中华皮肤科杂志 ›› 2025, Vol. 58 ›› Issue (11): 1020-1026.doi: 10.35541/cjd.20250379

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[开放获取]    国产卡泊三醇倍他米松软膏治疗稳定性斑块状银屑病的临床有效性与安全性：一项多中心、随机、双盲、对照研究

夏立新1,向光2,刁庆春3,黄琨4,张守民5,李珊山6,李遇梅7,宋志强8,孙青9,杨秀敏10,潘萌11,史玉玲12,郭书萍13,王惠平14,雷铁池15,周小勇16,耿松梅17,侯素春18,粟娟19,崔勇20,陈日新21,冯燕艳22,冯红霞23,夏汝山24,孟祖东25,尹芳26,王晶晶26,高兴华1   

  1. 1中国医科大学附属第一医院皮肤性病科，沈阳  110001；2重庆三峡医药高等专科学校附属人民医院皮肤科，重庆  404000；3重庆市中医院皮肤科，重庆  400021；4重庆医科大学附属第一医院皮肤科，重庆  400042；5河南省人民医院皮肤科，郑州  450003；6吉林大学第一医院皮肤科，长春  130021；7江苏大学附属医院皮肤科，镇江  212050；8中国人民解放军陆军军医大学第一附属医院皮肤性病科，重庆  400038；9山东大学齐鲁医院皮肤科，济南  250012；10首都医科大学附属北京同仁医院皮肤科，北京  100730；11上海交通大学医学院附属瑞金医院皮肤科，上海  200025；12上海市皮肤病医院皮肤科，上海  200443；13山西医科大学第一医院皮肤科，太原  030012；14天津医科大学总医院皮肤性病科，天津  300052；15武汉大学人民医院皮肤性病科，武汉  430060；16武汉市中西医结合医院（武汉市第一医院）皮肤科，武汉  430030；17西安交通大学第二附属医院皮肤科，西安  710004；18香港大学深圳医院皮肤科，深圳  518000；19中南大学湘雅医院皮肤科，长沙  410008；20中日友好医院皮肤科，北京  100029；21南阳市第一人民医院皮肤科，南阳  473003；22成都市第二人民医院皮肤科，成都  610021；23温岭市第一人民医院皮肤科，台州  317599；24江阴市中医院皮肤科，无锡  214499；25十堰市人民医院皮肤科，十堰  442000；26上海博佳医药科技有限公司，上海  201203
  • 收稿日期:2025-07-08 修回日期:2025-09-09 发布日期:2025-11-03
  • 通讯作者: 高兴华 E-mail:gaobarry@hotmail.com

Clinical efficacy and safety of a domestic calcipotriol/betamethasone dipropionate ointment in the treatment of stable plaque psoriasis: a multicenter, randomized, double-blind, controlled study

Xia Lixin1, Xiang Guang2, Diao Qingchun3, Huang Kun4, Zhang Shoumin5, Li Shanshan6, Li Yumei7, Song Zhiqiang8, Sun Qing9, Yang Xiumin10, Pan Meng11, Shi Yuling12, Guo Shuping13, Wang Huiping14, Lei Tiechi15, Zhou Xiaoyong16, Geng Songmei17, Hou Suchun18, Su Juan19, Cui Yong20, Chen Rixin21, Feng Yanyan22, Feng Hongxia23, Xia Rushan24, Meng Zudong25, Yin Fang26, Wang Jingjing26, Gao Xinghua1   

  1. 1Department of Dermatology and Venereology, the First Affiliated Hospital of China Medical University, Shenyang 110001, China; 2Department of Dermatology, People's Hospital Affiliated to Chongqing Three Gorges Medical College, Chongqing 404000, China; 3Department of Dermatology, Chongqing Traditional Chinese Medicine Hospital, Chongqing 400021, China; 4Department of Dermatology, the First Affiliated Hospital of Chongqing Medical University, Chongqing 400042, China; 5Department of Dermatology, Henan Provincial People's Hospital, Zhengzhou 450003, China; 6Department of Dermatology, the First Hospital of Jilin University, Changchun 130021, China; 7Department of Dermatology, Affiliated Hospital of Jiangsu University, Zhenjiang 212050, China; 8Department of Dermatology and Venereology, the First Affiliated Hospital of Army Medical University, Chongqing 400038, China; 9Department of Dermatology, Qilu Hospital of Shandong University, Jinan 250012, China; 10Department of Dermatology, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, China; 11Department of Dermatology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; 12Department of Dermatology, Shanghai Skin Disease Hospital, Shanghai 200443, China; 13Department of Dermatology, the First Hospital of Shanxi Medical University, Taiyuan 030012, China; 14Department of Dermatology and Venereology, Tianjin Medical University General Hospital, Tianjin 300052, China; 15Department of Dermatology and Venereology, Renmin Hospital of Wuhan University, Wuhan 430060, China; 16Department of Dermatology, Wuhan Hospital of Traditional Chinese and Western Medicine （Wuhan No.1 Hospital）, Wuhan 430030, China; 17Department of Dermatology, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China; 18Department of Dermatology, the University of Hong Kong-Shenzhen Hospital, Shenzhen 518000, Guangdong, China; 19Department of Dermatology, Xiangya Hospital, Central South University, Changsha 410008, China; 20Department of Dermatology, China-Japan Friendship Hospital, Beijing 100029, China; 21Department of Dermatology, Nanyang First People's Hospital, Nanyang 473003, Henan, China; 22Department of Dermatology, Chengdu Second People's Hospital, Chengdu 610021, China; 23Department of Dermatology, Wenling First People's Hospital, Taizhou 317599, Zhejiang, China; 24Department of Dermatology, Jiangyin Hospital of Traditional Chinese Medicine, Wuxi 214499, Jiangsu, China; 25Department of Dermatology, Shiyan People's Hospital, Shiyan 442000, Hubei, China; 26Shanghai Bojia Pharmaceutical Technology Co., Ltd., Shanghai 201203, China
  • Received:2025-07-08 Revised:2025-09-09 Published:2025-11-03
  • Contact: Gao Xinghua E-mail:gaobarry@hotmail.com

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摘要： 【摘要】 目的 评估国产和原研卡泊三醇倍他米松软膏治疗稳定性斑块状银屑病的临床等效性。方法 采用多中心、随机、双盲、三臂、平行、参比制剂和安慰剂对照的研究设计，纳入中国医科大学附属第一医院等25家医院449例18 ~ 65岁稳定性斑块状银屑病患者，患者基线研究者整体评分（PGA） ≥ 3分，基线皮损累及体表面积（BSA）5% ~ 30%，且靶部位皮损的银屑病严重程度指数（靶皮损PASI）斑块肥厚 ≥ 3分。纳入的受试者按2∶2∶1随机分配至受试制剂组（179例）、参比制剂组（180例）、安慰剂组（90例），分别每晚1次外用国产卡泊三醇倍他米松软膏、原研卡泊三醇倍他米松软膏和空白软膏，疗程4周。于用药1、2、4周后观察临床疗效及安全性，主要疗效指标为用药4周后每个治疗组的治疗成功率和临床成功率。疗效评价以符合方案数据集（PPS）作为主分析，意向性分析集（ITT）作为辅助评价，采用校正随机分层因素的Cochran-Mantel-Haenszel对受试制剂组和参比制剂组进行等效性检验，对受试制剂组、参比制剂组与安慰剂组进行优效性检验。3组计量资料的比较采用方差分析或非参数检验，治疗成功率、临床成功率、不良反应发生率的比较采用卡方检验。结果 本研究纳入ITT 447例，PPS 420例，安全性数据集448例。ITT患者年龄（43.6 ± 12.8）岁，男320（71.6%）例，女127（28.4%）例，病程（11.21 ± 9.05）年，PGA评分3分316（70.7%）例，4 ~ 5分131（29.3%）例，3组受试者的年龄、性别、病程及疾病严重程度差异均无统计学意义（P > 0.05）。基于PPS，受试制剂组、参比制剂组和安慰剂组治疗成功率分别为57.9%（99/171例）、50.3%（86/171例）和7.7%（6/78例），临床成功率分别为57.9%（99/171例）、50.3%（86/171例）和10.3%（8/78例），受试制剂组、参比制剂组治疗成功率和临床成功率均高于安慰剂组（均P < 0.001）；受试制剂组与参比制剂组的治疗成功率组间率差（90% CI：-1.3% ~ 16.4%）、临床成功率组间率差（90% CI：-1.3% ~ 16.3%），均完全落在等效区间（-20.0% ~ 20.0%）范围内。按基线PGA 3分和4 ~ 5分分层统计治疗成功率和临床成功率，PGA 3分患者受试制剂组、参比制剂组和安慰剂组治疗成功率60.8%（73/120例）、52.1%（62/119例）、11.1%（6/54例），临床成功率61.7%（74/120例）、53.8%（64/119例）、13%（7/54例），受试制剂组与参比制剂组治疗成功率、临床成功率差异均无统计学意义（均P > 0.05），但均高于安慰剂组（均P < 0.001）；基线PGA 4 ~ 5分患者3组间统计结果的比较与PGA 3分患者一致。治疗1、2、4周后3组PGA、靶部位PASI评分较基线下降百分比组间差异均有统计学意义，受试制剂组和参比制剂组各项指标较基线下降百分比差异均无统计学意义（P > 0.05），且两制剂组各项指标较基线下降百分比均高于安慰剂组（均P < 0.001）。观察到的主要不良反应为皮肤相关局部反应如瘙痒、皮肤疼痛、红斑等，3组不良反应发生率分别为8.9%（16/179例）、7.3%（13/179例）、7.8%（7/90例），差异无统计学意义（P > 0.05）。结论 国产卡泊三醇倍他米松软膏与原研卡泊三醇倍他米松软膏治疗稳定性斑块状银屑病具有临床等效性，两制剂针对不同严重程度的患者疗效相当，两制剂改善病情的速度和程度也相当，安全性均良好。

关键词: 银屑病, 卡泊三醇倍他米松软膏, 临床等效性, 维生素D3衍生物, 糖皮质激素, 外用复方制剂

Abstract: 【Abstract】 Objective To evaluate the clinical equivalence between a domestic calcipotriol/betamethasone dipropionate ointment and the originator product in the treatment of stable plaque psoriasis. Methods A multicenter, randomized, double-blind, three-arm, parallel-group, active- and placebo-controlled study was conducted, and 449 patients aged 18 - 65 years with stable plaque psoriasis were enrolled from 25 hospitals （such as the First Affiliated Hospital of China Medical University）. Eligible patients had a baseline physician's global assessment （PGA） score of ≥ 3 points, baseline body surface area （BSA） involvement of 5% - 30%, and a target lesion psoriasis area and severity index （TL-PASI） for plaque elevation of ≥ 3 points. Participants were randomly assigned in a 2:2:1 ratio to the test group （n = 179）, reference group （n = 180）, and placebo group （n = 90）, and applied the domestic calcipotriol/betamethasone dipropionate ointment, originator product, and ointment base respectively, once daily in the evening for 4 weeks. Efficacy and safety were assessed at weeks 1, 2, and 4. The primary efficacy endpoints were the treatment success rates and clinical success rates in each group at week 4. The per-protocol set （PPS） was used for the primary efficacy analysis, and the intention-to-treat （ITT） set for supplementary efficacy analysis. Equivalence between the test and reference preparations was tested using the Cochran-Mantel-Haenszel method adjusted for randomization strata. Superiority of the test and reference preparations over the placebo was also tested. Measurement data were compared among the 3 groups using analysis of variance or non-parametric tests, while treatment success rates, clinical success rates, and incidence rates of adverse reactions were compared using the chi-square test. Results The ITT, PPS, and safety sets included 447, 420, and 448 patients, respectively. In the ITT set, patients were aged 43.6 ± 12.8 years, including 320 （71.6%） males and 127 （28.4%） females, and the disease duration was 11.21 ± 9.05 years; 316 （70.7%） had a PGA score of 3 points and 131 （29.3%） had a PGA score of 4 - 5 points. No significant differences in the baseline characteristics （including age, sex, disease duration and disease severity） were observed among the 3 groups （all P > 0.05）. Based on the PPS analysis, the treatment success rates were 57.9% （99/171） in the test group, 50.3% （86/171） in the reference group, and 7.7% （6/78） in the placebo group, and the clinical success rates were 57.9% （99/171）, 50.3% （86/171）, and 10.3% （8/78）, respectively; both the test and reference groups were superior to the placebo group in both treatment and clinical success rates （all P < 0.001）; the rate differences for treatment success （90% confidence interval ［CI］: -1.3% - 16.4%） and clinical success （90% CI: -1.3% - 16.3%） between the test and reference groups were entirely within the pre-defined equivalence margin （-20% - 20%）. Subgroup analyses by baseline PGA scores: for patients with a baseline PGA score of 3 points, the treatment success rates in the test, reference, and placebo groups were 60.8% （73/120）, 52.1% （62/119）, and 11.1% （6/54）, respectively, and the corresponding clinical success rates were 61.7% （74/120）, 53.8% （64/119）, and 13% （7/54）, respectively; the test and reference groups did not differ significantly in treatment or clinical success rates （both P > 0.05）, but both showed higher success rates than the placebo group （all P < 0.001）; the results of statistical comparisons among the 3 groups in patients with a baseline PGA score of 4 - 5 points were consistent with those observed in patients with a baseline PGA score of 3 points. The percentage reductions in PGA and TL-PASI scores from baseline to weeks 1, 2, and 4 showed significant differences among the 3 groups, which were significantly higher in the test and reference groups than in the placebo group （all P < 0.001）, but did not differ between the test and reference groups （all P > 0.05）. The primary adverse reactions were local skin reactions, such as pruritus, pain, and erythema. The incidence rates of adverse reactions were 8.9% （16/179） in the test group, 7.3% （13/179） in the reference group, and 7.8% （7/90） in the placebo group, with no significant difference among the 3 groups （P > 0.05）. Conclusions The domestic calcipotriol/betamethasone dipropionate ointment demonstrated clinical equivalence to the originator product in the treatment of stable plaque psoriasis, and the two agents exhibited comparable efficacy for patients with varying degrees of disease severity, and were comparable in the speed and degree of clinical improvement, with similar favorable safety profiles.

Key words: Psoriasis, Calcipotriol/betamethasone dipropionate ointment, Clinical equivalence, Vitamin D3 derivatives, Glucocorticoid, Topical compound preparations

引用本文

夏立新 向光 刁庆春 黄琨 张守民 李珊山 李遇梅 宋志强 孙青 杨秀敏 潘萌 史玉玲 郭书萍 王惠平 雷铁池 周小勇 耿松梅 侯素春 粟娟 崔勇 陈日新 冯燕艳 冯红霞 夏汝山 孟祖东 尹芳 王晶晶 高兴华. [开放获取]    国产卡泊三醇倍他米松软膏治疗稳定性斑块状银屑病的临床有效性与安全性：一项多中心、随机、双盲、对照研究[J]. 中华皮肤科杂志, 2025,58(11):1020-1026. doi:10.35541/cjd.20250379

Xia Lixin, Xiang Guang, Diao Qingchun, Huang Kun, Zhang Shoumin, Li Shanshan, Li Yumei, Song Zhiqiang, Sun Qing, Yang Xiumin, Pan Meng, Shi Yuling, Guo Shuping, Wang Huiping, Lei Tiechi, Zhou Xiaoyong, Geng Songmei, Hou Suchun, Su Juan, Cui Yong, Chen Rixin, Feng Yanyan, Feng Hongxia, Xia Rushan, Meng Zudong, Yin Fang, Wang Jingjing, Gao Xinghua. Clinical efficacy and safety of a domestic calcipotriol/betamethasone dipropionate ointment in the treatment of stable plaque psoriasis: a multicenter, randomized, double-blind, controlled study[J]. Chinese Journal of Dermatology, 2025, 58(11): 1020-1026.doi:10.35541/cjd.20250379