A Multicenter Study of the Efficacy and Safety of the Human Anti-TNF Monoclonal Antibody Adalimumab as Maintenance Therapy in Subjects Requiring High Dose Corticosteroids for Active Non-infectious Intermediate-, Posterior-, or Pan-uveitis (M10-877)


Status: Recruiting
Keywords: Masked trial for people with active uveitis randomized to placebo or adilibumab , uveitis , retina , ophthalmology
IRB Number: 00042501
Specialty: Ophthalmology, Ophthalmology
Sub Specialties: Uveitis, Retinal Diseases

Brief Summary

The objective of this study is to evaluate the efficacy and safety of adalimumab 80 mg loading dose followed by 40 mg given every other week subcutaneously compared with placebo as maintenance therapy in subjects requiring high dose corticosteroids for active non-infectious intermediate-, posterior- or pan-uveitis (inflammation of the iris, ciliary body, choroid, and sometimes retina).

Principal Investigator: Albert Vitale
Department: Ophthalmology-Services
Co Investigator:

Contact Information

Name:Kimberley Wegner
Phone: 801-581-6265
Email: kimberley.wegner@hsc.utah.edu

Inclusion Criteria

Inclusion Criteria:
A subject will be eligible for study participation if she/he meets the following criteria:

1. Subject is greater than or equal to 18 years of age.
2. Subject is diagnosed with non-infectious intermediate-, posterior- or pan-uveitis.
3. Subject must have active disease at Baseline as defined by the presence of at least 1 of the following parameters in at least one eye despite at least 2 weeks of prednisone greater than or equal to 10 mg/day to less than or equal to 60 mg/day (or oral corticosteroid equivalent):
• Active, inflammatory, chorioretinal and/or inflammatory retinal vascular lesion
• Greater than or equal to 2+ anterior chamber cells (Standardization of Uveitis Nomenclature [SUN] criteria)
• Greater than or equal to 2+ vitreous haze (National Eye Institute [NEI]/SUN criteria)

4. Subject is on prednisone greater than or equal to 10 mg/day to less than or equal to 60 mg/day (or corticosteroid equivalent) for at least 2 weeks prior to Screening and remains on the same dose from Screening to Baseline visit.
5. If female, subject is either not of childbearing potential, defined as postmenopausal for at least 1 year or surgically sterile (bilateral tubal ligation, bilateral oophorectomy or hysterectomy) or is of childbearing potential and is practicing an approved method of birth control throughout the study and for 150 days after the last dose of study drug. The results of the serum pregnancy test performed during the Screening period and urine pregnancy test performed at the Baseline visit must be negative.
Examples of approved methods of birth control include the following:
• Condoms, sponge, foams, jellies, diaphragm or intrauterine device (IUD)
• Oral, parenteral or intravaginal contraceptives for 90 days prior to study drug administration
• A vasectomized partner

6. Subject is judged to be in good health as determined by the Principal Investigator based upon the results of medical history, laboratory profile, physical examination, chest x-ray, and a 12-lead electrocardiogram (ECG) performed during Screening.
7. Subject must be able and willing to self-administer sub-cutaneous injections or have a qualified person available to administer sub-cutaneous injections.
8. Subject must be able and willing to provide written informed consent and comply with the requirements of this study protocol.

9. Subjects who do not have previous, active or latent TB. Only one TB test is required to allow the subject in the study. Subjects with either negative PPD (< 5 mm of induration) or negative QuantiFERON®-TB Gold test (or IGRA equivalent) are eligible. Subjects with a repeat indeterminate QuantiFERON®-TB Gold test (or IGRA equivalent) result are not eligible.

Note, that only one TB screening test is allowed and required. A repeat QuantiFERON®-TB Gold test (or IGRA equivalent) is not permitted if the PPD skin test is positive.

The TB screening tests are diagnostic tests. In the event of a negative TB screening test, the results are to be interpreted in the context of the patient's epidemiology, history, exam findings, etc. and it is the responsibility of the investigator to determine if a patient has previous, active or latent tuberculosis or not. Under no circumstances can a patient with a positive PPD result or positive QuantiFERON®-TB Gold test (or IGRA equivalent) enter the study.

10. Subject with documented prior adequate response to oral corticosteroids (equivalent of oral prednisone up to 1 mg/kg/day).

Exclusion Criteria

Exclusion Criteria
1. Subject with isolated anterior uveitis.
2. Subject with prior inadequate response to or intolerance to high-dose corticosteroids (equivalent of prednisone 1 mg/kg/day or 60 to 80 mg/day).
3. Subject with confirmed or suspected infectious uveitis, including but not limited to infectious uveitis due to TB, CMV (cytomegalovirus), Lyme disease, Human T-Lymphotropic Virus Type 1 (HTLV-1) infection, Whipple's disease, toxoplasmosis, herpes zoster virus, and HSV (herpes simplex virus).
4. Subject with presumed ocular histoplasmosis syndrome.
5. Subject with ocular masquerade syndromes, such as ocular lymphoma.
6. Subject with serpiginous choroidopathy.
7. Subject has a contraindication to pupil dilation with mydriatic eyedrops.
8. Subject with corneal or lens opacity that precludes visualization of the fundus or that likely requires cataract surgery during the duration of the trial.
9. Subject with intraocular pressure of greater than or equal to 25 mmHg and on greater than or equal to 2 glaucoma medications or evidence of glaucomatous optic nerve injury.
10. Subject with best corrected visual acuity (BCVA) score to less than 20 letters (ETDRS) in at least one eye at the baseline visit.
11. Subject with intermediate uveitis or panuveitis that has signs of intermediate uveitis (e.g., presence or history of snowbanking or snowballs) and symptoms and/or Magnetic Resonance Imaging (MRI) findings suggestive of a demyelinating disease such as multiple sclerosis. All subjects with intermediate uveitis or panuveitis that have signs of intermediate uveitis (e.g., presence or history of snowbanking or snowballs) must have a brain MRI within 90 days prior to the Baseline visit.

12. Subject has previous exposure to anti-TNF therapy and any biologic therapy (except intravitreal anti-vascular endothelial growth factor [VEGF] therapy) with a potential therapeutic impact on non-infectious uveitis.
13. Subject on more than 1 immunosuppressive therapy (not including corticosteroids) at Baseline.
14. Subject on concomitant immunosuppressive therapy other than methotrexate, cyclosporine, mycophenolate mofetil (or mycophenolate mofetil equivalent)  azathioprine, or tacrolimus at Baseline.
15. If entering the study on 1 concomitant immunosuppressive therapy, dose has been increased within the last 28 days prior to Baseline visit and is not within the following allowable doses:
• Methotrexate < or equal to 25 mg per week
• Cyclosporine < or equal to 4 mg/kg per day
• Mycophenolate mofetil < or equal to 2 grams per day
• Azathioprine < or equal to 175 mg per day

Tacrolimus (oral formulation) 8 mg per day

16. Subject with prior or current use of chlorambucil.

17. Subject has received glucocorticosteroid implant (Retisert®) within 3 years prior to the baseline visit or that have had complications related to the device.
18. Subject has received intraocular or periocular corticosteroids within 30 days prior to the Baseline visit.
19.  Subject with history of prior ocular surgery within 90 days prior to the Baseline visit with the exception of refractive laser surgery or retinal laser photocoagulation or YAG (neodymium-doped yttrium aluminium garnet) posterior capsulotomy. These three exceptions are exclusionary within 30 days prior to Baseline.

 20. Subject with any planned (elective) eye surgery within the next 80 weeks from Baseline.
21. Subject with proliferative or severe non-proliferative diabetic retinopathy or clinically significant macular edema due to diabetic retinopathy.
22. Subject with neovascular/wet age-related macular degeneration.
23. Subject with abnormality of vitreo-retinal interface (i.e., vitreomacular traction, epiretinal membranes, etc.) with the potential for macular structural damage independent of the inflammatory process.
24. Subject with a systemic inflammatory disease that requires continued therapy with oral corticosteroids or a prohibited immunosuppressive agent at Screening or Baseline visits.
25. Subject has been treated with any investigational drug of chemical or biologic nature within a minimum of 30 days or 5 half lives (whichever is longer) of the drug prior to the Baseline visit.
26. Prior exposure to Tysabri® (natalizumab) or Raptiva® (efalizumab).
27. Infection(s) requiring treatment with intravenous (IV) anti-infectives within 30 days prior to the Baseline visit or oral anti-infectives within 14 days prior to the Baseline visit.
28. History of moderate to severe congestive heart failure (NYHA class III or IV), recent cerebrovascular accident and any other condition which, in the opinion of the Investigator, would put the subject at risk by participation in the protocol.
29. History of CNS (central nervous system) demyelinating disease or neurologic symptoms suggestive of CNS demyelinating disease.
30. subjects with chronic recurring infections, active TB result at screening visit and/or a history of invasive infection (ie, listeriosis and histoplasmosis), chronic or active Hepatitis B infection, human immunodeficiency virus (HIV) infection, or immunodeficiency syndrome.
31. Known hypersensitivity to adalimumab or its excipients
32. Positive pregnancy test at Screening or Baseline.
33. Female subjects who are breast-feeding or considering becoming pregnant during the study.
34. Evidence of dysplasia or history of malignancy (including lymphoma and leukemia) other than a successfully treated non-metastatic cutaneous squamous cell, basal cell carcinoma or localized carcinoma in situ of the cervix.
35. History of clinically significant drug or alcohol abuse in the last 12 months.
36. Subject is considered by the Investigator, for any reason, to be an unsuitable candidate for the study.
37. Clinically significant abnormal screening laboratory results as evaluated by the Investigator.
38. Subject with a positive Syphilis Test (FTA).
39. Subject is not in compliance with Section 5.2.3. (Subjects will be allowed to continue on one ongoing non-biologic immunosuppressive therapy at study entry provided the dose has been not been increased within the past 28 days prior to Baseline and must remain unchanged throughout the study. In addition, doses must be within the acceptable limits listed below:

MTX 25 mg per week

Cyclosporine 4 mg/kg per day

Mycophenolate mofetil 2 grams per day

Azathioprine 175 mg per day

Tacrolimus (oral formulation) 8 mg per day

These non-biologic immunosuppressive therapies may have efficacy in uveitis. However, because we are not allowing increase in doses 28 days prior and doses must be stable throughout the entire study, whatever therapeutic benefit these drugs might have on uveitis would have been achieved prior to study entry and should not fluctuate for the duration of the study.

For subjects who are on > 1 systemic immunosuppressive therapy at screening, all but 1 should be discontinued prior to Baseline. There is no required washout period for the discontinued concomitant immunosuppressive.

For subjects with glaucoma, prostaglandin ophthalmic solutions (e.g., latanoprost, bimatoprost, travoprost, etc.) cannot be initiated nor discontinued during the study. Dosage of other topical eye drops for glaucoma may be adjusted as medically necessary during the study. Live vaccines may not be given concurrently while on study drug or for 70 days after the last dose of study drug.)
40. Subject with severe vitreous haze that precludes visualization of the fundus at the Baseline visit.

41. Subject has received Ozurdex® (dexamethasone implant) within 6 months prior to Baseline visit.

42. Subject has received intravitreal MTX within 90 days prior to the Baseline visit.

43. Subject has received intravitreal anti-VEGF therapy:

within 45 days of the Baseline visit for Lucentis® (ranibizumab) or Avastin® (bevacizumab);

or within 60 days of the Baseline visit for anti-VEGF Trap (Aflibercept).

44. History of marijuana use, including medical or recreational marijuana in the last 12 months.

45. Hepatitis B: HBsAg positive (+) or detection at or above level of sensitivity on the HBV-DNA PCR qualitative test for HBcAb, Total and/or HBsAb positive subjects. 

46. Subject with an active systemic viral infection or any active viral infection that based on the investigator's clinical assessment makes the subject an unsuitable candidate for the study.

47. Subject on systemic carbonic anhydrase inhibitor within 1 week prior to Screening visit.

48. Subject with macular edema as the only sign of uveitis.

49. Subject with a history of scleritis.

50. Subjects who require TB prophylaxis.

51. Subject with intolerance to high-dose oral corticosteroids (equivalent of oral prednisone 1 mg/kg/day or 60 to 80 mg/day).

52. Subject on cyclophosphamide within 30 days prior to the Baseline visit.