Chronic GvHD affects about 30-60% of patients after allogeneic hematopoietic cell transplant (allo-HCT), and a majority exhibit ocular manifestations with significant impact on quality of life. In severe cases, oGvHD can lead to permanent vision loss. There is no FDA-approved treatment to date as the current options are limited and mostly ineffective. Forehead application of 1% progesterone gel (Pro-ocular^TM) increases resistance to painful corneal stimuli in animal studies, as well as improves tear film in human volunteer studies. While the precise mechanism of action is unclear, a cranial nerve V1 mediated neuro-pathway has been implicated.

We conducted a prospective, randomized, placebo-controlled, double-masked phase II clinical trial of adult patients with chronic oGvHD who underwent allo-HCT at Dana-Farber/Brigham and Women's Hospital sponsored by Glia LLC. All subjects had moderate to severe eye symptoms, were free of other major ocular comorbidities, and remained on previous ocular treatments and systemic immune suppression through the trial. Subjects were randomized in a 2:1 treatment to placebo fashion. The trial drug or placebo was self-applied to the forehead in the home settings twice a day for a total of 10 weeks. All subjects kept daily diaries to document their medication use and symptoms, and were evaluated in the clinic at baseline, 2 weeks, 6 weeks and 10 weeks. The endpoints of the study were patient reported ocular symptoms and physician recorded ocular signs such as ocular surface staining and tear film. Safety assessments included blood tests of hematology, chemistry and endocrine panels.

A total of 33 patients were enrolled. 21 out of 22 patients in the active arm and all 11 patients in the placebo arm completed the trial. Only 1 was lost to follow-up. Treatment was well tolerated and compliance was high. There was no severe adverse event in the active arm. There was a significant reduction of inferior (-1.38 vs -0.19, p=0.0055) and central cornea (-1.18 vs -0.10, p=0.0010) fluorescein staining in the active arm compared to placebo at 10 weeks (Figure 1). No difference was noted in superior cornea staining. The Symptom Assessment Questionnaire iN Dry Eye (SANDE) quantifies ocular symptoms on a visual analog scale filled by the patients. Strikingly, the reduction of global score (-25.87 vs +1.04, p = 0.0006), symptom frequency (-30.72 vs -2.18, p = 0.0002) and severity (-19.82 vs +1.64, p=0.0048) were all significantly superior in the active arm at 10 weeks (Figure 2). Other endpoints are currently under analysis. All subjects in the placebo arm have chosen to receive active treatment in the ongoing open label study.

In conclusion, forehead application of 1% progesterone gel significantly improved ocular symptoms and signs in just 10 weeks. It appears to be a safe and effective novel treatment for chronic oGvHD. A larger randomized phase III trial to confirm the results is warranted.

异基因造血细胞移植（allo-HCT）后，慢性GvHD影响约30-60％的患者，并且大多数表现出对生活质量有重大影响的眼部表现。在严重的情况下，oGvHD可能导致永久性视力丧失。到目前为止，由于目前的选择有限且大多无效，因此尚无FDA批准的治疗方法。在动物研究中，额头使用1％的孕酮凝胶（Pro-ocular ^TM）可以增加对痛苦的角膜刺激的抵抗力，并在人类志愿者研究中改善泪膜。虽然尚不清楚确切的作用机制，但已牵涉到颅神经V1介导的神经通路。

我们对由Dlia-Farber / Brigham和妇女医院（由Glia LLC赞助）进行allo-HCT的慢性oGvHD成人患者进行了一项前瞻性，随机，安慰剂对照，双掩蔽的II期II期临床试验。所有受试者均具有中度至重度的眼部症状，没有其他主要的眼部合并症，并且在整个试验过程中仍接受先前的眼部治疗和全身性免疫抑制。以2：1的治疗方式将受试者随机分为安慰剂组。在家庭环境中，每天两次将试验药物或安慰剂自我涂在额头上，共10周。所有受试者每天记录日记以记录其药物使用和症状，并在基线，2周，6周和10周时在诊所进行评估。研究的终点是患者报告眼部症状，医师记录眼部症状，例如眼表染色和泪膜。安全评估包括血液学检查，血液学检查，化学检查和内分泌检查。

总共招募了33名患者。主动组22例患者中有21例，安慰剂组11例全部完成了试验。仅有1人失访。治疗耐受性好，依从性高。活动手臂无严重不良事件。与安慰剂组相比，在第10周时，活动臂中的荧光素染色明显降低（-1.38 vs -0.19，p = 0.0055）和中央角膜（-1.18 vs -0.10，p = 0.0010）（图1）。上角膜染色未发现差异。症状评估问卷《干眼症》（SANDE）以患者填充的视觉模拟量表对眼部症状进行量化。令人惊讶的是，总体评分（-25.87 vs + 1.04，p = 0.0006），症状发生频率（-30.72 vs -2.18，p = 0.0002）和严重程度（-19.82 vs + 1.64，p = 0）降低。0048）均在第10周时在活动臂上均明显优于（图2）。当前正在分析其他端点。在正在进行的开放标签研究中，安慰剂组中的所有受试者都选择接受积极治疗。

总之，仅在10周内使用1％的孕酮凝胶额头即可显着改善眼部症状和体征。对于慢性oGvHD，这似乎是一种安全有效的新型治疗方法。有必要进行一项较大的随机III期试验以确认结果。