A Multicenter Study of the Efficacy and Safety of the Human Anti-TNF Monoclonal Antibody Adalimumab in Subjects with Inactive Non-infectious Intermediate-, Posterior-, or Pan-uveitis (M10-880)

Overview

Status: Enrolling by invitation
Keywords: uveitis , retina , ophthalmology
IRB Number: 00043122
Specialty: Ophthalmology, Ophthalmology, Ophthalmology
Sub Specialties: Uveitis, Retinal Diseases,

Brief Summary

Adalimumab is a recombinant full-length immunoglobulin that binds to human tumor necrosis factor- a naturally occurring cytokine that is involved in normal inflammatory and immune responses. It was first approved by the Food and Drug Administration (FDA) for the treatment of subjects with rheumatoid arthritis (RA) in the United States (US) in December 2002. In addition to RA, indication claims for psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, and psoriasis have been approved in the US, the EU, and a number of other countries worldwide.
 

 
The objective of this study is to evaluate the efficacy and safety of adalimumab 80 mg loading dose followed by 40 mg dose given every other week subcutaneously starting at compared with placebo as maintenance therapy in subjects requiring high dose corticosteroid therapy for inactive non-infectious intermediate-, posterior-, or pan-uveitis.

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 18 years of age or older.
 
2. Subject is diagnosed with non-infectious intermediate-, posterior- or pan-uveitis.
 
3. Subject with inactive disease for > or equal to 28 days prior to Baseline and is taking greater than or equal to 10 mg of oral prednisone to maintain this inactive state and, based on the Investigators' clinical judgment, fulfills all 3 of the following criteria at the Screening and Baseline visits for both eyes:
 
• Subject without active, inflammatory chorioretinal and/or inflammatory retinal vascular lesion.
 
• Subject with Anterior Chamber Cell grade < or equal to 0.5+ according to SUN criteria.
 
• Subject with Vitreous Haze grade < or equal to 0.5+ according to NEI/SUN criteria.
 

 
4. Subject is on prednisone 10 to 35 mg (or corticosteroid equivalent) at Baseline and the dose has not been increased in the past 28 days or decreased in the past 14 days.
 
5. Subject must have a documented history of experiencing at least one disease flare within 18 months of the Screening visit. This flare has to occur during or up to a maximum of 28 days after tapering off the oral corticosteroid therapy.

6. 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
 

 
7. 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 (CXR), and a 12-lead electrocardiogram (ECG) performed during Screening.
 
8. Subject must be able and willing to self-administer sub-cutaneous injenctions or have a qualified person available to administer sub-cutaneous injections.

9. Subjectmust be able and willing to provide written informed consent and comply with the requirements of this study protocol.

10. 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. Subjects with a BCG vaccination and postive PPD are excluded.  Subjects with a positive TB test (either PPD or QuantiFERON®-TB Gold test) are excluded irrespective of BCG vaccination history.

Subjects with previous TB are also not eligible for this study

Exclusion Criteria

Exclusion Criteria
 
1. Subject with isolated anterior uveitis.
 
2. Subject with confirmed or suspected infectious uveitis, including but not limited to infectious uveitis due to TB, CMV (cytomegalovirus), Lyme disease, toxoplasmosis, human T-lymphotropic virus type 1 infection (HTLV-1), Whipple's disease, herpes zoster virus (HZV) and HSV (herpes simplex virus).
 
3. Subject with presumed ocular histoplasmosis syndrome.
 
4. Subject with ocular masquerade syndromes, such as ocular lymphoma.
 
5. Subject with serpiginous choroidopathy.
 
6. Subject has a contraindication to pupil dilation with mydriatic eyedrops.
 
7. Subject with corneal or lens opacity that precludes visualization of the fundus or that likely requires cataract surgery during the duration of the trial.
 
8. Subject with intraocular pressure of > or equal to 25 mmHg and on 2 or more glaucoma medications or evidence of glaucomatous optic nerve injury.
 
9. Subject with best corrected visual acuity (BCVA) score  less than 20 letters (ETDRS [Early Treatment Diabetic Retinopathy Study]) in at least one eye at the Baseline visit only.
 
10. 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.

 
11. Subject has previous exposure to anti-TNF therapy and any biologic therapy with a potential therapeutic impact on non-infectious uveitis. Subject has previous exposure to anti-TNF therapy or any biologic therapy (except intravitreal anti-VEGF therapy with a potential therapeutic impact on non-infectious uveitis)
 
12. Subject on more than 1 immunosuppressive therapy (not including corticosteroids) within the last 28 days prior to the Baseline visit.
 
13. Subject on concomitant immunosuppressive therapy other than methotrexate, cyclosporine, mycophenolate mofetil or an equivalent drug to mycophenolate mofetile (e.g., mycophenolic acid), tacrolimus, or azathioprine within 28 days of Baseline.
 
14. If entering the study on one concomitant immunosuppressive therapy, dose has not been stable for at least 28 days prior to the Baseline visit and is not within the following allowable doses:
 
• Methotrexate less than or equal to 25 mg per week
 
• Cyclosporine less than or equal to 4 mg/kg per day
 
• Mycophenolate mofetil (or equivalent) less than or equal to 2 grams per day
 
• Azathioprine less than or equal to 175 mg per day

  • Tacrolimus (oral formulation) less than or equal to 8 mg per day.

 

 
15. Subject with prior or current use of chlorambucil.
 
16. Subject has received glucocorticosteroid implant (Retisert®) within 3 years prior to the baseline visit or that have had complications related to the device.  Subject has had Retisert (glucocorticosteroid implant) removed within 90 days prior to the Baseline visit or has had complications within 90 days prior to the baseline visit.

17. Subject has received intraocular or periocular corticosteroids within 90 days prior to the Baseline visit.
 
18.  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.

19. Subject with any planned (elective) eye surgery within the next 80 weeks from Baseline.
 
20. Subject with proliferative or severe non-proliferative diabetic retinopathy or clinically significant macular edema due to diabetic retinopathy.
 
21. Subject with neovascular/wet age-related macular degeneration.
 
22. 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.
 
23. Subject with a systemic inflammatory disease that requires continued therapy with oral corticosteroids or a prohibited immunosuppressive agent at Screening or Baseline visits.
 
24. 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.
 
25. Prior exposure to Tysabri® (natalizumab) or Raptiva® (efalizumab).
 
26. 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.
 
27. 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.
 
28. History of CNS (central nervous system) demyelinating disease or neurologic symptoms suggestive of CNS demyelinating disease, including scleritis
 
29. History of listeriosis, histoplasmosis, chronic or active Hepatitis B infection, human immunodeficiency virus (HIV) infection or immunodeficiency syndrome. Subjects with chronic recurring infections or active TB.
 
30. Known hypersensitivity to adalimumab or its excipients.
 
31. Positive pregnancy test at Screening or Baseline.
 
32. Female subjects who are breast-feeding or considering becoming pregnant during the study.
 
33. 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.
 
34. History of clinically significant drug or alcohol abuse in the last 12 months, including recreational or medical marijuana use.
 
35. Subject is considered by the Investigator, for any reason, to be an unsuitable candidate for the study.
 
36. Clinically significant abnormal screening laboratory results as evaluated by the Investigator.
 
37. Subject with a positive syphilis Test. Syphilis testing will consist of Fluorescent Treponemal Antibody (FTA) testing.
 
38. 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 stable for at least 28 days prior to the Baseline visit 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

These non-biologic immunosuppressive therapies may have efficacy in uveitis. However, because we are requiring stable doses 28 days prior and 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. If subjects enter the study on none of the above non-biologic immunosuppressive therapies, the subject must have discontinued non-biologic immunosuppressive therapies including methotrexate, cyclosporine, mycophenolate mofetil or azathioprine > 28 days prior to Baseline and remain off of the medications throughout the study.  For subjects with glaucoma, prostaglandin ophthalmic solutions (e.g., latanoprost, bimatoprost, travoprost, etc.) cannot be initiated nor discontinued 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. 
 
39. Subject with cystoid macular edema unless documented retinal changes are persistent, residual, and stable as defined by the Standardization of Uveitis Nomenclature (SUN) criteria (persistent is greater than 3 months duration).

 
40. Subject has received Ozurdex (dexamethasone implant) within 6 months prior to baseline visit.

41. Subject has received intravitreal MTX within 90 days prior to the baseline visit.

42. 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).

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

44. 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.

45. 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.

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

47. Subject with a history of scleritis.

48. Subjects who require TB-prophylaxis.

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