Ординатура / Офтальмология / Английские материалы / Nutrition and the Eye A Practical Approach_Eperjesi, Beatty_2006

●or if <20 soft drusen, focal hyperpigmentation must be present

●visual acuity ≥6/12 or 0.3 logMAR in the study eye (which may be both eyes).

Exclusion criteria

●any retinal laser therapy in the study eye

●history of any unstable medical condition that would preclude scheduled study visits or completion of the study

●history of ophthalmic disease in the study eye (other than ARM) that would compromise the visual acuity of the study eye

●patients currently on supplements containing the antioxidants vitamins C, E, Zn, L and Z will be asked to discontinue them. After a washout period of 3 months they may be eligible for randomisation into the study.

STUDY PROCEDURE

General study design

General information

CARMA is a two-arm double-masked trial of an antioxidant preparation versus placebo given orally in subjects with ARM. Approximately 500 patients enrolled in two centres, Belfast and Waterford, Ireland, fulfilling the eligibility criteria will be randomised to receive either Carmavite or placebo. Outcomes will be monitored by measuring psychophysical retinal functions, Raman spectroscopy and serological levels of antioxidants.

Duration of the trial

The trial will last 2 years, with recruitment being undertaken in the first 12 months.

Frequency of follow-up

Patients will undergo periodic ophthalmic and serological evaluations at baseline, 6 and 12 months after study entry.

Arrangements for allocating participants to trial groups

The investigator or study staff will enrol eligible patients into the study. A computer-generated randomisation will secure the randomisation code. The ready-prepared masked test articles will be kept in the hospital pharmacy and released by the pharmacist on randomisation of each patient in a sequential manner by patient number, beginning with the first number in the numerical series assigned to each site.

Protecting against sources of bias

Subjects can only be entered into the study following a reading-centre grading of ARM status. In order to minimise potential bias toward the outcome of this study by patients, investigators and study personnel regarding the safety or efficacy of the test articles, the study will be doublemasked. Patients will be randomly assigned to receive either Carmavite or the placebo. Allocation of treatment status is concealed from investigators and the study medication will be dispensed in appropriately labelled containers. The hospital pharmacist will hold the key to the randomisation code. A sealed envelope containing the identification of the test article will be provided for each patient and, in the event that it becomes necessary to know which test article the patient received, this will be made available to the principal investigator.

Study population

The study population includes patients of either sex, of any race, aged 50 years and over, fulfilling the inclusion criteria (see above).

CLINICAL EXAMINATIONS/PROCEDURES TO BE PERFORMED DURING THE STUDY

A full ophthalmic examination will be performed at each study visit. This will include:

●slit-lamp examination and biomicroscopy of the anterior segment

●dilated fundus examination to include an evaluation of the posterior segment

●best corrected logMAR visual acuity following refraction.

Contrast sensitivity

Evaluations of contrast sensitivity will be conducted using Pelli–Robson charts.

Colour photography

Colour stereo pair fundus photographs will be taken of both eyes.

General physical examination

A general physical examination will be performed at baseline and will include the following:

●recording of anthropomorphic measurements

height and body weight

blood pressure

heart rate

●routine evaluation of other organ systems.

●best corrected logMAR visual acuity (using the Early Treatment of Diabetic Retinopathy Study chart)

●evaluation of contrast sensitivity using the Pelli–Robson assessment procedure

●other macular psychophysical tests

●an ophthalmic examination of both eyes

●stereo pair digital colour fundus photographs with documentation

●patient eligibility on the basis of ARM severity confirmed by the fundus photograph reading centre at Belfast

●clinical data collected on appropriate data collection forms

●following completion of the screening procedures, patients will be randomised to receive the first course of supplemental antioxidant treatment or placebo treatment

●the following questionnaires will be completed: food frequency, general lifestyle and visionrelated quality of life

●schedule patients for their next visit.

Masking of study personnel

Procedures for maintaining masking of study personnel must be observed throughout the 12month study.

The following study personnel must be masked to participant study status:

●the examining ophthalmologist(s)

●the study coordinator(s)

●the study photographer(s)

●the study visual acuity examiner(s)

●the photographic graders.

STUDY VISITS AND EVALUATIONS

Visit 1: screening visit

This will include:

●informed consent form signed and dated by the patient and the investigator

●documentation of the patient’s medical and ophthalmic histories, current medications, vitamin and mineral supplements and demographic information

Visit 2: month 6 (± 7 days)

This visit will include the following:

●best corrected logMAR visual acuity (using the Early Treatment of Diabetic Retinopathy Study chart) measured

●evaluation of contrast sensitivity using Pelli– Robson assessment

●photopic interferometry

●an ophthalmic examination of both eyes

●stereo digital colour fundus photographs with documentation

●record of any changes in the patient’s concomitant medications

●schedule patients for their next visit

●issue the second course of supplemental antioxidant treatment or placebo treatment.

Visit 3: month 12: exit (± 7 days)

This visit will include:

●best corrected logMAR visual acuity (using the Early Treatment of Diabetic Retinopathy Study chart) measured

●evaluation of contrast sensitivity using Pelli– Robson assessment

●photopic interferometry

●an ophthalmic examination of both eyes

●digital colour photographs with documentation

●record any changes in the patient’s concomitant medications

●complete the exit form for the patient.

DISCONTINUATION OF PATIENTS

Discontinuations are defined as those patients who end the treatment phase of the study before completing all regularly scheduled study visits. Patients may discontinue from the study at any time for any reason.

Please note that an exit form must be completed for all discontinued patients, clearly stating the reason for their early exit from the study.

If a patient is to be discontinued from the study between scheduled visits, the following activities must occur:

●completion of an exit visit

●completion of an exit visit form.

Patients discontinued from the study will not be replaced and their patient and/or clinical unit number(s) will not be reused.

Pelli–Robson contrast sensitivity

All contrast sensitivity measurements will be performed in accordance with the agreed procedure.

Photopic interferometry

Visometry is undertaken using monochromatic light at a wavelength of 555 nm. To remove any effects of transverse chromatic aberration, interferometric acuity is measured (two alternative forced-choice orientation discriminations) using the green monochromatic light and an ascending method of limit resolution task where the subject must indicate the orientation of the gratings.

Resonance Raman spectroscopy

Recent studies have demonstrated that Raman spectroscopy, which is a non-invasive method for measuring the macular pigment signal in vivo, is highly reproducible and simple to use in older people.2 Heterochromatic flicker, which is an alternative method, is time-consuming and difficult to use in older people. The Raman signal correlates well with macular carotenoid concentrations in in vitro studies. Measurements of in vivo macular carotenoid levels will therefore be performed using the Raman spectrometer.

UNSCHEDULED EXAMINATIONS

Unscheduled visits may be conducted at the discretion of the investigator, recording the information on unscheduled-visit forms. If a patient discontinues at an unscheduled visit, an exit form must be completed.

DOSING GUIDELINES

Patients will be randomised to receive either supplemental antioxidants or placebo.

STANDARDISED METHODS

Distance visual acuity

Best corrected visual acuity measurements are performed in strict accordance with agreed procedure.

STATISTICAL ANALYSIS

Primary analysis

The primary analysis will be a repeated-measures logistic regression analysis stratified by ARM category with outcomes measured every 6 months for 1 year.

The form will be a stratified block randomised design. Strata will be location (Belfast/Waterford), gender and patient category (category 1 = unilateral; category 2 = bilateral). It is anticipated that participants will be split equally across locations, that approximately 60% of participants will be female and 67% will be category 2 and potentially may have both eyes entered into the study. The size of the block will not be disclosed but will be set at a level to ensure reasonable balance within the smallest stratum.

Handling of data from category 2 participants

Several papers have cited the problem of statistical independence when dealing with outcomes on eyes.3 Briefly, this arises because outcomes relating to two eyes within one individual are likely to be more closely related than outcomes on eyes from different individuals. Earlier references have tended to cite dichotomous outcomes and so the solution becomes a particular application of interclass correlation. In this study the main outcome will be treated as continuously distributed.

One possible solution is simply to use data from one eye only from subjects in whom both eyes fit the entry criteria. This method thereby imposes a strict regime of one eye per participant. The disadvantage of this approach is that it does not utilise all readily available data and is therefore cost-inefficient. Collecting all data and treating them as independent outcomes can also be flawed, for the reasons stated above. A compromise solution is suggested that follows parallel arguments to that for interclass correlation.

Category 1 patients will only have one study eye (the fellow eye having already been lost to exudative AMD). Let the variance associated with contrast sensitivity in this group be s12. Category 2 patients may have both eyes eligible for the study and thus have two components of variance that can be estimated. That between participants will be denoted s2B2 and that between eyes within the same participant will be s2W2. In practice the study will yield some large sample estimators: s12, s2B2 and s2W2. A reasonable prior expectation might be for homogeneity of variance across all participants where s12 = s2B2 + s2W2.

However, the approach suggested will actually permit heterogeneity of variance between groups. It is usual, in situations of heterogeneity of variance, to weight cases by the reciprocal of the variation associated with each case. We propose, therefore, that all data be collected and the variance estimates described above calculated. Data will then be aggregated to one result per participant – the sole result will stand for category 1 participants and the mean of the two results will be applied to category 2 participants. The variance associated with category 1 participants will be s12,

while that associated with the mean of category 2 participants will be s2B2 + s2W2/2. So in the main analysis, category 1 participants will be given a weight of 1, while category 2 participants will be given a weight:

w2 = s12/(s2B2 + s2W2/2)

We note that, if most of the variation lies between participants, then w2 will tend to be close to 1. Here the second eye from bilateral participants provides very little additional information. However, if most of the variation lies within participants then w2 will tend to be close to 2. Here the second eye from bilateral participants provides much additional information and we are actually moving towards a situation where the two eyes have been entered as independent observations.

QUESTIONNAIRES

Questionnaires used include: (1) the food frequency questionnaire; (2) the general well-being questionnaire; and (3) vision-related quality-of- life questionnaire.

INVESTIGATOR RESPONSIBILITIES

Informed consent

All patients in this study are completely informed, according to informed consent guidelines, about the pertinent details and purpose of the study. A written informed consent form is signed and dated by each patient before enrolment into the study. The investigator keeps the original signed and dated consent forms in each patient’s chart, and provides the patient with a copy. This study is conducted in accordance with principles set forth in the Declaration of Helsinki.

Data collection

The clinical investigator maintains detailed records on all study patients. Data for this study are recorded on the case report forms provided for each patient completely, promptly, accurately and legibly. The investigator makes one copy of all the case report forms and sends the original to the

main study site. The investigator maintains a copy of all completed case report forms in his/her study files.

Study records

Investigator file content

The principal investigator maintains the following documentation in his/her study file:

●copy of the approved clinical protocol (and any amendments)

●approval letter from the local ethics committee (for study protocol and study consent form)

●approval letter(s) for any amendment(s)

●periodic/annual report to the local regional ethics committee

●final report to the local regional ethics committee

●original signed and dated informed consent forms for each patient

●copy of signed receipt of clinical supplies

●copy of clinical supplies dispensing records

●copy of all signed, completed case report forms

●copies of monitoring log

●study personnel log (list of all personnel involved in the study)

●patient enrolment log, showing the patient name and study patient number

●notification of any clinical supply expiry date extensions.

Inspection of investigator records

The investigator permits any trial-related monitoring visits, audits, local regional ethics committee review and inspections by regulatory agencies by providing direct access to data and documents. These inspections are for the purpose of verifying adherence to the protocol, the completeness and exactness of the data being entered in the case report form and compliance with regulations.

Test article storage

Test articles are stored in a secure area at the investigational site.

1.The Age-Related Eye Disease Study Group. A randomized, placebo-controlled, clinical trial of highdose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss. AREDS report no. 8. Arch Ophthalmol 2001; 119:1417–1436.

2.Neelam K, O’Gorman N, Nolan J et al. Measurement of macular pigment: Raman spectroscopy versus heterochromatic flicker photometry. Invest Ophthalmol Vis Sci 2005; 46:1023–1032.

3.Ederer F. Shall we count numbers of eyes or numbers of subjects? Arch Ophthalmol 1973; 89:1–2.

CHAPTER CONTENTS

Introduction 231

Contraindications 232

Adverse reactions 237

Summary 238

References 239

INTRODUCTION

People are increasingly taking an active interest in their well-being, and seeking alternative medical therapies.1,2 Traditional health care providers have been perceived as having a negative attitude towards these therapies.3 This may explain why many people do not consider their medical practitioner a major source of nutritional informa- tion4–6 and do not always report unconventional therapy use to their physicians.7

Use of ocular nutritional supplementation has been investigated with regard to prevention of onset or progression of glaucoma, cataract and age-related macular disease. There is particular interest in the use of nutrition as a prevention and treatment strategy for age-related macular degeneration (AMD) as it is the leading cause of visual disability in the developed world,8 and because treatment options are currently lacking.9

Eye care practitioners require information about the benefits, and potential hazards, of ocular nutritional supplements in order to be able to discuss their use with patients. It should be emphasised that the risk of side-effects from nutrients is much lower than from over-the-counter or prescription drugs. As an example, the National Health and Nutrition Examination Survey II estimated that 35% of the US population use vitamin A supplements,10 and the rate of toxic reactions has been reported as 1 case per 1.1 million per year exposed.

Here, we aim to highlight possible contraindications and the potential for adverse reactions for

those nutrients reported to be beneficial to ocular health. An overview of these nutrients can be found in Table 6.1, and drug interactions of nutrients considered beneficial for ocular health are summarised in Table 6.2.

CONTRAINDICATIONS

Provitamin A

In a review of the literature, b-carotene was promoted as a preferred source of vitamin A due to

A common side-effect of misoprostol is diarrhoea, which is aggravated by magnesium100