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

Inclusion Criteria:

• Adults, age ≥ 18 years;
• Able to give informed consent and attend all study visits;
• Have diagnosis of non-necrotizing scleritis determined by the Investigator to benon-infectious;
• Have active scleirits, defined as:
• Characteristic clinical presentation of active disease: painful inflammation, edemaand tenderness to touch radiating to the forehead, the brow, the jaw, or the sinuses.Severity of pain associated with scleritis will be based on pain intensity, NRS scale.
• Scleral inflammation ranging from +1 to +3 as assessed by central reading center basedon standardized scleritis grading scale. and:
• are receiving no other treatment; or,
• are receiving prednisone (or equivalent dose of another corticosteroid) and/or atleast 1 other systemic immunosuppressant;
• Have anterior scleritis.
• Sufficient inflammation to require systemic treatment or long-term regional treatment.
• Subjects whom the investigators feel may only need short-term topical therapy shouldnot be enrolled.
• Best-corrected visual acuity (ETDRS method) of 20/20 to 20/400 in the study eye;
• Best- corrected visual acuity (ETDRS method) of 20/400 or better in the fellow eye
• Must have a chest radiograph within 3 months prior to enrollment with no evidence ofmalignancy, infection or fibrosis.
• Females of childbearing potential must have a negative urine pregnancy test atscreening. In addition, sexually active females of childbearing potential must agreeto use TWO of the following adequate forms of contraception while on study medication:oral, injectable, or implantable hormonal contraceptives; tubal ligation; intrauterinedevice; barrier contraceptive with spermicide; or vasectomized partner.
• Males must agree to use barrier contraception (latex condoms) when engaging in sexualactivity while on study medication and for 28 days after taking the last dose of studymedication.
• Prior to study screening, potential subjects must have been evaluated and screened forinfectious etiologies by the investigators, possibly as part of standard clinicalacre; all testing to rule out infectious causes must be performed within 3 months ofscreening for the ATLAS study.
• Currently active and uncontrolled scleritis, that at the determination of theinvestigator, requires the initiation of corticosteroid monotherapy (or equivalent),or prednisone therapy and immunomodulatory therapy or injections of corticosteroid (periocular); or scleritis in subjects for whom oral corticosteroid iscontraindicated, relatively or absolutely.
• Evidence of active non-infectious scleral inflammation that at the determination ofinvestigator requires therapy. Such evidence can be documented by clinicalexamination, photography, or ancillary testing (e.g. B-scan ultrasonography,fluorescein angiography, optical coherence tomography). As long as the investigatordetermines that the degree of inflammation can be monitored for regression orprogression, the inflammation criterion can be met.
• Not planning to undergo elective ocular surgery during the first 6 months of thestudy.
• Subjects who have developed scleritis as ocular manifestation of an underlyingsystemic disease can be enrolled in the study only if the systemic therapy will not bealtered throughout the study span. If at any point during the study, the ongoingsystemic therapy needs to be altered (e.g. increase in the dose), the subject willhave to exit the study.
• If scleritis is the initial manifestation of an underlying systemic disease, and thesubjects need to be started on systemic therapy in the form of corticosteroids orimmunomodulatory therapy for the underlying disease, then the subjects will not beeligible to participate in the study.
• Subjects with any or all of the following ocular complications associated with orsecondary to scleritis may also be eligible for enrollment:
• Evidence of active anterior uveitis (defined as +1 cells or more in the anteriorchamber or evidence of anterior vitreous inflammation on slit-lamp examination atpresentation).
• Ocular hypertension, defined as intraocular pressure of ≥ 21 mmHg.
• Peripheral keratitis; defined as peripheral interstitial keratitis or thinning witheither ulcerative or non-ulcerative component.10
• Subjects who have been on immunomodulatory therapy (IMT) prior to enrollment mayparticipate in the study if they have been on a stable dose of IMT (at least 4 weekswith no change in IMT dosing or addition of new IMT agents).

Exclusion Criteria:

• Any significant ocular disease that could compromise vision in the study eye. Theseinclude, but are not limited to:
• Diabetic retinopathy: proliferative diabetic retinopathy (PDR) ornon-proliferative diabetic retinopathy (NPDR) that compromise the vision.
• Age-related macular degeneration;
• Myopic degeneration with active subfoveal choroidal neovascularization.
• Advanced glaucoma status post trabeculectomy or tube/valve placement
• Any of the following treatments within 90 days prior to Day 0 or anticipated use ofany of the following treatments to the study eye:
• Intravitreal injections (including but not limited to steroids or anti-vascularendothelial growth factors);
• Posterior subtenon's steroids.
• 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 studyeye anticipated within the first 180 days following Day 0;
• Presence of posterior scleritis as the only type of scleritis (without concurrentpresence of any type of anterior scleritis;
• Intraocular pressure ≥25 mmHg in the study eye (glaucoma subjects maintained on nomore than 2 topical medications with IOP <25 mmHg are allowed to participate);
• Pupillary dilation inadequate for quality stereoscopic fundus photography in the studyeye;
• Media opacity that would limit clinical visualization;
• Presence of any form of ocular malignancy in the study eye, including choroidalmelanoma;
• 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 daysprior to Day 0, or planning to participate in other investigational drug or deviceclinical trials within 180 days following Day 0. This includes both ocular andnon-ocular clinical trials.
• Major surgery (including joint surgery) within 8 weeks prior to screening or plannedmajor surgery within 6 months following randomization.
• Prior treatment with any cell-depleting therapies, including investigational agents orapproved therapies, some examples are CAMPATH, anti-CD4, anti-CD5, anti¬CD3, anti-CD19and anti- CD20.
• Treatment with intravenous gamma globulin, plasmapheresis or Prosorba column within 6months 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 totallymphoid irradiation. Exclusions for General Safety:
• History of severe allergic or anaphylactic reactions to proteins of porcine origin.
• Evidence of serious uncontrolled concomitant cardiovascular (including history ofcongestive heart failure, uncontrolled hypertension), nervous system (includemyasthenia gravis), pulmonary (including obstructive pulmonary disease), renal,hepatic, endocrine (includeAdrenocortical hyperfunction and primary adrenocorticalinsufficiency, uncontrolled diabetes mellitus, hypothyroidism), gastrointestinaldisease (including history of or presence peptic ulcer disease, complicateddiverticulitis, ulcerative colitis, or Crohn's disease), Scleroderma or Osteoporosis.
• Current liver disease as determined by principal investigator unless related toprimary disease under investigation.
• Known active current or history of recurrent bacterial, viral, fungal, mycobacterialor other infections (including but not limited to tuberculosis and atypicalmycobacterial disease, Hepatitis B and C, and herpes zoster, but excluding fungalinfections of nail beds).
• Any major episode of infection requiring hospitalization or treatment with IVantibiotics within 4 weeks of screening or oral antibiotics within 2 weeks prior toscreening.
• Active TB requiring treatment within the previous 3 years. Subjects should beevaluated for latent and/or active TB within one month of the screening as part of theevaluation by the investigator to rule out infectious scleritis or uveitis beforereferring the patient to the study. If positive, subjects should be managed followinglocal practice guidelines prior to initiating ACTH Gel. Subjects treated for TB withno recurrence in 3 years are permitted.
• Primary or secondary immunodeficiency (history of or currently active)
• Evidence of active malignant disease, malignancies diagnosed within the previous 5years (including hematological malignancies and solid tumors, except basal andsquamous cell carcinoma of the skin or carcinoma in situ of the cervix uteri that hasbeen excised and cured).
• Pregnant women or nursing (breast-feeding) mothers.
• Subjects with reproductive potential not willing to use an effective method ofcontraception.
• History of alcohol, drug or chemical abuse within 1 year prior to screening.
• Neuropathies or other conditions that might interfere with pain evaluation unlessrelated to primary disease under investigation. Laboratory Exclusion Criteria (at screening):
• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2 times upperlimit of normal (ULN)
• Total Bilirubin> 2 times ULN
• HbA1c > 10.0 %
• White Blood Cells < 3.0 x 109/L (3000/mm3)
• Absolute Neutrophil Count < 2.0 x 109/L (2000/mm3)
• Absolute Lymphocyte Count < 0.5 x 109/L (500/mm3)
• TSH > 4U/ml or greater than normal cut-off for the lab conducting the test
• BMD (Bone Mineral Density) < -2.5 T score