背景:干眼病(DED)包括神经感觉异常作为其多因素病因的一部分。神经生长因子对于维持角膜神经完整性和伤口愈合很重要。Cenegermin(重组人神经生长因子)是一种局部生物制剂,可促进神经营养性角膜炎患者的角膜愈合。这项研究的目的是评估cenegermin在中度至重度DED中的疗效和安全性,并确定最佳给药策略。
方法:这是第二阶段,多中心,随机化,双面蒙面,车辆控制,中度至重度DED患者的剂量范围临床试验,包括Sjögren的DED(NCT03982368)。患者每天3次接受1滴cenegermin(t.i.d.;20mcg/mL),cenegermin每天2次(b.i.d.;20mcg/mL)和载体每天一次,或车辆t.i.d.4周。继续随访12周。主要终点是SchirmerI评分从基线到第4周的变化。其他关键终点包括治疗后应答者的比率(SchirmerI测试>10mm/5分钟)和从基线到随访结束的干眼(SANDE)评分的症状评估的变化。使用单侧检验(α=0.025)来评估统计学显著性。
结果:在第4周,cenegermin组与媒介物组的SchirmerI评分的平均变化在统计学上没有显着差异(cenegermin与媒介物[治疗差异;95%CI]:t.i.d,2.60mm和b.i.d.,3.99mmvs1.68mm[t.i.d.:0.93;-1.47至3.32,P=0.078;b.i.d.:2.31;-0.08至4.70,P=0.066])。更多的患者对cenegermint.i.d.和b.i.d.的治疗有反应与载体(t.i.d.:25.9%[21/81,P=0.028];b.i.d.:29.3%[24/82,P=0.007]vs11.9%[10/84]),在b.i.d.组中观察到统计学意义(P<0.025)。与车辆相比,只有cenegermint.i.d.在SANDE评分方面有统计学意义的显着降低(P<0.025),一直持续到随访结束(P值范围,0.002-0.008)。眼睛疼痛,主要是轻度和短暂的,是最常见的因cenegermin治疗引起的不良事件。在Sjögren的DED患者中观察到类似的结果。
结论:Cenegermin的耐受性良好,尽管这项研究没有达到其主要终点,通过随访观察到患者报告的干眼症状有显著改善.有必要进行更大的研究来评估DED患者的cenegermin。
背景:NCT03982368;注册于2019年5月23日。
BACKGROUND: Dry eye disease (DED) includes neurosensory abnormalities as part of its multifactorial etiology. Nerve growth factor is important for maintaining corneal nerve integrity and wound healing. Cenegermin (recombinant human nerve growth factor) is a topical biologic that promotes corneal healing in patients with neurotrophic keratitis. The purpose of this
study was to evaluate efficacy and safety of cenegermin in moderate-to-severe DED and identify an optimal dosing strategy.
METHODS: This was a phase II, multicenter, randomized, double-masked, vehicle-controlled, dose-ranging clinical
trial in patients with moderate-to-severe DED, including Sjögren\'s DED (NCT03982368). Patients received 1 drop of cenegermin 3 times daily (t.i.d.; 20 mcg/mL), cenegermin 2 times daily (b.i.d.; 20 mcg/mL) and vehicle once daily, or vehicle t.i.d. for 4 weeks. Follow-up continued for 12 additional weeks. The primary endpoint was change in Schirmer I score from baseline to week 4. Other key endpoints included rate of responders (Schirmer I test > 10 mm/5 min) after treatment and change in Symptoms Assessment iN Dry Eye (SANDE) scores from baseline to end of follow-up. A 1-sided test (α = 0.025) was used to evaluate statistical significance.
RESULTS: At week 4, mean changes in Schirmer I scores were not statistically significantly different in either cenegermin group versus vehicle (cenegermin vs vehicle [treatment difference; 95% CI]: t.i.d., 2.60 mm and b.i.d., 3.99 mm vs 1.68 mm [t.i.d.: 0.93; -1.47 to 3.32, P = 0.078; b.i.d.: 2.31; -0.08 to 4.70, P = 0.066]). More patients responded to treatment with cenegermin t.i.d. and b.i.d. versus vehicle (t.i.d.: 25.9% [21/81, P = 0.028]; b.i.d.: 29.3% [24/82, P = 0.007] vs 11.9% [10/84]), with statistical significance (set at P < 0.025) observed in the b.i.d. group. Only cenegermin t.i.d. yielded statistically significant (P < 0.025) reductions in SANDE scores versus vehicle, which were sustained up to the end of follow-up (P value range, 0.002-0.008). Eye pain, primarily mild and transient, was the most frequently observed treatment-emergent adverse event with cenegermin. Similar results were observed in patients with Sjögren\'s DED.
CONCLUSIONS: Cenegermin was well tolerated and although this
study did not meet its primary endpoint, significant improvement in patient-reported symptoms of dry eye was observed through follow-up. Larger studies evaluating cenegermin in patients with DED are warranted.
BACKGROUND: NCT03982368; registered May 23, 2019.