A Clinical Study to Evaluate the Potential Role of ACTH Gel in Patients With Scleritis

ATLAS is an Investigator-initiated, open-labelled, multi-center, randomized, phase II clinical trial, to evaluate the effect of two dose regimens of subcutaneous ACTH gel in subjects with non-infectious anterior scleritis over a period of 12 months (52 weeks), with the primary endpoint at month 4 (week 16). ATLAS study will be conducted at up to 6 clinical sites in USA. The study will be coordinated by the Ocular Imaging Research and Reading Center (OIRRC), which will serve as the coordinating and reading center for the ATLAS Study. The ATLAS Study aims to evaluate the potential role of subcutaneous adrenocorticotropic hormone (ACTH) gel, in the management of non-infectious anterior scleritis. Specifically, the ATLAS Study aims to evaluate the safety and tolerability of 2 different dose regimens of ACTH gel administered by subcutaneous (SC) injection in patients with non-infectious anterior scleritis and to evaluate the bioactivity of 2 different dose regimens of ACTH gel administered by SC injection in patients with non-infectious anterior scleritis. Scleritis refers to red and painful inflammation, centered in the sclera that may involve adjacent ocular structures including the cornea, episclera and uvea. Scleritis may results in vision threatening ocular complications (corneal ulceration, cataract, glaucoma, retinal detachment, choroidal effusion) and subsequent blindness. Up to 50% of patients with scleritis have an associated systemic inflammatory disorder, such as sarcoidosis, rheumatoid arthritis, systemic lupus erythematosus, and polyangiitis with granulomatosis. Scleritis is classified based on the anatomic site, as anterior or posterior, with 90% of cases anterior. Anterior scleritis may manifest as necrotizing or non-necrotizing. Non-necrotizing, noninfectious scleritis is the most prevalent form. The course of scleritis is usually chronic, similar to uveitis, and requires systemic therapy with non-steroidal anti-inflammatory drugs and glucocorticoids, along with immunosuppression, as steroid-sparing therapy. Due to its treatment resistance nature, scleritis remains a therapeutic challenge for many ophthalmologists. The ultimate goal is to control the inflammation, which serves as the cornerstone of the scleritis pathophysiological basis. Adrenocorticotropic hormone (ACTH) is a member of a group of peptide hormones, called melanocortins (MCs). ACTH is released from the pituitary gland and acts primarily on the adrenals to stimulate and regulate steroid hormones production. It has been demonstrated that MCs can be produced by immune cells at the inflammation site, which created a special interest in immunomodulatory properties of these peptides. Latest evidence proposes other anti-inflammatory mechanisms of ACTH actions in addition to steroidogenesis, including leukocyte transmigration inhibition, cytokine synthesis reduction and generation of anti-inflammatory signals locally at the inflammation site. ACTH gel has been reported to be effective in various systemic inflammatory diseases including nephrotic syndrome, multiple sclerosis, opsoclonus myoclonus,dermatomyositis and polymyositis. These reports also include cases that were resistant to steroids and other immunomodulatory drugs, supporting the immune-modulating properties of ACTH. H.P. Acthar® Gel (Repository Corticotropin Injection, Mallinckrodt Pharmaceuticals) is a 39-amino-acid, pituitary-derived ACTH analogue. ACTH gel has been demonstrated to have additional therapeutic effects on the humoral immune system, independent of its role in the adrenal steroidogenesis regulation. It is approved by the US FDA for treatment of a number of inflammatory conditions, including multiple sclerosis, rheumatic and collagen disorders, as well as ophthalmologic diseases, such as ocular allergy, keratitis, uveitis and optic neuritis. However, due to the scarcity of data from clinical studies, many physicians are unaware of ACTH gel as a treatment option for inflammatory diseases. The proposed study aims to evaluate the potential role of ACTH gel in the management of non-infectious anterior scleritis. Given the established role of inflammation in the pathogenesis of scleritis and the ability of ACTH to bind to cellular and tissue melanocortin receptors, thus blocking various inflammatory pathways, a beneficial outcome could be anticipated from ACTH analogue in patients with scleritis. Thirty (30) subjects with non-infectious anterior scleritis will be enrolled in the study. The primary endpoint of the study will be at week 16, with an active, as-needed treatment extension phase from week 17 to week 52. All study participants will be randomized (1:1) at their Baseline (BL) visit (visit 2) to one of the two treatment arms. All subjects will be started on oral corticosteroids (at a maximum dosage of 1 mg/kg of prednisone or equivalence a day) at the screening visit which will continue to be administered at the same dose throughout the screening period until BL/Visit 2. Steroid dose will be tapered from BL/Visit 2 onwards until week 9 (Visit 5). If the scleritis is still greater than 0.5+ on the grading scale, the investigators have the discretion to continue on the tapering course of steroid while the subjects are also being treated with ACTH gel. The two treatment arms are as follows: 1. Mandatory 80 U twice weekly treatment with SC ACTH gel, starting at the Baseline visit (Day 0) until end of week 16. 2. Mandatory 80 U thrice weekly treatment with SC ACTH gel, starting at the Baseline visit (Day 0) until end of week 16. Starting at week 17, treatment regimen will be determined according to clinical response to treatment as follows: 1. No evidence of active disease/disease resolved - treatment dose will be reduced to 80 U once a week with SC ACTH gel. 2. Evidence of disease improvement, but still active/partial response - ACTH treatment will continue alone at the pre-assigned treatment dose. Steroids will not be added to the treatment due to several side effects of the combination of the drugs. 3. No evidence of improvement/disease progression - treatment with ACTH gel will be discontinued and rescue therapy will be initiated as per investigator based on standard of care. At the primary end point (week 16) and at the end of follow-up period (week 52) efficacy will be assessed by standard ophthalmic examination procedures and response to treatment, which will be graded according to established scleritis grading scale. Evaluation of response will be based on changes in scleral inflammation grade at various time points during the study, changes in pain grade scale at various time points during the study, changes in the dosage of prednisone required to maintain disease quiescence and stability and changes on ancillary testing such as FA, OCT, among others. Retreatment will be offered to study subjects who have demonstrated any level of response during the first 16 weeks and who meet any of the Retreatment Criteria listed below. Subjects receiving retreatment will receive the dose that was assigned to them at randomization. There is no placebo arm in this study.