Clinical trial NCT01835132: Gevokizumab for Active Scleritis
Official title: Gevokizumab Treatment for Active Scleritis By IL-1 Inhibition (GATSBY)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Scleritis
Keywords: Scleritis
IL-1
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
Collaborators: name: The Emmes Company, LLC
First posted: 2013-04-18
Enrollment: 8
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Subcutaneous injection of 60 mg gevokizumab
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: INCLUSION CRITERIA:

1. Participant must be 18 years of age or older.
2. Participant must have a diagnosis of non-infectious anterior scleritis requiring treatment.
3. Participant must agree not to undergo elective major surgery for the first 16 weeks of the study.
4. 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.
5. 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.
6. Participant must stop all immunosuppressives upon enrollment in the study, with the exception of ≤ 20 mg/day of prednisone or equivalent.
7. 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.
8. Participant must be cleared by internal medicine for enrollment.
9. 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.
10. 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).
11. Participant must be able to undergo slit lamp biomicroscopy on both eyes.
12. Participant must understand and sign the protocol's informed consent document.

EXCLUSION CRITERIA:

1. Participant has a significant active infection that requires treatment or has a history of recurrent systemic infections.
2. 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.
3. Participant is seropositive for human immunodeficiency virus (HIV) or Hepatitis C.
4. Participant has Hepatitis B. Positivity for Hepatitis B without evidence of active disease (per investigator judgment) is not exclusionary.
5. 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.
6. Participant has a history of severe allergic or anaphylactic reaction to monoclonal antibodies.
7. Participant has a history of previous treatment with gevokizumab.
8. 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.
9. Participant has received an investigational drug or device within the last three months.
10. Participant has active joint or systemic inflammation requiring immediate addition or increase in systemic anti-inflammatory medications.
11. 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:

1. Participant must have scleritis with a grade of ≥ +1 in the study eye.
2. Participant must have visual acuity of 20/640 or better in the study eye.
3. 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:

1. 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.
2. Participant has had intraocular surgery in the study eye in the last four weeks prior to enrollment.

Primary outcomes:
measure: 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.
timeFrame: Baseline and Week 16
Secondary outcomes:
measure: Mean Change in Visual Acuity in the Study Eye (or Eyes) at Week 2 Compared to Baseline
timeFrame: Baseline and Week 2
measure: Mean Change in Visual Acuity in the Study Eye (or Eyes) at Week 4 Compared to Baseline
timeFrame: Baseline and Week 4
measure: Mean Change in Visual Acuity in the Study Eye (or Eyes) at Week 8 Compared to Baseline
timeFrame: Baseline and Week 8
measure: Mean Change in Visual Acuity in the Study Eye (or Eyes) at Week 12 Compared to Baseline
timeFrame: Baseline and Week 12
measure: Mean Change in Visual Acuity in the Study Eye (or Eyes) at Week 16 Compared to Baseline
timeFrame: Baseline and Week 16
measure: Mean Change in Visual Acuity in the Study Eye (or Eyes) at Week 20 Compared to Baseline
timeFrame: Baseline and Week 20
measure: Mean Change in Visual Acuity in the Study Eye (or Eyes) at Week 24 Compared to Baseline
timeFrame: Baseline and Week 24
measure: Mean Change in Visual Acuity in the Study Eye (or Eyes) at Week 28 Compared to Baseline
timeFrame: Baseline and Week 28
measure: Mean Change in Visual Acuity in the Study Eye (or Eyes) at Week 32 Compared to Baseline
timeFrame: Baseline and Week 32
measure: Mean Change in Visual Acuity in the Study Eye (or Eyes) at Week 36 Compared to Baseline
timeFrame: Baseline and Week 36
measure: Mean Change in Visual Acuity in the Study Eye (or Eyes) at Week 40 Compared to Baseline
timeFrame: Baseline and Week 40
measure: Mean Change in Visual Acuity in the Study Eye (or Eyes) at Week 52 Compared to Baseline
timeFrame: Baseline and Week 52
measure: Mean Change in Visual Acuity in the Study Eye (or Eyes) at Week 52A Compared to Baseline
timeFrame: Baseline and Week 52A
measure: Mean Change in Visual Acuity in the Study Eye (or Eyes) at Week 54 Compared to Baseline
timeFrame: Baseline and Week 54
measure: Mean Change in Visual Acuity in the Study Eye (or Eyes) at Week 58 Compared to Baseline
timeFrame: Baseline and Week 58
measure: Mean Change in Visual Acuity in the Study Eye (or Eyes) at Week 62 Compared to Baseline
timeFrame: Baseline and Week 62
measure: Mean Change in Visual Acuity in the Study Eye (or Eyes) at Final Safety Visit Compared to Baseline
timeFrame: Baseline and Final Visit
measure: Mean Change in Intraocular Pressure in the Study Eye (or Eyes) at Week 2 Compared to Baseline
timeFrame: Baseline and Week 2
measure: Mean Change in Intraocular Pressure in the Study Eye (or Eyes) at Week 4 Compared to Baseline
timeFrame: Baseline and Week 4
measure: Mean Change in Intraocular Pressure in the Study Eye (or Eyes) at Week 8 Compared to Baseline
timeFrame: Baseline and Week 8
measure: Mean Change in Intraocular Pressure in the Study Eye (or Eyes) at Week 12 Compared to Baseline
timeFrame: Baseline and Week 12
measure: Mean Change in Intraocular Pressure in the Study Eye (or Eyes) at Week 16 Compared to Baseline
timeFrame: Baseline and Week 16
measure: Mean Change in Intraocular Pressure in the Study Eye (or Eyes) at Week 20 Compared to Baseline
timeFrame: Baseline and Week 20
measure: Mean Change in Intraocular Pressure in the Study Eye (or Eyes) at Week 24 Compared to Baseline
timeFrame: Baseline and Week 24
measure: Mean Change in Intraocular Pressure in the Study Eye (or Eyes) at Week 28 Compared to Baseline
timeFrame: Baseline and Week 28
measure: Mean Change in Intraocular Pressure in the Study Eye (or Eyes) at Week 32 Compared to Baseline
timeFrame: Baseline and Week 32
measure: Mean Change in Intraocular Pressure in the Study Eye (or Eyes) at Week 36 Compared to Baseline
timeFrame: Baseline and Week 36
measure: Mean Change in Intraocular Pressure in the Study Eye (or Eyes) at Week 40 Compared to Baseline
timeFrame: Baseline and Week 40
measure: Mean Change in Intraocular Pressure in the Study Eye (or Eyes) at Week 52 Compared to Baseline
timeFrame: Baseline and Week 52
measure: Mean Change in Intraocular Pressure in the Study Eye (or Eyes) at Week 52A Compared to Baseline
timeFrame: Baseline and Week 52A
measure: Mean Change in Intraocular Pressure in the Study Eye (or Eyes) at Week 54 Compared to Baseline
timeFrame: Baseline and Week 54
measure: Mean Change in Intraocular Pressure in the Study Eye (or Eyes) at Week 58 Compared to Baseline
timeFrame: Baseline and Week 58
measure: Mean Change in Intraocular Pressure in the Study Eye (or Eyes) at Week 62 Compared to Baseline
timeFrame: Baseline and Week 62
measure: Mean Change in Intraocular Pressure in the Study Eye (or Eyes) at Final Safety Visit Compared to Baseline
timeFrame: Baseline and Final Visit
measure: Number of Participants With Loss of ≥ 15 Early Treatment Diabetic Retinopathy Study (ETDRS) Letters
timeFrame: Post-injection through study completion, up to 78 weeks per participant
measure: Changes in Scleral Grading From Baseline to Week 52
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: Watson PG, Hayreh SS. Scleritis and episcleritis. Br J Ophthalmol. 1976 Mar;60(3):163-91. doi: 10.1136/bjo.60.3.163.
citation: Knickelbein JE, Tucker WR, Bhatt N, Armbrust K, Valent D, Obiyor D, Nussenblatt RB, Sen HN. Gevokizumab in the Treatment of Autoimmune Non-necrotizing Anterior Scleritis: Results of a Phase I/II Clinical Trial. Am J Ophthalmol. 2016 Dec;172:104-110. doi: 10.1016/j.ajo.2016.09.017. Epub 2016 Sep 20.