A Novel Transdermal Treatment of Chronic Ocular Graft-Vs-Host Disease (oGvHD): A Phase II Clinic Trial
Published on Mar 1, 2020in Biology of Blood and Marrow Transplantation3.599
· DOI :10.1016/J.BBMT.2019.12.102
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-ocularTM) 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.