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每周一次注射司美格鲁肽治疗肥胖合并膝关节骨关节炎患者
Once-Weekly Semaglutide in Persons with Obesity and Knee Osteoarthritis
背景
减轻体重已被证明可减轻包括疼痛在内的膝关节骨关节炎症状。胰高血糖素样肽-1受体激动剂对肥胖患者膝关节骨关节炎结局的影响尚未经过充分研究。
Weight reduction has been shown to alleviate symptoms of osteoarthritis of the knee, including pain. The effect of glucagon-like peptide-1 receptor agonists on outcomes in knee osteoarthritis among persons with obesity has not been well studied.
方法
我们在11个国家61个试验中心开展了一项为期68周的双盲、随机、安慰剂对照试验。肥胖（体质指数[BMI；体重{kg}除以身高{m}的平方]≥30），经临床和影像学诊断为中度膝关节骨关节炎且至少伴有中度疼痛的参与者被随机分成两组（2:1的比例），两组均接受体力活动和低热量饮食方面的指导，并且分别接受每周一次皮下注射司美格鲁肽（2.4 mg）或安慰剂治疗。主要终点是从基线到第68周，体重的变化百分比以及WOMAC（西安大略和麦克马斯特大学骨关节炎指数，Western Ontario and McMaster Universities Osteoarthritis Index）疼痛评分（评分范围为0~100，评分较高表示结局较差）的变化。一项关键确认性次要终点是SF-36（36项目健康调查简表，36-Item Short Form Health Survey）第2版中的身体功能评分（评分范围为0~100，评分较高表示健康状况较好）。
We conducted a 68-week, double-blind, randomized, placebo-controlled trial at 61 sites in 11 countries. Participants with obesity (a body-mass index [BMI; the weight in kilograms divided by the square of the height in meters] of ≥30) and a clinical and radiologic diagnosis of moderate knee osteoarthritis with at least moderate pain were randomly assigned, in a 2:1 ratio, to receive once-weekly subcutaneous semaglutide (2.4 mg) or placebo, in addition to counseling on physical activity and a reduced-calorie diet. The primary end points were the percentage change in body weight and the change in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score (on a scale of 0 to 100, with higher scores reflecting worse outcomes) from baseline to week 68. A key confirmatory secondary end point was the physical-function score on the 36-Item Short Form Health Survey (SF-36), version 2 (on a scale of 0 to 100, with higher scores indicating greater well-being).
结果
共计407名参与者被纳入研究。参与者平均年龄为56岁，平均BMI为40.3，平均WOMAC疼痛评分为70.9。共计81.6%的参与者为女性。从基线到第68周，体重的平均变化为司美格鲁肽组－13.7%，安慰剂组－3.2%（P<0.001）。第68周时，WOMAC疼痛评分的平均变化为司美格鲁肽组－41.7分，安慰剂组－27.5分（P<0.001）。司美格鲁肽组参与者的SF-36身体功能评分改善幅度超过安慰剂组（平均变化，12.0分 vs. 6.5分；P<0.001）。两组的严重不良事件发生率相似。导致永久性停用试验治疗方案的不良事件发生率为司美格鲁肽组6.7%，安慰剂组3.0%，其中胃肠道疾病是最常见的停药原因。
Result
A total of 407 participants were enrolled. The mean age was 56 years, the mean BMI 40.3, and the mean WOMAC pain score 70.9. A total of 81.6% of the participants were women. The mean change in body weight from baseline to week 68 was −13.7% with semaglutide and −3.2% with placebo (P<0.001). The mean change in the WOMAC pain score at week 68 was −41.7 points with semaglutide and −27.5 points with placebo (P<0.001). Participants in the semaglutide group had a greater improvement in SF-36 physical-function score than those in the placebo group (mean change, 12.0 points vs. 6.5 points; P<0.001). The incidence of serious adverse events was similar in the two groups. Adverse events that led to permanent discontinuation of the trial regimen occurred in 6.7% of the participants in the semaglutide group and in 3.0% in the placebo group, with gastrointestinal disorders being the most common reason for discontinuation.
结论
在患肥胖和膝关节骨关节炎并伴有中度至重度疼痛的参与者中，与安慰剂相比，每周一次注射司美格鲁肽显著更大幅降低了体重和膝关节骨关节炎相关疼痛。（由诺和诺德资助；STEP9在ClinicalTrials.gov注册号为NCT05064735）。
Conclusions
Among participants with obesity and knee osteoarthritis with moderate-to-severe pain, treatment with once-weekly injectable semaglutide resulted in significantly greater reductions in body weight and pain related to knee osteoarthritis than placebo. (Funded by Novo Nordisk; STEP 9 ClinicalTrials.gov number, NCT05064735.)
基于inavolisib的疗法治疗PIK3CA突变晚期乳腺癌试验
Inavolisib-Based Therapy in PIK3CA-Mutated Advanced Breast Cancer
背景
inavolisib是磷脂酰肌醇3-激酶复合物p110催化亚基α异构体（由PIK3CA编码）的非常强效且选择性抑制剂，也可促进突变p110α的降解。inavolisib联合哌柏西利-氟维司群已在临床前模型中显示出协同活性，并在早期试验中显示出良好抗肿瘤活性。
在一项3期、双盲、随机试验中，我们在辅助内分泌治疗期间或治疗结束后12个月内复发的PIK3CA突变、激素受体阳性、人表皮生长因子受体2（HER2）阴性局部晚期或转移性乳腺癌患者中比较了一线Inavolisib（口服剂量9 mg，每日一次）联合哌柏西利-氟维司群治疗（Inavolisib组）与安慰剂联合哌柏西利-氟维司群治疗（安慰剂组）。主要终点是由研究者判定的无进展生存期。
Methods
In a phase 3, double-blind, randomized trial, we compared first-line inavolisib (at an oral dose of 9 mg once daily) plus palbociclib–fulvestrant (inavolisib group) with placebo plus palbociclib–fulvestrant (placebo group) in patients with PIK3CA-mutated, hormone receptor–positive, human epidermal growth factor receptor 2 (HER2)–negative locally advanced or metastatic breast cancer who had had relapse during or within 12 months of the completion of adjuvant endocrine therapy. The primary end point was progression-free survival as assessed by the investigator.
共计161例患者被分配到inavolisib组，164例患者被分配到安慰剂组；中位随访时间分别为21.3个月和21.5个月。inavolisib组的中位无进展生存期为15.0个月（95%置信区间[CI]，11.3~20.5），安慰剂组为7.3个月（95% CI，5.6~9.3）（疾病进展或死亡的风险比，0.43；95% CI，0.32~0.59；P<0.001）。Inavolisib组58.4%的患者和安慰剂组25.0%的患者达到客观缓解。Inavolisib组的3级或4级中性粒细胞减少发生率为80.2%，安慰剂组为78.4%；两组的3级或4级高血糖发生率分别为5.6%和0%；3级或4级口腔炎或黏膜炎症发生率分别为5.6%和0%；3级或4级腹泻发生率分别为3.7%和0%。未观察到3级或4级皮疹。因不良事件停用任何试验药物的患者比例在Inavolisib组为6.8%，在安慰剂组为0.6%。
Result
A total of 161 patients were assigned to the inavolisib group and 164 to the placebo group; the median follow-up was 21.3 months and 21.5 months, respectively. The median progression-free survival was 15.0 months (95% confidence interval [CI], 11.3 to 20.5) in the inavolisib group and 7.3 months (95% CI, 5.6 to 9.3) in the placebo group (hazard ratio for disease progression or death, 0.43; 95% CI, 0.32 to 0.59; P<0.001). An objective response occurred in 58.4% of the patients in the inavolisib group and in 25.0% of those in the placebo group. The incidence of grade 3 or 4 neutropenia was 80.2% in the inavolisib group and 78.4% in the placebo group; grade 3 or 4 hyperglycemia, 5.6% and 0%, respectively; grade 3 or 4 stomatitis or mucosal inflammation, 5.6% and 0%; and grade 3 or 4 diarrhea, 3.7% and 0%. No grade 3 or 4 rash was observed. Discontinuation of any trial agent because of adverse events occurred in 6.8% of the patients in the inavolisib group and in 0.6% of those in the placebo group.
结论
在PIK3CA突变、激素受体阳性、HER2阴性局部晚期或转移性乳腺癌患者中，与安慰剂联合哌柏西利-氟维司群相比，inavolisib联合哌柏西利-氟维司群显著延长了无进展生存期，但毒性效应发生率较高。因不良事件而停用任何试验药物的患者比例很低。（由罗氏资助；INAVO120在ClinicalTrials.gov注册号为NCT04191499）
艾沙妥昔单抗、硼替佐米、来那度胺和地塞米松联合治疗多发性骨髓瘤试验
Isatuximab, Bortezomib, Lenalidomide, and Dexamethasone for Multiple Myeloma
背景
硼替佐米、来那度胺和地塞米松（VRd）联合治疗是新确诊多发性骨髓瘤患者的首选一线治疗方案。对于不符合移植条件的患者，将VRd方案联用抗CD38单克隆抗体艾沙妥昔单抗可否降低疾病进展或死亡风险，目前尚不清楚。
在一项国际性、开放标签、3期试验中，我们以3:2比例将年龄18~80岁、新确诊为多发性骨髓瘤且不符合移植条件的患者随机分组，两组分别接受艾沙妥昔单抗（isatuximab）联用VRd或单用VRd。主要疗效终点是无进展生存期。关键次要终点包括达到完全缓解或更好应答，以及完全缓解患者达到微小残留病变（MRD）阴性。
Methods
In an international, open-label, phase 3 trial, we randomly assigned, in a 3:2 ratio, patients 18 to 80 years of age with newly diagnosed multiple myeloma who were ineligible to undergo transplantation to receive either isatuximab plus VRd or VRd alone. The primary efficacy end point was progression-free survival. Key secondary end points included a complete response or better and minimal residual disease (MRD)–negative status in patients with a complete response.
共计446例患者接受随机分组。在中位59.7个月随访时，艾沙妥昔单抗-VRd组的估计60个月无进展生存率为63.2%，而VRd组为45.2%（疾病进展或死亡的风险比，0.60；98.5%置信区间，0.41~0.88；P<0.001）。艾沙妥昔单抗-VRd组达到完全缓解或更好应答的患者比例显著高于VRd组（74.7% vs. 64.1%，P=0.01），达到MRD阴性且完全缓解的患者比例也显著高于VRd组（55.5% vs. 40.9%，P=0.003）。艾沙妥昔单抗-VRd方案未发现新的安全性信号。两组患者在治疗期间的严重不良事件发生率和导致停药的不良事件发生率相似。
Result
A total of 446 patients underwent randomization. At a median follow-up of 59.7 months, the estimated progression-free survival at 60 months was 63.2% in the isatuximab-VRd group, as compared with 45.2% in the VRd group (hazard ratio for disease progression or death, 0.60; 98.5% confidence interval, 0.41 to 0.88; P<0.001). The percentage of patients with a complete response or better was significantly higher in the isatuximab-VRd group than in the VRd group (74.7% vs. 64.1%, P=0.01), as was the percentage of patients with MRD-negative status and a complete response (55.5% vs. 40.9%, P=0.003). No new safety signals were observed with the isatuximab-VRd regimen. The incidence of serious adverse events during treatment and the incidence of adverse events leading to discontinuation were similar in the two groups.
结论
对于不符合移植条件的18~80岁新确诊多发性骨髓瘤患者，艾沙妥昔单抗-VRd作为初始疗法比VRd更有效。（由赛诺菲和癌症中心支持基金[Cancer Center Support Grant]资助；IMROZ在ClinicalTrials.gov注册号为NCT03319667）。
全髋关节置换术与抗阻训练治疗重度髋关节骨关节炎的比较
Total Hip Replacement or Resistance Training for Severe Hip Osteoarthritis
背景
对于重度髋关节骨关节炎，通常建议行全髋关节置换术，但目前缺乏随机试验数据，无法比较该手术与抗阻训练等非手术疗法的效果。
我们开展了一项多中心、随机对照试验，目的是在年龄≥50岁，患重度髋关节骨关节炎且有手术指征的患者中比较全髋关节置换术和抗阻训练。主要结局是从基线到治疗开始后6个月，患者报告的髋关节疼痛和功能发生的变化，采用牛津髋关节评分（Oxford Hip Score，评分范围，0~48，评分较高表示疼痛较轻、功能较好）进行评估。本试验还评估了安全性。
Methods
We conducted a multicenter, randomized, controlled trial to compare total hip replacement with resistance training in patients 50 years of age or older who had severe hip osteoarthritis and an indication for surgery. The primary outcome was the change in patient-reported hip pain and function from baseline to 6 months after the initiation of treatment, assessed with the use of the Oxford Hip Score (range, 0 to 48, with higher scores indicating less pain and better function). Safety was also assessed.
共计109例患者（平均年龄，67.6岁）被随机分配接受全髋关节置换术（53人）或抗阻训练（56人）。在意向性治疗分析中，全髋关节置换组患者的牛津髋关节评分平均提高（表明病情改善）了15.9分，而抗阻训练组患者则提高了4.5分（差异，11.4分；95%置信区间，8.9~14.0；P<0.001）。6个月时，全髋关节置换组5例患者（9%）未接受手术，抗阻训练组12例患者（21%）接受了全髋关节置换术。两组患者在6个月时的严重不良事件发生率相似，其中大部分是全髋关节置换术的已知并发症。
Result
A total of 109 patients (mean age, 67.6 years) were randomly assigned to total hip replacement (53 patients) or resistance training (56 patients). In an intention-to-treat analysis, the mean increase (indicating improvement) in the Oxford Hip Score was 15.9 points in patients assigned to total hip replacement and 4.5 points in patients assigned to resistance training (difference, 11.4 points; 95% confidence interval, 8.9 to 14.0; P<0.001). At 6 months, 5 patients (9%) who had been assigned to total hip replacement had not undergone surgery, and 12 patients (21%) who had been assigned to resistance training had undergone total hip replacement. The incidence of serious adverse events at 6 months was similar in the two groups; the majority of such events were known complications of total hip replacement.
结论
对于年龄≥50岁，患重度髋关节骨关节炎且有手术指征的患者，6个月时，根据患者的报告，与抗阻训练相比，全髋关节置换术使髋关节疼痛实现有临床意义的更大幅减轻，并使髋关节功能改善。（由丹麦风湿病学会[Danish Rheumatism Association]等资助；PROHIP在ClinicalTrials.gov注册号为NCT04070027）。
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