Kent Justine M, Daly Ella, Kezic Iva, Lane Rosanne, Lim Pilar, De Smedt Heidi, De Boer Peter, Van Nueten Luc, Drevets Wayne C, Ceusters Marc
Janssen Research & Development, LLC, Titusville, NJ, USA.
Janssen Research & Development, LLC, Titusville, NJ, USA.
Prog Neuropsychopharmacol Biol Psychiatry. 2016 Jun 3;67:66-73. doi: 10.1016/j.pnpbp.2016.01.009. Epub 2016 Jan 20.
This phase 2a, randomized, multicenter, double-blind, proof-of-concept study was designed to evaluate, efficacy, safety and tolerability of JNJ-40411813/ADX71149, a novel metabotropic glutamate 2 receptor positive allosteric modulator as an adjunctive treatment for major depressive disorder (MDD) with significant anxiety symptoms. Eligible patients (18-64 years) had a DSM-IV diagnosis of MDD, Hamilton Depression Rating Scale-17 (HDRS17) score of ≥ 18, HDRS17 anxiety/somatization factor score of ≥ 7, and an insufficient response to current treatment with a selective serotonin reuptake inhibitor or serotonin-norepinephrine reuptake inhibitor. The doubly-randomized, 8-week double-blind treatment phase was comprised of two 4-week periods, from which a combined test statistic was generated, with pre-determined weights assigned to each of the 2 treatment periods. Period 1: patients (n=121) were randomly assigned (1:1) to JNJ-40411813 (n=62; 50mg to 150 mg b.i.d, flexibly dosed) or placebo (n=59); Period 2: placebo-treated patients (n=22) who continued to meet entry severity criteria were re-randomized (1:1) to JNJ-40411813 or placebo, while other patients underwent sham re-randomization and continued on their same treatment. Of 121 randomized patients, 100 patients (82.6%) were completers. No efficacy signal was detected on the primary endpoint, the 6-item Hamilton Anxiety Subscale (HAM-A6, p=0.51). Efficacy signals (based on prespecified 1-sided p<0.20) were evident on several secondary outcome measures of both depression (HDRS17 total score, 6-item subscale of HDRS17 assessing core depressive symptoms [HAM-D6], and Inventory of Depressive Symptomatology [IDS-C30]) and anxiety (HDRS17 anxiety/somatization factor, IDS-C30 anxiety subscale). Although well-tolerated, the results do not suggest efficacy for JNJ-40411813 as an adjunctive treatment for patients with MDD with significant anxious symptoms in the dose range studied.
这项2a期随机、多中心、双盲概念验证研究旨在评估新型代谢型谷氨酸2受体正向变构调节剂JNJ-40411813/ADX71149作为伴有显著焦虑症状的重度抑郁症（MDD）辅助治疗的疗效、安全性和耐受性。符合条件的患者（18至64岁）符合DSM-IV对MDD的诊断标准，汉密尔顿抑郁量表17项（HDRS17）评分≥18，HDRS17焦虑/躯体化因子评分≥7，且对当前使用的选择性5-羟色胺再摄取抑制剂或5-羟色胺-去甲肾上腺素再摄取抑制剂治疗反应不足。双随机、为期8周的双盲治疗阶段包括两个4周疗程，生成一个合并检验统计量，并为两个治疗疗程分别预先设定权重。疗程1：患者（n = 121）被随机分配（1:1）至JNJ-40411813组（n = 62；50mg至150mg，每日两次，灵活给药）或安慰剂组（n = 59）；疗程2：继续符合入组严重程度标准的接受安慰剂治疗的患者（n = 22）被再次随机分配（1:1）至JNJ-40411813组或安慰剂组，而其他患者接受假随机分组并继续原治疗。121名随机分组的患者中，100名患者（82.6%）完成了研究。在主要终点6项汉密尔顿焦虑量表（HAM-A6，p = 0.51）上未检测到疗效信号。在抑郁（HDRS17总分、评估核心抑郁症状的HDRS17 6项子量表[HAM-D6]以及抑郁症状量表[IDS-C30]）和焦虑（HDRS17焦虑/躯体化因子、IDS-C30焦虑子量表）的多项次要结局指标上，疗效信号（基于预先设定的单侧p<0.20）明显。尽管耐受性良好，但研究结果并不表明在所研究的剂量范围内，JNJ-40411813作为伴有显著焦虑症状的MDD患者的辅助治疗具有疗效。
