the efalizumab group (2%) profile suggest that efalizumab could another recently reported trial of efali- than in the placebo group (1%). There provide a viable treatment option for pa- zumab.34 Efalizumab-treated patients was no evidence to suggest clinically rel- tients with moderate to severe plaque demonstrated significant benefit on the evant increases in either infection or psoriasis. additional physician-assessed global pso- malignancy, including lymphoma, riasis scales, OLS and PGA, compared among efalizumab-treated patients; Author Contributions: Dr Gordon had full access to all the data in the study and takes responsibility for with placebo-treated patients. Consis- however, longer follow-up will be the integrity of the data and the accuracy of the data tent and significant improvements on needed to accurately characterize the analysis. Study concept and design: Gordon, Papp, Walicke, multiple dermatology- and psoriasis- risk of infection and malignancy. Dummer, Bresnahan. specific patient-reported end points were There were no clinically relevant Acquisition of data: Gordon, Papp, Hamilton, Dummer. observed throughout the study. laboratory abnormalities. Previous efali- Analysis and interpretation of data: Gordon, Papp, Walicke, Dummer, Li, Bresnahan, Menter. The magnitude of the percentage im- zumab studies in psoriasis patients have Drafting of the manuscript: Gordon, Dummer, Li, provement in HRQL was greater than shown that the discrete elevations in Bresnahan. Critical revision of the manuscript for important in- that for PASI in the early stage of treat- lymphocyte counts, white blood cell tellectual content: Gordon, Papp, Hamilton, Walicke, ment. Improvement in the individual counts, and other hematologic param- Dummer, Li, Bresnahan, Menter. Statistical expertise: Gordon, Li. PASI components occurred early; how- eters are transient, usually within nor- Obtained funding: Papp. ever, it is likely that the BSA compo- mal ranges, with values returning to Administrative, technical, or material support: Gordon, Papp, Hamilton, Walicke, Bresnahan. nent, which improves less rapidly, un- baseline following efalizumab discon- Study supervision: Gordon, Walicke, Dummer, Menter. 35-37 derestimates the improvement tinuation. There was no evidence of The Efalizumab Study Group: Jerry Bagel, MD, Ra- occurring in the lesions. This suggests general systemic toxicity reflected by diant Research, Lawrenceville, NJ; Karl R. Beutner, MD, Solano Clinical Research, Davis, Calif; Wayne Carey, that concentrating solely on PASI im- changes in hepatic or renal function. MD, Royal Victoria Hospital, Montreal, Quebec; Frank provement might underestimate the This investigation is limited by the E. Dunlap, MD, Radiant Research, Tucson, Ariz; Steven R. Feldman, MD, Wake Forest University, Winston- timing and overall response to efali- relatively short duration and by lack of Salem, NC; Gunnar Gibson, BGPDS Dermatology, Little zumab. an active comparator. Since psoriasis is Rock, Ark; Scott Glazer, MD, Buffalo Grove, Ill; Mitchell Goldman, MD, Dermatology Associates of San Diego, Efalizumab treatment reduced the a chronic disease, outcomes with Encinitas, Calif; J. John Goodman, MD, Radiant Re- frequency and severity of psoriasis longer-term use of efalizumab are im- search, West Palm Beach, Fla; Kenneth B. Gordon, MD, symptoms, particularly in the severity portant. The efficacy and safety of Loyola University, Maywood, Ill; Wayne P. Gulliver, MD, Newlab Clinical Research Inc, St John’s, New- of itching and scaling, the 2 most fre- longer-term efalizumab treatment has foundland; Tiffani K. Hamilton, MD, Atlanta Derma- quently reported subjective symp- been further evaluated in an exten- tology, Vein, and Research Center LLC, Alpharetta, 3 Ga; Dan C. Henderson, MD Rockwood Clinic, PS, Spo- toms. The severity and frequency of sion of this study that analyzes up to kane, Wash; Paul Krusinski, MD, Fletcher Allen Health other symptoms, including bleeding 24 weeks of continuous efalizumab Care, UHC, Burlington, Vt; Richard Langley, MD, QE II Health Science Centre, Halifax, Nova Scotia; Charles and burning or stinging, also were im- therapy. The preliminary analysis of Lynde, MD, Lynde Center for Dermatology, Markham, proved by efalizumab treatment. The data from this study suggests contin- Ontario; Robert Matheson, MD, Oregon Medical Re- search Center, Portland; Mark McCune, MD, Radi- significant improvement on the DLQI ued improvement in disease severity ant Research, Overland Park, Kan; Alan Menter, MD, indicated consistent improvements and maintenance of safety. Addition- Texas Dermatology Research Institute, Dallas; Kim across measures of social and mental as- ally, an ongoing open-label study evalu- Papp, MD, Probity Medical Research, Waterloo, On- tario; Jerold Powers, MD, Radiant Research, Scottsdale, sessment (Table 2), areas known to be ating the efficacy and safety of up to 3 Ariz; Elyse Rafal, MD, DermResearch Center of New adversely affected in patients with pso- years of continuous efalizumab therapy York Inc, Stony Brook; Michael Scannon, MD, St Jo- seph Comprehensive Research Institute, Tampa, Fla; riasis. Efalizumab-treated patients re- is currently being conducted. Efficacy Elaine Siegfried, MD, Central Dermatology, St Louis, ported greater improvement in their at- with continued use of efalizumab has Mo; James M. Swineheart, MD, Colorado Medical Re- search Center, Denver; Naji Tawfik, MD, PhD, Wel- titudes about their disease, their ability also been suggested in a recently re- born Clinic, Evansville, Ind; Darryl Toth, MD, Probity to participate in daily activities (includ- ported clinical trial.34 The current study Medical Research, Windsor, Ontario; Stephen Ty-

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ring, MD, University of Texas Medical Branch, Hous- 11. Wahl A, Loge JH, Wiklund I, Hanestad BR. The nium: position paper on behalf of the authors. JAm ton; Michael D. Zanolli, MD, Dermatology Consult- burden of psoriasis: a study concerning health- Acad Dermatol. 2003;49(2 suppl):S39-S43. ants, Nashville, Tenn. related quality of life among Norwegian adult pa- 25. Ashcroft DM, Wan Po AL, Williams HC, Griffiths Funding/Support: The data presented herein are de- tients with psoriasis compared with general popula- CE. Clinical measures of disease severity and out- rived from a clinical trial sponsored by Genentech Inc, tion norms. J Am Acad Dermatol. 2000;43(5 pt 1): come in psoriasis: a critical appraisal of their quality. which provided the study drug and placebo for this trial. 803-808. Br J Dermatol. 1999;141:185-191. Role of the Sponsor: Drs Walicke and Dummer, em- 12. Gupta MA, Gupta AK. Depression and suicidal ide- 26. Krueger GG, Feldman SR, Camisa C, et al. Two ployees of Genentech Inc, the sponsor of this clinical ation in dermatology patients with acne, alopecia ar- considerations for patients with psoriasis and their cli- trial, contributed to the design of this protocol and the eata, atopic dermatitis and psoriasis. Br J Dermatol. nicians: what defines mild, moderate, and severe pso- interpretation of the results. Additionally, the data- 1998;139:846-850. riasis? what constitutes a clinically significant improve- base derived from the findings of the individual in- 13. Gilhar A, David M, Ullmann Y, Berkutski T, Ka- ment when treating psoriasis? J Am Acad Dermatol. vestigators from 30 study sites was maintained by Ge- lish RS. T-lymphocyte dependence of psoriatic pa- 2000;43:281-285. nentech and statistical analyses were performed at thology in human psoriatic skin grafted to SCID mice. 27. Finlay AY, Khan GK. Dermatology Life Quality In- Genentech by Dr Li in conjunction with Dr Gordon, J Invest Dermatol. 1997;109:283-288. dex (DLQI)—a simple practical measure for routine the lead author of this article. Dr Gordon was respon- 14. Gottlieb SL, Gilleaudeau P, Johnson R, et al. Re- clinical use. Clin Exp Dermatol. 1994;19:210-216. sible for the development of the manuscript but all au- sponse of psoriasis to a lymphocyte-selective toxin 28. Shikiar R, Thompson C. Validity of Patient- thors, including those employed by Genentech, re- (DAB389IL-2) suggests a primary immune, but not ke- Reported Outcomes Used in Psoriasis: Results From viewed and edited the manuscript. ratinocyte, pathogenic basis. Nat Med. 1995;1:442- Two Randomized Clinical Trials. Bethesda, Md: MED- Acknowledgment: We acknowledge the contribu- 447. TAP International Inc; December 2002:1-95. tion of Kirsten M. Duncan, PharmD, to the develop- 15. Bos JD, De Rie MA. The pathogenesis of psoria- 29. 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rorism agents. Examining each of the 6 diseases individually, Acknowledgment: We thank Samuel Groseclose, DVM, MPH, of the US Centers for Disease Control and Prevention for his assistance with the contacts for the 4 the percentage of jurisdictions that mandate reporting ranged US territories that participate in the National Notifiable Disease Surveillance Sys- from a low of 44% (viral hemorrhagic fevers) to a high of 100% tem. We also thank James T. Rankin, DVM, PhD, of the Pennsylvania Depart- (anthrax, botulism). ment of Health for his comments on the survey instrument. Comment. To our knowledge, this is the first description of 1. Chorba TL, Berkman RL, Safford SK, Gibbs NP, Hull HF. Mandatory reporting of infectious diseases by clinicians. JAMA. 1989;262:3018-3026. the use of the Web by states and territories for reporting of in- 2. Konowitz PM, Petrossian GA, Rose DN. The underreporting of disease and phy- fectious diseases. Our results indicate that while most juris- sicians’ knowledge of reporting requirements. Public Health Rep. 1984;99:31-35. 3. American Medical Association. New AMA study shows physicians’ use of In- dictions maintain Web sites, many did not clearly describe what, ternet steadily rising. Available at: http://www.ama-assn.org/ama/pub/print when, how, and where health care providers should report dis- /article/1615-6477.html. Accessed July 19, 2002. eases. We also found considerable variation in Web-based in- 4. Centers for Disease Control and Prevention. Bioterrorism Agents/Diseases. Avail- able at: http://www.bt.cdc.gov/agent/agentlist-category.asp. Accessed Decem- formation on reporting requirements for diseases potentially ber 30, 2003. related to bioterrorism. Including explicit requirements to re- 5. Centers for Disease Control and Prevention. National Notifiable Disease Sur- veillance System. Available at: http://www.cdc.gov/epo/dphsi/nndsshis.htm. Ac- port all Category A diseases on a jurisdiction’s reportable dis- cessed December 29, 2003. ease list not only reduces uncertainty about what is report- 6. Horton HH, Misrahi JJ, Matthews GW, Kocher PL. Critical biological agents: 5,6 disease reporting as a tool for determining bioterrorism preparedness. J Law Med able, but also raises awareness of these threats. Ethics. 2002;30:262-266. Because most jurisdictions already maintain Web sites, up- dating them to provide complete, accessible disease reporting information should be relatively inexpensive. More effective use of the Web could strengthen the partnership among clini- CORRECTION cians and local public health officials that is vital for recogni- Incorrect Table: In the Original Contribution entitled “Efaluzimab for Patients With tion of and response to disease outbreaks and bioterrorism- Moderate to Severe Plaque Psoriasis: A Randomized Controlled Trial” published related events. in the December 17, 2003, issue of THE JOURNAL (2003;290:3073-3080), Table 2 contained erroneous numbers for mean (SD) and median (IQR) placebo group im- Nkuchia M. M’ikanatha, DrPH, MPH provement; additionally, erroneous PASI improvement percentage headings were [email protected] shown. The correct table is shown below. Division of Infectious Disease Epidemiology Table 3. DLQI Improvement Stratified by PASI Response at Week 12 Pennsylvania Department of Health PASI Improvement, % Harrisburg David P. Welliver, MS, MBA Ն75 50-74 Ͻ50 Penn State Milton S. Hershey Medical Center Placebo Hershey No. (%) of patients (n = 183)* 8 (4) 18 (10) 157 (86) Dale D. Rohn, MPH Mean (SD) improvement 6.5 (5.4) 8.2 (7.1) 0.6 (4.9) Maryland Department of Health and Mental Hygiene Median (IQR) improvement 5.5 (3 to 10.5) 6.5 (4 to 13) 1 (−2 to 3) Baltimore Efalizumab Kathleen G. Julian, MD No. (%) of patients (n = 363)* 97 (27) 117 (32) 149 (41) Penn State Milton S. Hershey Medical Center Mean (SD) improvement 8.8 (5.5) 6.8 (5.7) 2.5 (6.5) Ebbing Lautenbach, MD, MPH, MSCE Median (IQR) improvement 8 (5 to 12) 5 (2 to 11) 2 (−1 to 6) Center for Clinical Epidemiology and Biostatistics Abbreviations: DLQI, Dermatology Life Quality Index; IQR, interquartile range; PASI, Pso- University of Pennsylvania School of Medicine riasis Area and Severity Index. Philadelphia *Data are derived from the number of patients for whom values were available.

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