Intravitreal Adalimumab in Refractory Diabetic Retinopathy, Choroidal Neovascularization or Uveitis: A Pilot Study (ADA01)
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|ClinicalTrials.gov Identifier: NCT00855608|
Recruitment Status : Unknown
Verified September 2009 by Rafic Hariri University Hospital.
Recruitment status was: Recruiting
First Posted : March 4, 2009
Last Update Posted : July 22, 2011
|First Submitted Date ICMJE||March 2, 2009|
|First Posted Date ICMJE||March 4, 2009|
|Last Update Posted Date||July 22, 2011|
|Study Start Date ICMJE||March 2009|
|Estimated Primary Completion Date||March 2013 (Final data collection date for primary outcome measure)|
|Current Primary Outcome Measures ICMJE
||The main outcome measure will be visual acuity improvement (3 lines) [ Time Frame: 6 weeks ]|
|Original Primary Outcome Measures ICMJE||Same as current|
|Change History||Complete list of historical versions of study NCT00855608 on ClinicalTrials.gov Archive Site|
|Current Secondary Outcome Measures ICMJE
||central foveal thickness and angiographic lesion size [ Time Frame: 6 weeks ]|
|Original Secondary Outcome Measures ICMJE||Same as current|
|Current Other Outcome Measures ICMJE||Not Provided|
|Original Other Outcome Measures ICMJE||Not Provided|
|Brief Title ICMJE||Intravitreal Adalimumab in Refractory Diabetic Retinopathy, Choroidal Neovascularization or Uveitis: A Pilot Study|
|Official Title ICMJE||The Safety and Tolerability of Intravitreal Adalimumab in Patients With Refractory Diabetic Macular Retinopathy or Choroidal Neovascularization or Uveitis: A Pilot Study|
|Brief Summary||Direct intravitreal administration of medication is the preferred method of treatment for uveitis and retinal vascular disorders. The eye is a self contained organ relatively isolated from the systemic circulation by the tight blood retinal barrier. Effective intraocular drug levels can be achieved with a much smaller amount of medication if injected intravitreally and this also results in minimal systemic exposure to the patient. Preliminary studies have shown that adalimumab may have a positive role in the management of uveitis in humans and can be an effective treatment intravitreally in animal models. No data has been published yet on intravitreal use of adalimumab in human subjects.|
Abstract Purpose: Our aim is study to determine the efficacy and safety of intravitreal adalimumab in patients with active vision threatening uveitis, diabetic macular edema (DME) and choroidal neovascularization (CNV) despite standard treatment and to ensure its safety in intravitreal use in humans and its rapid onset of action.
Design: Pilot study, Non-Randomized, Open Label, Single Group Assignment, Safety Study.
Participants: 15 eyes with refractory CNV, DME, or uveitis will be injected with intravitreal adalimumab on a 3 week interval. Patients will satisfy the inclusion and exclusion criteria listed at the end.
Methods: Initial treatment will consist of intravitreal adalimumab injection (1.5 mg/ 0.03 mL) in the eyes of patients with refractory CNV, DME, or uveitis and with visual acuity less than or equal to 20/70. Patients will be followed up every 3 weeks for a total of 6 weeks. Patients will have a baseline best-corrected visual acuity (BCVA), slit lamp examination, dilated fundus examination, ocular coherence tomography (OCT), fluorescein angiography (F.A), and standard electroretinogram (ERG) and then these studies will be repeated every visit. If there is stabilization or improvement in visual acuity, decrease in edema on OCT and leakage on F.A after the first injection, then further injections will be given. The injection will be delayed if a patient develops an acute systemic infection and will be given when it subsides. If there is worsening of visual acuity after the first injection, patients will be shifted to the traditional treatment with intravitreal Avastin or intravitreal steroids. The paired sample Student t- test, Chi-square test, Pearson correlation and ANOVA will be used to analyze the mean visual acuity and central retinal thickness before and after treatment.
Main outcome measures: to study the response to intravitreal adalimumab injection of patients with different visual acuity at baseline measured in terms of improvement in visual acuity, shrinkage in central retinal thickness, reduction in fluid leakage, and decrease in the active inflammatory uveitis.
Conclusion: Our goal is to study the efficacy and intraocular safety of intravitreal adalimumab in the treatment of refractory CNV, DME, or uveitis.
Background and Significance Inflammatory mediators are involved in the pathogenesis of diabetic retinopathy, choroidal neovascularization and uveitis. Owing to the propensity for visual loss, immunosuppressive treatment in the form of systemic and/or local therapy is often required for the management of cystoids macular edema from posterior uveitis, diabetes or age-related macular degeneration. There have been changes in the management of these conditions over the last few years, with immunomodulatory agents and new intraocular delivery systems. After the new trend of intravitreal corticosteroid and anti-VEGF, the new wave of so-called biologic response modifiers, predominantly monoclonal antibodies directed against inflammatory mediators or their receptors, but also some cytokines, represent a very promising generation of immunomodulating agents. There is rising evidence that these biologic drugs might be superior regarding their anti-inflammatory potential to conventional immunosuppressive therapies. Unfortunately, these new drugs are also very expensive so far. The yearly cost for a regular weight patient is around 20,000 dollars for Adalimumab or Infliximab. Therefore, they may not be universally available in countries with poorly funded health systems and for individuals with low economic status.
Intravitreal injections of anti-VEGF and corticosteroids are currently the standard therapy in a multitude of retinal diseases such as choroidal neovascularization, diabetic maculopathy, proliferative diabetic retinopathy, and uveitis. However many patients respond only partially or develop complications like corticosteroid induced glaucoma or cataract. As such, we are looking for safe new therapies for various chorioretinal disorders aiming at visual improvement.
Adalimumab (Humira) is a genetically engineered antibody against a proinflammatory cytokine, namely, tumor necrosis factor alpha (TNF-α). Adalimumab is the first member of a new class of TNF antibody compounds developed to contain exclusively human sequences. Adalimumab (ADA) is a subcutaneously (SC) self-administered fully human Ig G1 monoclonal antibody directed against tumor necrosis factor alpha (TNFα) which will be used intravitreally.
We do not know if adalimumab injections into the eye are effective and safe in most people. We are performing this pilot study to determine its efficacy and safety in patients with active vision threatening uveitis despite standard immunosuppressive therapy.
Unlike infliximab, adalimumab contains no nonhuman sequences, making it indistinguishable in structure and function from naturally occurring human IgG1. Unlike infliximab, allergic reactions to adalimumab appear to be rare.
Subcutaneous Adalimumab is currently used for the treatment of systemic inflammatory conditions and inflammatory disease of the eye with a relatively favorable safety profile. However, systemic administration carries the risk of systemic side effects, which in the case of adalimumab can be severe, such as increased risk of infection, reactivation of tuberculosis or increased risk for lymphoma.
Intravitreal injection of Adalimumab The eye to be treated will be prepared with 5% povidone-iodine solution after which 1% lidocaine will be administered as a subconjunctival injection about 3 to 4 mm from the limbus to form a small bleb where the intravitreal injection will be given. Following that, 0.03ml of adalimumab will be injected intravitreally using a 30 gauge needle through the pars plana 3.5 mm from the limbus. Twenty minutes after the injection, a paracentesis will be performed in case the intraocular pressure was greater than 25 mmHg or if the optic nerve head was not adequately perfused. By the end of the procedure, the eyes will be covered by a patch for one day after which topical antibiotics (Ciloxan) will be applied 3 times per day for 3 days.
Potential risks Intravitreal adalimumab have never been tried but as any intravitreal intervention, the risks of anti-VEGF therapy consist of local complications including endophthalmitis (0.16% per injection), retinal detachment (0.08% per injection), cataract (0.07% per injection), subconjuntival hemorrhage mainly related to the size of the needle used, and uveitis (0.09% per injection). Systemic administration carries the risk of systemic side effects, which in the case of adalimumab can be severe, such as increased risk of infection, reactivation of tuberculosis or increased risk for lymphoma. However, because the eye is a self contained organ relatively isolated from the systemic circulation by the tight blood retinal barrier, it is unknown how much the amount of the drug injected intravitreally gets reabsorbed systemically.
Post-injection follow-up Patients will be examined every 3 weeks to measure the BCVA along with slit-lamp examination of the anterior segment, dilated fundus examination, OCT, F.A, and ERG. If any of the patients develops a decrease in visual acuity at least five letters of vision post first injection, he/she will be shifted to the traditional treatment with intravitreal avastin or intravitreal steroids. Else, if the vision is stable, patients will continue treatment
The total follow-up period of every patient will be 6 weeks.
Main outcome Our goal is to study the efficacy and intraocular safety of intravitreal adalimumab in the treatment of refractory CNV, DME, or uveitis and to ensure its rapid onset of action. The main outcome measure will be the proportion of patients who lose fewer than 15 letters (3 lines) in BCVA score at 6 weeks compared with baseline. Secondary visual acuity endpoints at 6 weeks include 1) mean change from baseline in BCVA score; 2) the proportion of patients who gain ≥15 letters in BCVA; and 3) the proportion of patients with a Snellen visual acuity of 20/70 or worse compared with baseline. Other secondary endpoints include the effect of adalimumab on the central retinal thickness (CRT) as assessed by OCT and on the lesion size assessed by F.A.
Literature Cited 1-Intravitreal Adalimumab
1A- Manzano et al evaluated the ocular toxicity of escalating doses of intravitreous adalimumab (Humira) in the rabbit eye. Slit-lamp biomicroscopy and fundoscopy were carried out at baseline, day 1, 7 and 14 following intravitreous injection. Escalating doses of intravitreous adalimumab in rabbit eyes caused no detectable functional or structural ocular toxicity up to a dose of 0.50 mg. Administration of 1.0 mg in 0.1 ml was associated with an inflammatory reaction. (Manzano RP et al Ocular toxicity of intravitreous adalimumab (Humira) in the rabbit. Graefes Arch Clin Exp Ophthalmol. 2008 Jun;246(6):907-11).
1B- Use of intravitreal etanercept, another TNF antagonist in humans, with improvement in vision in diabetic macular edema (Tsilimbaris MK,et al. The use of intravitreal etanercept in diabetic macular oedema Semin Ophthalmol 2007 Apr-Jun;22(2):75-9).
1C-Intravitreal Administration of the Anti-Tumor Necrosis Factor Agent Infliximab for Neovascular Age-related Macular Degeneration.Theodossiadis PG, Liarakos VS, Sfikakis PP, Vergados IA, Theodossiadis GP.Am J Ophthalmol. 2009 Feb 9. [Epub ahead of print]
|Study Type ICMJE||Interventional|
|Study Phase||Phase 1|
|Study Design ICMJE||Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
|Intervention ICMJE||Drug: adalimumab
intravitreal adalimumab injection 0.03 ml in volume (1.5mg) one dose to one eye
Other Name: Humira
|Study Arms||Experimental: adalimumab arm
intravitreal mode of delivery
Intervention: Drug: adalimumab
|Publications *||Theodossiadis PG, Liarakos VS, Sfikakis PP, Vergados IA, Theodossiadis GP. Intravitreal administration of the anti-tumor necrosis factor agent infliximab for neovascular age-related macular degeneration. Am J Ophthalmol. 2009 May;147(5):825-30, 830.e1. doi: 10.1016/j.ajo.2008.12.004. Epub 2009 Feb 10.|
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Unknown status|
|Estimated Enrollment ICMJE
|Original Estimated Enrollment ICMJE||Same as current|
|Estimated Study Completion Date||March 2013|
|Estimated Primary Completion Date||March 2013 (Final data collection date for primary outcome measure)|
|Eligibility Criteria ICMJE||
|Ages||17 Years to 88 Years (Child, Adult, Senior)|
|Accepts Healthy Volunteers||No|
|Contacts ICMJE||Contact information is only displayed when the study is recruiting subjects|
|Listed Location Countries ICMJE||Lebanon|
|Removed Location Countries|
|NCT Number ICMJE||NCT00855608|
|Other Study ID Numbers ICMJE||RHUH|
|Has Data Monitoring Committee||Yes|
|U.S. FDA-regulated Product||Not Provided|
|IPD Sharing Statement||Not Provided|
|Responsible Party||Professor Ahmad Mansour, RHUH|
|Study Sponsor ICMJE||Rafic Hariri University Hospital|
|Collaborators ICMJE||American University of Beirut Medical Center|
|PRS Account||Rafic Hariri University Hospital|
|Verification Date||September 2009|
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP