Purpose

To evaluate the safety and efficacy of topical recombinant human nerve growth factor (rhNGF) for treating moderate-to-severe neurotrophic keratitis (NK), a rare degenerative corneal disease resulting from impaired corneal innervation.

Design

Phase II multicenter, randomized, double-masked, vehicle-controlled trial.

Participants

Patients with stage 2 (moderate) or stage 3 (severe) NK in 1 eye.

Methods

The REPARO phase II study assessed safety and efficacy in 156 patients randomized 1:1:1 to rhNGF 10 μg/ml, 20 μg/ml, or vehicle. Treatment was administered 6 drops per day for 8 weeks. Patients then entered a 48- or 56-week follow-up period. Safety was assessed in all patients who received study treatment, whereas efficacy was by intention to treat.

Main Outcome Measures

Corneal healing (defined as <0.5-mm maximum diameter of fluorescein staining in the lesion area) was assessed by masked central readers at week 4 (primary efficacy end point) and week 8 (key secondary end point) of controlled treatment. Corneal healing was reassessed post hoc by masked central readers using a more conservative measure (0-mm staining in the lesion area and no other persistent staining).

Results

At week 4 (primary end point), 19.6% of vehicle-treated patients achieved corneal healing (<0.5-mm lesion staining) versus 54.9% receiving rhNGF 10 μg/ml (+35.3%; 97.06% confidence interval [CI], 15.88–54.71; P < 0.001) and 58.0% receiving rhNGF 20 μg/ml (+38.4%; 97.06% CI, 18.96–57.83; P < 0.001). At week 8 (key secondary end point), 43.1% of vehicle-treated patients achieved less than 0.5-mm lesion staining versus 74.5% receiving rhNGF 10 μg/ml (+31.4%; 97.06% CI, 11.25–51.49; P = 0.001) and 74.0% receiving rhNGF 20 μg/ml (+30.9%; 97.06% CI, 10.60–51.13; P = 0.002). Post hoc analysis of corneal healing by the more conservative measure (0-mm lesion staining and no other persistent staining) maintained statistically significant differences between rhNGF and vehicle at weeks 4 and 8. More than 96% of patients who healed after controlled rhNGF treatment remained recurrence free during follow-up. Treatment with rhNGF was well tolerated; adverse effects were mostly local, mild, and transient.

Conclusions

Topical rhNGF is safe and more effective than vehicle in promoting healing of moderate-to-severe NK.

中文翻译：

---

重组人神经生长因子治疗神经营养性角膜炎的II期随机，双层屏蔽，载体对照试验

目的

为了评估局部重组人类神经生长因子（rhNGF）治疗中度至重度神经营养性角膜炎（NK）的安全性和有效性，该疾病是一种由于角膜神经支配能力受损而引起的罕见的变性角膜疾病。

设计

II期多中心，随机，双掩蔽，车辆对照试验。

参加者

两只眼睛患有2期（中度）或3期（重度）NK的患者。

方法

REPARO II期研究评估了156例以1：1：1随机分配至rhNGF 10μg/ ml，20μg/ ml或赋形剂的患者的安全性和有效性。每天给予6滴治疗，持续8周。然后，患者进入48或56周的随访期。在接受研究治疗的所有患者中评估安全性，而疗效是根据治疗意图而定。

主要观察指标

在对照治疗的第4周（主要疗效终点）和第8周（主要次要终点），通过假面中央阅读器评估角膜愈合（定义为病变区域荧光素染色的最大直径<0.5 mm）。假面中央阅读器事后用更保守的方法（病变区域0mm染色，无其他持续染色）重新评估了角膜愈合。

结果

在第4周（主要终点），接受媒介物治疗的患者中有19.6％的患者角膜愈合（<0.5毫米病灶染色），而接受rhNGF 10μg/ ml的患者有54.9％（+ 35.3％； 97.06％的置信区间[CI]，15.88） –54.71；P <0.001）和58.0％的接受rhNGF 20μg/ ml（+ 38.4％； 97.06％CI，18.96-57.83；P <0.001）。在第8周（关键的次要终点），接受媒介物治疗的患者中43.1％的病变染色少于0.5mm，而接受rhNGF 10μg/ ml的患者为74.5％（+ 31.4％； 97.06％CI，11.25–51.49；P = 0.001） ）和74.0％的接受rhNGF 20μg/ ml（+ 30.9％; 97.06％CI，10.60–51.13; P= 0.002）。通过更保守的措施（0毫米病灶染色，无其他持续性染色）对角膜愈合进行事后分析，在第4周和第8周时，rhNGF和赋形剂之间在统计学上保持了显着差异。超过96％的患者在接受了rhNGF受控治疗后remained愈随访期间无复发。rhNGF的治疗耐受性良好。不良反应主要是局部的，轻度的和短暂的。

结论

局部用rhNGF在促进中至重度NK愈合方面比载剂安全且有效。