Infliximab, Sirolimus and Daclizumab to Treat Age-Related Macular Degeneration (AMDB1)

This study has been completed.
Sponsor:
Information provided by:
National Institutes of Health Clinical Center (CC)
ClinicalTrials.gov Identifier:
NCT00304954
First received: March 17, 2006
Last updated: April 13, 2011
Last verified: April 2011
  Purpose

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.


Condition Intervention Phase
Age-Related Macular Degeneration
Choroidal Neovascularization
Drug: Intravenous Daclizumab
Drug: Intravenous Infliximab
Other: Observation
Drug: Oral Rapamycin
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Treatment of Choroidal Subretinal Neovascularization With Agents Directed Against the Immune Response

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:
  • Monthly Rates of Anti-VEGF (Vascular Endothelial Growth Factor) Injections [ Time Frame: 24 Weeks ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Changes in Retinal Thickness as Assessed by Optical Coherence Tomography and Changes in Visual Acuity [ Time Frame: 24 Weeks ] [ Designated as safety issue: No ]

Enrollment: 13
Study Start Date: February 2006
Study Completion Date: January 2010
Primary Completion Date: January 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Intravenous Daclizumab
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.
Drug: Intravenous Daclizumab
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.
Other Name: Zenapax
Active Comparator: Intravenous Infliximab
Participants randomized to IV infliximab received 3 mg/kg of IV infliximab monthly for 6 months.
Drug: Intravenous Infliximab
Participants randomized to IV infliximab received 3 mg/kg of IV infliximab monthly for 6 months.
Other Name: Remicade
Active Comparator: Oral Rapamycin
Participants randomly assigned to rapamycin received 2 mg in capsule form every other day for 6 months.
Drug: Oral Rapamycin
Participants randomly assigned to rapamycin received 2 mg in capsule form every other day for 6 months.
Other Name: Sirolimus
Observation
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.
Other: Observation
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.

Detailed Description:

There has been much interest in the possible role of the immune system in AMD. Experimental models and patient material have, to date, suggested a role for macrophages and complement. This study hypothesized that the underlying mechanism that leads to choroidal neovascularization (CNV) is similar to those at play in atherosclerosis. If this is the case, the investigators believed that CNV treatment should be amenable to new immunomodulatory agents directed against specific parts of the immune system.

After therapy with anti-angiogenic agents not leading to a persistent remission of CNV due to AMD, participants were treated with one of three immunomodulatory agents or were observed in conjunction with their continued anti-angiogenic therapy. Thus the participant continued with the anti-angiogenic therapy they received after randomization. The investigators hypothesized that this combination therapy would inhibit progression of CNV associated with AMD.

This was an open-label, phase II, randomized, single center clinical trial of 18 study participants randomized to receive one of three immunomodulatory agents or was observed in conjunction with their anti-angiogenic therapy.

  Eligibility

Ages Eligible for Study:   55 Years to 92 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

INCLUSION CRITERIA:

  1. Understand and sign the 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 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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00304954

Locations
United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, United States, 20892
Sponsors and Collaborators
Investigators
Principal Investigator: Robert Nussenblatt, MD, MPH National Eye Institute (NEI)
  More Information

Publications:
Responsible Party: Robert B. Nussenblatt, MD, MPH/National Eye Institute, National Institutes of Health
ClinicalTrials.gov Identifier: NCT00304954     History of Changes
Other Study ID Numbers: 060111, 06-EI-0111
Study First Received: March 17, 2006
Results First Received: January 31, 2011
Last Updated: April 13, 2011
Health Authority: United States: Food and Drug Administration

Keywords provided by National Institutes of Health Clinical Center (CC):
Age-Related Macular Degeneration
Rapamycin
Remicade
Daclizumab
Immunosuppression
Infliximab
Choroidal Neovascularization
Sirolimus
AMD
Ocular Inflammation

Additional relevant MeSH terms:
Choroidal Neovascularization
Macular Degeneration
Neovascularization, Pathologic
Choroid Diseases
Eye Diseases
Metaplasia
Pathologic Processes
Retinal Degeneration
Retinal Diseases
Uveal Diseases
Daclizumab
Everolimus
Infliximab
Sirolimus
Analgesics
Analgesics, Non-Narcotic
Anti-Bacterial Agents
Anti-Infective Agents
Anti-Inflammatory Agents
Anti-Inflammatory Agents, Non-Steroidal
Antibiotics, Antineoplastic
Antifungal Agents
Antineoplastic Agents
Antirheumatic Agents
Central Nervous System Agents
Dermatologic Agents
Gastrointestinal Agents
Immunologic Factors
Immunosuppressive Agents
Peripheral Nervous System Agents

ClinicalTrials.gov processed this record on October 29, 2014