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

NCT00304954 | Completed Phase 2 Results DMC

• 2 other identifiers: 06011106-EI-0111
• Study Type: interventional
• Target: 13
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Age-Related Macular Degeneration; Choroidal Neovascularization

Keywords

Age-Related Macular Degeneration; Rapamycin; Remicade; Daclizumab; Immunosuppression; Infliximab; Choroidal Neovascularization; Sirolimus; AMD; Ocular Inflammation

Outcome Measures

Primary Outcomes (1)

• Monthly Rates of Anti-VEGF (Vascular Endothelial Growth Factor) Injections

  24 Weeks

Secondary Outcomes (2)

• Changes in Best-corrected Visual Acuity (BCVA) as Measured by the Standard Early Treatment Diabetic Retinopathy Study (ETDRS) Protocol From Baseline to 24 Weeks

  Baseline and 6 months (24 weeks) - Baseline and 3.5 months for Patient 7

• Changes in Retinal Thickness as Measured by Optical Coherence Tomography (OCT) From Baseline to 24 Weeks

  Baseline and 6 months (24 weeks) - Baseline and 3.5 months for Patient 7

Study Arms (4)

Intravenous Daclizumab

ACTIVE COMPARATOR

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

Intravenous Infliximab

ACTIVE COMPARATOR

Participants randomized to IV infliximab received 3 mg/kg of IV infliximab monthly for 6 months.

Drug: Intravenous Infliximab

Oral Rapamycin

ACTIVE COMPARATOR

Participants randomly assigned to rapamycin received 2 mg in capsule form every other day for 6 months.

Drug: Oral Rapamycin

Observation

OTHER

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

Interventions

Intravenous Daclizumab DRUG

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.

Also known as: Zenapax

Intravenous Daclizumab

Intravenous Infliximab DRUG

Participants randomized to IV infliximab received 3 mg/kg of IV infliximab monthly for 6 months.

Also known as: Remicade

Intravenous Infliximab

Observation OTHER

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.

Observation

Oral Rapamycin DRUG

Participants randomly assigned to rapamycin received 2 mg in capsule form every other day for 6 months.

Also known as: Sirolimus

Oral Rapamycin

Eligibility Criteria

• Age: 55 Years - 92 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Understand and sign the institutional review board (IRB)-approved informed consent document for the study.
• Age greater than 55 years.
• In the study eye, diagnosis of AMD defined by the presence of drusen larger than 63 microns.
• Any anti-angiogenic therapy in the study eye within 7 days of beginning immunosuppressive therapy.
• In the study eye, the participant's study eye vision is between 20/20 and 20/400.
• 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:
• Early stippled hyperfluorescence of flat retinal pigment epithelium (RPE)and little or mild leakage in the late frames of the fluorescein (occult).
• 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).
• 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).
• 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).
• For all CNV lesions considered to have occult CNV with no classic CNV, one of the following criteria must be met:
• 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).
• Documented FA evidence of a 10% increase in the lesion greatest linear dimension over the 3 months prior to enrollment.
• Documented blood associated with CNV.
• 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.

You may not qualify if:

• CNV, in the study eye, associated with other ocular diseases such as pathologic myopia, ocular histoplasmosis or posterior uveitis, etc.
• Presence of geographic atrophy under the fovea in the study eye.
• 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.
• The presence of a chorio-retinal anastomosis.
• 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.
• 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.
• Presence of fibrosis, hemorrhage, pigment epithelial detachments and other hypofluorescent lesions obscuring greater than 50% of the CNV lesion.
• 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.
• 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.
• Participant with a corneal melting, necrotizing keratitis, or impending vision loss.
• Participants with history of allergy to/or exposure to mouse protein.
• Participant with scleritis of infectious etiology.
• 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.
• Participant has significant active infection requiring hospitalization.
• Participant with multiple sclerosis.

Sponsors & Collaborators

• National Eye Institute (NEI): lead

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (4)

• Aeberli D, Oertle S, Mauron H, Reichenbach S, Jordi B, Villiger PM. Inhibition of the TNF-pathway: use of infliximab and etanercept as remission-inducing agents in cases of therapy-resistant chronic inflammatory disorders. Swiss Med Wkly. 2002 Jul 27;132(29-30):414-22. doi: 10.4414/smw.2002.10031.

  PMID: 12428187 BACKGROUND

• Antoni C, Dechant C, Hanns-Martin Lorenz PD, Wendler J, Ogilvie A, Lueftl M, Kalden-Nemeth D, Kalden JR, Manger B. Open-label study of infliximab treatment for psoriatic arthritis: clinical and magnetic resonance imaging measurements of reduction of inflammation. Arthritis Rheum. 2002 Oct 15;47(5):506-12. doi: 10.1002/art.10671.

  PMID: 12382299 BACKGROUND

• Bian ZM, Elner SG, Strieter RM, Kunkel SL, Lukacs NW, Elner VM. IL-4 potentiates IL-1beta- and TNF-alpha-stimulated IL-8 and MCP-1 protein production in human retinal pigment epithelial cells. Curr Eye Res. 1999 May;18(5):349-57. doi: 10.1076/ceyr.18.5.349.5353.

  PMID: 10372996 BACKGROUND

• Nussenblatt RB, Byrnes G, Sen HN, Yeh S, Faia L, Meyerle C, Wroblewski K, Li Z, Liu B, Chew E, Sherry PR, Friedman P, Gill F, Ferris F 3rd. A randomized pilot study of systemic immunosuppression in the treatment of age-related macular degeneration with choroidal neovascularization. Retina. 2010 Nov-Dec;30(10):1579-87. doi: 10.1097/IAE.0b013e3181e7978e.

  PMID: 20847709 RESULT

MeSH Terms

Conditions

Macular Degeneration; Choroidal Neovascularization

Interventions

Daclizumab; Infliximab; Observation; Sirolimus

Condition Hierarchy (Ancestors)

Retinal Degeneration; Retinal Diseases; Eye Diseases; Choroid Diseases; Uveal Diseases; Neovascularization, Pathologic; Metaplasia; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Methods; Investigative Techniques; Macrolides; Lactones; Organic Chemicals

Results Point of Contact

• Title: Dr. Robert Nussenblatt, MD, MPH
• Organization: NEI

robert.nussenblatt@nih.gov

301-496-3123

Study Officials

• Robert Nussenblatt, MD, MPH

  National Eye Institute (NEI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 17, 2006
• First Posted: March 20, 2006
• Study Start: February 1, 2006
• Primary Completion: January 1, 2010
• Study Completion: January 1, 2010
• Last Updated: November 29, 2016
• Results First Posted: April 12, 2011

Record last verified: 2016-11

Locations

US (1)