Metropolitan Eye Research and Surgery Institute | Palisades Park, NJ
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ATLAS study is a clinical trial to evaluate the potential role of subcutaneous adrenocorticotropic hormone (ACTH) gel in the management of non-infectious scleritis.
Specifically, the ATLAS Study aims to evaluate the safety, tolerability and effect of 2 different dose regimens of ACTH gel administered by subcutaneous (SC) injection in patients with scleritis, over a period of 12 months.
Scleritis is an inflammatory disease affecting the sclera (white outer coating of the eye), which causes blurring of vision, redness, tearing and painful ocular inflammatory episodes in one or both eyes. Scleritis may results in vision threatening ocular complications, if left untreated. Treatment of scleritis is usually chronic and requires systemic therapy with non-steroidal anti-inflammatory drugs, corticosteroids and immunosuppressive therapy. Due to its treatment resistance nature, scleritis remains a therapeutic challenge for many ophthalmologists.
H.P. Acthar Gel (ACTH Gel) is a highly purified preparation of adrenocorticotropic hormone (ACTH) in a gel that is designed to provide extended release of the ACTH following injection. It is a FDA approved treatment for flares or on a regular basis (maintenance) in people with systemic lupus erythematosus (lupus), infantile spasms, adults with acute relapses or flares of multiple sclerosis (MS), patients with kidney diseases, among other indications. ACTH Gel is also approved for a wide range of allergic and inflammatory diseases of the eye.
Given the established role of inflammation in the pathogenesis of scleritis and the anti-inflammatory effects of ACTH Gel treatment by blocking various inflammatory pathways, a beneficial outcome could be anticipated from ACTH Gel treatment in patients with scleritis.
Full description
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:
Starting at week 17, treatment regimen will be determined according to clinical response to treatment as follows:
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.
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Inclusion criteria
and:
Exclusion criteria
Any significant ocular disease that could compromise vision in the study eye. These include, but are not limited to:
Any of the following treatments within 90 days prior to Day 0 or anticipated use of any of the following treatments to the study eye:
Intraocular surgery within 90 days prior to Day 0 in the study eye;
Capsulotomy within 30 days prior to Day 0 in the study eye;
Any known ocular surgery (including cataract extraction or capsulotomy) of the study eye anticipated within the first 180 days following Day 0;
Presence of posterior scleritis as the only type of scleritis (without concurrent presence of any type of anterior scleritis;
Intraocular pressure ≥25 mmHg in the study eye (glaucoma subjects maintained on no more than 2 topical medications with IOP <25 mmHg are allowed to participate);
Pupillary dilation inadequate for quality stereoscopic fundus photography in the study eye;
Media opacity that would limit clinical visualization;
Presence of any form of ocular malignancy in the study eye, including choroidal melanoma;
History of herpetic infection in the study eye or adnexa;
Presence of known active or inactive toxoplasmosis in either eye;
Presence of ocular or periocular infection in either eye;
Participation in other investigational drug or device clinical trials within 30 days prior to Day 0, or planning to participate in other investigational drug or device clinical trials within 180 days following Day 0. This includes both ocular and non-ocular clinical trials.
Major surgery (including joint surgery) within 8 weeks prior to screening or planned major surgery within 6 months following randomization.
Prior treatment with any cell-depleting therapies, including investigational agents or approved therapies, some examples are CAMPATH, anti-CD4, anti-CD5, anti¬CD3, anti-CD19 and anti- CD20.
Treatment with intravenous gamma globulin, plasmapheresis or Prosorba column within 6 months of baseline.
Immunization with a live/attenuated vaccine within 4 weeks prior to baseline.
Previous treatment with ACTH within 3 months of day 0 of study visit.
Any previous treatment with alkylating agents such as chlorambucil, or with total lymphoid irradiation.
Exclusions for General Safety:
Laboratory Exclusion Criteria (at screening):
Primary purpose
Allocation
Interventional model
Masking
30 participants in 2 patient groups
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Central trial contact
David S. Chu, MD; Atlas Study
Data sourced from clinicaltrials.gov
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