Infliximab, Sirolimus and Daclizumab to Treat Age-Related Macular Degeneration
Condition: Age-Related Macular Degeneration; Choroidal Neovascularization
MeSH terms: Macular Degeneration; Choroidal Neovascularization; Neovascularization, Pathologic
Intervention: Intravenous Daclizumab; Intravenous Infliximab; Observation; Oral Rapamycin
Intervention description: Participants randomly assigned to intravenous (IV) daclizumab received 8 mg/kg of IV daclizumab at baseline, then 4 mg/kg of IV daclizumab at Week 2 and then 2 mg/kg of IV daclizumab monthly for the rest of the 6-month study.; Participants randomized to IV infliximab received 3 mg/kg of IV infliximab monthly for 6 months.; Participants randomly assigned to the observation group were given injections of either bevacizumab (1.25 mg/0.05 mL or 2.5 mg/0.1 mL) or ranibizumab (0.5 mg) if they presented with recurrence of intraretinal or subretinal fluid as seen on Stratus Optical Coherence Tomography.; Participants randomly assigned to rapamycin received 2 mg in capsule form every other day for 6 months.
Intervention MeSH terms: Sirolimus; Infliximab; Daclizumab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 13.0
Sex: All
Minimum age: 55 Years
Maximum age: 92 Years
Healthy volunteers: No
Keywords: Age-Related Macular Degeneration; Rapamycin; Remicade; Daclizumab; Immunosuppression; Infliximab; Choroidal Neovascularization; Sirolimus; AMD; Ocular Inflammation

Summary:

      This study examined whether the anti-inflammatory medicines infliximab, sirolimus or
      daclizumab, when given with a participant's current therapies, would prevent the growth of
      new blood vessels in the eye in participants with age-related macular degeneration (AMD).

      Participants 55 years of age and older with AMD and drusen larger than 63um may be eligible
      for this study. Vision in the study eye was between 20/20 and 20/400.

      Participants were randomly assigned to one of three treatments - infliximab, sirolimus, or
      daclizumab - or to observation only. In addition, participants may have been treated by their
      ophthalmologist as needed for their AMD.

      Infliximab and daclizumab were given intravenously (through a vein); infusions were given at
      enrollment in the study, then at 2 weeks, and then monthly.

      Sirolimus was a pill that was taken every other day for the duration of the study. At 6
      months, participants were evaluated to see whether continuing treatment would be beneficial.

      In addition to treatment or observation, participants underwent the following procedures:

      Physical examination at enrollment and 6 months.

      Photographs of the back of the eye, fluorescein angiography, indocyanine green angiography
      and measurement of retinal thickness at enrollment and months 1, 3 and 6.

        -  Fluorescein angiography evaluated the eye's blood vessels. A yellow dye was injected
           into an arm vein and traveled to the blood vessels in the eyes. Pictures of the retina
           were taken using a camera that flashed a blue light into the eye. The pictures show if
           any dye has leaked from the vessels into the retina, indicating possible blood vessel
           abnormality.

        -  Indocyanine green angiography identified feeder vessels that may have supplied abnormal
           blood vessels. This procedure is similar to fluorescein angiography, but uses a green
           dye and flashes an invisible light.

        -  Optical coherence tomography measures retinal thickness. This test shines a light into
           the eye and produces cross-sectional pictures of the retina. These measurements are
           repeated during the study to determine whether retinal thickening is getting better or
           worse, or staying the same.

      Tuberculin skin test and chest x-ray at enrollment and 6 months.

      Blood tests at enrollment and months 1, 3 and 6.
    

Eligibility criteria:

        INCLUSION CRITERIA:

          1. Understand and sign the institutional review board (IRB)-approved informed consent
             document for the study.

          2. Age greater than 55 years.

          3. In the study eye, diagnosis of AMD defined by the presence of drusen larger than 63
             microns.

          4. Any anti-angiogenic therapy in the study eye within 7 days of beginning
             immunosuppressive therapy.

          5. In the study eye, the participant's study eye vision is between 20/20 and 20/400.

          6. In the study eye, the presence of CNV under the fovea determined by the investigators
             and defined as any one of the following fluorescein angiographic (FA) features:

               1. Early stippled hyperfluorescence of flat retinal pigment epithelium (RPE)and
                  little or mild leakage in the late frames of the fluorescein (occult).

               2. Irregular elevation of the RPE that does not exhibit discrete or bright
                  hyperfluorescence in the early transit phase of the angiogram. Stippled
                  hyperfluorescence may be present. Late frames may show persistent fluorescein
                  staining or leakage within a sensory retinal detachment overlying this area
                  (occult).

               3. Late-phase leakage of undetermined source with leakage at the level of the RPE in
                  the late-phase frames of the angiogram in which the source of the late leakage
                  cannot be determined from earlier-phase frames of the angiogram (occult).

               4. A well-demarcated area of bright hyperfluorescence in the early phase of the
                  angiogram with leakage through the mid- and late-phase frames which obscures the
                  boundaries of the area (classic).

          7. For all CNV lesions considered to have occult CNV with no classic CNV, one of the
             following criteria must be met:

               1. A documented loss of visual acuity (5 or more letters of best-corrected visual
                  acuity if both measurements are made using an Early Treatment for Diabetic
                  Retinopathy Study (ETDRS) chart or, a doubling of the visual angle if Snellen
                  acuities are available from either an outside referral center or within the
                  participating center (e.g., 20/80 to 20/160) a doubling of the visual angle is
                  required because of the measurement variability of Snellen acuities).

                  OR

               2. Documented FA evidence of a 10% increase in the lesion greatest linear dimension
                  over the 3 months prior to enrollment.

                  OR

               3. Documented blood associated with CNV.

          8. The greatest linear dimension of the entire lesion (classic CNV, occult CNV and any
             features that could obscure the identification of classic or occult CNV) has to be
             less than or equal to 5400 microns in greatest linear dimension on the retina as
             measured by the treating ophthalmologist.

          9. Retinal photographs and angiography of sufficient quality, allowing assessment of the
             macular area according to standard clinical practice, can be obtained.

         10. Women of childbearing potential must not be pregnant or lactating, must have a
             negative pregnancy test at screening and must be practicing an adequate method of
             birth control. Acceptable methods of birth control include intrauterine device (IUD);
             oral, dermal, implanted or injected contraceptives; tubal ligation; and barrier
             methods with spermicide.

         11. Willingness to comply with the protocol.

        EXCLUSION CRITERIA:

          1. CNV, in the study eye, associated with other ocular diseases such as pathologic
             myopia, ocular histoplasmosis or posterior uveitis, etc.

          2. Presence of geographic atrophy under the fovea in the study eye.

          3. Evidence of retinal angiomatous proliferation as suspected by the presence of
             intraretinal hemorrhage, intraretinal leakage, adjoining serous pigment epithelial
             detachment (PED) or the presence of a connecting retinal vessel.

          4. The presence of a chorio-retinal anastomosis.

          5. Decreased vision, in the study eye, due to retinal disease not attributable to CNV,
             such as nonexudative forms of AMD, geographic atrophy, inherited retinal dystrophy,
             uveitis or epiretinal membrane. Participants who have any additional ocular diseases
             that have irreversibly compromised or, during follow-up, could likely compromise the
             visual acuity (VA) of the study eye including amblyopia, anterior ischemic optic
             neuropathy, clinically significant diabetic macular edema, severe non-proliferative
             diabetic retinopathy, or proliferative diabetic retinopathy.

          6. Decreased vision, in the study eye, due to significant media opacity such as corneal
             disease or cataract, or opacity precluding photography of the retina; a tear (rip) of
             the RPE; a vitelliform-like lesion of the outer retina (e.g., as in pattern
             dystrophies or basal laminar drusen), idiopathic parafoveal telangiectasis, or central
             serous retinopathy.

          7. Presence of fibrosis, hemorrhage, pigment epithelial detachments and other
             hypofluorescent lesions obscuring greater than 50% of the CNV lesion.

          8. History of other systemic antiangiogenic treatment or treatment for CNV (not including
             photodynamic therapy and pegaptanib sodium injections) in the study eye with
             transpupillary thermotherapy or other local treatment (such as submacular surgery).
             Previous laser photocoagulation therapy is acceptable, provided it was not subfoveal.

          9. Participant with a known underlying systemic disease with evidence of serious or
             potentially lethal uncontrolled active disease in one or more extraocular organ
             systems for which a defined effective medical regimen is indicated.

         10. Participant with a corneal melting, necrotizing keratitis, or impending vision loss.

         11. Participants with history of allergy to/or exposure to mouse protein.

         12. Participant with scleritis of infectious etiology.

         13. Participant receiving any other investigational therapy or another anti-tumor necrosis
             factor (TNF) agent that would interfere with the ability to evaluate the safety or
             efficacy of infliximab.

         14. Participant has significant active infection requiring hospitalization.

         15. Participant with multiple sclerosis.

         16. Participant has severe (class 3/4) congestive heart failure.

         17. Participant has a history of cancer within the past 5 years other than basal or
             squamous cell carcinoma.

         18. Participant is pregnant or lactating.

         19. Participant with posterior scleritis.

         20. Participant has evidence of liver disease (any etiology). History of moderate to
             severe abnormal liver function, unless documented evidence of normal liver enzymes is
             provided.

         21. Participant has positive PPD (tuberculosis test) unless cleared by Internal Medicine.

         22. Participant has positive Chest X-ray showing acute pulmonary disease.

         23. Participant has unexplained hematuria.

         24. Participant has a history of alkylating therapy use.

         25. Current exam evidence of ocular toxoplasmosis; pseudoexfoliation; external ocular
             infection, including conjunctivitis; chalazion; significant blepharitis; or aphakia in
             the study eye (pseudophakic participants are eligible).

         26. Intraocular surgery (including lens replacement surgery) within 6 weeks prior to
             randomization.

         27. Recent history of (within the last 6 months), or current acute ocular or periocular
             infection (including any history of ocular herpes zoster or simplex).

         28. Known hypersensitivity/allergy to verteporfin, porfimer sodium, or other porphyrins,
             porphyria or other porphyrin sensitivity, or hypersensitivity to sunlight or bright
             artificial light. Participation in any other clinical study or are receiving, or have
             received any experimental systemic treatment for AMD (e.g., retinoic acid,
             thalidomide). Local therapy for AMD is permitted.

         29. Medical problems that make consistent follow-up over the treatment period unlikely
             (e.g., stroke, severe myocardial infarction (MI), end stage malignancy), any
             contraindications to performing the necessary diagnostic studies (i.e., known allergy
             to fluorescein dyes etc.), or in general a poor medical risk because of other systemic
             diseases or active uncontrolled infections.

         30. Participant has a history of moderate to severe abnormal liver function, unless
             documented evidence of normal liver enzymes is provided.

         31. Participant has a history of active pulmonary tuberculosis.

         32. Participant has a history of active viral hepatitis.

         33. Participant has chronic continued Ketoconazole use.