Retinitis Pigmentosa
Conditions
Keywords
Retinitis Pigmentosa, Inherited Retinal Degeneration
Brief summary
The purpose of this trial is to determine whether lutein in addition to vitamin A will slow the course of retinitis pigmentosa.
Detailed description
Retinitis pigmentosa (RP) is a group of inherited retinal degenerations with a worldwide prevalence of approximately 1 in 4,000. Patients typically report night blindness and difficulty with mid-peripheral visual field in adolescence. As the condition progresses, they lose far peripheral visual field. Most patients have reductions in central vision by 60 years if left untreated. Vitamin A palmitate, 15,000 International Units (IU)/d and an omega-3 rich diet have been shown to slow the progression of this condition among adults with the typical forms.(see Archives of Ophthalmology,111:761-772,1993 ; Archives of Ophthalmology 122: 1306-1314, 2004; Archives of Ophthalmology 130(6):701-711,2013). The present study was a randomized, controlled, double-masked trial with a planned duration of 5 years.Two hundred and forty adults with the typical forms of RP were assigned to either lutein 12mg/d or a control group. Patients in both groups received 15,000 IU/day of vitamin A palmitate in addition to the supplement under study. Participants agreed not to know the contents of the supplement or their group assignment until the end of the trial. The main outcome measurement was the total point score for the 30-2 program of the Humphrey Field analyzer (HFA). In addition,the total point score for the 60-4 program ,the total point score of the 30-2 and 60-4 programs combined, computer-averaged 30-Hz cone Electroretinogram (ERG) amplitude and Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity were measured annually as secondary endpoints.
Interventions
DRUGLutein
12mg/d
DIETARY_SUPPLEMENTCornstarch control
Daily intake of cornstarch control plus 15,000 IU/d Vitamin A palmitate
Sponsors
National Eye Institute (NEI)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
No
Inclusion criteria
Ocular Criteria * RP, typical forms(i.e. elevated final dark adaptation threshold,retinal arteriolar narrowing,and reduced and delayed full-field ERGs). * Best-corrected visual acuity 20/100 or better * HFA program 30-2 total point score \>= 250 decibels(dB)to a size V white test light * No confounding ocular disease such as glaucoma,uveitis,diabetic retinopathy,posterior subcapsular cataract more than 11% of total lens area (ie equivalent to P3 on Lens Opacity Classification System III)and pupil diameter after dilation less than 6 mm. Dietary Criteria * Fruit and vegetable intake \< 10 servings/d * Spinach or kale intake \< 1 serving/d, i.e. \<1/2 cup of cooked spinach or kale per day * Dietary lutein intake \<=5.4 mg/d as estimated from food frequency questionnaire * No intake of cod liver oil or omega-3 capsules * Dietary preformed vitamin A intake \<= 10,000 IU/d * Supplement intake \<= 5,000 IU/d of Vitamin A and \<= 30 IU/d of Vitamin E * Consumption \<= 3 alcoholic beverages/d Medical and other criteria * Age 18-60 y * Body mass index \< 40 and weight \>= 5th percentile for age,gender,and height * Serum retinol level \<= 100 micrograms/deciliter and serum retinyl ester level \<= 380 nanomoles/Liter * Serum cholesterol \< 300 micrograms/deciliter and serum triglyceride level \<400 micrograms/deciliter * No clinically significant abnormality on blood cell count, glucose level, blood urea nitrogen level, serum lipid panel results or serum liver function profile. * Not pregnant or planning to become pregnant * Not smoking currently * Agreed not to know tablet content or course of condition until the end of the trial. * No other disease which might affect absorption or metabolism of lutein or vitamin A. * Only one patient per family was accepted into the study.
Exclusion criteria
* Women who are pregnant or planning to become pregnant (Vitamin A supplements can increase the risk of birth defects.) * Current participation in another clinical trial for RP * Patients with atypical forms such as paravenous RP, pericentral RP, sector RP,unilateral RP,Refsum disease, Bardet-Biedl syndrome, retinitis punctata albescens and cone-rod dystrophy were excluded as were patients with RP and profound congenital deafness.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Central Visual Field (vf) Change Assessed Using the 30-2 Program of the Humphrey Field Analyzer (HFA). | assessed at each of 4 annual visits after baseline | Sum of visual field sensitivity readings in decibel(dB) to a size V target out to the 30 degree meridian in each direction of the visual field. The value presented represents annual change in dB over 4 years. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mid-peripheral Field Change Assessed With the 60-4 Program of the Humphrey Field Analyzer. | assessed at each of 4 annual visits after baseline | Sum of visual field sensitivity readings in dB to a size V target from the 30 degree meridian to the 60 degree meridian in each direction of the visual field. The value presented represents annual change in dB over 4 years. |
| Total Field Change Assessed by the Combined 30-2 and 60-4 Programs of the Humphrey Field Analyzer. | assessed at each of 4 annual visits after baseline | Sum of visual field sensitivity readings in dB to a size V target obtained with the 30-2 and 60-4 programs of the Humphrey Field Analyzer combined for those patients on whom both measures were available. |
| Annual Change in 30 Hertz(Hz)Electroretinogram(ERG )Amplitude in Natural Log (ln) Microvolts/yr Over a 4 Year Period. | assessed at each of 4 annual visits after baseline | Computer averaged 30 Hz ERG amplitudes in microvolts for those with initial amplitudes of \>= 0.68 microvolts. Presented on the ln scale. |
| Early Treatment Diabetic Retinopathy Study (ETDRS) Visual Acuity | assessed at each of 4 annual visits after baseline | Annual change in number of letters read. |
Countries
United States
Participant flow
Recruitment details
We performed screening examinations in the Berman-Gund Laboratory at the Massachusetts Eye & Ear Infirmary, Boston Massachusetts from July 15, 2003 to October 28, 2004.
Pre-assignment details
We screened patients for eligibility according to ocular, dietary, and medical criteria & performed a baseline examination on eligible patients within 8 weeks. At the baseline visit patients were randomized to 1 of 2 groups taking into account genetic type and initial serum lutein level (\<= 6.4 micrograms/deciliter (mg/dL) or \> 6.4 mg/dL).
Participants by arm
| Arm | Count |
|---|---|
| Control Plus Vitamin A cornstarch control plus 15,000IU Vitamin A palmitate daily | 121 |
| Lutein Plus Vitamin A 12mg Lutein plus 15,000IU Vitamin A palmitate daily | 119 |
| Total | 240 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 1 | 0 |
| Overall Study | unwilling or unable to continue | 4 | 8 |
Baseline characteristics
| Characteristic | Control Plus Vitamin A | Lutein Plus Vitamin A | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 121 Participants | 119 Participants | 240 Participants |
| Age, Continuous | 38 years STANDARD_DEVIATION 1 | 40 years STANDARD_DEVIATION 1 | 39 years STANDARD_DEVIATION 1 |
| Age of participants by 10-year age groups 18-29 years of age | 34 Participants | 25 Participants | 59 Participants |
| Age of participants by 10-year age groups 30-39 years of age | 26 Participants | 35 Participants | 61 Participants |
| Age of participants by 10-year age groups 40-49 years of age | 41 Participants | 36 Participants | 77 Participants |
| Age of participants by 10-year age groups 50-60 years of age | 20 Participants | 23 Participants | 43 Participants |
| Genetic type Dominant | 30 participants | 28 participants | 58 participants |
| Genetic type Isolate | 58 participants | 60 participants | 118 participants |
| Genetic type Recessive | 20 participants | 19 participants | 39 participants |
| Genetic type Undetermined | 5 participants | 5 participants | 10 participants |
| Genetic type X-Linked | 8 participants | 7 participants | 15 participants |
| Sex: Female, Male Female | 51 Participants | 58 Participants | 109 Participants |
| Sex: Female, Male Male | 70 Participants | 61 Participants | 131 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 121 | 0 / 119 |
| serious Total, serious adverse events | 1 / 121 | 1 / 119 |
Outcome results
Primary
Central Visual Field (vf) Change Assessed Using the 30-2 Program of the Humphrey Field Analyzer (HFA).
Sum of visual field sensitivity readings in decibel(dB) to a size V target out to the 30 degree meridian in each direction of the visual field. The value presented represents annual change in dB over 4 years.
Time frame: assessed at each of 4 annual visits after baseline
Population: Intention to treat analysis;sample of 215 patients with all 4 years of followup and reliable, non missing data at all 4 years was analyzed. Eyes with an initial 30-2 total point score \>= 250 dB were included.The eye was the unit of analysis. Each patient contributed 2,1, or 0 eyes with non-missing data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Control Plus Vitamin A | Central Visual Field (vf) Change Assessed Using the 30-2 Program of the Humphrey Field Analyzer (HFA). | -51.5 annual change in db vf sensitivity | Standard Error 3.2 |
| Lutein Plus Vitamin A | Central Visual Field (vf) Change Assessed Using the 30-2 Program of the Humphrey Field Analyzer (HFA). | -49.6 annual change in db vf sensitivity | Standard Error 3.3 |
Comparison: Primary Analysis:Proc mixed of the Statistical Analysis System (SAS) was used to compare annual rates of change by treatment group over 4 years.~Power Calculation:240 patients were estimated to be needed to provide sufficient power (i.e. alpha=0.05;beta=0.10)to observe a statistically significant difference between mean change in the 2 groups on the HFA 30-2 total point score over a 4-year interval.p-value: 0.66Longitudinal regression analysis
Comparison: Secondary Analysis: As change distribution was non-normal, slope for each eye was calculated with least squares regression and converted to ranks. The Clustered Wilcoxon test was used to compare slope distributions between groups accounting for correlation between slopes for eyes within individuals.p-value: 0.52Clustered Wilcoxon
Secondary
Annual Change in 30 Hertz(Hz)Electroretinogram(ERG )Amplitude in Natural Log (ln) Microvolts/yr Over a 4 Year Period.
Computer averaged 30 Hz ERG amplitudes in microvolts for those with initial amplitudes of \>= 0.68 microvolts. Presented on the ln scale.
Time frame: assessed at each of 4 annual visits after baseline
Population: This was an intention to treat analysis;analyses of 30 Hz ERG data included those who had an initial amplitude of 0.68 microvolts or greater in at least 1 eye and data were censored when values declined to less than 0.34 microvolts. The unit of analysis was the eye.Each patient contributed 2,1,or 0 eyes with non-missing data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Control Plus Vitamin A | Annual Change in 30 Hertz(Hz)Electroretinogram(ERG )Amplitude in Natural Log (ln) Microvolts/yr Over a 4 Year Period. | -0.08 ln (microvolts)/year | Standard Error 0.12 |
| Lutein Plus Vitamin A | Annual Change in 30 Hertz(Hz)Electroretinogram(ERG )Amplitude in Natural Log (ln) Microvolts/yr Over a 4 Year Period. | -0.09 ln (microvolts)/year | Standard Error 0.01 |
Comparison: Proc MIXED of SAS was used to compare annual rates of change over four years between the treatment groups.p-value: 0.59Longitudinal regression analysis
Secondary
Early Treatment Diabetic Retinopathy Study (ETDRS) Visual Acuity
Annual change in number of letters read.
Time frame: assessed at each of 4 annual visits after baseline
Population: This was an intention to treat analysis and included all reliable, non-missing values. The unit of analysis was the eye.Each patient contributed 2,1, or 0 eyes with non-missing data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Control Plus Vitamin A | Early Treatment Diabetic Retinopathy Study (ETDRS) Visual Acuity | -0.49 Change in letters read per year | Standard Error 0.12 |
| Lutein Plus Vitamin A | Early Treatment Diabetic Retinopathy Study (ETDRS) Visual Acuity | -0.53 Change in letters read per year | Standard Error 0.12 |
Comparison: Proc MIXED of SAS was used to compare annual rates of change over 4 years between the 2 groups.p-value: 0.8Longitudinal regression analysis
Secondary
Mid-peripheral Field Change Assessed With the 60-4 Program of the Humphrey Field Analyzer.
Sum of visual field sensitivity readings in dB to a size V target from the 30 degree meridian to the 60 degree meridian in each direction of the visual field. The value presented represents annual change in dB over 4 years.
Time frame: assessed at each of 4 annual visits after baseline
Population: This was an intention to treat analysis;lower sample sizes for this endpoint reflect instances where test results were not available for this outcome variable.The ability to perform this test was not a criterion for study entry.Eyes with an initial score ≥ 10 were included. Values were set to zero for all visits after an initial value of zero.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Control Plus Vitamin A | Mid-peripheral Field Change Assessed With the 60-4 Program of the Humphrey Field Analyzer. | -34.1 annual change in dB vf sensitivity | Standard Error 3 |
| Lutein Plus Vitamin A | Mid-peripheral Field Change Assessed With the 60-4 Program of the Humphrey Field Analyzer. | -26.6 annual change in dB vf sensitivity | Standard Error 3.1 |
Comparison: Primary Analysis: Proc Mixed of SAS was used to compare annual rates of change by treatment group over four years.The unit of analysis was the eye. Each patient contributed 2, 1, or 0 eyes with non-missing data.p-value: 0.05Longitudinal regression analysis
Comparison: Secondary Analysis: As change distribution was non-normal, slope for each eye was calculated with least squares regression and converted to ranks. The Clustered Wilcoxon test was used to compare slope distributions between groups accounting for correlation between slopes for eyes within individuals.p-value: 0.03Clustered Wilcoxon
Secondary
Total Field Change Assessed by the Combined 30-2 and 60-4 Programs of the Humphrey Field Analyzer.
Sum of visual field sensitivity readings in dB to a size V target obtained with the 30-2 and 60-4 programs of the Humphrey Field Analyzer combined for those patients on whom both measures were available.
Time frame: assessed at each of 4 annual visits after baseline
Population: This was an intention to treat analysis. A total field was calculated for each eye using the 30-2 and 60-4 conditions after applying the eligibility criteria for each component. Total field for a given eye was not calculated if either was missing. The unit of analysis was the eye.Each patient contributed 2, 1, or 0 eyes with non-missing data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Control Plus Vitamin A | Total Field Change Assessed by the Combined 30-2 and 60-4 Programs of the Humphrey Field Analyzer. | -83.1 annual change in dB vf sensitivity | Standard Error 6.2 |
| Lutein Plus Vitamin A | Total Field Change Assessed by the Combined 30-2 and 60-4 Programs of the Humphrey Field Analyzer. | -92.9 annual change in dB vf sensitivity | Standard Error 5.7 |
Comparison: Primary analysis:Proc Mixed of SAS was used to compare annual rates of change by treatment group over four years.The unit of analysis was the eye.Each patient contributed 2,1,or 0 eyes with non-missing data.p-value: 0.24Longitudinal regression analysis
Comparison: Secondary Analysis: As change distribution was non-normal, slope for each eye was calculated with least squares regression and converted to ranks. The Clustered Wilcoxon test was used to compare slope distributions between groups accounting for correlation between slopes for eyes within individuals.p-value: 0.2Clustered Wilcoxon