Clinical Trial: Sirolimus Injections for Autoimmune Scleritis

Study Status: Completed
Recruit Status: Completed
Study Type: Interventional

Official Title: A Phase I/II Study to Investigate Subconjunctival Sirolimus for the Treatment of Active Autoimmune Non-Necrotizing Anterior 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

    Detailed Summary:

    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 bas
    Sponsor: National Eye Institute (NEI)

    Current Primary Outcome: 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. [ Time Frame: 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).



    Original Primary Outcome: The number of participants who experience at least 2-step reduction or reduction to grade 0 of scleral infammation in the study eye according to the NEI photographic scleritis grading system within 8 weeks post-injection.

    Current Secondary Outcome:

    • Number of Participants Who Experience a Disease Flare as Defined by a ≥ 1-step Increase in Scleral Inflammation [ Time Frame: 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)
    • Mean Change in Visual Acuity Via the Early Treatment Diabetic Retinopathy Study (ETDRS) [ Time Frame: 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) [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: Baseline and Week 52 ]
    • Number of Participants Who Experienced Systemic Toxicities [ Time Frame: Baseline and Week 52 ]
    • Number of Participants Who Tapered Off One or More Systemic Immunosuppressive Medications or Tapered Off Prednisone (≤10 mg) After Week 16 [ Time Frame: 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 [ Time Frame: 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 Who Experience a Substantial Rise in Elevated Intraocular Pressure (IOP) [ Time Frame: 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) [ Time Frame: Baseline and Week 52 ]


    Original Secondary Outcome:

    • Changes in vision, number of participants who experience a disease flare within 16 weeks, number tapered from immunosuppression after 16 weeks and, number of days to flare from baseline as well as number who require a second injection due to a f...
    • Number and severity of systemic and ocular toxicities and adverse events, the number who experience vision loss of & iexcl, & Yacute; 15 Early Treatment Diabetic Retinopathy Study letters and number of participants who experience a rise ...


    Information By: National Institutes of Health Clinical Center (CC)

    Dates:
    Date Received: January 24, 2012
    Date Started: January 2012
    Date Completion:
    Last Updated: August 31, 2016
    Last Verified: August 2016