Scleritis
Conditions
Keywords
Sirolimus, Scleritis, Autoimmune Scleritis
Brief summary
Background: Autoimmune scleritis is an inflammatory disease that affects the white outer part of the eye. It is associated with immune system disorders like rheumatoid arthritis. It can cause blindness in severe cases. Most treatments for scleritis involve steroid or immune-suppressing drugs, but these can cause side effects in the whole body. Sirolimus is a drug used to help prevent transplant rejection. It helps prevent the immune system from attacking the body. Researchers want to try giving sirolimus injections into the eye to treat severe scleritis. Objectives: To see if sirolimus is a safe and effective treatment for autoimmune scleritis. Eligibility: Individuals at least 18 years of age with autoimmune scleritis in at least one eye that has not responded to standard treatments. Design: * Participants will be screened with a medical history, physical exam, and eye exam. Blood and urine samples will also be collected. * One eye will be selected as the study eye to receive injections. * Participants will have six study visits over 4 months (initial visit and weeks 2, 4, 8, 12, and 16). The injection will be given at the first visit. If the study eye responds to the treatment, participants may have injections in the other eye at the second visit. * If there is still inflammation after the first injection, or if the scleritis improves but then returns, participants may have a second injection at Week 4. * Injections will be monitored with blood tests and eye exams. * Participants may have study visits and injections for up to 1 year if the injections seem to be working.
Detailed description
OBJECTIVE: Scleritis is a chronic, painful and potentially blinding inflammatory disease characterized by edema of the episcleral and scleral tissues and is commonly associated with systemic autoimmune disorders. Sirolimus suppresses cytokine-driven T-cell proliferation and thus, inhibits the production, signaling and activity of many growth factors relevant to scleritis. Subconjunctival sirolimus administration could reduce or eliminate the need for topical and/or systemic immunosuppressive drugs often taken with immunosuppressive disorders that could result in reduced morbidity. The study objective is to investigate the safety, tolerability and potential efficacy of subconjunctival sirolimus as a possible treatment for active, autoimmune, non-necrotizing, anterior scleritis. STUDY POPULATION: Five participants with active, autoimmune, non-necrotizing, anterior scleritis with scleral inflammatory grade ≥ 1+ in at least one quadrant will be initially enrolled. Participants must have a history of past flares requiring oral non-steroidal anti-inflammatory drugs (NSAIDS), or oral or topical corticosteroids or immunosuppressive medication. Up to seven participants may be enrolled, as up to two participants may be accrued to account for participants who withdraw from the study prior to receiving any investigational product. DESIGN: This is a phase I/II, single-center, open-label, non-randomized, prospective and uncontrolled pilot study to evaluate the safety and possible efficacy of subconjunctival sirolimus injections for active, autoimmune, non-necrotizing, anterior scleritis. If two eyes are active, the eye with worse inflammation will be injected first (study eye) at baseline followed two weeks later with injection of the second eye (fellow eye). If both eyes have equal inflammation, the study eye will be chosen at the physician's discretion after consultation with the participant. Participants that still demonstrate active inflammation or experience a flare-up after the initial study eye injection may be eligible for a re-injection at or after Week 4 (not to exceed a dose of 1,320 μg per eye within an eight-week period). OUTCOME MEASURES: The primary outcome is the number of participants who experience at least a 2-step reduction or reduction to grade 0 of scleral inflammation in the study eye according to a standardized photographic scleritis grading system developed at the National Eye Institute (NEI) by the Week 8 visit. Secondary outcomes include changes in visual acuity, step changes in scleral inflammation, the number of participants who experience a disease flare, the number of participants tapered from the standard immunosuppressive regimen after 16 weeks and, of the participants who experience a disease flare, the number of days to disease flare from baseline as well as the number of participants who require re-injection due to a flare. Safety outcomes include the number and severity of systemic and ocular toxicities and adverse events (AEs), the proportion of participants who experience vision loss ≥ 15 Early Treatment Diabetic Retinopathy Study (ETDRS) letters and the number of participants who experience a substantial rise in elevated intraocular pressure (IOP).
Interventions
DRUGSirolimus
Subconjunctival injection
Sponsors
National Eye Institute (NEI)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Participant has the ability to understand and sign the informed consent document. 2. Participant is 18 years of age or older. 3. Participant has a diagnosis of active, autoimmune, non-necrotizing, anterior scleritis. 4. Participant, if currently taking immunosuppressive medications, is on a stable regimen of immunosuppressive medications (no increase and/or start of new immunosuppressive medications) over the last four weeks. 5. Participant has tried therapy such as oral non-steroidal anti-inflammatory drugs (NSAIDs), or oral or topical corticosteroids or immunosuppressive medication at any time in the past to control scleritis flares, or has intolerance or contraindications to these medications. 6. Participant is willing and able to comply with the study procedures. 7. Female participants of childbearing potential must not be pregnant or breast-feeding, have a negative pregnancy test at screening and must be willing to undergo pregnancy tests throughout the study. 8. Both female participants of childbearing potential and male participants able to father children 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).
Exclusion criteria
1. Participant has a significant active intraocular infection in either eye that requires antibiotic treatment. 2. Participant has an active serious infection or a history of recurring serious infections such as human immunodeficiency virus (HIV) or syphilis that in the best medical judgment of the investigators would pose unnecessary risk to the participant. 3. Participant has active joint or systemic inflammation requiring immediate addition or increase in systemic anti-inflammatory medications. 4. Participant is taking systemic azole anti-fungal medication (e.g., ketoconazole, voriconazole, itraconazole). STUDY EYE ELIGIBILITY CRITERIA: The participant must have at least one eye meeting all inclusion criteria and none of the
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Experience at Least 2-step Reduction or Reduction to Grade 0 of Scleral Inflammation in the Study Eye According to the National Eye Institute (NEI) Photographic Scleritis Grading System Within 8 Weeks Post-injection. | Baseline and Week 8 | The primary efficacy outcome was a 2-step reduction in scleritis grading out of a scale of 0 to 4+ (where 0.5+ is recognized as an ordinal step between 1+ and 0+). 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). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change in Visual Acuity Via the Early Treatment Diabetic Retinopathy Study (ETDRS) | Baseline and Week 52 | 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. |
| Median Change in Visual Acuity Via the Early Treatment Diabetic Retinopathy Study (ETDRS) | Baseline and Week 52 | 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. |
| Number of Participants Needing a Second Injection | Baseline and Week 52 | Participants that still demonstrate active inflammation (incomplete or no response to initial injection) or experience a flare-up (as defined by a ≥1-step increase in scleral inflammation) after the initial injection will be eligible for a re-injection in the study eye at or after Week 4 (not to exceed a dose of 1,320 μg per eye within an eight-week period). |
| Mean Number of Days Between the First Injection to the Second Injection | Baseline and Week 52 | For participants who demonstrate active inflammation (incomplete or no response to initial injection) or experience a flare-up (as defined by a ≥1-step increase in scleral inflammation) after the initial injection |
| Number of Participants Who Experienced Ocular Toxicities | Baseline and Week 52 | — |
| Number of Participants Who Experience a Disease Flare as Defined by a ≥ 1-step Increase in Scleral Inflammation | Baseline and Week 52 | 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) |
| Number of Participants Who Tapered Off One or More Systemic Immunosuppressive Medications or Tapered Off Prednisone (≤10 mg) After Week 16 | Week 16 and Week 52 | Four (4) out of 5 participants were on immunosuppressive medications at enrollment. |
| Proportion of Participants With Loss of ≥ 15 Early Treatment Diabetic Retinopathy Study (ETDRS) Letters | Baseline to Week 52 | 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. |
| Number of Participants Who Experience a Substantial Rise in Elevated Intraocular Pressure (IOP) | Baseline and Week 52 | A substantial rise in intraocular pressure can be defined as ≥10 mmHg change in pressure. |
| Step Changes in Scleral Inflammation According to the Standardized Photographic Grading System Developed at National Eye Institute (NEI) | Baseline and Week 52 | 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) |
| Number of Participants Who Experienced Systemic Toxicities | Baseline and Week 52 | — |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Sirolimus Participants will receive a15 μL (660 μg) subconjunctival injection of sirolimus in the study eye at baseline if a single quadrant or two adjacent quadrants are involved. If greater than two quadrants are involved (i.e., 3 or 4 quadrant involvement) or two non-adjacent quadrants are involved, two 15 μL (660 μg) injections will be given in two quadrants 180 degrees apart (total dose of 30 μL or 1,320 μg). Participants that still demonstrate active inflammation (incomplete or no response to initial injection) or experience a flare-up (as defined by a ≥1-step increase in scleral inflammation) after the initial injection will be eligible for a re-injection in the study eye at or after Week 4 (not to exceed a dose of 1,320 μg per eye within an eight-week period). | 5 |
| Total | 5 |
Baseline characteristics
| Characteristic | Sirolimus |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 5 Participants |
| Age, Continuous | 50.6 years STANDARD_DEVIATION 15.9 |
| Region of Enrollment United States | 5 participants |
| Sex: Female, Male Female | 3 Participants |
| Sex: Female, Male Male | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 5 / 5 |
| serious Total, serious adverse events | 1 / 5 |
Outcome results
Primary
Number of Participants Who Experience at Least 2-step Reduction or Reduction to Grade 0 of Scleral Inflammation in the Study Eye According to the National Eye Institute (NEI) Photographic Scleritis Grading System Within 8 Weeks Post-injection.
The primary efficacy outcome was a 2-step reduction in scleritis grading out of a scale of 0 to 4+ (where 0.5+ is recognized as an ordinal step between 1+ and 0+). 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).
Time frame: Baseline and Week 8
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sirolimus | Number of Participants Who Experience at Least 2-step Reduction or Reduction to Grade 0 of Scleral Inflammation in the Study Eye According to the National Eye Institute (NEI) Photographic Scleritis Grading System Within 8 Weeks Post-injection. | 5 participants |
Secondary
Mean Change in Visual Acuity Via the Early Treatment Diabetic Retinopathy Study (ETDRS)
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.
Time frame: Baseline and Week 52
Population: Mean change in visual acuity at Week 52 from Baseline is presented for the study and fellow eyes for participants who completed follow-up through Week 52.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sirolimus | Mean Change in Visual Acuity Via the Early Treatment Diabetic Retinopathy Study (ETDRS) | -0.25 letters read | Standard Deviation 3.69 |
| Fellow Eye | Mean Change in Visual Acuity Via the Early Treatment Diabetic Retinopathy Study (ETDRS) | -2.25 letters read | Standard Deviation 2.06 |
Secondary
Mean Number of Days Between the First Injection to the Second Injection
For participants who demonstrate active inflammation (incomplete or no response to initial injection) or experience a flare-up (as defined by a ≥1-step increase in scleral inflammation) after the initial injection
Time frame: Baseline and Week 52
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Sirolimus | Mean Number of Days Between the First Injection to the Second Injection | 65.3 Days |
Secondary
Median Change in Visual Acuity Via the Early Treatment Diabetic Retinopathy Study (ETDRS)
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.
Time frame: Baseline and Week 52
Population: Median change in visual acuity at Week 52 from Baseline is presented for the study and fellow eyes for participants who completed follow-up through Week 52.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Sirolimus | Median Change in Visual Acuity Via the Early Treatment Diabetic Retinopathy Study (ETDRS) | 0.00 letters read |
| Fellow Eye | Median Change in Visual Acuity Via the Early Treatment Diabetic Retinopathy Study (ETDRS) | -2.50 letters read |
Secondary
Number of Participants Needing a Second Injection
Participants that still demonstrate active inflammation (incomplete or no response to initial injection) or experience a flare-up (as defined by a ≥1-step increase in scleral inflammation) after the initial injection will be eligible for a re-injection in the study eye at or after Week 4 (not to exceed a dose of 1,320 μg per eye within an eight-week period).
Time frame: Baseline and Week 52
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sirolimus | Number of Participants Needing a Second Injection | 3 participants |
Secondary
Number of Participants Who Experience a Disease Flare as Defined by a ≥ 1-step Increase in Scleral Inflammation
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)
Time frame: Baseline and Week 52
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sirolimus | Number of Participants Who Experience a Disease Flare as Defined by a ≥ 1-step Increase in Scleral Inflammation | 3 participants |
Secondary
Number of Participants Who Experience a Substantial Rise in Elevated Intraocular Pressure (IOP)
A substantial rise in intraocular pressure can be defined as ≥10 mmHg change in pressure.
Time frame: Baseline and Week 52
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sirolimus | Number of Participants Who Experience a Substantial Rise in Elevated Intraocular Pressure (IOP) | 0 participants |
Secondary
Number of Participants Who Experienced Ocular Toxicities
Time frame: Baseline and Week 52
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sirolimus | Number of Participants Who Experienced Ocular Toxicities | 2 participants |
Secondary
Number of Participants Who Experienced Systemic Toxicities
Time frame: Baseline and Week 52
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sirolimus | Number of Participants Who Experienced Systemic Toxicities | 0 participants |
Secondary
Number of Participants Who Tapered Off One or More Systemic Immunosuppressive Medications or Tapered Off Prednisone (≤10 mg) After Week 16
Four (4) out of 5 participants were on immunosuppressive medications at enrollment.
Time frame: Week 16 and Week 52
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sirolimus | Number of Participants Who Tapered Off One or More Systemic Immunosuppressive Medications or Tapered Off Prednisone (≤10 mg) After Week 16 | 1 participants |
Secondary
Proportion 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.
Time frame: Baseline to Week 52
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Sirolimus | Proportion of Participants With Loss of ≥ 15 Early Treatment Diabetic Retinopathy Study (ETDRS) Letters | 0 Participants |
| Fellow Eye | Proportion of Participants With Loss of ≥ 15 Early Treatment Diabetic Retinopathy Study (ETDRS) Letters | 1 Participants |
Secondary
Step Changes in Scleral Inflammation According to the Standardized Photographic Grading System Developed at National Eye Institute (NEI)
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)
Time frame: Baseline and Week 52
Population: Scleral inflammation scores are presented at Baseline and Week 52 and the step change in scores at Week 52 from Baseline for participants who completed follow-up through Week 52.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Sirolimus | Step Changes in Scleral Inflammation According to the Standardized Photographic Grading System Developed at National Eye Institute (NEI) | Participant 001 | 3 score on a scale |
| Sirolimus | Step Changes in Scleral Inflammation According to the Standardized Photographic Grading System Developed at National Eye Institute (NEI) | Participant 002 | 1 score on a scale |
| Sirolimus | Step Changes in Scleral Inflammation According to the Standardized Photographic Grading System Developed at National Eye Institute (NEI) | Participant 003 | 3 score on a scale |
| Sirolimus | Step Changes in Scleral Inflammation According to the Standardized Photographic Grading System Developed at National Eye Institute (NEI) | Participant 005 | 3 score on a scale |
| Fellow Eye | Step Changes in Scleral Inflammation According to the Standardized Photographic Grading System Developed at National Eye Institute (NEI) | Participant 005 | 0 score on a scale |
| Fellow Eye | Step Changes in Scleral Inflammation According to the Standardized Photographic Grading System Developed at National Eye Institute (NEI) | Participant 001 | 0 score on a scale |
| Fellow Eye | Step Changes in Scleral Inflammation According to the Standardized Photographic Grading System Developed at National Eye Institute (NEI) | Participant 003 | 0 score on a scale |
| Fellow Eye | Step Changes in Scleral Inflammation According to the Standardized Photographic Grading System Developed at National Eye Institute (NEI) | Participant 002 | 0 score on a scale |
| Step Changes in Scleral Inflammation at Week 52 From Baseline | Step Changes in Scleral Inflammation According to the Standardized Photographic Grading System Developed at National Eye Institute (NEI) | Participant 005 | -4 score on a scale |
| Step Changes in Scleral Inflammation at Week 52 From Baseline | Step Changes in Scleral Inflammation According to the Standardized Photographic Grading System Developed at National Eye Institute (NEI) | Participant 002 | -2 score on a scale |
| Step Changes in Scleral Inflammation at Week 52 From Baseline | Step Changes in Scleral Inflammation According to the Standardized Photographic Grading System Developed at National Eye Institute (NEI) | Participant 003 | -4 score on a scale |
| Step Changes in Scleral Inflammation at Week 52 From Baseline | Step Changes in Scleral Inflammation According to the Standardized Photographic Grading System Developed at National Eye Institute (NEI) | Participant 001 | -4 score on a scale |