Gilead Filgotinib GS-US-432-4097

Principal Investigator: Albert Vitale
Keywords: Ocular inflammation , Uveitis , Oral medication Department: Ophthalmology-Services
IRB Number: 00103949 Co Investigator:  
Specialty: Ophthalmology, Ophthalmology
Sub Specialties: Uveitis, Retinal Diseases
Recruitment Status: Not yet recruiting

Contact Information

Kimberley Wegner
kimberley.wegner@hsc.utah.edu
801-581-6265

Brief Summary

The primary objective of this study is:

  • To evaluate the efficacy of filgotinib versus placebo for the treatment of the signs and symptoms of non-infectious uveitis as measured by the proportion of subjects failing treatment for active non-infectious uveitis by Week 24

The secondary objectives of this study are:

  • To evaluate the efficacy of filgotinib versus placebo for the treatment of non-infectious uveitis as measured by the time to treatment failure on or after Week 6

  • To evaluate the efficacy of filgotinib versus placebo for the treatment of non-infectious uveitis as measured by the change in vitreous haze (VH) grade in each eye (National Eye Institute /Standardization of Uveitis Nomenclature [NEI/SUN] criteria), from best state achieved prior to Week 6 to Week 52/ End of Treatment (EOT) visit or Early Termination (ET) visit 

  • To evaluate the efficacy of filgotinib versus placebo for the treatment of non-infectious uveitis as measured by the change in anterior chamber (AC) cell grade in each eye, from best state achieved prior to Week 6 to Week 52/ EOT visit or ET visit

  • To evaluate the effects of filgotinib versus placebo as measured by the change in logarithm of the minimal angle of resolution (logMAR) best corrected visual acuity (BCVA) in each eye, from best state achieved prior to Week 6 to Week 52/EOT visit or ET visit

  • To evaluate the efficacy of filgotinib versus placebo for the treatment of non-infectious uveitis as measured by the change in central retinal thickness in each eye, from best state achieved prior to Week 6 to Week 52/ EOT visit or ET visit

  • To evaluate the efficacy of filgotinib versus placebo for the treatment of non-infectious uveitis as measured by the time to development of macular edema in at least one eye as determined by optical coherence tomography (OCT) on or after Week 6

  • To evaluate the safety and tolerability of filgotinib

  • To evaluate the pharmacokinetics of filgotinib and its metabolite GS-829845

The exploratory objectives of this study are:

  • To evaluate the efficacy of filgotinib versus placebo for the treatment of non-infectious uveitis as measured by the change in severity of retinal vascular leakage in each eye, from best state achieved prior to Week 6 to Week 52/EOT visit or ET visit

  • To evaluate the efficacy of filgotinib versus placebo on the change in the NEI Visual Functioning Questionnaire (VFQ-25) composite score and subscore measures (distance vision, near vision, ocular pain), from best state achieved prior to Week 6 to Week 52/EOT visit or ET visit

  • To evaluate the efficacy of filgotinib versus placebo on general quality of life as measured by the Short-Form Health Survey (SF-36) and EuroQoL 5-dimension score (EQ-5D)

  • To evaluate the efficacy of filgotinib versus placebo on work productivity and activity as measured by the Work Productivity and Activity Impairment Questionnaire: Specific Health Problem Questionnaire (WPAI-UVEITIS)

  • To evaluate the efficacy of filgotinib versus placebo for the treatment of non-infectious uveitis on peripheral blood markers of inflammation and immune status

  • To evaluate the association of changes in systemic biomarkers with clinical outcomes

  • To characterize the association of host genetics and other biomarkers with disease severity, disease progression and treatment response to filgotinib

Inclusion Criteria

  1. Judged to be in good health as determined by the investigator based on the results of medical history, laboratory screening profile, physical examination, chest x-ray, and 12-lead electrocardiogram performed during Screening

  2. A negative serum pregnancy test is required for female subjects of childbearing potential.

  3. Male subjects and female subjects of childbearing potential who engage in heterosexual intercourse must agree to use protocol specified method(s) of contraception

    1. Preferred birth control methods include:  Intrauterine device (IUD) with a failure rate of <1% per year, Tubal sterilization, Essure micro-insert system (with confirmation of success 3 months after procedure), Vasectomy in male partner (provided that the partner is the only sexual partner and had confirmation of surgical success at least 3 months after procedure)

    2. Acceptable hormonal methods (must be used with a barrier method): Oral contraceptives (either combined or progesterone only), Injectable progesterone, Implants of levonorgestrel, Transdermal contraceptive patch or Contraceptive vaginal ring

    3. Acceptable barrier methods (must be used with a hormonal method): Male or female condom with or without spermicide, Diaphragm with spermicide, Cervical cap with spermicide or Sponge with spermicide

  4. Lactating females must agree to discontinue nursing before the study drug is administered.

  5. Male or female subjects who are ≥ 18 years of age on the day of signing informed consent

  6. Diagnosed with non-infectious intermediate-, posterior-, or pan-uveitis

  7. Active uveitic disease at the Day 1/Baseline visit as defined by the presence of at least 1 of the following parameters in at least one eye despite at least 2 weeks of maintenance therapy with oral prednisone (≥ 10 mg/day to ≤ 60 mg/day) or an oral corticosteroid equivalent:

    1. Active, inflammatory, chorioretinal and/or inflammatory retinal vascular lesion

    2. ≥ 2+ anterior chamber cells (SUN criteria)

    3. ≥ 2+ vitreous haze (NEI/SUN criteria)

  8. On oral prednisone ≥ 10 mg/day to ≤ 60 mg/day (or oral corticosteroid equivalent) for 2 or more weeks prior to Day 1/Baseline and remains on the same dose until Day 1/Baseline visit

  9. Documented prior adequate response to oral corticosteroids (equivalent of oral prednisone up to 1 mg/kg/day)

  10. No evidence of active tuberculosis (TB), history of prior TB or latent TB. Subjects must meet both of the following screening criteria:

    1. A negative QuantiFERON® TB-Gold In-Tube test at screening,  AND

    2. A chest radiograph (views as per local guidelines) taken at screening or within the 3 months prior to screening (with the report or films available for investigator review) without evidence of active or latent TB infection, Subjects with an indeterminate QuantiFERON-TB Gold test result may undergo a repeat test.  --  Subjects with a repeat indeterminate test result (two indeterminate results in total) are not eligible to participate in this trial. In the event of a negative TB screening test, the results will be interpreted in the context of the subject’s epidemiology, history, exam findings, etc. It is the responsibility of the investigator to determine whether a subject has previous, active, or latent tuberculosis. No subject with a positive QuantiFERON-TB Gold test or two indeterminate results (see above) are eligible for rescreening.

  11. Able and willing to sign the informed consent as approved by the Independent Ethics Committee (IEC)/Institutional Review Board (IRB). Written consent must be provided before initiating any screening evaluations. Subjects must have read and understood the ICF, must fully understand the requirements of the study, and must be willing to comply with all study visits and assessments. Subjects who cannot understand the ICF may not be enrolled by a guardian or any other individual.

Exclusion Criteria

  1. The presence of isolated anterior uveitis

  2. The presence of macular edema as the only sign of uveitis

  3. Intolerance to or prior inadequate response to high-dose oral corticosteroids (equivalent of oral prednisone 1 mg/kg/day or 60 to 80 mg/day)

  4. Confirmed or suspected infectious uveitis, including but not limited to infectious uveitis due to TB, cytomegalovirus (CMV), Human T-Lymphotropic Virus Type 1 (HTLV-1), Whipple's disease, Herpes Zoster virus (HZV), Lyme disease, toxoplasmosis and herpes simplex virus (HSV)

  5. Presumed ocular histoplasmosis syndrome (as determined by the investigator)

  6. Ocular masquerade syndromes such as ocular lymphoma (as determined by the investigator)

  7. Serpiginous choroidopathy

  8. Corneal or lens opacity that precludes visualization of the fundus or that likely requires cataract surgery during the duration of the trial

  9. Severe glaucoma at screening defined as:

    1. Intraocular pressure of ≥ 25 mmHg and on ≥ 2 glaucoma medications and/or

    2. Any evidence of glaucomatous optic nerve injury

  10. Exposure to a systemic carbonic anhydrase inhibitor within 1 week prior to Screening

  11. Best Corrected Visual Acuity (BCVA) less than 20 letters (Early Treatment Diabetic Retinopathy Study[ETDRS]) in at least one eye at the Day 1/Baseline Visit 

  12. Previous exposure to a JAK inhibitor

  13. Prior exposure to anti-TNF therapy or any biologic therapy (except intravitreal anti-vascular endothelial growth factor [VEGF] therapy) with a potential therapeutic impact on non-infectious uveitis within 90 days of Day 1/Baseline

  14. Prior failure of anti- TNF therapy in controlling uveitis, or failure of any biologic therapy (except intravitreal anti-vascular endothelial growth factor [VEGF] therapy) with a potential therapeutic impact on non-infectious uveitis.

  15. Received intravitreal anti-VEGF therapy within 45 days of the Day 1/Baseline visit for Lucentis® (ranibizumab) or Avastin® (bevacizumab) or within 60 days of the Day 1/Baseline visit for anti-VEGF Trap (aflibercept)

  16. Use of more than 1 immunosuppressive therapy (not counting corticosteroids) at Day 1/Baseline

  17. Using concomitant immunosuppressive therapy at Day 1/Baseline other than methotrexate, cyclosporine, mycophenolate mofetil or an equivalent drug (eg, mycophenolic acid), azathioprine, or tacrolimus

  18. If entering the study on 1 concomitant immunosuppressive therapy, dose has been increased within 28 days prior to Day 1/Baseline visit or is not within the following allowable doses:

    1. Methotrexate (MTX) ≤ 25 mg per week

    2. Cyclosporine ≤ 4 mg/kg per day

    3. Mycophenolate mofetil ≤ 2 g per day or an equivalent drug to mycophenolate mofetil (e.g. mycophenolic acid) at an equivalent dose approved by the Medical Monitor

    4. Azathioprine ≤ 175 mg per day

    5. Tacrolimus (oral formulation) ≤ 8 mg per day

  19. Systemic inflammatory disease requiring continued therapy with oral corticosteroids or a prohibited immunosuppressive agent at screening or Day 1/Baseline

  20. Received Retisert® (glucocorticosteroid implant) within 3 years prior to the Day 1/Baseline visit or has had complications related to the device

  21. Received intraocular or periocular corticosteroids within 30 days prior to Day 1/Baseline visit

  22. Presence of proliferative or severe non-proliferative diabetic retinopathy or clinically significant macular edema due to diabetic retinopathy

  23. Presence of neovascular/wet age-related macular degeneration

  24. Presence of a clinically significant abnormality of vitreo-retinal interface per investigator discretion (i.e., vitreomacular traction, epiretinal membranes, etc.) with the potential for macular structural damage independent of the inflammatory process

  25. Presence of severe vitreous haze that precludes visualization of the fundus at the Day 1/Baseline visit

  26. Received Ozurdex® (dexamethasone implant) within 3 months prior to the Day 1/Baseline visit

  27. Received intravitreal methotrexate within 90 days prior to the Day 1/Baseline visit

  28. Use of cyclophosphamide within 30 days prior to the Day 1/Baseline visit

  29. Evidence of any clinically significant (as per the judgement of the investigator) active or chronic recurring infection, opportunistic infection, or immunodeficiency syndrome

  30. Severe (anaphylactic) reactions to fluorescein or unwillingness to perform fluorescein angiograms

  31. Known hypersensitivity to filgotinib, its metabolites, or formulation excipients

  32. Contraindication to pupil dilation with mydriatic eye drops

  33. History of major surgery (requiring regional block or general anesthesia) or trauma within 30 days prior to screening 

  34. History of prior ocular surgery within 90 days before Day 1/Baseline with the exception of refractive laser surgery, retinal laser photocoagulation, or neodymium-doped yttrium aluminium garnet posterior capsulotomy. These 3 exceptions are exclusionary within 30 days before Day 1/Baseline

  35. Planned (elective) eye surgery within 52 weeks after Day 1/Baseline

  36. Any infection requiring hospitalization or treatment with intravenous anti-infectives within 60 days of screening; or any infection requiring oral anti-infective therapy within 30 days of screening

  37. A positive test result for HIV-1 antibody

  38. Evidence of active HCV infection. Subjects with positive HCV antibody (Ab) at screening, require reflex testing for HCV RNA. Subjects with positive HCV RNA at screening will be excluded. Subjects with positive HCV Ab, but negative HCV RNA are eligible per investigator judgment, but require ongoing monitoring as outlined in the schedule of assessments. Subjects with active HCV during the study, as evidenced by HCV RNA positivity will be discontinued from study drug as outlined in the protocol.

  39. Evidence of active HBV infection. Subjects with positive Hepatitis B surface antigen (HBsAg) at screening are excluded from the study. Subjects with positive HBV core Ab and negative HBsAg, require reflex testing for HBV DNA. Subjects with positive HBV DNA at screening will be excluded. Subjects with positive HBV core Ab, and negative HBV DNA are eligible per investigator judgment, but may require prophylactic treatment in accordance with HBV treatment guidelines/local standard of care and require ongoing monitoring with blood tests for HBV DNA every 3 months. Subjects with evidence of active Hepatitis B during the study, as evidenced by HBV DNA positivity, will be discontinued from study drug as outlined in the protocol.

  40. Positive test for syphilis (fluorescent treponemal antibody)

  41. History of malignancy within the last 5 years prior to screening (except for adequately treated basal cell carcinoma or non-metastatic squamous cell carcinoma of the skin or cervical carcinoma in situ, with no evidence of recurrence)

  42. History of lymphoproliferative disorder or current lymphoproliferative disease

  43. History of gastrointestinal perforation

  44. History of organ or bone marrow transplant

  45. History of leukocytapheresis ≤ 6 months prior to screening

  46. Use of any prohibited concomitant medications as described in Section 5.4.2

  47. Any chronic, uncontrolled medical condition (including, but not limited to, cardiac or pulmonary disease) or psychiatric problem (including, but not limited to alcohol or drug abuse) which would put the subject at increased risk during study participation, such as uncontrolled: diabetes, hypertension, morbid obesity, thyroid, adrenal, pulmonary, hepatic, renal, neurologic or psychiatric disease, or other disease of concern, as per judgment of investigator

  48. Administration of a live or attenuated vaccine within 30 days of Day 1/Baseline

  49. Not willing to refrain from administration of live or attenuated vaccines during the study and for 6 weeks after last dose

  50. Currently on any chronic systemic (oral or intravenous) anti-infective therapy for chronic infection (such as pneumocystis, cytomegalovirus [CMV], herpes zoster, and atypical mycobacteria).

  51. History of disseminated Staphylococcus aureus

  52. History of symptomatic herpes zoster or herpes simplex within 12 weeks of screening, or any history of disseminated herpes simplex, herpes zoster, ophthalmic zoster, or central nervous system zoster

  53. Current drug (including marijuana), tobacco or alcohol abuse, per investigator judgment

  54. Any condition or circumstances which in the opinion of the investigator or sponsor may make a subject unlikely or unable to complete the study or comply with study procedures and requirements

  55. Participation in any clinical study of an investigational drug/device within 4 weeks or 5 half-lives (whichever is longer) of the drug prior to Day 1/Baseline. Exposure to investigational biologics should be discussed with the sponsor.

  56. Tests performed at the central laboratory at screening that meet any of the criteria below (out of range lab values may be retested one time, at the discretion of the investigator before subject is considered a screen-failure):

    1. Hemoglobin < 8.0 g/dL (International System of Units [SI]: < 80 g/L);

    2. White blood cells < 3.0 x 103 cells/mm3 (SI: < 3.0 x 109 cells/L);

    3. Neutrophils < 1.5 x 103 cells/mm3 (SI: < 1.5 x 109 cells/L);

    4. Lymphocytes < 0.5 x 103 cells/mm3 (SI: < 0.5 x 109 cells/L);

    5. Platelets < 100 x 103 cells/mm3 (SI: < 100 x 109cells/L);

    6. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥ 1.5 x ULN;

    7. Total bilirubin level ≥ 2x ULN unless the subject has been diagnosed with Gilbert’s disease and this is clearly documented;

    8. Estimated creatinine clearance < 40 mL/min based on the Cockroft Gault formula {Cockcroft 1976}