Ignite Creation Date:
2024-05-05 @ 6:34 PM
Last Modification Date:
2024-10-26 @ 9:34 AM
Study NCT ID:
NCT00505947
Status:
TERMINATED
Last Update Posted:
2009-02-20
First Post:
2007-07-23
Brief Title:
Treatment of Refractory Diabetic Macular Edema With Infliximab
Sponsor:
University of Athens
Organization:
University of Athens
Study Overview
Official Title:
Infliximab for Diabetic Macular Edema Refractory to Laser Photocoagulation a Randomized Double-Masked Placebo-Controlled Cross-Over 32 Weeks Study
Status:
TERMINATED
Status Verified Date:
2009-02
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
The number of the anticipated participants was not achieved
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
The purpose of this study is to determine if treatment with infliximab improves macular edema which is refractory to laser photocoagulation in patients with diabetes
Detailed Description:
Retinopathy affects on average 30 of all patients with diabetes Good glycaemic control delays the onset and progression of retinopathy in subjects with both type 1 and type 2 diabetes However the incidence of retinopathy has not been declining in type 1 diabetes over the last decades even if visual acuity may be better preserved As many as 20 of the patients with type 2 diabetes mellitus have already retinopathy at the time of diagnosis of diabetes Diabetic macular edema DME is a serious manifestation of diabetic retinopathy that produces loss of central vision Data from the Wisconsin Epidemiological Study of Diabetic Retinopathy WESDR estimate that after 15 years of known duration of diabetes the prevalence of DME is 20 in patients with type 1 diabetes mellitus 25 in patients with type 2 diabetes who are treated with insulin and 14 in the patients with type 2 diabetes who are not treated with insulin Concerning the natural history a previous study has shown that 53 of the eyes with DME involving the centre of the macula lost two or three lines of visual acuity over a two year period In addition in the Early Treatment Diabetic Retinopathy Study ETDRS 33 of untreated eyes available for follow-up at the 3-year visit all with oedema involving the centre of the macula at baseline had experienced a 15 or more letter decrease in visual acuity score
The federal budgetary cost of blindness was estimated to be 41 billion in the US for the year 1990 and 97 of these costs were accounted for by the working-age adult group Health care and economic burdens are further compounded by the resulting decline in quality of life thus the true impact on society cannot be estimated on a monetary basis alone
Although the etiology of DME is unclear an altered local expression of the pleiotropic cytokine tumor necrosis factor TNF may play an important role in pathogenesis Standard treatment of clinically significant DME ie reduction of visual acuity due to DME consists of laser photocoagulation two sessions for optimal results However this treatment effectively reduces the risk of vision loss in only 50 of cases Even among those patients who achieve an initial response recurrences are common requiring ongoing treatment Vitreomacular traction or the vitreous itself may play a role in increased retinal vascular permeability Removal of the vitreous or relief of mechanical traction with pars plana vitrectomy and membrane stripping may be followed by substantial resolution of macular edema and improvement in visual acuity However this treatment may be applicable only in specific subset of eyes with DME It also requires a complex surgical intervention with its inherent risks recovery time and expenses Other treatment modalities such as pharmacologic therapy with oral protein kinase C inhibitors antibodies targeted at vascular endothelial growth factor VEGF intravitreal corticosteroid injection or high doses of non-steroidal anti-inflammatory agents that lower retinal expression of TNF are under investigation
Infliximab is a chimeric IgG1 monoclonal antibody with an approximate molecular weight of 149100 Dalton It is composed of human constant and murine variable regions Infliximab binds specifically to human tumour necrosis factor alpha TNF-a with an association constant of 1010 M-1 Infliximab is produced by a recombinant cell line cultured by continuous perfusion and is purified by a series of steps that includes measures to inactivate and remove viruses
Infliximab is currently used for the treatment of inflammatory arthritic conditions and inflammatory disease with a favorable safety profile Because of the limitations of current treatments for DME and based on our recent findings indicating that infliximab is an effective therapy for cystoid ME associated with uveitis we decided to assess whether infliximab is effective for patients with diabetes type 1 or 2 and sight-threatening DME
We have found that a clinically meaningful anatomic and functional improvement was achieved after two infliximab infusions in 4 of 6 eyes with severe diffuse DME ie macular thickness 400 μm in contrast the remaining 2 eyes with coexisting epiretinal membranes did not improve The observed recovery of useful vision represents a very significant clinical result especially for those eyes in which DME was refractory to laser photocoagulation Comparable beneficial results have been obtained in our patients with severe chronic cystoid ME complicating intermediate uveitis Adamantiades-Behcets disease or adult type vascular pseudotumor Repeated treatment in one diabetic patient produced a further significant improvement of DME indicating that the clinical response to anti-TNF dosing regimens is individualized as it has also been observed in patients with arthritis or in patients with uveitic ME Thus a sustained beneficial effect of infliximab for DME may require long-term treatment Infliximab was well tolerated by our patients in all studies conducted at our site
Results from a preliminary study suggest a central role for TNF-mediated pathogenesis mechanisms in DME Recent experimental evidence also indicates that low-grade subclinical inflammation is responsible for many of the signature vascular lesions of diabetic retinopathy On the other hand studies in patients with arthritis have shown that anti-TNF therapy negatively affects vascular permeability and angiogenesis by decreasing the potent angiogenic vascular endothelial growth factor which has been implicated directly in the pathogenesis of DME and diabetic retinopathy
Four women aged 52 to 76 years with type 2 diabetes who were in danger of vision loss due to severe DME were included in this prospective non-comparative case series They all used oral antidiabetic agents for 14 to 20 years while one patient required exogenous insulin therapy for the last 4 years Patients were free of other major medical disorders and they had no evidence of infection Following full discussion and after obtaining informed consent 2 infusions of infliximab 5mgkg Remicade Schering-Plough Greece with one month interval were given intravenously over 3 hours in an outpatient setting on a compassionate basis Additional infusions were offered in 3 patients Concomitant medications remained unchanged
Complete ophthalmic examination and Optical Coherence Tomography OCT Model 3000 Zeiss Humphrey Systems were performed immediately before each infliximab infusion as well as 2 months after the last infusion The main outcome measurements were best corrected visual acuity BCVA and macular thickness The OCT-derived maximum height of DME was recorded as described previously in detail The student t-test for paired data was used to compare logarithm of minimum angle of resolution logMAR transformed BCVA as well as macular thickness between baseline and post-treatment
DME was present in 7 eyes 6 of which were refractory to previous treatment with laser photocoagulation DME was classified as severe in 6 eyes range of macular thickness 420-720 μm and as mild in 1 eye macular thickness of 290 μm after vitrectomy A dense epiretinal membrane was present in 2 eyes with severe DME BCVA at baseline was profoundly impaired ranging from hand motion to 01 at the Snellen chart At one month after the first infliximab infusion macular thickness had decreased in 5 from 7 eyes from meanSD503 171 to 426 165 μm p0033 The 2 eyes with coexisting epiretinal membranes did not improve Two months after the second infusion the macular thickness had further regressed to 330 134 μm range 170 to 515 μm p0028 compared to baseline The BCVA was increased in all 5 eyes from a baseline mean at the Snellen chart of 003 to 015 logMAR 142 045 to 082 027 p001
At 3 months post-baseline a third infliximab infusion was offered in those 3 patients who had the least improvement of DME Repeated OCT after 2 months revealed a further decrease of macular thickness in 3 of 5 eyes by 7 15 and 23 respectively At this point the patient who still had the most severe condition received a fourth infliximab infusion remarkably a repeated OCT two months later revealed a marked resolution of severe DME while BCVA had improved from counting fingers at baseline to 02 Infliximab therapy was well tolerated and no ocular or extra-ocular side effects were noted In further available follow-up ranging from 4 to 7 months post-treatment a recurrence of DME was observed in 2 of 5 eyes albeit at a less severe level
For detailed information about the safety of infliximab please refer to summary of product characteristics Active tuberculosis may develop soon after the initiation of treatment with infliximab Before prescribing the drug physicians should screen patients for latent tuberculosis infection or active disease
Based on the above we believe that administration of infliximab may be a reasonable therapeutic approach in diabetic patients who are in danger of vision loss due to refractory DME Therefore a controlled study on the safety and efficacy of infliximab treatment in DME refractory to laser photocoagulation is warranted Because of our preliminary results 27 we feel that all patients who will participate in such a study should be granted the opportunity to receive infliximab therefore a cross-over design is proposed A cross-over design would also enhance the statistical power of the study achieving the same statistical power with fewer patients
Within this study additional questions could be addressed For example TNF in patients with diabetes is secreted mainly by the fat cells and is involved in the development of insulin resistance and decline in the pancreatic beta-cell function Previous studies examined the effect of anti-TNF treatment on indices of insulin resistance in non-diabetic subjects and showed that chronic treatment with anti-TNF agents may improve insulin sensitivity in humans
The research programme will involve one country Greece and will include a total of 26 patients with type 1 or type 2 diabetes The planned treatment period will be 32 weeks Patients with clinically significant DME ie BCVA 04 refractory to at least two sessions of laser photocoagulation or who have leaking microaneurysms within the foveal avascular zone FAZ making laser photocoagulation unsafe for the central vision will be included in the study The study will be conducted in compliance with the protocol ICH guidelines Good Clinical Practice GCP and the applicable regulatory requirements
The federal budgetary cost of blindness was estimated to be 41 billion in the US for the year 1990 and 97 of these costs were accounted for by the working-age adult group Health care and economic burdens are further compounded by the resulting decline in quality of life thus the true impact on society cannot be estimated on a monetary basis alone
Although the etiology of DME is unclear an altered local expression of the pleiotropic cytokine tumor necrosis factor TNF may play an important role in pathogenesis Standard treatment of clinically significant DME ie reduction of visual acuity due to DME consists of laser photocoagulation two sessions for optimal results However this treatment effectively reduces the risk of vision loss in only 50 of cases Even among those patients who achieve an initial response recurrences are common requiring ongoing treatment Vitreomacular traction or the vitreous itself may play a role in increased retinal vascular permeability Removal of the vitreous or relief of mechanical traction with pars plana vitrectomy and membrane stripping may be followed by substantial resolution of macular edema and improvement in visual acuity However this treatment may be applicable only in specific subset of eyes with DME It also requires a complex surgical intervention with its inherent risks recovery time and expenses Other treatment modalities such as pharmacologic therapy with oral protein kinase C inhibitors antibodies targeted at vascular endothelial growth factor VEGF intravitreal corticosteroid injection or high doses of non-steroidal anti-inflammatory agents that lower retinal expression of TNF are under investigation
Infliximab is a chimeric IgG1 monoclonal antibody with an approximate molecular weight of 149100 Dalton It is composed of human constant and murine variable regions Infliximab binds specifically to human tumour necrosis factor alpha TNF-a with an association constant of 1010 M-1 Infliximab is produced by a recombinant cell line cultured by continuous perfusion and is purified by a series of steps that includes measures to inactivate and remove viruses
Infliximab is currently used for the treatment of inflammatory arthritic conditions and inflammatory disease with a favorable safety profile Because of the limitations of current treatments for DME and based on our recent findings indicating that infliximab is an effective therapy for cystoid ME associated with uveitis we decided to assess whether infliximab is effective for patients with diabetes type 1 or 2 and sight-threatening DME
We have found that a clinically meaningful anatomic and functional improvement was achieved after two infliximab infusions in 4 of 6 eyes with severe diffuse DME ie macular thickness 400 μm in contrast the remaining 2 eyes with coexisting epiretinal membranes did not improve The observed recovery of useful vision represents a very significant clinical result especially for those eyes in which DME was refractory to laser photocoagulation Comparable beneficial results have been obtained in our patients with severe chronic cystoid ME complicating intermediate uveitis Adamantiades-Behcets disease or adult type vascular pseudotumor Repeated treatment in one diabetic patient produced a further significant improvement of DME indicating that the clinical response to anti-TNF dosing regimens is individualized as it has also been observed in patients with arthritis or in patients with uveitic ME Thus a sustained beneficial effect of infliximab for DME may require long-term treatment Infliximab was well tolerated by our patients in all studies conducted at our site
Results from a preliminary study suggest a central role for TNF-mediated pathogenesis mechanisms in DME Recent experimental evidence also indicates that low-grade subclinical inflammation is responsible for many of the signature vascular lesions of diabetic retinopathy On the other hand studies in patients with arthritis have shown that anti-TNF therapy negatively affects vascular permeability and angiogenesis by decreasing the potent angiogenic vascular endothelial growth factor which has been implicated directly in the pathogenesis of DME and diabetic retinopathy
Four women aged 52 to 76 years with type 2 diabetes who were in danger of vision loss due to severe DME were included in this prospective non-comparative case series They all used oral antidiabetic agents for 14 to 20 years while one patient required exogenous insulin therapy for the last 4 years Patients were free of other major medical disorders and they had no evidence of infection Following full discussion and after obtaining informed consent 2 infusions of infliximab 5mgkg Remicade Schering-Plough Greece with one month interval were given intravenously over 3 hours in an outpatient setting on a compassionate basis Additional infusions were offered in 3 patients Concomitant medications remained unchanged
Complete ophthalmic examination and Optical Coherence Tomography OCT Model 3000 Zeiss Humphrey Systems were performed immediately before each infliximab infusion as well as 2 months after the last infusion The main outcome measurements were best corrected visual acuity BCVA and macular thickness The OCT-derived maximum height of DME was recorded as described previously in detail The student t-test for paired data was used to compare logarithm of minimum angle of resolution logMAR transformed BCVA as well as macular thickness between baseline and post-treatment
DME was present in 7 eyes 6 of which were refractory to previous treatment with laser photocoagulation DME was classified as severe in 6 eyes range of macular thickness 420-720 μm and as mild in 1 eye macular thickness of 290 μm after vitrectomy A dense epiretinal membrane was present in 2 eyes with severe DME BCVA at baseline was profoundly impaired ranging from hand motion to 01 at the Snellen chart At one month after the first infliximab infusion macular thickness had decreased in 5 from 7 eyes from meanSD503 171 to 426 165 μm p0033 The 2 eyes with coexisting epiretinal membranes did not improve Two months after the second infusion the macular thickness had further regressed to 330 134 μm range 170 to 515 μm p0028 compared to baseline The BCVA was increased in all 5 eyes from a baseline mean at the Snellen chart of 003 to 015 logMAR 142 045 to 082 027 p001
At 3 months post-baseline a third infliximab infusion was offered in those 3 patients who had the least improvement of DME Repeated OCT after 2 months revealed a further decrease of macular thickness in 3 of 5 eyes by 7 15 and 23 respectively At this point the patient who still had the most severe condition received a fourth infliximab infusion remarkably a repeated OCT two months later revealed a marked resolution of severe DME while BCVA had improved from counting fingers at baseline to 02 Infliximab therapy was well tolerated and no ocular or extra-ocular side effects were noted In further available follow-up ranging from 4 to 7 months post-treatment a recurrence of DME was observed in 2 of 5 eyes albeit at a less severe level
For detailed information about the safety of infliximab please refer to summary of product characteristics Active tuberculosis may develop soon after the initiation of treatment with infliximab Before prescribing the drug physicians should screen patients for latent tuberculosis infection or active disease
Based on the above we believe that administration of infliximab may be a reasonable therapeutic approach in diabetic patients who are in danger of vision loss due to refractory DME Therefore a controlled study on the safety and efficacy of infliximab treatment in DME refractory to laser photocoagulation is warranted Because of our preliminary results 27 we feel that all patients who will participate in such a study should be granted the opportunity to receive infliximab therefore a cross-over design is proposed A cross-over design would also enhance the statistical power of the study achieving the same statistical power with fewer patients
Within this study additional questions could be addressed For example TNF in patients with diabetes is secreted mainly by the fat cells and is involved in the development of insulin resistance and decline in the pancreatic beta-cell function Previous studies examined the effect of anti-TNF treatment on indices of insulin resistance in non-diabetic subjects and showed that chronic treatment with anti-TNF agents may improve insulin sensitivity in humans
The research programme will involve one country Greece and will include a total of 26 patients with type 1 or type 2 diabetes The planned treatment period will be 32 weeks Patients with clinically significant DME ie BCVA 04 refractory to at least two sessions of laser photocoagulation or who have leaking microaneurysms within the foveal avascular zone FAZ making laser photocoagulation unsafe for the central vision will be included in the study The study will be conducted in compliance with the protocol ICH guidelines Good Clinical Practice GCP and the applicable regulatory requirements
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| EU-0129 | None | None | None |