The Adalimumab M04-688 study investigators: Hajime Iizuka (Asahikawa Medical College); Daisuke Sawamura, Riichiro Abe (Hokkaido University School of Medicine); Toshihide Akasaka (Iwate Medical University School of Medicine); Ryuhei Okuyama (Tohoku University School of Medicine); Fumio Kaneko, Koichiro Nakamura (Fukushima Medical University School of Medicine); Kenji Takamori (Juntendo University Urayasu Hospital); Tadashi Terui (Nihon University School of Medicine); Atsuyuki Igarashi (Kanto Medical Center NTT EC); Makoto Kawashima (Tokyo Women’s Medical University); Ryoji Tsuboi (Tokyo Medical University); Mayumi Komine (The University of Tokyo Faculty of Medicine); Tsuyoshi Mitsuishi (Nippon Medical School); Kazuhito Hayakawa (Kyorin University Faculty of Medicine); Hirohiko Sueki, Amane Kitami (Showa University School of Medicine); Makoto Adachi (Kanto Rosai Hospital); Akira Ozawa (Tokai University School of Medicine); Hideki Mukai (Yokohama Rosai Hospital); Kazuhiko Takehara (Kanazawa University College of Medical, Pharmaceutical and Health Sciences); Hajime Takagi, Yoshiro Ichiki (Gifu University School of Medicine); Kayoko Iwasaki (Shizuoka Kousei Hospital); Masahiro Takigawa (Hamamatsu University School of Medicine); Akimichi Morita (Nagoya City University Medical School); Koji Habe (Mie University Faculty of Medicine); Saburo Kishimoto (Kyoto Prefectural University of Medicine); Kenzo Takahaski (Kyoto University Faculty of Medicine); Shigetoshi Sano, Mamori Tani, Shoji Taniguchi, Yukiko Shoda (Sumitomo Hospital); Mari Higashiyama (Nissay Hospital); Masahito Tarutani (Osaka University Faculty of Medicine); Kiyofumi Yamanishi (Hyogo College of Medicine); Takashi Ohno (Okayama University Faculty of Medicine); Yoshikazu Kameyoshi (Hiroshima University Faculty of Medicine); Masahiko Muto (Yamaguchi University School of Medicine); Hajimu Oura (The University of Tokushima Faculty of Medicine); Hajime Kodama (Kochi University Medical School); Shinichiro Yasumoto (Kurume University School of Medicine); Juichiro Nakayama (Fukuoka University Faculty of Medicine); Hisashi Kokuba, Masakazu Takahara (Kyushu University School of Medicine); Shinichi Sato (Nagasaki University School of Medicine); Yuko Higashi, Noriko Yoshii (Kagoshima University Faculty of Medicine). The committee for evaluation of efficacy and safety: Nobuyuki Miyasaka and Yasuyuki Yoshizawa (Tokyo Medical and Dental University). Central respiratory evaluation members for chest X-ray: Yakuyuki Yoshizawa, Shuji Miyake, Yutaka Usui, Naohiko Inase, Nobuyuki Koyama, Susumu Isogai, Yasunari Miyazaki, Yoshio Otani, and Masashi Furuie (Tokyo Medical and Dental University).
Adalimumab in Japanese patients with moderate to severe chronic plaque psoriasis: Efficacy and safety results from a Phase II/III randomized controlled study
Article first published online: 26 FEB 2010
© 2010 Japanese Dermatological Association
The Journal of Dermatology
Volume 37, Issue 4, pages 299–310, April 2010
How to Cite
ASAHINA, A., NAKAGAWA, H., ETOH, T., OHTSUKI, M. and THE ADALIMUMAB M04-688 STUDY GROUP (2010), Adalimumab in Japanese patients with moderate to severe chronic plaque psoriasis: Efficacy and safety results from a Phase II/III randomized controlled study. The Journal of Dermatology, 37: 299–310. doi: 10.1111/j.1346-8138.2009.00748.x
- Issue published online: 25 MAR 2010
- Article first published online: 26 FEB 2010
- Received 14 July 2009; accepted 6 September 2009.
- Japanese plaque psoriasis;
- tumor necrosis factor antagonist
Incidence of psoriasis vulgaris in Asians is estimated at 0.05–0.3%. Studies in North America and Europe demonstrated that adalimumab, a fully human, recombinant, immunoglobulin G1 monoclonal antibody, was efficacious and well-tolerated in patients with chronic plaque psoriasis. This 24-week, placebo-controlled study evaluated the efficacy and safety of three different dosing regimens of adalimumab in Japanese patients with moderate to severe chronic plaque psoriasis (n = 169). Patients were randomized to receive adalimumab 40 mg every other week (eow), adalimumab 80-mg loading dose at week 0 followed by adalimumab 40 mg eow starting at week 2, adalimumab 80 mg eow, or placebo eow given as s.c. injections. The primary efficacy endpoint was the percentage of patients achieving a 75% or greater improvement in Psoriasis Area and Severity Index (PASI 75) score at week 16. At week 16, PASI 75 response rates were significantly greater for all three adalimumab groups (40 mg eow: 57.9%, P < 0.001; 40 mg eow plus loading dose: 62.8%, P < 0.001; 80 mg eow: 81.0%, P < 0.001) versus placebo (4.3%). As early as week 4, the 40-mg eow plus loading dose and 80-mg eow groups achieved significantly greater PASI 75 response rates compared with placebo. Injection-site reactions and hepatic events occurred in greater percentages of adalimumab-treated patients compared with placebo. Adalimumab therapy demonstrated efficacy and safety at all three dosage regimens. Rapid response rate in patients receiving 40 mg eow plus loading dose supports using an 80-mg loading dose in the treatment of psoriasis.
Psoriasis is a chronic, inflammatory, immune-mediated skin disease.1,2 Although its symptoms may range in severity, the disease can be painful and disabling, and have a significant impact on quality of life (QOL).1,2 There are several types of psoriasis, with 80–90% of cases classified as chronic plaque psoriasis.2 Studies of Asian populations have estimated the incidence of psoriasis to be 0.05–0.3%.3,4 According to a survey of patients with psoriasis in Japan, men were affected twice as frequently as women (65.8% and 34.2%, respectively). Eighty-six percent of cases were plaque psoriasis, and one-half of cases were considered moderate (40.6%) or severe (10.3%).5
Long-term use of common systemic therapies for the treatment of psoriasis, methotrexate (not approved in Japan for psoriasis treatment), cyclosporine, and retinoids are limited by potential adverse effects (AE), and cumulative toxicities.2,6,7 Recent findings implicate T lymphocytes and tumor necrosis factor (TNF) in the pathogenesis of plaque psoriasis.1,8 Based on this research, adalimumab was investigated for the treatment of moderate to severe chronic plaque psoriasis. Adalimumab is a fully human recombinant immunoglobulin G1 monoclonal antibody that binds specifically to TNF and blocks its interaction with the p55 (TNFR1) and p75 (TNFR2) cell surface TNF receptors.9,10 Recent published studies show adalimumab to be efficacious and well-tolerated in chronic plaque psoriasis.11–13 Adalimumab is approved for the treatment of rheumatoid arthritis, ankylosing spondylitis, Crohn’s disease, psoriatic arthritis, plaque psoriasis, and juvenile idiopathic arthritis in the USA, Europe, and many other countries throughout the world.10 Most recently, adalimumab has been studied for the treatment of rheumatoid arthritis in Japanese patients.14
The objective of this multicenter, prospective, Phase II/III, placebo-controlled study was to evaluate the efficacy and safety of three different dosing regimens of adalimumab for moderate to severe chronic plaque psoriasis over a 24-week period. In addition, this study investigated the benefit of a single loading dose of 80 mg for patients randomized to a 40-mg every-other-week (eow) dosage regimen.
Men and women aged 20 years or older were recruited from 42 sites in Japan. Eligible patients had a clinical diagnosis of moderate to severe chronic plaque psoriasis for at least 6 months, during which time plaque psoriasis was stable for at least the recent two months. Moderate to severe chronic plaque psoriasis was 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.
Patients were excluded if they had been previously exposed to anti-TNF therapy, had other active skin diseases or skin infections, or had a diagnosis of systemic lupus erythematosus, scleroderma or rheumatoid arthritis. Those with a history of central nervous system demyelinating disease, cancer, lymphoma, leukemia, tuberculosis, or lymphoproliferative disease also were excluded. Patients with a 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 also were excluded.
Weak- or medium-potency topical corticosteroids were allowed to be applied to the palms, soles, face, scalp, and groin only. Before the baseline visit, the washout periods for prior psoriasis therapies were at least 14 days for topical psoriasis therapies (“strong”, “very strong”, and “strongest” corticosteroids and vitamin D analogs), 14 days for phototherapy (ultraviolet A, including ultraviolet A with topical treatment of psoralen [topical PUVA] or ultraviolet B), and 28 days for systemic therapies (cyclosporine, retinoids, methotrexate, tacrolimus, azathioprine, hydroxyurea, sulfasalazine, glucocorticoids) and oral PUVA. Before enrollment, all patients were evaluated for latent tuberculosis (TB) using a purified protein derivative test and a chest X-ray. Those patients with evidence of latent TB (purified protein derivative ≥5 mm of induration) could be enrolled if prophylactic treatment (isoniazid 300 mg/day for 9 months) was initiated 21 days before initiation of study drug.
Before entering the study, women of childbearing potential were required to have had a negative urine pregnancy test and to be using an approved method of birth control. All patients provided written informed consent. This study was conducted in compliance with the ethical principles of the Declaration of Helsinki (2000), the Pharmaceutical Affairs Law, the Guideline for Good Clinical Practice, and the study protocol.
This was a Phase II/III, multicenter, double-blind, placebo-controlled trial evaluating the efficacy and safety of adalimumab versus placebo and the benefit of a single loading dose of 80 mg of adalimumab in the treatment of adult Japanese patients with moderate to severe chronic plaque psoriasis. It was performed from September 2005 to December 2006.
Patients were randomized 1:1:1:1 to one of four treatment regimens: (i) adalimumab 40 mg eow; (ii) adalimumab 40 mg eow starting at week 2 with a loading dose of adalimumab 80 mg at week 0; (iii) adalimumab 80 mg eow; or (iv) placebo eow. Adalimumab 40 mg/0.8 mL and placebo 0.8 mL were supplied in two-vial cartons (adalimumab + adalimumab, adalimumab + placebo, or placebo + placebo). The study drug was given as two s.c. injections starting at week 0 for 24 weeks by a physician or supervised nurse at two sites—either in the abdomen (preferred), upper arms, or thighs.
The study included a screening period of up to 6 weeks and a blinded 24-week treatment period. On or after week 16 of the treatment period, all patients defined as non-responders (i.e., less than a 50% improvement from baseline in PASI [PASI 50]) had the option of rescue treatment with three classes of topical steroids (“strong”, “medium”, or “weak”) or a vitamin D3 formulation without any restrictions for the application site on the body. After study completion, patients were eligible to rollover in to a 28-week extension study during which all patients received adalimumab.
The primary efficacy endpoint was the percentage of patients achieving a 75% or greater improvement in PASI score (PASI 75) at week 16 compared with baseline. Percentages of patients achieving PASI 50, PASI 75, PASI 90, and Physician’s Global Assessment (PGA) of “clear” or “minimal” also were evaluated. Changes in health-related QOL were assessed by the Dermatology Life Quality Index (DLQI) and Short Form 36 (SF-36) Health Survey. This study also evaluated the benefit of a single loading dose of 80 mg in the 40-mg eow plus loading dose group.
Safety assessments were conducted throughout the study. Adverse events (AE) were assessed at each eow visit from weeks 0–24. Laboratory evaluations and vital signs were conducted at baseline (week 0) and at weeks 2, 4, 8, 12, 16, 20, and 24. Abnormal laboratory values were considered AE if they resulted in study discontinuation, they necessitated therapeutic medical intervention, or the investigator considered them to be AE. AE data were collected during the treatment period until week 24 or until 70 days after the last dose of study drug for patients who terminated early or did not enroll in the open-label evaluation.
Serum adalimumab concentrations and serum anti-adalimumab antibody (AAA) concentrations were evaluated at weeks 0, 16, and 24 or, for patients who discontinued the study, at early termination, and follow-up visits. In addition, serum adalimumab concentrations also were sampled at weeks 2, 4, 8, 12, and 20. Serum adalimumab concentrations and serum AAA concentrations were determined using a validated enzyme-linked immunosorbent assay method.
Sample size calculations were based on PASI 75 responses (the primary efficacy variable) from previous studies performed outside of Japan and assumed to be: 50% for 40 mg eow, 55% for 40 mg eow plus loading dose, 67% for 80 mg eow, and 18% for placebo, respectively. A sample size of 40 patients per regimen was estimated to provide approximately 81% power to detect a difference between adalimumab 40 mg eow and placebo, 90% power to detect a difference between adalimumab 40 mg eow with loading dose and placebo, 93% power to detect a difference between at least one of the 40-mg eow groups and placebo, and 99% power to detect a difference between at least one of the adalimumab regimens and placebo. To investigate the benefit of a single loading dose of 80 mg of adalimumab, we compared the times to reach PASI 75, PASI 50, and PASI 90 on or before week 16 and week 24 between the 40-mg-eow and 40-mg-eow with loading dose regimens.
Patient demographics and baseline characteristics were analyzed to assess the comparability of the four treatment groups. These analyses were conducted using one-way anova for continuous variables and the Fisher exact test for discrete variables. Primary and secondary efficacy analyses were conducted for the full analysis set population, defined as all patients who were randomized, received at least one dose of double-blind study drug, and had at least one assessment of efficacy under double-blind treatment. All statistical tests were to be two-tailed with the significance level set at P = 0.05. The effect of study centers was not included in any analyses because patient sample sizes per treatment arm within each center were insufficient to provide a meaningful analysis. Primary efficacy analysis was the comparison of each adalimumab treatment group vs placebo for the percentage of responders at week 16 using the Fisher exact test. Patients without evaluation results at week 16 were considered non-responders for the primary analysis. A supportive analysis was performed using the last-observation-carried-forward approach to impute missing values. Secondary efficacy analyses using the Fisher exact test, one-way anova and log–rank test were used to assess potential treatment differences for each adalimumab treatment group versus the placebo group.
All patients who received at least one injection of double-blind study drug were included in the safety analysis. The Fisher exact test was used to compare the percentages of patients experiencing an AE in each adalimumab treatment group versus the placebo group. Analyses were performed using SAS ver. 8.2.
A total of 235 patients consented and 169 patients were randomized to the four treatment groups (adalimumab 40 mg eow, n = 38; adalimumab 40 mg eow plus the 80-mg loading dose, n = 43; adalimumab 80 mg eow, n = 42; placebo, n = 46). These patients received at least one dose of study treatment and were included in the efficacy and safety analyses. Most patients (87.0%, n = 147) completed the study and entered the extension phase. A total of 22 patients discontinued during the course of the 24-week study. The reasons for study discontinuation were AEs for 10 patients (two, three, two, and three in the 40-mg eow, 40-mg eow plus loading dose, 80-mg eow, and placebo groups, respectively), withdrawal of consent for 10 patients (two, four, two, and two in the 40-mg eow, 40-mg eow plus loading dose, 80-mg eow, and placebo groups, respectively), worsening of psoriasis for one patient (placebo group) and use of a prohibited medication for one patient (40-mg eow plus loading dose group). Isoniazid TB prophylaxis was prescribed for 11 patients in the 40-mg eow treatment group, seven patients in the 40-mg eow plus the 80-mg loading dose group, 13 patients in the 80-mg eow group, and 12 patients in the placebo group.
Baseline and disease-state characteristics are included in Table 1. All patients were Japanese, and 84.6% were male. The mean age and weight of patients was 44.8 years (range, 23–79 years) and 70.1 kg (range, 36–120 kg). The average duration of psoriasis was 13.9 years (range, 8 months to 40 years), with the majority having BSA involvement of 30–49% or 50% or more (36.7% and 40.8%, respectively).
|40 mg eow (n = 38)||40 mg eow + loading dose (n = 43)||80 mg eow (n = 42)||Placebo (n = 46)||Total (n = 169)||Overall P-value|
|Age, years||47.8 ± 12.81||44.2 ± 14.32||43.5 ± 12.40||43.9 ± 10.75||44.8 ± 12.59||0.405|
|Male, n (%)||32 (84.2)||35 (81.4)||35 (83.3)||41 (89.1)||143 (84.6)||0.772|
|Weight†, kg||69.7 ± 15.48||67.4 ± 9.94||72.0 ± 16.09||71.3 ± 15.28||70.1 ± 14.36||0.456|
|Duration of psoriasis, years||14.2 ± 9.29||14.0 ± 7.36||11.6 ± 7.45||15.5 ± 8.83||13.9 ± 8.31||0.187|
|Family history of psoriasis, n (%)||1 (2.6)||2 (4.7)||1 (2.4)||4 (8.7)||8 (4.7)||0.581|
|BSA, %||43.3 ± 19.41||48.3 ± 19.57||46.1 ± 20.11||46.7 ± 19.98||46.2 ± 19.69||0.716|
|BSA, n (%)|
|10–29%||9 (23.7)||9 (20.9)||10 (23.8)||10 (21.7)||38 (22.5)|
|30–49%||16 (42.1)||14 (32.6)||15 (35.7)||17 (37.0)||62 (36.7)|
|≥50%||13 (34.2)||20 (46.5)||17 (40.5)||19 (41.3)||69 (40.8)|
|PASI score||25.44 ± 8.977||30.24 ± 10.946||28.27 ± 11.029||29.10 ± 11.767||28.36 ± 10.838||0.235|
|PASI score, n (%)|
|12–19||15 (39.5)||10 (23.3)||13 (31.0)||14 (30.4)||52 (30.8)|
|20–29||11 (28.9)||11 (25.6)||12 (28.6)||13 (28.3)||47 (27.8)|
|≥30||12 (31.6)||22 (51.2)||17 (40.5)||19 (41.3)||70 (41.4)|
|PGA||3.8 ± 0.55||4.1 ± 0.67||3.8 ± 0.69||3.9 ± 0.67||3.9 ± 0.66||0.169|
|PGA, n (%)|
|“Mild”||0||0||1 (2.4)||0||1 (0.6)|
|“Moderate”||9 (23.7)||8 (18.6)||13 (31.0)||13 (28.3)||43 (25.4)|
|“Severe”||26 (68.4)||24 (55.8)||23 (54.8)||25 (54.3)||98 (58.0)|
|“Very Severe”||3 (7.9)||11 (25.6)||5 (11.9)||8 (17.4)||27 (16.0)|
|Currently swollen, tender or stiff joints, n (%)||7 (18.4)||11 (25.6)||8 (19.0)||13 (28.3)||39 (23.1)||0.638|
|Topical treatment received within 6 months before screening, n (%)||36 (94.7)||41 (95.3)||42 (100.0)||44 (95.7)||163 (96.4)||0.582|
|Corticosteroids||34 (89.5)||37 (86.0)||39 (92.9)||39 (84.8)||149 (88.2)||0.658|
|Vitamin D3 analogs||32 (84.2)||31 (72.1)||37 (88.1)||39 (84.8)||139 (82.2)||0.229|
|Phototherapy received within 6 months before screening, n (%)||7 (18.4)||10 (23.3)||7 (16.7)||19 (41.3)||43 (25.4)||0.031*|
|Systemic therapy of non-biologics received within 6 months before screening, n (%)||18 (47.4)||18 (41.9)||18 (42.9)||17 (37.0)||71 (42.0)||0.815|
During the 6 months before study initiation, 96.4% of patients received treatment with topical corticosteroids or topical vitamin D3 analogs (88.2% and 82.2%, respectively). Patients also reported treatment with phototherapy (25.4%) and systemic administration of non-biologics (42.0%) during the 6 months before study initiation.
Overall, 68.6% of study patients received treatment with protocol-approved topical corticosteroids during the study, which occurred for 64.5% of study patients from weeks 0–16 and 45.6% of study patients from weeks 16–24. Although frequency of use was greater for placebo-treated patients, the most significant difference occurred during weeks 16–24 when topical corticosteroids were used for 37.4% of adalimumab-treated patients compared with 67.4% for the placebo group.
At week 16, significantly more adalimumab-treated patients achieved PASI 75 compared with placebo (P < 0.001) (Fig. 1). Relative to baseline, a dosage-dependent trend was observed for the percentages of adalimumab-treated patients achieving PASI 75 (57.9%, 22 of 38 in the 40-mg eow group; 62.8%, 27 of 43 in the 40-mg eow plus loading dose group; 81.0%, 34 of 42 in the 80-mg eow group). Significantly more patients achieved PASI 75 at week 4 with the 40-mg eow plus loading dose and 80-mg eow treatment regimens compared with placebo (P = 0.010 and P = 0.022, respectively), suggesting a rapid onset of action in these patients. In adalimumab-treated patients, the percentages of patients achieving PASI 75 continued to increase until week 16 and were maintained through week 24.
Significantly more patients treated with adalimumab than placebo achieved PASI 50, PASI 75, PASI 90, and PGA “clear” or “minimal” at week 16 (Table 2). By week 8, significantly more patients in the 40-mg eow plus loading dose and 80-mg eow groups achieved PASI 90 vs placebo (P = 0.002 and P = 0.022, respectively) (Fig. 2). At week 4, the numerically greatest mean percentage change in PASI was demonstrated for the 40-mg eow plus loading dose group (48.6% vs 3.6% for placebo, P < 0.001), indicating rapid response and fast reduction of signs and symptoms (Fig. 3). Thereafter, and especially from week 12, the mean changes in PASI for the 40-mg eow plus loading dose group were between those of the 80-mg eow and 40-mg eow groups.
|Assessment, n (%)||Week 4||Week 16||Week 24|
|40 mg eow (n = 38)||40 mg eow + loading (n = 43)||80 mg eow (n = 42)||Placebo (n = 46)||40 mg eow (n = 38)||40 mg eow + loading (n = 43)||80 mg eow (n = 42)||Placebo (n = 46)||40 mg eow (n = 38)||40 mg eow + loading (n = 43)||80 mg eow (n = 42)||Placebo (n = 46)|
|PASI 50||14 (36.8)**||21 (48.8)**||20 (47.6)**||2 (4.3)||28 (73.7)**||35 (81.4)**||38 (90.5)**||9 (19.6)||28 (73.7)**||33 (76.7)**||36 (85.7)**||9 (19.6)|
|PASI 75||2 (5.3)||6 (14.0)*||5 (11.9)*||0||22 (57.9)**||27 (62.8)**||34 (81.0)**||2 (4.3)||25 (65.8)**||30 (69.8)**||34 (81.0)**||6 (13.0)|
|PASI 90||0†||1 (2.3)||0†||0||14 (36.8)**||17 (39.5)**||26 (61.9)**||0||20 (52.6)**||19 (44.2)**||28 (66.7)**||2 (4.3)|
|PGA “Clear” or “Minimal”||0†||6 (14.0)*||5 (11.9)*||0||17 (44.7)**||26 (60.5)**||33 (78.6)**||4 (8.7)||20 (52.6)**||25 (58.1)**||33 (78.6)**||5 (10.9)|
Clinically significant improvements in PASI scores were noted for all adalimumab treatment groups regardless of sex, age group, or baseline weight. Subgroup analyses of PASI score, PGA, and BSA demonstrated efficacy of adalimumab regardless of psoriasis severity or previous treatments.
Figure 4 presents the results of adalimumab treatment in a 68-year-old man enrolled in the study. The patient received adalimumab 40 mg eow throughout the 24-week double-blind period and continued on the same dosage for an additional 28 weeks in the extension study.
Changes in QOL measures are summarized in Table 3. Compared with placebo, adalimumab-treated patients had statistically significant improvements in DLQI at week 16 and week 24 (P < 0.001). Marked improvements were observed via SF-36 Physical Component Summary and Mental Com-ponent Summary scores for adalimumab-treated patients at week 16 and week 24.
|Adalimumab||Placebo (n = 46)|
|40 mg eow (n = 38)||40 mg eow plus loading dose (n = 43)||80 mg eow (n = 41)†|
|Change from BL at week 16||−3.9 ± 5.83***||−5.1 ± 5.73***||−6.8 ± 5.53***||1.0 ± 6.96|
|Change from BL at week 24||−4.6 ± 6.09***||−5.5 ± 6.06***||−7.0 ± 5.49***||1.3 ± 6.73|
|Physical Component Summary|
|Change at week 16||3.7 ± 7.68*||4.6 ± 7.62**||4.9 ± 6.65***||−0.4 ± 7.34|
|Change at week 24||3.6 ± 8.06**||4.2 ± 8.61**||4.8 ± 7.28***||−1.1 ± 7.90|
|Mental Component Summary|
|Change at week 16||2.5 ± 9.54*||2.4 ± 10.24*||6.8 ± 10.50***||−2.6 ± 10.56|
|Change at week 24||2.8 ± 9.89*||3.3 ± 11.12**||7.0 ± 11.26***||−3.0 ± 10.47|
The percentage of patients achieving a PASI 75 response in the group treated with 40-mg eow plus loading dose was similar to that observed with 80 mg eow at week 4. Thereafter, the response rate for the adalimumab 40-mg eow plus loading dose group was greater than what was observed for the 40-mg eow group and lower than what was observed for the 80-mg eow group (Fig. 1). For PASI 90 responses (Fig. 2) and the mean change in PASI at weeks 4 and 8, results for the group receiving 40 mg eow plus loading dose resembled those of the 80-mg eow group (Fig. 3).
At week 16, all non-responders had the option of receiving with rescue medication. In total, 30 (65.2%) patients in the placebo group and eight (6.5%) patients in the adalimumab groups used rescue medications. After week 16, more patients in the placebo group received rescue therapy (topical treatment) compared with the adalimumab-treated groups; topical corticosteroids of “strong” class were used by 19 (41.3%) placebo-treated and five (4.1%) adalimumab-treated patients, and topical vitamin D3 analogs were used in 13 (28.3%) placebo-treated and two (1.6%) adalimumab-treated patients.
No significant differences between adalimumab treatment groups and placebo were observed in serious AEs (SAEs), severe AEs, AEs leading to premature discontinuation of the drug, AEs probably not related or infectious AEs (Table 4). A significant difference was observed between the 80-mg eow and placebo groups in the number of patients reporting an AE considered by the investigator to be at least possibly related to the study drug (P = 0.020). The incidences of treatment-emergent AEs were similar for adalimumab-treated and placebo-treated patients. AEs were mostly mild to moderate. Injection-site reactions were reported more frequently in the adalimumab treatment groups compared with the placebo group. These reactions were considered mild and did not lead to significant clinical problems or cause study discontinuation.
|AE, n (%)||Adalimumab||Placebo (n = 46)|
|40 mg eow (n = 38)||40 mg eow plus loading dose (n = 43)||80 mg eow (n = 42)|
|Any AE||37 (97.4)||39 (90.7)||38 (90.5)||41 (89.1)|
|Any SAE||0||3 (7.0)||1 (2.4)||2 (4.3)|
|Any severe AE||0||1 (2.3)||0||1 (2.2)|
|AE leading to discontinuation||2 (5.3)||5 (11.6)||3 (7.1)||5 (10.9)|
|AE at least possibly drug-related||24 (63.2)||25 (58.1)||28 (66.7)*||19 (41.3)|
|AE at least probably not related||34 (89.5)||34 (79.1)||36 (85.7)||35 (76.1)|
|Any infectious AE||21 (55.3)||18 (41.9)||21 (50.0)||23 (50.0)|
|Injection-site reactions||6 (15.8)||8 (18.6)||6 (14.3)||3 (6.5)|
|Hepatic event||15 (39.5)**||13 (30.2)*||10 (23.8)||4 (8.7)|
|Hepatobiliary disorders||3 (7.9)||3 (7.0)||5 (11.9)*||0|
|Clinical laboratory test||12 (31.6)*||10 (23.3)||6 (14.3)||4 (8.7)|
|Alanine aminotransferase increase||6 (15.8)||7 (16.3)||2 (4.8)||3 (6.5)|
|Aspartate aminotransferase increase||3 (7.9)||4 (9.3)||1 (2.4)||2 (4.3)|
|γ-Glutamyltransferase increase||5 (13.2)*||1 (2.3)||1 (2.4)||0|
Six patients experienced an SAE during the study: three patients receiving 40 mg eow plus loading dose, one patient receiving 80 mg eow and two patients receiving placebo. Of the three SAE reported with 40 mg eow plus loading dose, only one (epididymitis occurring 117 days after the first dose of adalimumab) was considered probably related to the study drug by study investigators. The other two SAEs, in patients receiving 40 mg eow plus loading dose, were classified as not related (joint dislocation) and probably not related (glaucoma). Rib fracture occurred in one patient receiving 80 mg eow and was considered to be an SAE not related to the study drug. Of the two placebo-treated patients reporting SAEs, both had erythrodermic psoriasis considered unrelated to the study drug and both led to discontinuation from the study.
Fifteen patients discontinued owing to AEs during the course of the study. Ten adalimumab-treated patients experienced 14 events that led to study discontinuation. One of these patients discontinued because of an SAE (glaucoma) requiring hospitalization and four others discontinued owing to events associated with psoriasis (aggravation of psoriasis and psoriatic arthropathy). Reasons for discontinuation for the remaining five adalimumab-treated patients included drug eruption, hepatic function abnormality, edema, anorexia/nausea/vomiting, and adverse drug reaction resulting from isoniazid treatment. Five placebo-treated patients discontinued the study after experiencing AEs associated with psoriasis (aggravation of psoriasis [n = 3], erythrodermic psoriasis [n = 2], psoriatic arthropathy [n = 1, this patient also experienced aggravation of psoriasis]). Causal relationship was rated as probably related to study medication for one patient (drug eruption), possibly related for one patient (edema) and probably not related (psoriasis, hepatic function abnormality, glaucoma, anorexia/nausea/vomiting) or not related (psoriasis, adverse drug reaction) in the remaining events. Frequency of AE leading to study withdrawal was low and comparable across the adalimumab-treated and placebo-treated groups.
Opportunistic infection, TB, malignancy, congestive heart failure, demyelinating disease, allergic reaction, lupus-like syndrome, and hematologic events were not reported for any adalimumab-treated patients.
Adalimumab-treated patients experienced decreases in platelets and segmented neutrophils and an increase in lymphocytes. There was no difference in the incidence of AE associated with these laboratory changes; therefore, it is unlikely that they posed clinical problems (Table 5).
|Adalimumab||Placebo (n = 46)|
|40 mg eow (n = 38)||40 mg eow plus loading dose (n = 43)||80 mg eow (n = 41)|
|Change from BL to final visit||−4.2 ± 5.69*||−3.6 ± 4.34||−5.8 ± 6.90***||−1.6 ± 4.65|
|Segmented neutrophils (%)|
|Change from BL to final visit||−7.6 ± 9.44**||−6.9 ± 9.10**||−11.2 ± 10.97***||0.0 ± 11.89|
|Change from BL to final visit||9.7 ± 9.00***||8.4 ± 8.73**||11.4 ± 10.25***||2.3 ± 9.11|
The percentage of hepatic events was greater in each of the adalimumab groups compared with the placebo group (P = 0.001 in the 40-mg eow group; P = 0.014 in the 40-mg eow plus loading dose group). Alanine aminotransferase changes from the normal range to concentrations greater than the upper normal limit were observed for three placebo-treated and 15 adalimumab-treated patients (six patients receiving 40 mg eow, seven receiving 40 mg eow plus loading dose, and two receiving 80 mg eow). Aspartate aminotransferase changes from the normal range to concentrations greater than the upper normal limit were observed for two placebo-treated and eight adalimumab-treated patients (three patients receiving 40 mg eow, four receiving 40 mg eow plus loading dose, and one receiving 80 mg eow). Most of hepatic AEs were mild, non-dosage-dependent, and did not require treatment.
Mean steady-state adalimumab trough serum concentrations for the 40-mg eow plus loading dose regimen were approximately 4 μg/mL, which were similar to those for 40 mg eow (Fig. 5). In patients receiving the 80-mg loading dose, adalimumab concentrations reached steady state as early as week 2, whereas steady-state concentrations were not reached until week 12 in patients receiving 40 mg eow. The mean steady-state trough concentration for patients treated with 80 mg eow was approximately 14 μg/mL and the concentrations approached steady state by approximately week 12.
The overall rate of AAA, was low in the three adalimumab groups (10.6%, n = 13). Presence of AAAs significantly reduced exposure to adalimumab, with AAA-positive patients having significantly lower PASI 75 (23.1% vs 72.7% in AAA-positive patients vs AAA-negative patients, respectively), PASI 50 (38.5% vs 87.3%), and PASI 90 (0% vs 51.8%) at week 16 and also week 24 (P < 0.001 for all measures and time points). Two AAA-positive patients reported “psoriasis aggravated” (day 91 and day 97) leading to study discontinuation. AAA-positive patients had numerically greater rates of infectious AEs (53.8% vs 48.2%), injection-site reactions AEs (23.1% vs 15.5%), and hepatic-related AEs (38.5% vs 30.0%).
Patients with psoriasis may be discouraged with treatment options and available therapies.15,16 Systemic therapies—methotrexate, cyclosporine, and retinoids—may be limited by AEs and toxicities.2,6,7 Thus, there is an unmet need to make treatment options available that can substantially improve psoriasis and the accompanying psychological and emotional effects.
In this double-blind, placebo-controlled study, adalimumab demonstrated significant efficacy and safety for Japanese patients with moderate to severe chronic plaque psoriasis. At week 16, approximately 60–80% of patients receiving adalimumab achieved PASI 75 (P < 0.001). Clinical response was most rapid in patients treated with 40-mg eow plus loading dose and 80-mg eow regimens. Patients receiving adalimumab showed continued and sustained improvement throughout the 24-week study period. During the course of this study, approximately one out of every two adalimumab-treated patients achieved a PASI 90 (54.5%, 67/123 cases) or a PGA score of “clear” or “minimal” (63.4%, 78/123 cases). In addition to significant improvements in QOL measures, one in three adalimumab-treated patients reported a DLQI = 0 (33.3% [41/123 cases] vs 2.2% [1/46 cases]) of placebo-treated patients). On or after week 16, the need for rescue medication was minimal for adalimumab-treated patients compared with placebo-treated patients (6.5% vs 65.2%).
This study demonstrated that treatment with adalimumab improved psoriasis symptoms and QOL for Japanese patients with moderate to severe chronic plaque psoriasis. These results occurred for patients with extensive skin disease, with a mean baseline BSA affected of 46% overall.
Use of an 80-mg loading dose provided earlier responses compared with placebo. In addition to earlier response, the 40-mg eow plus loading dose group achieved adalimumab steady-state serum concentrations as early as week 2, in contrast to the 12 weeks to achieve steady-state concentrations without the loading dose. Despite differences in the rapidity of response, the three adalimumab treatment groups had similar frequencies of reported AEs. These results demonstrate that a dosing regimen of an initial loading dose of 80-mg adalimumab at week 0 followed by 40 mg eow of adalimumab eow beginning at week 2 elicited an earlier response and maintained efficacy better than a dosing regimen of adalimumab 40 mg eow starting at week 0.
Adalimumab was well-tolerated in this study, with most AEs considered mild or moderate. No cases of opportunistic infection, TB, congestive heart failure, demyelinating disease, allergic reaction, lupus-like syndrome or hematologic events were reported for adalimumab-treated patients. The observed changes in hematologic values are consistent with values noted with previous experience of adalimumab.17
A small number of patients (n = 13) developed antibodies to adalimumab, which led to reduced exposure to adalimumab and significantly diminished PASI response rates compared with patients who did not develop antibodies to adalimumab. There was no evidence of a clinically relevant difference in safety profile for patients who had developed AAAs. Similar changes were noted for Japanese patients with rheumatoid arthritis treated with adalimumab.14 Miyasaka et al.14 also observed that AAA-positive patients with rheumatoid arthritis had diminished response rates and lower adalimumab concentrations compared with AAA-negative patients.
Study limitations include the small number of patients and limited follow-up period (24 weeks). Although there are published studies in the USA on long-term therapy with adalimumab,12 the results from the open-label extension portion of this study will provide a foundation regarding the efficacy and safety of long-term adalimumab therapy in Japanese patients with chronic plaque psoriasis.
In conclusion, this was the first large-scale study of adalimumab in Japanese patients with moderate to severe chronic plaque psoriasis. The results of this study are consistent with those from recent publications demonstrating the efficacy and safety of adalimumab for moderate to severe chronic plaque psoriasis in white patients.11–13 This study demonstrated the efficacy and safety of adalimumab given s.c., at dosages of 40 mg eow, 40 mg eow with an 80-mg loading dose, and 80 mg eow, in reducing the signs and symptoms of psoriasis and improving the QOL for Japanese patients with moderate to severe chronic plaque psoriasis.
This study was sponsored by Abbott Japan, Tokyo, Japan, and Eisai, Tokyo, Japan. The authors would like to thank Christa Hooper-Wood, PharmD, and Michael A. Nissen, ELS, of Abbott Laboratories (North Chicago, IL, USA) for medical writing support. This support was funded by Abbott.
- 9Adalimumab. In: BoehnckeWH, RadekeHH eds. Biologics in General Medicine, 1st edn. New York: Springer-Verlag Berlin Heidelberg, 2007; 14–31., .
- 10HUMIRA® [Prescribing Information]. North Chicago, IL: Abbott Laboratories, 2009.
- 17Radiographic, Clinical and Functional Outcomes With Adalimumab (a Human Anti-TNF Monoclonal Antibody) in the Treatment of Patients With Active Rheumatoid Arthritis on Concomitant Methotrexate Therapy: A Randomized, Placebo-Controlled, 52-Week Trial. Arthritis Rheum 2004; 50: 1400–1411., , et al.