Utilization of narrow-band ultraviolet light B Therapy and Etanercept for the Treatment of Psoriasis : efficacy, safety, and patient-reported outcomesLeon Kircik
Psoriasis is a chronic, systemic, debilitating inflammatory disease involving the skin, and potentially the joints in patients with psoriatic arthritis. (1) It has an important impact on patient wellbeing, potentially resulting in embarrassment, self-consciousness, (2) and depression, (3) which may affect patients' social activities and work. (2,4,5)
An American Academy of Dermatology consensus statement recommends that patients with moderate to severe plaque psoriasis be treated with systemic therapy or phototherapy. (6) Traditionally, small molecule systemic therapies such as methotrexate and cyclosporine have been effective in treating moderate to severe plaque psoriasis, but these therapies may be associated with both short-term and long-term toxicities. Narrow-band (310-312 nm wavelength) ultraviolet light B (NB-UVB) phototherapy studies have shown significant clearing of skin lesions after a course of 20 treatments (3 times per week). (6-10) In another study, 62% of patients achieved at least 75% improvement from baseline in the Psoriasis Area and Severity Index (PASI 75) after 12 weeks of UVB therapy. (11) Other than the average remission time induced, NB-UVB phototherapy is nearly as effective as psoralen-ultraviolet light A (PUVA) phototherapy, but is more convenient and has fewer adverse events. (12,13)
Targeted biologic therapies may offer some patients with effective treatment for their psoriasis, with fewer adverse effects than traditional systemic agents. (14-20) The fully human, soluble tumor necrosis factor (TNF) receptor, etanercept, has demonstrated efficacy in relieving the skin signs and symptoms and in improving health-related quality of life in patients with moderate to severe plaque psoriasis. (18-23) After 3 and 6 months of treatment, respectively, approximately 50% and 60% of patients in these trials experienced at least 75% improvement from baseline (PASI 75). Additionally, a recent publication reported that etanercept treatment was associated with improvement in the exploratory endpoints for fatigue and symptoms of depression. (21) Extensive clinical trial experience with etanercept has also demonstrated a favorable safety profile in this population. (24)
In clinical practice, it is recognized that in some patients, particularly those with recalcitrant disease, combination therapy may be required for optimal response. Topical steroids and phototherapy, in particular, have traditionally been used effectively to enhance the efficacy of other systemic treatments. (25) The reported efficacy of NB-UVB phototherapy may warrant use as an adjunct for systemic agents such as etanercept. The objectives of this open-label study were to evaluate the effectiveness, tolerability, and patient-reported outcomes of etanercept in combination with NB-UVB phototherapy for the treatment of moderate to severe psoriasis over a 12-week period.
Patients were enrolled from 16 sites in the United States and Canada. The institutional review boards of participating medical centers approved the protocol. Patients provided written informed consent to participate in the trial before any study procedures were conducted. To be eligible for study inclusion, patients had to be at least 18 years of age with stable active plaque psoriasis (PASI [greater than or equal to]15 and 25% of the individual plaques had to be considered severe) involving [greater than or equal to]5% of body surface area (BSA). Patients were excluded if they had received prior phototherapy; current or prior treatment with any TNF soluble receptor (etanercept) or monoclonal antibody (infliximab or adalimumab); other systemic therapies within 4 weeks of study initiation; topical corticosteroids, vitamin A or D analogues, or dithranol within 2 weeks of study initiation; or current or previous treatment with cyclophosphamide. Patients with the following conditions were also excluded: erythrodermic, pustular, or guttate psoriasis; skin conditions (eg, eczema) other than psoriasis that would interfere with study-related evaluations; active infection; history of immunocompromised health (eg, positive for human immunodeficiency virus); history of any cutaneous malignancy at any time; history of any noncutaneous malignancy within 5 years; actinic keratoses or atypical nevi; history of alcohol or drug abuse within 12 months of screening visit; evidence of photosensitivity disorder; severe comorbidities; current enrollment in a clinical trial or receipt of an investigational drug within 30 days of etanercept administration; or pregnancy.
This multicenter, open-label, single-arm, prospective study (the Utilization of NB-UVB Light Therapy and Etanercept for the Treatment of Psoriasis [UNITE] study) evaluated the efficacy and safety of combination therapy with etanercept and NB-UVB phototherapy in patients with moderate to severe psoriasis. Patients could not receive PUVA phototherapy, broadband UVB therapy (including excimer laser), or use tanning booths or salons from the date of screening through the week 12 visit.
All patients received open-label treatment with subcutaneous etanercept 50 mg twice weekly and NB-UVB phototherapy using TL-01 lamps (310-312 nm) was administered thrice weekly (Mondays, Wednesdays, and Fridays) for 12 weeks. The starting NB-UVB dose was determined according to the patient's skin type using the Fitzpatrick skin typing system (26) and was increased each visit by 10% to 15% depending on the patient's response to previous NB-UVB treatment. Dose adjustments were made according to the following guidelines: increase the dose if the patient had no erythema; maintain the dose if the patient had asymptomatic erythema; return to the previous dose (reduce dose) if the patient had symptomatic erythema that had subsided; and withhold phototherapy and reduce the next NB-UVB treatment dose by 25% if the patient had erythema and tenderness that was present after 24 hours. Dose escalation of etanercept was not permitted.
Patients who experienced a clear or almost clear status according to the Physician Global Assessment (PGA; scale: 0 = clear, 5 = severe) of psoriasis had their NB-UVB phototherapy dose held at the current level, and dose escalation was resumed upon relapse to clear or almost clear status (score of 0 or 1). Patients who experienced burning that caused blisters or vesicles were withdrawn from the study. If a session was missed, every effort was made to resume the original schedule, and increases in NB-UVB dose were made according to the duration of the interruption and the patient's skin type.
The primary outcome measure was the proportion of patients achieving PASI 75 at week 12. (27) The time to PASI 75 response was also recorded as a secondary outcome measure. Another secondary outcome measure was the proportion of patients experiencing at least a 90% improvement from baseline in PASI score (PASI 90). A post-hoc analysis was conducted to determine the proportion experiencing a 100% improvement from baseline in PASI score (PASI 100) at 12 weeks. The PGA, BSA, Dermatology Life Quality Index (DLQI), and the Patient Global Assessment (PtGA) of psoriasis were assessed at baseline and at weeks 4, 8, and 12. The DLQI is a 10-item questionnaire that evaluates the domains of daily activities, symptoms and feelings, leisure, work/school, personal relationships, and treatment (scores from 0 to 30, with higher scores representing greater disease impact). The PtGA of psoriasis is a self-administered, static, numeric scale ranging from 0 to 5 designed to evaluate a patient's perception of his/her psoriasis, with 5 representing the most severe disease.
A number of exploratory outcome measures were assessed at baseline and 12 weeks. These included the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), the Beck Depression Inventory (BDI), patient satisfaction survey, the European Quality-of-Life Group Feeling Thermometer (EuroQoL-FT), and the patient pruritus assessment. The FACIT-F is a self-administered, 13-item questionnaire that assesses fatigue in the previous 7 days, with scores ranging from 0 to 52 (lower scores indicate greater fatigue). (28) The BDI is a 21-item questionnaire that assesses a patient's symptoms of depression, with total scores ranging from 0 to 63 (higher scores indicating greater degrees of depression). (29) The BDI was categorized as follows: minimal (0-9), mild (10-16), moderate (17-29), and severe (30-63) symptoms of depression. The patient satisfaction survey is a self-administered questionnaire that assesses a patient's total symptom relief (7 questions) and overall satisfaction with treatment (1 question). The EuroQoL-FT is a visual analog scale that assesses the patient's health status, with scores ranging from 0 (worst imaginable health state) to 100 (best imaginable health state). (30) The patient pruritus assessment is a self-administered numeric scale that assesses a patient's perception of his or her overall state of pruritus.
Safety endpoints included adverse events, serious adverse events, and events of medical interest. The Medical Dictionary for Regulatory Activities' preferred term "radiation skin injury" is referred to as "UVB-induced skin injury" in this article.
Patient demographics and disease characteristics were summarized using descriptive statistics. This was a single-armed study. Therefore, no hypothesis testing was performed. Efficacy and safety analyses were conducted on all patients receiving at least 1 dose of both etanercept and phototherapy as the full analysis subset. For the primary endpoint, assuming the PASI 75 response at week 12 is 0.80 with a 95% confidence interval (CI) of 0.70 to 0.90 with 80 patients, there is an 81% chance that the observed PASI 75 rate is at least 75%.
The proportions of PASI 75, PASI 90, and PASI 100 responders were summarized by visit, and 95% CIs were calculated. Summary descriptions of absolute and percentage changes from baseline in patient-reported outcomes with 95% CIs were also performed. With the exception of the FACIT-F, the percentage improvement from baseline in patient-reported outcomes for each patient was calculated by the following formula: [(Baseline score-week 12 score)/(baseline score)] X100. For FACIT-F, the following formula was used: [(Week 12 score-baseline score)/(baseline score)] X 100. The mean percentage improvement was the average of the percent improvements for all patients.
Eighty-six patients who received at least 1 dose of etanercept and 1 dose of NB-UVB phototherapy comprised the full analysis set. Three patients who had no postbaseline assessment were counted as nonresponders for PASI response and were counted as missing for other assessments. The last observation carried forward (LOCF) method was used to impute missing data for all measures except the exploratory endpoints, which were evaluated as observed because these measures were only collected at baseline and at 12 weeks. All analyses using the LOCF method were also analyzed as observed. The effects of baseline demographics and disease characteristics, including baseline PASI score, were evaluated using regression analyses. Time to PASI 75 response was analyzed using the Kaplan-Meier method.
A total of 86 patients enrolled in the trial (Table 1). Approximately two thirds of the patients were men; the mean age was 40.6 years; and about three quarters were white. The mean duration of psoriasis was 14.7 years, and the mean percentage of BSA affected by psoriasis was 28.0%. Most patients had moderate to severe cases at the time of enrollment, as assessed by the PGA (32.6% moderate, 57.0% marked, and 8.1% severe). Mean PtGA and DLQI scores at baseline were 4.2 and 15.5, respectively.
Of the 86 patients who enrolled, 83 (96.5%) completed the study. Of the 3 patients who discontinued, 1 patient was determined to be ineligible (PASI score of 4.1 at baseline and <25% of the patient's individual plaques were classified as severe), 1 patient was lost to follow-up, and 1 patient discontinued because of an adverse event (photosensitivity reaction). These 3 patients did not have any postbaseline evaluations and were counted as nonresponders for PASI response and as missing for other assessments. For phototherapy compliance, 63 (73.3%) completed [greater than or equal to]30 phototherapy sessions, 19 (22.1%) completed 20 to 29 sessions, and the remaining 4 patients (4.7%) completed <20 sessions.
At 12 weeks, 26.0% of patients achieved PASI 100, 58.1% achieved PASI 90, and 84.9% achieved PASI 75 (Figure 1), with most patients (69.8%) achieving PASI 75 at week 8. The median time to documentation of PASI 75 response was 57 days. Twenty-five percent of the patients achieved PASI 75 by 52 days and 75% achieved PASI 75 by 84 days of treatment. Mean PASI scores improved from baseline by 56.2% at week 4, 80.2% at week 8, and 88.5% at week 12.
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Mean BSA affected by psoriasis improved by 83.6% from baseline over the 12 weeks, from 28.1% to 4.2%. Similar mean percentage improvement from baseline was seen in the PGA (72.7%), from a mean score of 3.7 at baseline to 1.0 at week 12. Almost three quarters of patients (74.4%) had a clear or almost clear status in the PGA (score of 0 or 1) at week 12. Figure 2 illustrates a typical response to etanercept/NB-UVB therapy at 12 weeks.
Mean DLQI scores improved from 15.5 at baseline to 5.6 at week 4 (58.1% mean percentage improvement), to 2.8 at week 8 (76.8% mean percentage improvement), and to 2.0 at week 12 (84.4% mean percentage improvement) (Figure 3 top). Mean percentage improvements from baseline in the DLQI subscale scores were consistent with improvements in the DLQI total score: 55.8% for personal relationships, 52.8% for treatment, 78.5% for symptoms and feelings, 86.9% for daily activities, 78.8% for leisure, and 49.8% for work and school.
The mean PtGA of psoriasis score at baseline was 4.2. Improvement from baseline in PtGA of psoriasis score was observed at the first visit at week 4 (mean score 2.5), and continued to improve at weeks 8 and 12 (mean scores 1.4 and 0.9, respectively), resulting in a 78.4% mean percentage improvement at the end of the study (Figure 3 middle). Other patient-reported outcomes improved after combination treatment with etanercept and NB-UVB phototherapy. The FACIT-F improved from a mean baseline score of 36.9 to 44.5 at week 12 (34.4% mean percentage improvement), BDI improved from a mean score of 10.1 to 4.5 at week 12 (54.2% mean percentage improvement), and patient satisfaction survey total symptoms scores improved from 2.1 at baseline to 2.5 at week 12 (70.1% mean percentage improvement). At baseline, 10.9% of patients indicated that they were satisfied with their psoriasis therapy in general, compared with 82.9% at week 12. Additionally, mean EuroQoL-FT score improved from 74.2 at baseline to 85.9 at week 12 (25.9% mean percentage improvement), and mean pruritus assessment scores improved from 3.9 at baseline to 0.9 at week 12 (74.2% mean percentage improvement) (Figure 3 bottom).
A summary of adverse events is presented in Table 2. The most commonly reported adverse events were UVB-induced skin injury and injection site reactions. Two serious adverse events were reported. The first was a case of angina pectoris reported in a patient with known coronary artery disease during the treatment phase, but this was not considered by the investigator to be related to study treatment. The second was a case of cellulitis, which occurred after the 12-week study period and was considered by the investigator to be possibly related to study treatment. One patient withdrew from the study because of a photosensitivity reaction.
One patient tested positive for both hepatitis B and hepatitis C after the 12-week study period. However, these events were incidental findings that were discovered after the study had ended, and were not considered by the investigator to be related to treatment with etanercept, phototherapy, or the etanercept/NB-UVB interaction. The patient was asymptomatic throughout the 12-week study period.
Psoriasis is associated with a significant burden of illness that has a major impact on patient well-being. In this study, the combination of etanercept plus NB-UVB phototherapy was generally well tolerated and produced clinically meaningful improvements in psoriasis symptoms, as shown by improvements in PASI scores, as well as improvements in patient-reported outcomes, in patients with moderate to severe plaque psoriasis.
The percentage of PASI 75 responders after 12 weeks of combination therapy was 84.9%, with most of the patients achieving a PASI 75 response within 8 weeks (69.8% achieved a PASI 75 response by week 8). While separate treatment arms with monotherapy of NB-UVB and etanercept were not included in this study, certain assumptions may be made. The 12-week PASI 75 response rate for etanercept 50 mg twice weekly in 2 previous phase III studies in psoriasis was approximately 50%, and the PASI 90 response rate was approximately 20%. (19,21) The PASI 75 response rate at 12 weeks for UVB phototherapy thrice weekly has been reported to be approximately 62%. (11) Assuming that the effects of the 2 therapies are additive and independent, we expected that the PASI 75 rate for the combination of etanercept and NB-UVB phototherapy would be 81%. The rate of 84.9% obtained in this study is consistent with an additive and independent effect.
Notably, more than 25% of patients achieved PASI 100 after 12 weeks of etanercept and NB-UVB treatment, indicating a complete resolution of the skin signs of psoriasis. Moreover, population PASI responses did not plateau at 12 weeks, suggesting that the response rate may have continued to rise with a longer study duration.
The entry criteria for this study (PASI [greater than or equal to]15 and BSA [greater than or equal to]5%) were slightly different than those of previous phase III trials of etanercept in moderate to severe plaque psoriasis (PASI [greater than or equal to]10 and BSA [greater than or equal to]10%). Therefore, patients in this study tended to exhibit greater disease severity at baseline than those in previous studies, as measured by the PASI and the proportion of patients with marked or severe status in the PGA. More than 90% of patients had severe disease (>10% of BSA affected) as defined by the National Psoriasis Foundation and almost all consensus statements. (31-34) However, only 8.1% of patients were classified with severe psoriasis at baseline by PGA, indicating a significant disparity between physician evaluation and current guidelines, and suggesting that patients with severe disease in general are possibly underdiagnosed and undertreated.
The patient-reported outcomes in this study were consistent with those from randomized, placebo-controlled clinical trials of etanercept 50 mg twice-weekly monotherapy. (19,21,22) Other studies have shown improvements from baseline in DLQI of approximately 45% to 50% at week 4 (19,22) and 60% to 70% at week 12. (19,21,22) Mean percentage improvements from baseline in DLQI at weeks 4 and 12 in the present study were higher (58.1% and 84.4%, respectively) than those observed in the studies of etanercept monotherapy, possibly reflecting the additional benefit attained with the combination phototherapy.
In addition to improvement in the patient's health-related quality of life, as measured by the DLQI, exploratory endpoints for fatigue (FACIT-F) and symptoms of depression (BDI) also showed improvement from baseline at week 12, consistent with results from a 12-week, randomized, placebo-controlled clinical trial of etanercept in patients with moderate to severe plaque psoriasis. (21) Most patients in the present study did not have significant symptoms of depression at baseline, although baseline BDI values were higher in the current study population than in the controlled clinical study population. The absolute improvement in FACIT-F and BDI scores at week 12 (5.6 points and 7.6 points, respectively) was also higher in this study than those previously reported for etanercept monotherapy (3.9 points and 5.0 points, respectively). These results extend our knowledge of the effects of etanercept and NB-UVB treatment on the psychological aspects associated with psoriasis.
The safety profile of the combination therapy of etanercept and NB-UVB phototherapy, as assessed by the low incidence of serious adverse events, shows that the combination therapy was generally well tolerated in this population. Typical of other trials, UVB-induced skin injury was the most commonly reported adverse event related to phototherapy, and injection site reactions were the most commonly reported event related to etanercept treatment.
Important study limitations include the open-label study design, the lack of a comparative arm, and the relatively short study duration. However, the PASI and patient-reported outcome data from this study add to our knowledge of previous findings from randomized controlled trials of etanercept in psoriasis.
Etanercept monotherapy has demonstrated benefits in terms of symptom control and patient-reported outcomes in a number of clinical trials. (18-21) The results from this study expand those data and demonstrate that the efficacy of etanercept may be extended by the addition of NB-UVB phototherapy. This benefit may potentially offset the impact of office visits for phototherapy as reflected by the strong DLQI results. The safety profile was consistent with those known for the individual therapies alone. Longer-term studies are needed to determine the optimal etanercept/NB-UVB schedule to maximize the percentage of patients who ultimately achieve a PASI 100 response if continued on this combination treatment regimen. In addition, it would be interesting to see if PASI responses can be sustained after tapering and discontinuation of NB-UVB phototherapy.
In conclusion, this study demonstrated that the combination of etanercept and NB-UVB for 12 weeks resulted in improvements in psoriasis disease parameters with a safety profile that was consistent with those known for the individual therapies alone. These results suggest that NB-UVB phototherapy may be appropriately used as an adjunct treatment with etanercept therapy to treat moderate to severe plaque psoriasis in adults, and therefore, further investigation of the safety and efficacy of the use of such combination for this indication in controlled clinical trials would be of interest.
UNITE Study Investigators
Bernard Goffe MD, Seattle, WA; Jerry Bagel MD, East Windsor, NJ; Jeffrey Crowley MD, Bakersfield, CA; David Fivenson MD, Ann Arbor, MI; Mark Jackson MD, Louisville, KY; Leon Kircik MD, Louisville, KY; Neil Korman MD, Cleveland, OH; Craig Elmets MD, Birmingham, AL; Francisco Kerdel MD, Miami, FL; Alexa Kimball MD, Boston, MA; Julie Letsinger MD, San Francisco, CA; Michael Zanoli MD, Nashville, TN; Joshua Zeichner MD, New York, NY; Alan Menter MD, Dallas, TX; Angela Moore MD, Arlington, TX; Henry Wong MD, Detroit, MI.
This research was funded by Immunex Corporation, a wholly owned subsidiary of Amgen and Wyeth Pharmaceuticals.
Dr. Kircik has been a consultant, speaker, investigator, and advisory board member for Amgen.
Dr. Bagel has been a speaker, investigator, and an advisory board member for Amgen.
Dr. Korman has been an investigator and speaker for Amgen.
Dr. Menter has participated on speakers' bureaus, has consulting/advisory board arrangements, and has been an investigator for Amgen and Wyeth Pharmaceuticaticals.
Dr. Elmets has been an investigator, speaker, advisory board member, and consultant for Amgen.
Dr. Koo has been an investigator, speaker, and advisory board member for Amgen.
Dr. Dann is a former employee of, current speaker for, and stockholder of Amgen.
Drs. Yang, Chiou, and Stevens are present or previous employees of Amgen, and have received stocks/stock options from Amgen.
The authors would like to thank Rick Davis MS RPh, on behalf of Amgen, and Ting Chang PhD, of Amgen, for writing assistance.
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ADDRESS FOR CORRESPONDENCE
Leon Kircik MD
1169 Eastern Parkway, Suite 2310
Louisville, KY 40217
Leon Kircik MD, (a) Jerry Bagel MD, (b) Neil Korman MD PhD, (c) Alan Menter MD, (d) Craig A. Elmets MD, (e) John Koo MD, (f) Yu-Ching Yang PhD, (g) Chiun-Fang Chiou PhD, (g) Frank Dann MD, (g) Seth R. Stevens MD; (g) on behalf of the UNITE Study Group
a. Department of Dermatology, Indiana University School of Medicine, Indianapolis, IN
b. Psoriasis Treatment Center of Central New Jersey, East Windsor, NJ
c. Department of Dermatology, University Hospitals Case Medical Center, Cleveland, OH
d. Division of Dermatology, Department of Internal Medicine, Baylor University Medical Center, Dallas, TX
e. Department of Dermatology, University of Alabama, Birmingham, AL
f. Department of Dermatology, University of California, San Francisco Medical Center, San Francisco, CA
g. Amgen Inc, Thousand Oaks, CA
Table 1. Baseline demographics and disease characteristics. Characteristic Patients Number of patients 86 Mean (SD) age, years 40.6 (12.6) Men: n (%) 56 (65.1) White: n (%) 63 (73.3) Fitzpatrick skin type: n (%) 1 (burn and no tan, pale white) 9 (10.5) 2 (burn and minimal tan, pale white) 37 (43.0) 3 (burn then tan well, white) 22 (25.6) 4 (tan, no burn, light brown) 9 (10.5) 5 (tan, no burn, brown) 8 (9.3) 6 (tan, no burn, dark brown) 1 (1.2) Mean (SD) duration of psoriasis, years 14.7 (10.8) Mean (SD) affected BSA (%) 28.0 (18.0) Mean (SD) PASI score 22.9 (9.5) Mean (SD) severe psoriatic plaques (%) 57.0 (25.1) Physician Global Assessment of psoriasis: n (%) Clear 0 (0) Almost clear 1 (1.2) Mild 1 (1.2) Moderate 28 (32.6) Marked 49 (57.0) Severe 7 (8.1) Mean (SD) PGA of psoriasis score 3.7 (0.7) Mean (SD) PtGA of psoriasis score 4.2 (0.9) Mean (SD) DLQI total score 15.5 (7.4) Prior psoriasis therapies: n (%) Systemic therapies: Methotrexate 13 (15.1) Steroids 13 (15.1) Oral retinoids 12 (14.0) Alefacept 4 (4.7) Cyclosporine 4 (4.7) Tacrolimus 1 (1.2) Other 9 (10.5) Topical therapies: Steroids 61 (70.9) Vitamin D analogues 42 (48.8) Tar compounds 22 (25.6) Vitamin A analogues 8 (9.3) Other 20 (23.3) Photosensitizing therapies: Nonsteroidal anti-inflammatory drugs 10 (11.6) Retinoids 6 (7.0) Tetracyclines 1 (1.2) BSA = body surface area; DLQI = Dermatology Life Quality Index; PASI = Psoriasis Area and Severity Index; SD = standard deviation; n = number of patients. Table 2. Summary of adverse events.* Event Patients, n (%) Number of patients 86 Patients with at least 1 adverse event 71 (82.6) Most common adverse events ([dagger]) UVB-induced skin injury 54 (62.8) Injection site reactions 14 (16.3) Nasopharyngitis 5 (5.8) Headache 5 (5.8) Upper respiratory tract infection 3 (3.5) Pruritus 3 (3.5) Nasal congestion 3 (3.5) Pharyngolaryngeal pain 3 (3.5) Nausea 3 (3.5) Muscle strain 3 (3.5) Serious adverse events 2 (2.3) Angina pectoris 1 (1.2) Cellulitis 1 (1.2) Events of medical interest 1 (1.2) Hepatitis B positive ([double dagger]) 1 (1.2) Hepatitis C positive ([double dagger]) 1 (1.2) *Including adverse events that start on or after the date of first dose of study drug and within 30 days of the last dose. ([dagger]) Events reported in >3% of patients. ([double dagger]) Hepatitis B and hepatitis C events occurred in the same patient (see discussion in text).
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