Trial record 1 of 340 for:    macular degeneration | Open Studies
Previous Study | Return to List | Next Study

Complement Factor H Haplotypes and Smoking in Age-related Macular Degeneration (CFH&AMD)

This study is currently recruiting participants.
Verified January 2014 by Department of Veterans Affairs
Sponsor:
Information provided by (Responsible Party):
Department of Veterans Affairs
ClinicalTrials.gov Identifier:
NCT01115231
First received: April 15, 2010
Last updated: February 3, 2014
Last verified: January 2014

April 15, 2010
February 3, 2014
October 2010
September 2014   (final data collection date for primary outcome measure)
Assessment of Age-related Macular Degeneration [ Time Frame: patients will be examined for AMD at a routine visit; if they present themselves with AMD or qualify as control, they will be recruited to the study. Information will be used in publication at the end of the 4-year study. ] [ Designated as safety issue: No ]
Assessment of Age-related Macular Degeration [ Time Frame: patients will be examined for AMD at a routine visit; if they present themselves with AMD or qualify as control, they will be recruited to the study. Information will be used in publication at the end of the 4-year study. ] [ Designated as safety issue: No ]
Complete list of historical versions of study NCT01115231 on ClinicalTrials.gov Archive Site
  • Visual field test [ Time Frame: Visual field test will be part of the patient's routine eye exam to determine why they complain about vision loss. Information will be used in publication at the end of the 4-year study. ] [ Designated as safety issue: No ]
  • OCT [ Time Frame: OCT will be part of the patient's routine eye exam to determine why they complain about vision loss. Information will be used in publication at the end of the 4-year study. ] [ Designated as safety issue: No ]
  • Fluorescein Angiography [ Time Frame: Day 1 of study. ] [ Designated as safety issue: No ]
  • assessment of smoking status [ Time Frame: Day 1 of study ] [ Designated as safety issue: No ]
  • Eye exam with fundus photography [ Time Frame: Day 1 of study. ] [ Designated as safety issue: No ]
  • genotyping for signal nucleotide polymorphisms for I62V and Y402H in CFH gene [ Time Frame: within a month of obtaining blood sample ] [ Designated as safety issue: No ]
  • Complement pathway protein analysis [ Time Frame: within a month of obtaining blood sample ] [ Designated as safety issue: No ]
Same as current
Not Provided
Not Provided
 
Complement Factor H Haplotypes and Smoking in Age-related Macular Degeneration
Complement Factor H Haplotypes and Smoking in Age-related Macular Degeneration

Risk factors for Age-related Macular Degeneration (AMD) involves genetic variations in the alternative pathway of complement inhibitor factor H. The complement system is part of the innate and adaptive immune system. Smoking is the only environmental factor known to increase the risk of Age-related Macular Degeneration (AMD). Using serum samples of Age-related Macular Degeneration (AMD) patients and controls we will test the hypothesis that smoking increases Age-related Macular Degeneration (AMD) by increasing complement activation; and that this is positively correlated with known disease variations in the complement factor H (CFH) gene.

ABSTRACT Age-related macular degeneration (AMD) is a slowly progressing multifactorial disease involving genetic abnormalities and environmental insults. AMD is the leading cause of blindness for Americans over the age of sixty. As the population ages, the prevalence of AMD will continue to grow, reaching a maximum risk rate of ~30% by the age of 70 years. Since smoking increases the risk of AMD, and there is a 20% higher incidence of smoking in the veteran population than in the U.S. adult civilian population, the U.S. Department of Veterans Affairs healthcare system will have to provide care for potentially up to 7 million or more AMD cases. Currently available treatments focus on the late stage of the disease (choroidal neovascularization); however, those treatments come with significant risks and only target subpopulations of AMD patients. No treatment is available for early AMD disease which includes >85% of all cases. Thus, it is of paramount importance that we learn how to detect AMD early and develop treatments that allow for early disease prevention. While mechanistic studies have shown that inflammation and smoking are fundamental components of both the wet and dry forms of AMD, genetic studies have demonstrated that polymorphisms in different complement proteins each increase the risk for developing AMD. One of the most detrimental mutations occurs in factor H, an essential inhibitor in the complement cascade. Overall, it has been hypothesized that inadequate control of complement-driven inflammation may be a major factor in disease pathogenesis in AMD. Here we wish to answer an essential question: do smoking and complement act synergistically in the AMD disease process. For this proposal we will be guided by our overall hypothesis that pathological activation of the alternative complement pathway has direct effect on the retinal pigment epithelium, generating a permissive cellular environment for AMD pathology. Thus, we will recruit case subjects with AMD and control subjects, selecting both smokers and non-smokers in both groups, to determine whether smoking influences complement activation, or whether smoking acts through a yet undefined pathway to promote AMD development. A complete eye exam to determine pathology and visual impairment will be performed on Day 1 of the study. Serum will be analyzed to measure complement factor H activity. Plasma will be analyzed to measure complement breakdown products such as C3a, C5a and Bb. The cells that remain will be used for genotyping.

RESEARCH DESIGN AND METHODS

A) Study design

This study is designed to determine whether smoking increases complement activation and whether there are specific AMD genotypes that are particularly sensitive to this elevated level of serum complement components.

Thus, we will recruit patients with AMD and age-matched (within 5 years) control subjects, selecting both smokers and non-smokers, to determine whether smoking influences complement activation, or whether smoking acts through a yet undefined pathway to promote AMD development. A complete eye exam to determine pathology and visual impairment will be performed on Day 1 of the study. Serum will be analyzed to measure complement factor H activity. Plasma will be analyzed to measure complement breakdown products such as C3a, C5a and Bb. The cells that remain will be used for genotyping.

Data collection and analysis will be performed by trained professionals who will be masked to the patient evaluation data.

B) Selection of subjects and controls

Case subjects and age-matched (within 5 years) control subjects will be recruited under a protocol approved by the Johnson and DeBakey VA Medical Centers, and the Medical University of South Carolina (MUSC) Human Investigation Review Board. All patients will be provided a written informed-consent form for their signature of acceptance before participation in the study. The case subjects and the control subjects will be derived from military service veteran populations. The following criteria will be used for inclusion and exclusion, sample size, and recruitment of subjects in the study based on a previous, successful study conducted by our consultant, Dr. A O Edwards.

Inclusion Criteria

  1. Case subjects will have a clear diagnosis of AMD and at least a 20/40 view of the fundus.
  2. Control subjects will have <5 small (<63 um each) hard drusen and at least a 20/40 view of the fundus.
  3. All subjects will have the ability to provide a blood sample.
  4. All subjects will demonstrate the absence of exclusion criteria listed below.
  5. All subjects must be able to provide their own consent, or have a legal representative available to provide consent for them.
  6. All subjects must be able to complete all aspects of testing, or have a legal representative available to complete all aspects of testing for them.
  7. All subjects must be in generally good medical health in the opinion of the study physician.

Exclusion Criteria

  1. Individuals who are unable to provide consent and who lack a legal representative.
  2. Individuals whose best corrected visual acuity for both eyes is worse than 20/40.
  3. Individuals who are taking a medication known to cause retinopathy.
  4. Individuals unable to cooperate to complete testing.
  5. Individuals who present themselves with media opacity (cataract) that will prevent visualization of the macula; or ocular disease that might simulate AMD or preclude its diagnosis (e.g., prior laser photocoagulation, cryopexy, media opacity, or inflammatory diseases).
  6. Individuals who exhibit diseases that phenotypically overlap with AMD such as drusen or pigmentary disturbance of the retinal pigment epithelium; or provide insufficient evidence to diagnose AMD.
  7. Individuals who present themselves with macular dystrophies, toxoplasmosis, histoplasmosis, degenerative myopia, central serous chorioretinopathy, or any disease or treatment that would diminish the ability to recognize drusen such as laser photocoagulation, prior retinal detachment surgery, posterior uveitis, and trauma.

Sample Size and Power Estimation

A total of 150 case subjects and 150 control subjects (age-matched within 5 years) will be recruited for this study. This sample size was determined by statistically simulating the study findings 1,000-times using the following assumptions: an alpha level of 0.05; 2-sided hypothesis testing; and an expected distribution across the CC, CT, and TT factor H genotypes of 8.1%, 52%, and 39.9%, respectively, (combining observed data for Caucasians and African Americans [1]). We also assumed approximately 35% of the case and control subjects would be current smokers (see http://www.mit.edu/people/jeffrey/HarrisVARept97.pdf; a report commissioned by the Department of Veterans Affairs Assistant Secretary for Policy and Planning). Finally, we assumed that smoking status in combination with haplotype status had a multiplicative interactive effect on the measurement parameter of interest (i.e., complement protein Ba, D and C3d levels). That is, smoking was allowed to have a negligible impact on the measurement parameter among those in the low-risk genotype, but those in the heterozygous and homozygous risk genotypes had a 1.5-fold and 2-fold greater measurement, respectively. The simulation also included a direct effect of AMD status (case/control), with AMD cases having higher values than controls. Through this simulation process, we were able to show that the sample size of 150 cases and 150 controls would provide 85% power to detect a significant smoking by genotype interaction, the main focus of this study. Note that our sample size is comparable to similar prior studies, one of which used 112 AMD patients and 67 controls [2], and another that used 274 samples [3] and was conducted by our collaborator, Dr. Edwards.

Recruitment

Case and age-matched (within 5 years) control subjects will be recruited. Recruitment will take place in two ways: 1) If patients that have been seen at the VA within the last two years, have been diagnosed with AMD or qualify as a control subject, they will be called to see whether they wish to participate in the study. Those subjects wishing to participate will be given a consent form to read and sign at their next VA visit. They will then be asked to provide information about their smoking status, and a blood sample (two 3 mL tubes) will be collected. 2) Patients will also be recruited after the diagnosis in the doctor's office (i.e., they have been diagnosed with AMD or qualify as a control subject). Upon signed consent, these subjects will also be asked to provide information about their smoking status, and a blood sample (two 3 mL tubes) will be collected. Flyers will be posted at the VA to alert patients of this clinical trila and flyers will be made available to ophthalmologists in the area to provide to their patients.

C) Clinical tests in the diagnosis of AMD

Flowchart of patient medical history workup

  1. Chief complaint of vision changes.
  2. History taken of vision changes. If AMD-related symptoms (blurry vision, metamorphopsia, scotoma, etc.), the approximate time it started in the affected eye, particularly noting whether the patient is taking vitamins (specific type and dosing), and whether previous treatments for AMD have been provided (type, dosing, frequency).
  3. If any other eye problems or disease, stroke or heart attack history, surgery planned for the future, rheumatologic disease, and kidney disease (MPGN-II).
  4. Any family history of AMD.
  5. Medications currently taking.
  6. Social history, including smoking behavior (years smoked and packs/ week and packs/ year.

Eye examination, including Snellen visual acuity with pinhole testing

  1. Pupillary exam, followed by confrontational visual fields or visual field test to determine the amount of vision loss.
  2. Intraocular pressure assessed by Tonopen tonometry.
  3. Pharmacologically-dilated pupils using phenylephrine 2.5% and 1% tropicamide.
  4. Slit-lamp examination including non-contact-lens exam of the macula and peripheral retina to determine anatomical alteration of the fundus.
  5. If recent significant vision changes have occurred, or blood, exudate or subretinal fluid were noted on the fundus exam, ancillary testing including macular SD-OCT (both eyes) and fluorescein angiography (both eyes) will be performed with arterial phase of the eye of most concern.

Treatment options

  1. If active choroidal neovascular membranes are found on examination and ancillary testing, treatment options (anti-VEGF-based therapies such as Lucentis, Macugen, Avastin) will be discussed.
  2. If intermediate AMD is determined in both eyes, or advanced AMD in one eye, treatment options (the AREDS vitamin supplements, and the need to self-monitor central vision changes) will be discussed.

Tests

Confrontational visual field

The examiner will ask the patient to cover one eye and stare at the examiner. The examiner will then move his/her hand out of the patient's visual field and then bring it back in. The patient will signal when the hand comes back into view. This will be frequently done by the examiner as a simple and preliminary test.

Tonometry

Intraocular pressure will be measured with a Tonopen in the central cornea in both primary-gaze and up-gaze.

Eye exam

Eyes will be dilated (mydriasis with one drop of each (2.5% phenylepinephrin and 1% tropicamide) to achieve at least 6 mm pupil diameter, and the back of the eye examined by slit-lamp.

OCT imaging

OCT images will be acquired with a Stratus-OCT imaging system (Carl Zeiss Meditec). Images will be obtained using the high-resolution "Radial Lines" protocol of six high-resolution B-scans (transverse resolution of 512 A-scans per B-scan). Total retinal volume values will be provided by the "Retinal Map Analysis" program of the Stratus software. Data will be analyzed qualitatively or based on the automated measurements provided by the Stratus-OCT software. Choroidal neovascularization (CNV) size will be quantitatively measured, including the maximum CNV diameter as well as the maximum CNV thickness. Retinal structure will be qualitatively judged as (1) wet, revealing unchanged fluid conditions; (2) dry, revealing no fluid; or (3) less edema, revealing incomplete fluid regression.

Fluorescein angiography

The fluorescein angiogram will contain stereoscopic views of 2 fields at specified times after injection. These fields include the macula (Field 2) and the disc field (Field 1). Stereoscopic red-free photographs will be taken of the macula prior to the injection of the fluorescein dye. Fluorescein is injected rapidly (less than 5 seconds) into either the anticubital or other convenient vein according to usual clinic protocol. Photographs will be taken at time zero and at the moment the injection is complete as control photographs, to document the integrity of the interference filters and to document the rate of injection. Stereo pairs of Field 2 and then of Field 1M of the study eyes will be taken between minutes 1 and 3, followed by two additional pairs at 5 minutes and 10 minutes.

Biospecimens

Two tubes (3 mL each) of whole blood will be collected in the Johnson or DeBakey VA Medical Center by the laboratory services personnel and processed to the freezer (-80 C) within 3 hours from collection. One tube will be collected and allowed to clot. Serum will be separated from this clot by centrifugation (10 minutes at 3,000 rpm) and frozen at -80 degrees centigrade until analyzed. Serum will be used to measure complement factor H activity. The other tube will contain dipotassium ethylenediaminetetraacetic acid (EDTA), resulting in a final EDTA concentration of 4.5 mM when the blood is added. Plasma will be separated from this whole blood by centrifugation (10 minutes at 3,000 rpm) and frozen at -80 degrees centigrade until analyzed. Plasma will be used to measure complement breakdown products. The cells that remain will be used for genotyping assays.

ELISA protein analyses

ELISA examinations have been described in detail by our collaborator, Dr. Edwards [3]; however, the protocol is described here in brief.

  • Factor B will be quantified using a monoclonal capture antibody P21/15 which recognizes an epitope present on factor B and Ba and a biotinylated rabbit anti-Bb as a detection antibody. For measurement of Ba, plasma will be depleted of factor B using Biomag magnetic beads coupled to an anti-B/Bb antibody (mAb M13/12), followed by Ba quantification using an anti-B/Ba antibody (mAb P21/15) as a capture antibody and a biotinylated antibody specific for an epitope on B/Ba (mAb M20/6) as a detection antibody.
  • Factor D will be measured by paired capture and detection antibodies (mAb D10/4 and biotinylated mAb I8/1) specific to factor D. The capture antibody used in the C3d assay (mAb I3/15) reacts with a neoepitope present on C3b, iC3b and C3dg and will be in combination with a biotinylated rabbit anti-C3d detection antibody for quantification of C3d. For all assays, incubation with the detection antibody will be followed by application of streptavidin-horseradish peroxidase conjugate. The substrate, 2 mM ABTS (2,2'-azino-di-(3-ethyl benzthiazolinesulfonate)) in buffer containing 2.5 mM peroxide, will be added and absorbance at 410 nm (490 nm reference) will be read using a microplate photometer. All samples will be run in triplicate.

Assessment of smoking

Regular cigarette smoking will be assessed by a brief questionnaire administered by clinic staff, to determine whether the subject has ever smoked on a regular basis and whether he/she is a current smoker; and if so, their pack/month and pack/year history.

D) Outcome measures

Incidence

The incidence of AMD will be defined based on the published definition of the Rotterdam Study, a population-based prospective cohort study in Rotterdam, The Netherlands, in which 6,780 out of a total population of 10,275 participants over the age of 55 years, participated in ophthalmic examination [4].

Fundus photographs

The fundus photographs will be graded at 12.5x magnification, according to the International Classification and Grading System for ARM and AMD (The International ARM Epidemiological Study Group, 1995). In this system, all ARM fundus signs within a standard circular area (diameter 6,000 m) around the fovea will be recorded. Graders, trained according to the Wisconsin ARM grading system will grade the photographs blinded to the patient information.

AMD definitions

  • AMD will be defined as the presence of large ( 63 um), soft, distinct drusen with pigmentary irregularities, or indistinct (125 um) or reticular drusen, or atrophic or neovascular AMD. Atrophic AMD will be defined as any sharply demarcated round or oval areas of apparent absence of the retinal pigment epithelium larger than 175 um, irrespective of the distance from the fovea, but within the grid, with visible choroidal vessels and no neovascular AMD.
  • Neovascular AMD will be defined as the presence of a serous or hemorrhagic neuro-retinal or retinal pigment epithelium detachment, and/or a subretinal neovascular membrane, and/or a subretinal hemorrhage, and/or a peri-retinal fibrous scar. Lesions that are considered to be the result of generalized disease (see exclusion criteria) will be excluded from AMD diagnosis.

Additional outcome measurements

Additional outcome measures that will help characterize the severity of AMD disease include the following. In the visual field test, the loss of vision occurring predominantly in the central retina, will be quantified. The choroidal and retinal vasculature will be analyzed using fluorescein angiograms, which should reveal abnormal blood vessels and leakage in subjects with systemic vascular problems.

E) Data analyses

  • Data assembled as normalized serum levels of complement factors Ba, C3d and fD levels will be initially evaluated with univariate statistics to assure that the quality of the data is adequate for further analyses. The association between each measured parameter (i.e., serum levels of complement factors), AMD diagnosis, and smoking will be assessed in a stratified bivariate fashion using Student t tests or Wilcoxon rank sum tests, as appropriate, and standard measure assessments will be used to check for normality, skewing, etc.
  • Multivariate analyses will be conducted through the use of general linear mixed models [5]. The models will include random subject effects to account for dependence among repeated measurements of subjects. This type of model is ideal when there are multiple measurements on subjects, such as when laboratory measurements are performed in triplicate. The dependent variables of interest will be the complement level measurements (log transformed, if necessary), while independent variables will include AMD status (case/control), factor H genotype (CC, CT, TT), smoking (current, former, never), and an interaction-term involving factor H genotype and smoking status. The interaction-term will help us to determine whether the impact of factor H genotype and smoking on serum complement levels is linear (additive), or non-linear (e.g., multiplicative). The model will also include adjustments for age, gender, and race, which may all affect complement factors. Thus, any differences among haplotypes will be adjusted (corrected) for effects that may be attributed to age, gender, or race. Different correlation structures will be examined for the random subject effects, and we will use Akaike's Information Criterion to select the most appropriate model. Secondary analyses will involve excluding never smokers, to assess the nature of the association (if any) between pack/year histories. factor H genotypes. and their complement levels. An additional analysis (using conditional logistic regression) will be conducted to determine whether smoking interacts with a subject's factor H genotype with respect to the risk of AMD. Again, this model will be adjusted for age, gender, and race, and the results will be expressed as odds ratios associated with the risk of AMD.

F) Predicted results and interpretation

Published results, as well as data from our collaborator, Dr. Edwards, have provided ample evidence that AMD is correlated with increased serum levels of Ba, C3d and fD; whereas elevated levels of Ba and C3d were documented in V62I subjects. We expect to confirm and extend the findings in V62I subjects, and to identify a positive correlation between elevated levels of complement activation proteins and Y402H. Since smoke exposure has been shown to result in increased levels of alternative pathway (AP) activation [6], we predict that some components (i.e., C3d or Ba) might be further elevated in the factor H risk population that smokes.

G) Potential risks

Subjects will receive a comprehensive eye examination as part of this study. This examination will include visual inspection by a trained ophthalmologist, assessment of visual acuity, SD-OCT, visual fields, and fluorescein angiography. The subjects and their physicians will be made aware of any identified abnormalities. The potential risk to subjects is modest. All of the planned tests are identical to those test routinely performed for purposes of diagnosing AMD or other diseases of the eye. Such studies are performed routinely in out-patient settings by ophthalmologists. In addition, information obtained from this study may provide an important link to understanding the pathogenesis of AMD, and its link with complement factor H haplotypes and smoking. Any relationship between the three could potentially lead to future therapies for AMD.

  • Visual field testing. The risks of visual field testing include fatigue of the neck; pain in the neck; pressure under the chin; sweating; photophobia; or tearing. None of these are permanent or substantial losses. Change in position or rest will resolve the complication.
  • Tonometry. The risks of tonometry include fatigue of the neck; pain in the neck; pressure under the chin; or feeling of temporary pressure against the eye. None of these are permanent or substantial losses. Change in position or rest will resolve the complication.
  • Pupil dilation. The risks of pupil dilation include fatigue of the neck; pain in the neck; pressure under the chin; sweating; photophobia; acute angle-closure lasting for less than 30 minutes, due to the dilating drops; conjunctival injection (red eye), due to the dilating drops; impaired near vision for less than 24 hours, due to dilating drops; burning for less than 5 minutes, due to the dilating drops; or anesthesia of the eye for less than 2 hours, due to the dilating drops. None of these are permanent or substantial losses. Rest and time will resolve the complication.
  • Stratus-OCT. The risks of Stratus-OCT imaging include fatigue of the neck; pain in the neck; pressure under the chin; sweating; photophobia; or tearing. None of these are permanent or substantial losses. Change in position or rest will resolve the complication.
  • Fluorescein angiography. The risks of fluorescein angiography include pain from the needle stick; inflammation at the injection site; allergy to the fluorescein dye; feeling of warmth or cold, due to the dye; infection at the site of the needle stick; anaphylactic reaction to the dye; nausea (20% of cases); vomiting (0-7% of cases); headache; hypotension; convulsions; basilar artery ischemia; cardiac arrest; severe shock; or thrombophlebitis at the injection site. Clinical staff are trained to deal with these complications.
  • Venipuncture for whole blood. The risks of venipuncture are pain or bruising at the site of venipuncture; fainting or dizziness; or infection at the site of the needle stick. None of these are permanent or substantial losses. Clinical staff are trained to deal with these complications.
  • Personal information. Sharing of personal information (blood specimens, personal history, genetic information, etc.) is not without risk. Research to identify genes that cause or contribute to a disease or trait is an increasingly important way to try to understand the role of genes in human disease. You were given a consent form because the Johnson and DeBakey VA Medical Centers investigators want to include your blood sample in a research project, or because they want to save such biological specimens for future research.

There are several things you should know before allowing your blood to be studied or to be saved.

  1. Your blood sample will be stored under an alphanumeric identifier which could eventually be linked to you. Sometimes these samples are shared for research purposes with other investigators at other research sites. If this is done, the other investigators would not know your name.
  2. In addition to your name, other information about you might be connected to your blood sample. For instance, information about race, ethnicity, sex, your medical history, and so forth might be available to investigators studying your blood. Such information is important for scientific reasons and sometimes for public health. It is possible that genetic information might come to be associated with your racial or ethnic group.
  3. Genetic information about you will often apply (to one degree or another) to your family members. It is not generally the Johnson or DeBakey VA Medical Center's policy to provide information about you to your family members. However, certain studies called "pedigree studies", share such information among family members. For this and related research, you will be asked if you are willing to share your genetic information with your family members.
  4. You have the right to refuse to allow your blood to be studied or saved for future research studies. You may withdraw from this study at any time and remove any samples that contain identifiers from research use after the date of your withdrawal. This means that while the Johnson or DeBakey VA Medical Centers or Medical University of South Carolina might retain the identified blood samples - the law often requires this - the samples would not be used for research.
  5. South Carolina and Texas law mandates that your genetic information, obtained from any tests or from this research, be kept confidential. South Carolina and Texas law prohibits any insurer using this information in a discriminatory manner against you or any member of your family in issuing or renewing insurance coverage for you or your family. South Carolina and Texas law further prohibits our sharing your genetic information with anyone except in a few narrow circumstances, one of these being a research project of this type, approved by the Institutional Review Board, and then we must take all steps to protect your identity. You will still be responsible for paying for health care, however. The Charleston or DeBakey VA Medical Centers will not be responsible for such costs, even if care is provided for a condition revealed during research or clinical testing.
  6. Genetic research raises difficult questions about informing you and other subjects of any results, or of future results. Some people feel anxious about the possibility of having a defective gene that would place them or their children at risk. Some people want to know what is found out about them, others do not. The risks of knowing include anxiety and other psychological distress. The risks of not knowing what is found include not being aware if there is treatment for the problem being studied. But these risks can change depending on whether there is a treatment or cure for a particular disease, and on how clear the results are. If there is a medical reason to seek specific information from you, your doctor will tell you this. A process called "genetic counseling" is often appropriate in such cases; you should ask your doctor about this if you have any questions.

    Investigators in this study may try to recontact you in the future to find out about your health. If you are recontacted and want to know what the investigators have learned about your samples, you should understand that the following are the kind of things the investigators or your health team might tell you:

    1. The information is too sketchy to give you particular details at this time, but you will receive a newsletter informing you about the results of the project.
    2. You carry a gene for a particular disease that can be treated.
    3. You carry a gene for a particular disease for which there is no current treatment. This news might cause severe anxiety or other psychological distress, depending on the severity of the disease.
    4. You may carry a gene for a disease and might consider informing relatives that they, too, might carry the gene. It can be very difficult to decide whether to share such information with relatives. Genetic counselors can help sort out the various options in such a case.

    Also for any future research, you may be recontacted with a new consent form giving you additional information for a new study.

  7. If you are concerned about a potential genetic disorder, you and your doctor might choose to test specifically for it. This would require additional blood or tissue samples and would not be part of this research project. You should discuss this option with your doctor or genetic counselor.
  8. The presence of a genetic marker for a disease does not necessarily mean that you will develop that disease. Informing people of all such markers independent of medical need can cause unnecessary anxiety. On the other hand, the absence of a marker does not mean that you will not get the disease. Genetic diseases appear as a result of a complex mixture of heredity, environment, behavioral and other factors.

These are the best-known risks and challenges of genetic research. There might be other risks we do not know about yet. It is important that you talk to your doctor, nurse, or genetic counselor if you have any questions or concerns about this research study.

- Unknown risks. The researchers will let you know if they learn of anything that might make you change your mind about participating in this study.

H) Literature cited

  1. Weale R. (2006) Lancet 368, 1235-1236.
  2. Bailey TA, Kanuga N, Romero IA, Greenwood J, Luthert PJ, Cheetham ME. (2004) Invest Ophthalmol Vis Sci 45, 675-684.
  3. Thurman JM, Renner B, Kunchithapautham K, Ferreira VP, Pangburn MK, Ablonczy Z, Tomlinson S, Holers VM, Rohrer B. (2009) J Biol Chem 284, 16939-16947.
  4. van Leeuwen R, Chakravarthy U, Vingerling JR, Brussee C, Hooghart AJ, Mulder PG, de Jong PT, (2003) Ophthalmology 110, 1540-1544.
  5. Schmidt-Erfurth U, Michels S, Michels R, Aue A. (2005) Eur J Ophthalmol 15, 482-485.
  6. Husain D, Ambati B, Adamis AP, Miller JW. (2002) Ophthalmol Clin North Am 15, 87-91.
Observational
Observational Model: Cohort
Time Perspective: Prospective
Not Provided
Retention:   Samples With DNA
Description:

Whole blood will be collected into dipotassium ethylenediaminetetraacetic acid (EDTA) tubes resulting in a final EDTA concentration of 4.5 mM. Plasma will be separated from whole blood by centrifugation (10 minutes at 3000 RPM) and frozen at -80 degrees C until further use. Subjects will be genotyped for signal nucleotide polymorphisms for I62V and Y402H using TaqMan single nucleotide polymorphisms (SNP) genotyping assays. Complement pathway protein analysis will be performed by ELISAs.

Probability Sample

The case and control subjects will be derived from a group of veterans at the Charleston, SC VA Medical Center.

Macular Degeneration
Not Provided
  • Group 1
    Case control subjects will be recruited (150 persons). Controls are subjects without AMD diagnosis
  • Group 2
    Case (i.e., within 5 years) subjects will be recruited (150 persons). Cases are defined as subjects with diagnosed AMD.
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
300
September 2014
September 2014   (final data collection date for primary outcome measure)

Inclusion Criteria:

  • Inclusion criteria for subjects will be a clear diagnosis of Age-related Macular Degeneration (AMD)
  • Inclusion criteria for controls will be less than five small (< 63 um) hard drusen
  • At least a 20/40 view of the fundus
  • The ability to provide a blood sample, and the absence of exclusion criteria listed

Exclusion Criteria:

  • We will exclude individuals with ocular diseases that might simulate Age-related Macular Dengeration (AMD) or preclude its diagnosis.
  • Those might include prior laser photocoagulation, cryopexy, media opacity, and inflammatory diseases.
  • It is important for potential control subjects not to exhibit media opacity (e.g., cataract), which will prevent visualization of the macula.
  • Also, subjects will be excluded if they exhibit diseases that phenotypically overlap with Age-related Macular Degeneration (AMD) such as drusen or pigmentary disturbance of the retinal pigment epithelium (RPE), or that provided insufficient evidence to diagnose Age-related Macular Degeneration (AMD).
  • In addition, subjects with pattern dystrophies, toxoplasmosis, histoplasmosis, degenerative myopia, central serous chorioretinopathy, or any disease or treatment that would diminish the ability to recognize drusen such as laser photocoagulation, prior retinal detachment surgery, posterior uveitis, and trauma will be excluded.
Both
40 Years to 80 Years
Yes
Contact: Barbel M Rohrer, PhD (843) 792-5086 Barbel.Rohrer@va.gov
Contact: John Gross, MD (843) 609-7564 grossjd@musc.edu
United States
 
NCT01115231
C7428-R
No
Department of Veterans Affairs
Department of Veterans Affairs
Not Provided
Principal Investigator: Barbel M. Rohrer, PhD Ralph H Johnson VA Medical Center, Charleston
Department of Veterans Affairs
January 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP