Gevokizumab for Active Scleritis

Study Overview
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Brief Summary
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Background: - Scleritis is the inflammation of the white outer coating of the eye, known as the sclera. In severe cases, it can cause blindness. It is commonly associated with autoimmune disorders such as rheumatoid arthritis. Mild scleritis can be treated with drugs such as ibuprofen. More severe scleritis may need oral steroids or immunosuppressive treatments; however, these treatments can cause side effects in the whole body. Gevokizumab is a newer anti-inflammatory drug that is under investigation to treat other inflammatory diseases. It may not have as severe side effects as some other drugs. However, it has not yet been used to treat scleritis. Researchers want to see if it can be given as a safe and effective treatment for scleritis. Objectives: - To see if gevokizumab is a safe and effective treatment for scleritis. Eligibility: - Individuals at least 18 years of age who have active scleritis. Design: There is an initial phase and a two-part extension phase in this study. The extension phase is optional. The initial phase of the study requires seven visits to the National Eye Institute (NEI). Participants will be screened with a physical exam and eye exam, and medical history will be obtained. Blood and urine samples will be collected. Eligible participants will receive an injection of 60 mg of gevokizumab at the first study visit and at Weeks 4, 8, and 12. They will be given under the skin by the stomach, or in the upper arm or thigh. Participants will have additional visits after the first study visit at Weeks 2, 16, and 28. No injection will be given at these visits. Eye exams will be done, and blood and tear samples will be collected. If the scleritis improves by Week 16, participants may choose to continue the study in the extension phase. In the 1st extension, they will have a visit every 4 weeks until Week 36 and then two additional monitoring visits at Weeks 40 and 52 for a total of 13 study visits. Participants who are eligible at Week 52 may continue in the as needed (PRN) extension phase (2nd extension) and receive gevokizumab injections (60 mg) at Weeks 52, 54, 58 and 62.

Detailed Description
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Objective: Scleritis is a chronic, painful and potentially blinding inflammatory disease characterized by edema of the episcleral and sclera tissues and is commonly associated with systemic autoimmune disorders. Gevokizumab is an interleukin-1β (IL-1β) inhibitor, thus possibly preventing the IL-1β that may be responsible for scleral breakdown in patients with anterior scleritis. The study objective is to evaluate the safety and potential efficacy of gevokizumab as a possible treatment of non-infectious, active, anterior scleritis. Study Population: Ten participants with non-infectious, active, anterior scleritis with a scleral inflammatory grade of ≥ +1 in at least one eye were to be initially enrolled. However, only eight participants were enrolled. Participants may be on ≤ 20 mg/day of prednisone or the equivalent at the time of enrollment but all other immunosuppressive drugs will be stopped with the initiation of study drug. Design: This is a Phase 1/2, open label, non-randomized, prospective, single-arm, pilot trial to evaluate the safety and potential efficacy of gevokizumab in non-infectious, active, anterior scleritis. The study consists of an initial phase followed by a two-part extension phase. For the initial phase, all participants will receive one subcutaneous injection of 60 mg gevokizumab at Baseline and Weeks 4, 8 and 12. At Week 16 of the initial phase, participants will be assessed for eligibility in the first extension phase of the study. Participants from the initial phase, who do not continue in the first extension phase of the study will discontinue the study drug and may receive salvage therapy using standard-of-care treatment at the investigator's discretion. Participants from the initial phase who do not continue in the first extension phase will return for a final safety visit at Week 28. Participants from the initial phase who are determined eligible for the first extension phase may continue in the first extension phase and receive one gevokizumab injection (60 mg) every four weeks until the Week 36 visit. Participants entering the first extension phase will have follow-up safety visits at Weeks 40 and 52. At Week 52 follow-up of the first extension phase, participants will be assessed for eligibility in the 2nd extension phase, which is a PRN extension phase of the study. Participants who are eligible may continue in the PRN extension phase (2nd extension) and receive gevokizumab injections (60 mg) at Weeks 52, 54, 58, and 62. Subjects that have already completed the week 52 visit will be eligible to return and be assessed for entry into this 2nd extension phase. If they have already completed the Week 52 exit visit from the protocol and are returning to enroll in the PRN extension phase (2nd extension), the visits will be labeled as Weeks 52 (PRN-week0), 54 (PRN-week2), 58 (PRN-week6), and 62 (PRN-week10). Participants in the PRN extension phase (2nd extension) will have a final safety visit at least 16 weeks following their last injection in the PRN extension phase (2nd extension). Outcome Measures: The primary outcome is the number of participants with at least a 2-step reduction or reduction to grade 0 in scleral inflammation in the study eye (or eyes, if both eyes meet study eye criteria), according to a standardized photographic scleritis grading system developed at NEI, on or before the Week 16 visit as compared to Baseline. Secondary outcomes include changes in visual acuity, changes in intraocular pressure and changes in scleral grading. Safety outcomes include the number and severity of systemic and ocular toxicities and adverse events (AEs), and the proportion of participants with loss of ≥ 15 ETDRS letters at any follow-up visit.

Official Title
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Gevokizumab Treatment for Active Scleritis By IL-1 Inhibition (GATSBY)

Conditions
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Scleritis

Intervention / Treatment
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* Device: Gevokizumab


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: Participant must be 18 years of age or older. Participant must have a diagnosis of non-infectious anterior scleritis requiring treatment. Participant must agree not to undergo elective major surgery for the first 16 weeks of the study. Participant must not have received any the following: Another systemic biologic immunosuppressive agent within the last three months prior to enrollment (e.g., infliximab, daclizumab, etanercept, adalimumab, anakinra); Rituximab or alkylating agent (e.g., cyclophosphamide) within the last 12 months prior to enrollment. Participants on systemic anti-inflammatory therapy (including corticosteroids) must not have had a dose escalation in any of their immunosuppressive treatments within the last four weeks prior to enrollment. Participant must stop all immunosuppressives upon enrollment in the study, with the exception of ≤ 20 mg/day of prednisone or equivalent. Participant must have chest X-ray results (frontal and lateral) within the last 12 weeks prior to enrollment with no evidence of active pulmonary infection, active tuberculosis (TB) or malignancy. Participant must be cleared by internal medicine for enrollment. Female participants of childbearing potential must not be pregnant or breast-feeding, must have a negative pregnancy test at screening and must be willing to undergo pregnancy tests throughout the study. Both female participants of childbearing potential and male participants able to father a child must have (or have a partner who has) had a hysterectomy or vasectomy, be completely abstinent from intercourse or must agree to practice two acceptable methods of contraception throughout the course of the study and for four months after the last investigational product injection. Acceptable methods of contraception include: hormonal contraception (i.e., birth control pills, injected hormones, dermal patch or vaginal ring), intrauterine device, barrier methods (diaphragm, condom) with spermicide, or surgical sterilization (tubal ligation). Participant must be able to undergo slit lamp biomicroscopy on both eyes. Participant must understand and sign the protocol's informed consent document. EXCLUSION CRITERIA: Participant has a significant active infection that requires treatment or has a history of recurrent systemic infections. Participant has a history of TB and s/he has not received a full course of TB treatment, OR participant has a history of latent TB infection [or a positive Interferon-Gamma Release Assay (IGRA)] and has not received prophylactic treatment with isoniazid [also known as isonicotinylhydrazine (INH)] or rifampicin within the last six months prior to enrollment. Participant is seropositive for human immunodeficiency virus (HIV) or Hepatitis C. Participant has Hepatitis B. Positivity for Hepatitis B without evidence of active disease (per investigator judgment) is not exclusionary. Participant has a history of cancer (other than a non-melanoma skin cancer or carcinoma in situ of the cervix) diagnosed within the last five years. Participant has a history of severe allergic or anaphylactic reaction to monoclonal antibodies. Participant has a history of previous treatment with gevokizumab. Participant received live (attenuated) vaccine within the last three months prior to enrollment. Live seasonal flu and H1N1 vaccines are permitted ≥ two weeks prior to enrollment. Recombinant or killed vaccines are permitted at any time. Participant has received an investigational drug or device within the last three months. Participant has active joint or systemic inflammation requiring immediate addition or increase in systemic anti-inflammatory medications. Participant has a condition (e.g., psychiatric illness, severe alcoholism or drug abuse) or situation that may put the participant at significant risk, may confound the study results or may interfere significantly with his/her participation or cooperation in the study. STUDY EYE ELIGIBILITY CRITERIA: The participant must have at least one eye meeting all inclusion criteria and none of the exclusion criteria listed below. STUDY EYE INCLUSION CRITERIA: Participant must have scleritis with a grade of ≥ +1 in the study eye. Participant must have visual acuity of 20/640 or better in the study eye. Participant must agree not to undergo elective ocular surgery (e.g., cataract extraction) in the study eye for the first 16 weeks of the study. STUDY EYE EXCLUSION CRITERIA: Participant has had any of the following in the study eye: periocular, intravitreal steroid injection within the last six weeks prior to enrollment, Ozurdex within the last six months prior to enrollment, or Retisert within the last three years prior to enrollment. Participant has had intraocular surgery in the study eye in the last four weeks prior to enrollment.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: Subcutaneous injection of 60 mg gevokizumab
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Gevokizumab<br>Subcutaneous injection of 60 mg gevokizumab | Device: Gevokizumab<br>* Subcutaneous injection of 60 mg gevokizumab<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With at Least a 2-step Reduction or Reduction to Grade 0 in Scleral Inflammation in the Study Eye (or Eyes), According to the National Eye Institute (NEI) Photographic Scleritis Grading System, on or Before the Week 16 Visit. | Scleral inflammation was graded following 10% Phenylephrine application with an ordinal scale of 0 (no scleral inflammation with complete blanching of vessels), 0.5+ (minimal/trace inflammation with localized pink appearance of the sclera around minimally dilated deep episcleral vessels), 1+ (mild inflammation with diffuse pink appearance of the sclera around mildly dilated deep episcleral vessels), 2+ (moderate inflammation with purplish pink appearance of the sclera with tortuous and engorged deep episcleral vessels), 3+ (severe inflammation with diffuse significant redness of sclera, the details of superficial and deep episcleral vessels can't be observed), and 4+ (necrotizing inflammation with diffuse redness of the sclera with scleral thinning and uveal show). | Baseline and Week 16 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change in Visual Acuity in the Study Eye (or Eyes) at Week 2 Compared to Baseline | Visual acuity was measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) protocol. Acuity is measured as letters read on an ETDRS eye chart and the letters read equate to Snellen measurements. For example, if a participant reads between 84 and 88 letters, the equivalent Snellen measurement is 20/20. | Baseline and Week 2 | 
| Mean Change in Visual Acuity in the Study Eye (or Eyes) at Week 4 Compared to Baseline | Visual acuity was measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) protocol. Acuity is measured as letters read on an ETDRS eye chart and the letters read equate to Snellen measurements. For example, if a participant reads between 84 and 88 letters, the equivalent Snellen measurement is 20/20. | Baseline and Week 4 | 
| Mean Change in Visual Acuity in the Study Eye (or Eyes) at Week 8 Compared to Baseline | Visual acuity was measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) protocol. Acuity is measured as letters read on an ETDRS eye chart and the letters read equate to Snellen measurements. For example, if a participant reads between 84 and 88 letters, the equivalent Snellen measurement is 20/20. | Baseline and Week 8 | 
| Mean Change in Visual Acuity in the Study Eye (or Eyes) at Week 12 Compared to Baseline | Visual acuity was measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) protocol. Acuity is measured as letters read on an ETDRS eye chart and the letters read equate to Snellen measurements. For example, if a participant reads between 84 and 88 letters, the equivalent Snellen measurement is 20/20. | Baseline and Week 12 | 
| Mean Change in Visual Acuity in the Study Eye (or Eyes) at Week 16 Compared to Baseline | Visual acuity was measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) protocol. Acuity is measured as letters read on an ETDRS eye chart and the letters read equate to Snellen measurements. For example, if a participant reads between 84 and 88 letters, the equivalent Snellen measurement is 20/20. | Baseline and Week 16 | 
| Mean Change in Visual Acuity in the Study Eye (or Eyes) at Week 20 Compared to Baseline | Visual acuity was measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) protocol. Acuity is measured as letters read on an ETDRS eye chart and the letters read equate to Snellen measurements. For example, if a participant reads between 84 and 88 letters, the equivalent Snellen measurement is 20/20. | Baseline and Week 20 | 
| Mean Change in Visual Acuity in the Study Eye (or Eyes) at Week 24 Compared to Baseline | Visual acuity was measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) protocol. Acuity is measured as letters read on an ETDRS eye chart and the letters read equate to Snellen measurements. For example, if a participant reads between 84 and 88 letters, the equivalent Snellen measurement is 20/20. | Baseline and Week 24 | 
| Mean Change in Visual Acuity in the Study Eye (or Eyes) at Week 28 Compared to Baseline | Visual acuity was measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) protocol. Acuity is measured as letters read on an ETDRS eye chart and the letters read equate to Snellen measurements. For example, if a participant reads between 84 and 88 letters, the equivalent Snellen measurement is 20/20. | Baseline and Week 28 | 
| Mean Change in Visual Acuity in the Study Eye (or Eyes) at Week 32 Compared to Baseline | Visual acuity was measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) protocol. Acuity is measured as letters read on an ETDRS eye chart and the letters read equate to Snellen measurements. For example, if a participant reads between 84 and 88 letters, the equivalent Snellen measurement is 20/20. | Baseline and Week 32 | 
| Mean Change in Visual Acuity in the Study Eye (or Eyes) at Week 36 Compared to Baseline | Visual acuity was measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) protocol. Acuity is measured as letters read on an ETDRS eye chart and the letters read equate to Snellen measurements. For example, if a participant reads between 84 and 88 letters, the equivalent Snellen measurement is 20/20. | Baseline and Week 36 | 
| Mean Change in Visual Acuity in the Study Eye (or Eyes) at Week 40 Compared to Baseline | Visual acuity was measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) protocol. Acuity is measured as letters read on an ETDRS eye chart and the letters read equate to Snellen measurements. For example, if a participant reads between 84 and 88 letters, the equivalent Snellen measurement is 20/20. | Baseline and Week 40 | 
| Mean Change in Visual Acuity in the Study Eye (or Eyes) at Week 52 Compared to Baseline | Visual acuity was measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) protocol. Acuity is measured as letters read on an ETDRS eye chart and the letters read equate to Snellen measurements. For example, if a participant reads between 84 and 88 letters, the equivalent Snellen measurement is 20/20. | Baseline and Week 52 | 
| Mean Change in Visual Acuity in the Study Eye (or Eyes) at Week 52A Compared to Baseline | This visit represents the beginning of the as-needed 2nd Extension Phase at Week 52. If eligible, participants continued with injections at Wks 52, 54, 58 and 62. Visual acuity was measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) protocol. Acuity is measured as letters read on an ETDRS eye chart and the letters read equate to Snellen measurements. For example, if a participant reads between 84 and 88 letters, the equivalent Snellen measurement is 20/20. | Baseline and Week 52A | 
| Mean Change in Visual Acuity in the Study Eye (or Eyes) at Week 54 Compared to Baseline | Visual acuity was measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) protocol. Acuity is measured as letters read on an ETDRS eye chart and the letters read equate to Snellen measurements. For example, if a participant reads between 84 and 88 letters, the equivalent Snellen measurement is 20/20. | Baseline and Week 54 | 
| Mean Change in Visual Acuity in the Study Eye (or Eyes) at Week 58 Compared to Baseline | Visual acuity was measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) protocol. Acuity is measured as letters read on an ETDRS eye chart and the letters read equate to Snellen measurements. For example, if a participant reads between 84 and 88 letters, the equivalent Snellen measurement is 20/20. | Baseline and Week 58 | 
| Mean Change in Visual Acuity in the Study Eye (or Eyes) at Week 62 Compared to Baseline | Visual acuity was measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) protocol. Acuity is measured as letters read on an ETDRS eye chart and the letters read equate to Snellen measurements. For example, if a participant reads between 84 and 88 letters, the equivalent Snellen measurement is 20/20. | Baseline and Week 62 | 
| Mean Change in Visual Acuity in the Study Eye (or Eyes) at Final Safety Visit Compared to Baseline | Visual acuity was measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) protocol. Acuity is measured as letters read on an ETDRS eye chart and the letters read equate to Snellen measurements. For example, if a participant reads between 84 and 88 letters, the equivalent Snellen measurement is 20/20. | Baseline and Final Visit | 
| Mean Change in Intraocular Pressure in the Study Eye (or Eyes) at Week 2 Compared to Baseline | Intraocular pressure (IOP) is measured in millimeters of mercury (mmHg). | Baseline and Week 2 | 
| Mean Change in Intraocular Pressure in the Study Eye (or Eyes) at Week 4 Compared to Baseline | Intraocular pressure (IOP) is measured in millimeters of mercury (mmHg). | Baseline and Week 4 | 
| Mean Change in Intraocular Pressure in the Study Eye (or Eyes) at Week 8 Compared to Baseline | Intraocular pressure (IOP) is measured in millimeters of mercury (mmHg). | Baseline and Week 8 | 
| Mean Change in Intraocular Pressure in the Study Eye (or Eyes) at Week 12 Compared to Baseline | Intraocular pressure (IOP) is measured in millimeters of mercury (mmHg). | Baseline and Week 12 | 
| Mean Change in Intraocular Pressure in the Study Eye (or Eyes) at Week 16 Compared to Baseline | Intraocular pressure (IOP) is measured in millimeters of mercury (mmHg). | Baseline and Week 16 | 
| Mean Change in Intraocular Pressure in the Study Eye (or Eyes) at Week 20 Compared to Baseline | Intraocular pressure (IOP) is measured in millimeters of mercury (mmHg). | Baseline and Week 20 | 
| Mean Change in Intraocular Pressure in the Study Eye (or Eyes) at Week 24 Compared to Baseline | Mean Change in Intraocular pressure (IOP) is measured and reported as change in IOP between baseline and 24 weeks in millimeters of mercury (mmHg). | Baseline and Week 24 | 
| Mean Change in Intraocular Pressure in the Study Eye (or Eyes) at Week 28 Compared to Baseline | Intraocular pressure (IOP) is measured in millimeters of mercury (mmHg). | Baseline and Week 28 | 
| Mean Change in Intraocular Pressure in the Study Eye (or Eyes) at Week 32 Compared to Baseline | Intraocular pressure (IOP) is measured in millimeters of mercury (mmHg). | Baseline and Week 32 | 
| Mean Change in Intraocular Pressure in the Study Eye (or Eyes) at Week 36 Compared to Baseline | Intraocular pressure (IOP) is measured in millimeters of mercury (mmHg). | Baseline and Week 36 | 
| Mean Change in Intraocular Pressure in the Study Eye (or Eyes) at Week 40 Compared to Baseline | Intraocular pressure (IOP) is measured in millimeters of mercury (mmHg). | Baseline and Week 40 | 
| Mean Change in Intraocular Pressure in the Study Eye (or Eyes) at Week 52 Compared to Baseline | Intraocular pressure (IOP) is measured in millimeters of mercury (mmHg). | Baseline and Week 52 | 
| Mean Change in Intraocular Pressure in the Study Eye (or Eyes) at Week 52A Compared to Baseline | This visit represents the beginning of the as-needed 2nd Extension Phase at Week 52. If eligible, participants continued with injections at Wks 52, 54, 58 and 62. Intraocular pressure (IOP) is measured in millimeters of mercury (mmHg). | Baseline and Week 52A | 
| Mean Change in Intraocular Pressure in the Study Eye (or Eyes) at Week 54 Compared to Baseline | Intraocular pressure (IOP) is measured in millimeters of mercury (mmHg). | Baseline and Week 54 | 
| Mean Change in Intraocular Pressure in the Study Eye (or Eyes) at Week 58 Compared to Baseline | Intraocular pressure (IOP) is measured in millimeters of mercury (mmHg). | Baseline and Week 58 | 
| Mean Change in Intraocular Pressure in the Study Eye (or Eyes) at Week 62 Compared to Baseline | Intraocular pressure (IOP) is measured in millimeters of mercury (mmHg). | Baseline and Week 62 | 
| Mean Change in Intraocular Pressure in the Study Eye (or Eyes) at Final Safety Visit Compared to Baseline | Intraocular pressure (IOP) is measured in millimeters of mercury (mmHg). | Baseline and Final Visit | 
| Number of Participants With Loss of ≥ 15 Early Treatment Diabetic Retinopathy Study (ETDRS) Letters | Visual acuity was measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) protocol. Acuity is measured as letters read on an ETDRS eye chart and the letters read equate to Snellen measurements. For example, if a participant reads between 84 and 88 letters, the equivalent Snellen measurement is 20/20. | Post-injection through study completion, up to 78 weeks per participant | 
| Changes in Scleral Grading From Baseline to Week 52 | Scleral inflammation was summarized on an ordinal scale as either none, minimal/trace, mild, moderate, severe or necrotizing inflammation in the four quadrants of the study eye (superonasal [SN], superotemporal [ST], inferotemporal [IT], and inferonasal [IN]) for each participant at each visit. The exact change from Baseline to Week 52 for each participant (such as from mild to severe) cannot be quantified; therefore, we chose not to report due to the difficulty of reporting a quantitative change in each quadrant for each participant within the limited parameters allowed by PRS. | Baseline and Week 52 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Scleritis, IL-1