Clinical trial NCT01517074: Sirolimus Injections for Autoimmune Scleritis
Official title: A Phase I/II Study to Investigate Subconjunctival Sirolimus for the Treatment of Active Autoimmune Non-Necrotizing Anterior Scleritis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Scleritis
Keywords: Sirolimus
Scleritis
Autoimmune Scleritis
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
First posted: 2012-01-25
Enrollment: 5
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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).

Eligibility criteria: 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 exclusion criteria listed below.

STUDY EYE INCLUSION CRITERIA:

1. Participant has anterior scleritis with greater than or equal to 1 plus in at least one quadrant of the study eye.
2. Participant has visual acuity in the study eye of 20/640 or better.
3. Participant agrees not to undergo elective intraocular surgery in the study eye (e.g., cataract extraction) for three months after the last injection.
4. Participant has not received a periocular or intravitreal injection in the study eye in the last six weeks.

STUDY EYE EXCLUSION CRITERIA:

1. Participant has necrotizing scleritis in the study eye.
2. Participant had intraocular surgery in the study eye in the last four weeks.

Primary outcomes:
measure: 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.
timeFrame: Baseline and Week 8
Secondary outcomes:
measure: Number of Participants Who Experience a Disease Flare as Defined by a ≥ 1-step Increase in Scleral Inflammation
timeFrame: Baseline and Week 52
measure: Mean Change in Visual Acuity Via the Early Treatment Diabetic Retinopathy Study (ETDRS)
timeFrame: Baseline and Week 52
measure: Median Change in Visual Acuity Via the Early Treatment Diabetic Retinopathy Study (ETDRS)
timeFrame: Baseline and Week 52
measure: Number of Participants Needing a Second Injection
timeFrame: Baseline and Week 52
measure: Mean Number of Days Between the First Injection to the Second Injection
timeFrame: Baseline and Week 52
measure: Number of Participants Who Experienced Ocular Toxicities
timeFrame: Baseline and Week 52
measure: Number of Participants Who Experienced Systemic Toxicities
timeFrame: Baseline and Week 52
measure: Number of Participants Who Tapered Off One or More Systemic Immunosuppressive Medications or Tapered Off Prednisone (≤10 mg) After Week 16
timeFrame: Week 16 and Week 52
measure: Proportion of Participants With Loss of ≥ 15 Early Treatment Diabetic Retinopathy Study (ETDRS) Letters
timeFrame: Baseline to Week 52
measure: Number of Participants Who Experience a Substantial Rise in Elevated Intraocular Pressure (IOP)
timeFrame: Baseline and Week 52
measure: Step Changes in Scleral Inflammation According to the Standardized Photographic Grading System Developed at National Eye Institute (NEI)
timeFrame: Baseline and Week 52
Other outcomes:
Locations:
city: Bethesda
country: United States
facility: National Institutes of Health Clinical Center, 9000 Rockville Pike
state: Maryland
Study officials:
affiliation: National Eye Institute (NEI)
name: Hatice N Sen, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Rothova A, Suttorp-van Schulten MS, Frits Treffers W, Kijlstra A. Causes and frequency of blindness in patients with intraocular inflammatory disease. Br J Ophthalmol. 1996 Apr;80(4):332-6. doi: 10.1136/bjo.80.4.332.
citation: Jabs DA, Mudun A, Dunn JP, Marsh MJ. Episcleritis and scleritis: clinical features and treatment results. Am J Ophthalmol. 2000 Oct;130(4):469-76. doi: 10.1016/s0002-9394(00)00710-8.
citation: Sen HN, Suhler EB, Al-Khatib SQ, Djalilian AR, Nussenblatt RB, Buggage RR. Mycophenolate mofetil for the treatment of scleritis. Ophthalmology. 2003 Sep;110(9):1750-5. doi: 10.1016/S0161-6420(03)00570-0.
citation: Bhatt N, Dalal M, Tucker W, Obiyor D, Nussenblatt R, Sen HN. Subconjunctival sirolimus in the treatment of autoimmune non-necrotizing anterior scleritis: results of a phase I/II clinical trial. Am J Ophthalmol. 2015 Mar;159(3):601-6. doi: 10.1016/j.ajo.2014.12.009. Epub 2014 Dec 17.