Ustekinumab (STELARA) for the Treatment of Active Sight-Threatening Uveitis (STAR Study)

A Pilot Study to Investigate Ustekinumab (STELARA) for the Treatment of Active Sight-Threatening Uveitis

Background: Uveitis is an inflammation of the eye that can cause vision loss. It is treated with medications and sometimes surgery. However, in many people, treatment does not always prevent loss of vision. A new medication, ustekinumab, reduces inflammation in patients with other inflammatory diseases. Therefore, it might be helpful in treatment of uveitis. Objective: To see if ustekinumab is safe and can help people with uveitis. Eligibility: People ages 18 and older with uveitis Design: Participants will be screened with: Medical and eye disease history Physical exam Eye exam: The pupil is dilated with eye drops. A machine scans the back of the eye. Pictures are taken of the inside of the eye. Blood and urine tests Tuberculosis test Participants will have 6 clinic visits over 28 weeks. Visits lasts 2-3 hours and include: Medical and eye disease history Physical and eye exams Blood and urine tests Fluorescein angiography: A needle guides a thin plastic tube into an arm vein. A dye is injected into the tube. The dye travels through the veins up to the blood vessels in the eyes. A camera takes pictures of the dye as it flows through the blood vessels in the eyes. Cohort 1 - Ustekinumab injections at Weeks 0, 4, and 8: The injection is under the skin of the upper arm, leg, or abdomen. Participants will have their uveitis monitored and receive standard uveitis care during the study. Cohort 2 - Ustekinumab injections via intravenous (IV) injection at first visit, followed by a single 90 mg injection of ustekinumab under the skin of the upper arm, leg or abdomen. For the IV injection a needle will be used to guide a thin plastic tube (catheter) into one of the arm veins. The needle will be removed, leaving only the catheter in the vein.

Objective: Uveitis refers to intraocular inflammatory diseases that are an important cause of visual loss. Standard systemic immunosuppressive medications for uveitis can cause significant adverse effects and many patients continue to experience disease flare-ups. Ustekinumab is a human IL-12 and -23 antagonist. The involvement of IL-12 and IL-23 in the pathophysiology of uveitis and other autoimmune diseases known to be associated with uveitis suggests that ustekinumab could be a potential treatment for uveitis. The study objective is to investigate the safety, tolerability and potential efficacy of ustekinumab as a possible treatment for active intermediate uveitis, posterior uveitis or panuveitis. Study Population: The first cohort will consist of five participants with active intermediate uveitis, posterior uveitis or panuveitis who meet the inclusion criteria. The second cohort will include up to four participants with active intermediate uveitis, posterior uveitis or panuveitis who meet the inclusion criteria. Up to eleven participants may be enrolled, as up to two participants may be accrued in the second cohort to account for participants who withdraw from the study prior to Week 16. Design: This is a prospective, non-randomized, uncontrolled, two-arm pilot study to evaluate of ustekinumab as a possible treatment for active intermediate uveitis, posterior uveitis or panuveitis. Five participants in the first cohort will receive a 90 mg subcutaneous (SC) injection of ustekinumab at baseline and a second and third injection at Week 4 and 8 for a total of 3 injections. For the second cohort, up to four participants will receive an initial high, weight-based dose of ustekinumab via intravenous (IV) injection (up to 55 kg, 260 mg (2 vials); greater than 55 kg to 85 kg, 390 mg (3 vials); greater than 85 kg, 520 mg (4 vials)), followed by a single 90 mg subcutaneous injection at Week 8. In participants who demonstrate allergic reaction to the first dose, the second dose can also be administered as IV infusion with pre-infusion desensitization instead of a subcutaneous injection as it allows better control on the rate of drug administration. Participants will continue in the study for a total of 28 weeks and will be able to receive standard of care after the first 16 weeks. Outcome Measures: For each cohort, the primary outcome is the number of participants who experience treatment response by Week 16. Secondary outcomes for each cohort include changes in visual acuity, the number of participants who experience a recurrence, the number of days to recurrence, presence or extent of macular edema, the amount of retino-vascular leakage, changes in retinal thickening, the length of time to quiescence and the ability to taper concomitant immunosuppressive medications. Safety outcomes for each cohort include the number and severity of systemic and ocular toxicities and adverse events, the proportion of participants who experience vision loss of greater than or equal to 15 letters as measured by Electronic Visual Acuity (EVA) and the number of participants who experience a substantial rise in elevated intraocular pressure (IOP).

Initial IV infusion of ustekinumab at baseline followed by one subcutaneous injection at Week 8. In participants who demonstrate an allergic reaction to the baseline IV infusion, the second dose at Week 8 can also be administered as an IV infusion instead of a subcutaneous injection.

The primary outcome is the number of participants in each cohort who experience a treatment response by Week 16. Treatment response is defined as experiencing all of the following for both/eligible eyes: no active inflammatory chorioretinal lesion and/or absent or decreased retinal vascular leakage; ≤ 0.5+ anterior chamber (AC) cells; ≤ 0.5+ vitreous haze.

Mean change in visual acuity in the right eye at all follow-up visits (Week 4, Week 8, Week 12, Week 16, and Week 28) compared to baseline as measured by electronic visual acuity (EVA).

Mean change in visual acuity in the left eye at all follow-up visits (Week 4, Week 8, Week 12, Week 16, and Week 28) compared to baseline as measured by electronic visual acuity (EVA).

Median change in visual acuity in the right eye at all follow-up visits (Week 4, Week 8, Week 12, Week 16, and Week 28) compared to baseline as measured by electronic visual acuity (EVA).

Median change in visual acuity in the left eye at all follow-up visits (Week 4, Week 8, Week 12, Week 16, and Week 28) compared to baseline as measured by electronic visual acuity (EVA).

Number of participants in each cohort who experience a recurrence of uveitis at each follow-up visit (Week 4, Week 8, Week 12, and Week 16). Recurrence of uveitis is defined as the presence of one of the following in at least one eye: 1) new active inflammatory chorioretinal lesion and/or retinal vascular leakage; 2) a 2+ increase in anterior chamber (AC) cells relative to Baseline; 3) a 2-step increase in vitreous haze (VH) relative to Baseline; 4) worsening of best-corrected visual acuity (BCVA) by ≥ 15 letters relative to Baseline.

Mean number of days following the baseline injection until first recurrence (of the participants who recur). Recurrence of uveitis is defined as the presence of one of the following in at least one eye: 1) new active inflammatory chorioretinal lesion and/or retinal vascular leakage; 2) a 2+ increase in anterior chamber (AC) cells relative to Baseline; 3) a 2-step increase in vitreous haze (VH) relative to Baseline; 4) worsening of best-corrected visual acuity (BCVA) by ≥ 15 letters relative to Baseline.

Median number of days following the baseline injection until first recurrence (of the participants who recur). Recurrence of uveitis is defined as the presence of one of the following in at least one eye: 1) new active inflammatory chorioretinal lesion and/or retinal vascular leakage; 2) a 2+ increase in anterior chamber (AC) cells relative to Baseline; 3) a 2-step increase in vitreous haze (VH) relative to Baseline; 4) worsening of best-corrected visual acuity (BCVA) by ≥ 15 letters relative to Baseline.

Presence or Extent of Macular Edema as Determined by Optical Coherence Tomography (OCT) in the Right Eye at All Follow-up Visits

Presence or extent of macular edema as determined by optical coherence tomography (OCT) in the right eye at all follow-up visits (Week 4, Week 8, Week 12, Week 16, and Week 28). The number of participants that did and did not have macular edema present is presented.

Presence or Extent of Macular Edema as Determined by Optical Coherence Tomography (OCT) in the Left Eye at All Follow-up Visits

Presence or extent of macular edema as determined by optical coherence tomography (OCT) in the left eye at all follow-up visits (Week 4, Week 8, Week 12, Week 16, and Week 28). The number of participants that did and did not have macular edema present is presented.

Presence or Extent of Macular Edema as Determined by Fluorescein Angiogram (FA) in the Right Eye at All Follow-up Visits

Presence or extent of macular edema as determined by fluorescein angiogram (FA) in the right eye at all follow-up visits (Week 4, Week 8, Week 12, Week 16, and Week 28). The number of participants that did and did not have macular edema present is presented.

Presence or Extent of Macular Edema as Determined by Fluorescein Angiogram (FA) in the Left Eye at All Follow-up Visits

Presence or extent of macular edema as determined by fluorescein angiogram (FA) in the left eye at all follow-up visits (Week 4, Week 8, Week 12, Week 16, and Week 28). The number of participants that did and did not have macular edema present is presented.

Amount of Retino-vascular Leakage as Measured by Fluorescein Angiogram (FA) in the Right Eye at All Follow-up Visits

Amount of retino-vascular leakage as measured by fluorescein angiogram (FA) in the right eye at all follow-up visits (Week 4, Week 8, Week 12, Week 16, and Week 28). The number of participants experiencing presence and new/increased lesions, presence and decreased lesions, presence and no new/increased or decreased lesions, and absence of lesions are presented.

Amount of Retino-vascular Leakage as Measured by Fluorescein Angiogram (FA) in the Left Eye at All Follow-up Visits

Amount of retino-vascular leakage as measured by fluorescein angiogram (FA) in the left eye at all follow-up visits (Week 4, week 8, Week 12, Week 16, and Week 28). The number of participants experiencing presence and new/increased lesions, presence and decreased lesions, presence and no new/increased or decreased lesions, and absence of lesions are presented.

Changes in Central Retinal Thickness as Measured by Optical Coherence Tomography (OCT) in the Right Eye at All Follow-up Visits Compared to Baseline

Mean change in central retinal thickness as measured by optical coherence tomography (OCT) in the right eye at all follow-up visits (Week 4, Week 8, Week 12, Week 16, and Week 28) compared to baseline.

Changes in Central Retinal Thickness as Measured by Optical Coherence Tomography (OCT) in the Left Eye at All Follow-up Visits Compared to Baseline

Mean change in central retinal thickness as measured by optical coherence tomography (OCT) in the left eye at all follow-up visits (Week 4, Week 8, Week 12, Week 16, and Week 28) compared to baseline.

Mean length of time to first experience of quiescence in the right eye. Quiescence refers to absence of active disease defined as not having the following conditions: +1 or more vitreous haze; and/or active chorioretinitis or leakage on fluorescein angiogram (FA) (that is more than one quadrant) that requires treatment.

Mean length of time to first experience of quiescence in the left eye. Quiescence refers to absence of active disease defined as not having the following conditions: +1 or more vitreous haze; and/or active chorioretinitis or leakage on fluorescein angiogram (FA) (that is more than one quadrant) that requires treatment.

Number of Participants Experiencing a Clinically Significant Increase in Elevated Intraocular Pressure (IOP) at Any Follow-up Visit

Number of participants experiencing a clinically significant increase in elevated intraocular pressure (IOP) at any follow-up visit in either eye. An increase in IOP ≥10 mmHg as compared with baseline is considered a clinically significant increase.

Proportion of participants with ≥15 letter loss in best-corrected visual acuity (BCVA) from baseline at any follow-up visit in either eye.

Number and severity of systemic and ocular toxicities and adverse events for participants in both cohorts. Severity of each event is classified as mild, moderate, or severe. Natural progression of disease adverse events are not included.

-INCLUSION CRITERIA: Participant has the ability to understand and sign the informed consent document. Participant is 18 years of age or older. Participant has negative purified protein derivative (PPD) or quantiferon testing done within three months prior to enrollment or had latent tuberculosis (TB) but has completed prophylactic anti-TB treatment. Participant has active intermediate uveitis, posterior uveitis or panuveitis in at least one eye requiring systemic therapy. Active disease is defined as: +1 or more vitreous haze (according to Standardization of Uveitis Nomenclature (SUN) criteria) AND/OR Active chorioretinitis or leakage on Fluorescein angiography (FA)(that is in more than one quadrant) that requires treatment. Participant has visual acuity in at least one eye of 20/400 or better. Participant is willing and able to comply with the study procedures. 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 testing 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 effective methods of contraception throughout the course of the study and for six weeks after the last investigational product injection. Acceptable methods of contraception for this study 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: Participant has a significant active infection (an infection requiring treatment as determined by the medical team), including active tuberculosis or human immunodeficiency virus (HIV). Participant received a live vaccination within the past six weeks. Participant is expected to receive a live vaccination at any time during the study. Participant received the Bacillus Calmette-Guerin (BCG) vaccine within the past year. Participant is expected to receive the BCG vaccine at any time during the study or up to one year after discontinuing ustekinumab. Participant has a history of cancer (other than a non-melanoma skin cancer) diagnosed within the past five years. Participant has received intraocular (or periocular) steroid or anti-vascular endothelial growth factor (VEGF) injections within the last six weeks. Participant received rituximab within the last six months or another biologic agent (e.g., infliximab, daclizumab, adalimumab) within the last two months. Participant has received alkylating agents (e.g., cyclophosphamide, chlorambucil) within the last nine months. Participant has a known hypersensitivity to ustekinumab or any of its components.