背景:SI-6603(condoliase)是一种化学核酸溶解剂,于2018年在日本批准用于治疗与神经根性腿疼痛相关的腰椎间盘突出症(LDH)。Condoliase,一种对糖胺聚糖(GAG)具有高底物特异性的粘多糖酶,通过髓核中GAG的降解提供了独特的作用机制。由于LDH管理目前仅限于保守方法和手术干预,对于LDH患者,condoliase可以提供比手术更少侵入性的治疗选择.
目的:Discover6603研究(NCT03607838)评估了单剂量注射SI-6603(condoliase)与假手术治疗LDH相关的神经根性腿痛的疗效和安全性。
方法:随机,双盲,假控制,在美国41个地点进行的第3阶段研究。
方法:男性和女性参与者(N=352;年龄30-70岁)患有后外侧LDH和单侧神经根病/神经根性腿痛超过6周。
方法:主要终点是13周时平均最严重腿部疼痛评分相对于基线(CFB)的变化,使用100毫米视觉模拟量表进行评估。关键次要终点是52周时平均最差腿部疼痛评分的CFB,13周时的疝体积,13周时Oswestry残疾指数(ODI)评分。安全性评价包括不良事件(AE)和影像学发现。
方法:参与者以1:1的比例随机分配,接受单次椎间盘内注射(1.25单位)或假注射,然后观察52周。对改良的意向治疗(mITT)人群使用重复测量混合模型(MMRM)分析和协议指定的多重填补(MI)敏感性分析评估主要和关键次要终点。预先指定的串行门控算法用于多次比较。安全终点包括AE,实验室测试,生命体征,成像(通过X射线和磁共振成像[MRI]),以及治疗后腰椎手术的发生。
结果:在352名随机参与者中,341构成mITT群体(糖脂酶n=169;假n=172)和安全群体(糖脂酶n=167;假n=174)。对于主端点,根据MMRM分析,与假注射(-34.2;LSM差异:-7.5;95%置信区间[CI]:-0.9;p=0.0263)相比,在第13周最严重的腿部疼痛中,condoliase组的CFB改善显著(最小二乘均值[LSM]CFB:-41.7).CFB在第52周时腿部疼痛最严重时,有利于condoliasevs假手术,但差异无统计学意义(p=0.0558),停止了连续的把关测试算法,并规定在第13周的脑疝体积和ODI评分中的CFB被认为是不重要的,不管他们的P值。在所有时间点,治疗组的脑疝体积和ODI评分的CFB差异均有利于condoliase组。MI敏感性分析显示,在第13周(p=0.0223)和第52周(p=0.0433)的最严重的腿部疼痛中,CFB的差异有利于condoliase组。与假手术组(≥1TEAE:60.3%;≥1治疗相关TEAE:10.3%)相比,DC酶组(≥1TEAE:71.9%;≥1治疗相关TEAE:28.1%)治疗引起的AE(TEAE)更常见。在团队中,脊柱MRI异常和背痛最常见。无治疗相关严重AE发生。
结论:Condoliase在第13周时达到了其主要终点,即显著改善神经根性腿痛,并且在LDH患者中通常具有良好的耐受性。对于那些对保守治疗策略无反应的人,使用旋糖酶进行化学核溶解具有比手术更小的侵入性治疗选择的潜力。
BACKGROUND: SI-6603 (condoliase) is a chemonucleolytic agent approved in Japan in 2018 for the treatment of lumbar disc herniation (LDH) associated with radicular leg pain. Condoliase, a mucopolysaccharidase with high substrate specificity for glycosaminoglycans (GAGs), offers a unique mechanism of action through the degradation of GAGs in the nucleus pulposus. As LDH management is currently limited to conservative approaches and surgical intervention, condoliase could offer a less invasive treatment option than surgery for patients with LDH.
OBJECTIVE: The Discover 6603
study (NCT03607838) evaluated the efficacy and safety of a single-dose injection of SI-6603 (condoliase) vs sham for the treatment of radicular leg pain associated with LDH.
METHODS: A randomized, double-blind, sham-controlled, phase 3
study conducted across 41 sites in the United States.
METHODS: Male and female participants (N=352; aged 30-70 years) with contained posterolateral LDH and unilateral
radiculopathy/radicular leg pain for greater than 6 weeks.
METHODS: The primary endpoint was the change from baseline (CFB) in average worst leg pain score at 13 weeks, assessed using the 100-mm visual analogue scale. Key secondary endpoints were CFB in average worst leg pain score at 52 weeks, herniation volume at 13 weeks, and Oswestry Disability Index (ODI) score at 13 weeks. Safety evaluations included adverse events (AEs) and imaging findings.
METHODS: Participants were randomized 1:1 to receive a single intradiscal injection of condoliase (1.25 units) or sham injection followed by 52 weeks of observation. The primary and key secondary endpoints were assessed using a mixed model for repeated measures (MMRM) analysis and a protocol-specified multiple imputation (MI) sensitivity analysis on the modified intention-to-treat (mITT) population. A prespecified serial gatekeeping algorithm was used for multiple comparisons. Safety endpoints included AEs, laboratory tests, vital signs, imaging (by X-ray and magnetic resonance imaging [MRI]), and occurrence of posttreatment lumbar surgery.
RESULTS: Of the 352 randomized participants, 341 constituted the mITT population (condoliase n=169; sham n=172) and the safety population (condoliase n=167; sham n=174). For the primary endpoint, the condoliase group showed significantly greater improvement in CFB in worst leg pain at Week 13 (least squares mean [LSM] CFB: -41.7) compared with sham injection (-34.2; LSM difference: -7.5; 95% confidence interval [CI]: -14.1, -0.9; p=.0263) based on the MMRM analysis. CFB in worst leg pain at Week 52 favored condoliase vs sham, but the difference was not statistically significant (p=.0558), which halted the serial gatekeeping testing algorithm and dictated that the CFB in herniation volume and ODI scores at Week 13 would be considered nonsignificant, regardless of their p-values. Treatment group differences in CFB in herniation volume and ODI score favored the condoliase group vs sham at all timepoints. The MI sensitivity analysis showed differences in CFB in worst leg pain at Week 13 (p=.0223) and Week 52 (p=.0433) in favor of the condoliase group. Treatment-emergent AEs (TEAEs) were more common in the condoliase group (≥1 TEAE: 71.9%; ≥1 treatment-related TEAE: 28.1%) compared with the sham group (≥1 TEAE: 60.3%; ≥1 treatment-related TEAE: 10.3%). Of the TEAEs, spinal MRI abnormalities and back pain occurred most frequently. No treatment-related serious AEs occurred.
CONCLUSIONS: Condoliase met its primary endpoint of significantly improving radicular leg pain at Week 13 and was generally well tolerated in patients with LDH. Chemonucleolysis with condoliase has the potential to provide a less invasive treatment option than surgery for those unresponsive to conservative treatment strategies.