Age-Related Macular Degeneration
Conditions
Brief summary
Because of its iron-chelating and antioxidant properties, alpha lipoic acid may be a treatment for geographic atrophy (GA) secondary to age-related macular degeneration. There is ample published data about the safety and pharmacokinetics of alpha lipoic acid in adults. However, there is not much data on the safety and tolerability of higher doses of alpha lipoic acid in the elderly population. The purpose of Phase I of this protocol is to determine if there are safety/tolerability concerns seen when higher doses of alpha lipoic acid are taken by subjects 65 years of age or older. The objective of Phase 2 of this protocol is to determine the effects of ALA on the progression of GA in subjects with AMD. The central hypothesis, based on the existing literature, is that oral ALA reduces the rate of enlargement of GA in AMD subjects. The rationale is that the antioxidant and iron chelating effects of ALA will slow down one of the major pathways responsible for GA progression.
Detailed description
Phase I (Apr 2016 completed): 15 subjects, 65 years of age or older will take alpha lipoic acid on the following schedule: 600 mg once daily with a meal for 5 days. If tolerated, then the subject will then take 800 mg once daily with a meal for 5 days. If tolerated, then the subject will then take 1200 mg once daily with a meal for 5 days. Phase II: Randomized, double-blind placebo controlled pilot trial. Upon the completion of the dose tolerability test, we plan to enroll 50 subjects into a randomized, double-blind, placebo-controlled trial. Subjects will be randomized (1:1) into one of two study arms: placebo capsules and ALA 1200 mg orally once daily, assuming that 1200 mg is well tolerated by subjects in Phase 1. If 1200 mg is not well-tolerated based on Phase 1 data, then the highest tolerable dose will be used. Four clinical sites are planned and the enrollment period is estimated to be 6 months. The primary endpoint is the mean rate of change of the area of GA in the study eye from baseline to 18 months as evaluated by fundus autofluorescence. Subjects will have a refracted electronic visual acuity and dilated exam at baseline, 6 months, 12 months, and 18 months. The study will be conducted on an outpatient basis and study visits will last approximately 2-3 hours. Two weeks after the 18 months study visit, the subject will be contacted to share with the investigators adverse events that developed after completing the 18 month visit. The Investigator shall ensure each subject has a follow-up eye exam scheduled within 6 months.
Interventions
DRUGalpha lipoic acid
DRUGPlacebo
Sponsors
University of Pennsylvania
Study design
Allocation
RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
55 Years to 90 Years
Healthy volunteers
Yes
Inclusion criteria
Phase I Inclusion Criteria: * Ages 65-90 * Female participants must be menopausal. Male participants are required to use contraception. * Able to give informed consent * For the study duration (15 days), the subject must remain in the country, remain within 4 hours of travel time (by car or airplane), have access to medical care if needed, and provide contact information so the subject can be reached as needed.
Exclusion criteria
* Blood Pressure greater than 190/100 at the baseline visit * Pulse greater than 100 at the baseline visit * Acute and ongoing systemic infection * History of dementia * Participant has a condition that, in the opinion of the investigator, gives them an unstable medical status. * Participant has geographic atrophy and the investigator believes the participant is a candidate for enrollment into the planned Phase 2 trial for geographic atrophy. Phase II Inclusion Criteria * Age 55-90 * Diagnosis of geographic atrophy from age-related macular degeneration in the study eye. The largest geographic atrophy (GA) lesion must be a minimum of 0.5 optic disk area (DA) (1.25 mm2) and no more than 6 DA in size (15.0 mm2). GA is defined as one or more well-defined, usually more or less circular patches of loss of the retinal pigment epithelium (RPE), typically with exposure of underlying choroidal blood vessels. If the GA is multifocal and the largest lesion is \< 0.5 DA, then there should be at least 3 lesions ≥ 250 microns in greatest linear diameter. * Best-Corrected Visual Acuity (BCVA) between 20/20 and 20/400 in the study eye. * Female participants must be menopausal. Male participants are required to use contraception and cannot donate sperm during study participation. * Presence of hyperfluorescence at the edge of GA on autofluorescence imaging. * Ability to give informed consent. * If a subject has two eligible eyes, then both eyes can be enrolled into the study. * Subject must have mailed back the medication bottle after the 10 day run-in phase, demonstrating that they have taken ≥ 80% of the capsules.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase I: Percentage of Participants With Adverse Events | 15 days | The percent of adverse events that develop will be stratified by the alpha lipoic acid dose. |
| Phase II: Mean Annual Growth of Geographic Atrophy (Fundus Autofluorescence) - Total Area of Geographic Atrophy (mm2) - Unadjusted | 18 months | The rate of change over time in area of Geographic Atrophy (GA) in the study eye. This is determined by masked grading of Fundus Autofluorescence by an image reading center, in participants randomized to placebo or 1200 mg once daily of ALA. The values represent the annualized change from baseline to 18 months. Mean annual geographic atrophy growth rate was calculated by taking the total atrophy area at 18 months minus the baseline area. This value was then divided by 18 months and then multiplied by 12 months to get the annual growth rate. Timepoints for the study were baseline, 0, 6, 12, and 18 months. The baseline and 18 month timepoints were used for the annualized calculations as noted below. |
| Phase II: Mean Annual Growth of Geographic Atrophy (Fundus Autofluorescence) - Total Area of GA (mm2) - Adjusted | 18 months | The rate of change over time in area of Geographic Atrophy (GA) in the study eye. This is determined by masked grading of Fundus Autofluorescence by an image reading center, in participants randomized to placebo or 1200 mg once daily of ALA. The values represent the annualized change from baseline to 18 months. Mean annual geographic atrophy growth rate was calculated by taking the total atrophy area at 18 months minus the baseline area. This value was then divided by 18 months and then multiplied by 12 months to get the annual growth rate. Timepoints for the study were baseline, 0, 6, 12, and 18 months. The baseline and 18 month timepoints were used for the annualized calculations as noted below. |
| Phase II: Mean Annual Growth of Geographic Atrophy (Fundus Autofluorescence) - Square Root of Area of GA (mm) - Unadjusted | 18 months | The rate of change over time in area of Geographic Atrophy (GA) in the study eye. This is determined by masked grading of Fundus Autofluorescence (FAF) by an image reading center, in participants randomized to placebo or 1200 mg once daily of ALA. The values represent the annualized change from baseline to 18 months. Mean annual geographic atrophy growth rate was calculated by taking the total atrophy area at 18 months minus the baseline area. This value was then divided by 18 months and then multiplied by 12 months to get the annual growth rate. For square root transformed data, the square root of area was used. Timepoints for the study were baseline, 0, 6, 12, and 18 months. The baseline and 18 month timepoints were used for the annualized calculations as noted below. |
| Phase II: Mean Annual Growth of Geographic Atrophy (Fundus Autofluorescence) - Square Root of Area of GA (mm) - Adjusted | 18 months | The rate of change over time in area of Geographic Atrophy (GA) in the study eye. This is determined by masked grading of Fundus Autofluorescence (FAF) by an image reading center, in participants randomized to placebo or 1200 mg once daily of ALA. The values represent the annualized change from baseline to 18 months. Mean annual geographic atrophy growth rate was calculated by taking the total atrophy area at 18 months minus the baseline area. This value was then divided by 18 months and then multiplied by 12 months to get the annual growth rate. For square root transformed data, the square root of area was used. Timepoints for the study were baseline, 0, 6, 12, and 18 months. The baseline and 18 month timepoints were used for the annualized calculations as noted below. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phase II: Mean Annual Change in Best-Corrected Visual Acuity (BCVA) | 18 months | Unit of Measure. Mean annual change in best-corrected visual acuity was calculated by taking the letter score at 18 months minus the baseline letter score. This value was then divided by 18 months and then multiplied by 12 months to get the mean annual change in visual acuity. Timepoints for the study were baseline, 0, 6, 12, and 18 months. The baseline and 18 month timepoints were used for the annualized calculations as noted below. |
Countries
United States
Participant flow
Pre-assignment details
Phase I: 15 subjects took escalating ALA doses (600mg, 800mg, 1200mg). 1 subject withdrew after 800mg due to wanting to delay start of 1200mg dose beyond planned completion date. Phase II: 52 subjects randomized to placebo or 1200mg ALA. 1 subject died due to unrelated event and was replaced in study; thus, 53 total subjects were enrolled.
Participants by arm
| Arm | Count |
|---|---|
| Alpha Lipoic Acid (ALA) 600, 800 &1200 mg Phase I: All subjects recruited to the Phase I part will take escalating doses of alpha lipoic acid (ALA) open label. Each enrolled subject will take 600 mg of oral ALA once daily with a meal for 5 days. If well-tolerated, each subject will then take 800 mg of oral ALA once daily with a meal for 5 additional days. If 800 mg of oral ALA is well-tolerated, then subjects will then take 1200 mg of oral ALA once daily with a meal for 5 days. | 15 |
| Placebo 1200mg Phase II: All subjects in Phase II will be double blinded and randomized to either placebo or ALA. Each will take one 600 mg capsule of ALA (or placebo) once daily with a meal for 2 weeks and then increase to two 600 mg capsules of ALA (or placebo) once daily with a meal for the entire remainder of the 18 month period of the study. | 27 |
| Alpha Lipoic Acid (ALA) 1200mg Phase II: All subjects in Phase II will be double blinded and randomized to either placebo or ALA. Each will take one 600 mg capsule of ALA (or placebo) once daily with a meal for 2 weeks and then increase to two 600 mg capsules of ALA (or placebo) once daily with a meal for the entire remainder of the 18 month period of the study. | 26 |
| Total | 68 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Phase II: Double-Blind Rand Plac Control | Death | 0 | 1 | 0 |
| Phase I: Tolerability, 600, 800, 1200 mg | Physician Decision | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Total | Alpha Lipoic Acid (ALA) 600, 800 &1200 mg | Alpha Lipoic Acid (ALA) 1200mg | Placebo 1200mg |
|---|---|---|---|---|
| Age, Continuous | 77.8 years STANDARD_DEVIATION 7.2 | 70.7 years STANDARD_DEVIATION 3.3 | 80.6 years STANDARD_DEVIATION 6.5 | 79.0 years STANDARD_DEVIATION 7 |
| Bilateral Geographic Atrophy No | 6 Participants | 0 Participants | 3 Participants | 3 Participants |
| Bilateral Geographic Atrophy Yes | 47 Participants | 0 Participants | 23 Participants | 24 Participants |
| Geographic Atrophy Lipoic Acid Study (GALA) Eligible Eyes Bilateral | 20 Participants | 0 Participants | 10 Participants | 10 Participants |
| Geographic Atrophy Lipoic Acid Study (GALA) Eligible Eyes Unilateral | 33 Participants | 0 Participants | 16 Participants | 17 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 3 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants | 0 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) White | 62 Participants | 12 Participants | 24 Participants | 26 Participants |
| Region of Enrollment United States | 68 participants | 15 participants | 26 participants | 27 participants |
| Sex: Female, Male Female | 44 Participants | 10 Participants | 18 Participants | 16 Participants |
| Sex: Female, Male Male | 24 Participants | 5 Participants | 8 Participants | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 15 | 0 / 15 | 0 / 14 | 1 / 27 | 0 / 26 |
| other Total, other adverse events | 11 / 15 | 10 / 15 | 10 / 14 | 24 / 27 | 23 / 26 |
| serious Total, serious adverse events | 0 / 15 | 0 / 15 | 0 / 14 | 5 / 27 | 10 / 26 |
Outcome results
Primary
Phase II: Mean Annual Growth of Geographic Atrophy (Fundus Autofluorescence) - Square Root of Area of GA (mm) - Adjusted
The rate of change over time in area of Geographic Atrophy (GA) in the study eye. This is determined by masked grading of Fundus Autofluorescence (FAF) by an image reading center, in participants randomized to placebo or 1200 mg once daily of ALA. The values represent the annualized change from baseline to 18 months. Mean annual geographic atrophy growth rate was calculated by taking the total atrophy area at 18 months minus the baseline area. This value was then divided by 18 months and then multiplied by 12 months to get the annual growth rate. For square root transformed data, the square root of area was used. Timepoints for the study were baseline, 0, 6, 12, and 18 months. The baseline and 18 month timepoints were used for the annualized calculations as noted below.
Time frame: 18 months
Population: Phase II: 52 subjects randomized to placebo or 1200mg ALA. 1 subject died due to unrelated event and was replaced in study; thus, 53 total subjects were enrolled, but 52 subjects were analyzed in this outcome.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Alpha Lipoic Acid (ALA) 600 mg | Phase II: Mean Annual Growth of Geographic Atrophy (Fundus Autofluorescence) - Square Root of Area of GA (mm) - Adjusted | 0.27 mm/year | Standard Deviation 0.04 |
| Alpha Lipoic Acid (ALA) 800 mg | Phase II: Mean Annual Growth of Geographic Atrophy (Fundus Autofluorescence) - Square Root of Area of GA (mm) - Adjusted | 0.32 mm/year | Standard Deviation 0.05 |
p-value: 0.14Mixed Models Analysis
Primary
Phase II: Mean Annual Growth of Geographic Atrophy (Fundus Autofluorescence) - Square Root of Area of GA (mm) - Unadjusted
The rate of change over time in area of Geographic Atrophy (GA) in the study eye. This is determined by masked grading of Fundus Autofluorescence (FAF) by an image reading center, in participants randomized to placebo or 1200 mg once daily of ALA. The values represent the annualized change from baseline to 18 months. Mean annual geographic atrophy growth rate was calculated by taking the total atrophy area at 18 months minus the baseline area. This value was then divided by 18 months and then multiplied by 12 months to get the annual growth rate. For square root transformed data, the square root of area was used. Timepoints for the study were baseline, 0, 6, 12, and 18 months. The baseline and 18 month timepoints were used for the annualized calculations as noted below.
Time frame: 18 months
Population: Phase II: 52 subjects randomized to placebo or 1200mg ALA. 1 subject died due to unrelated event and was replaced in study; thus, 53 total subjects were enrolled, but 52 subjects were analyzed in this outcome.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Alpha Lipoic Acid (ALA) 600 mg | Phase II: Mean Annual Growth of Geographic Atrophy (Fundus Autofluorescence) - Square Root of Area of GA (mm) - Unadjusted | 0.28 mm/year | Standard Deviation 0.02 |
| Alpha Lipoic Acid (ALA) 800 mg | Phase II: Mean Annual Growth of Geographic Atrophy (Fundus Autofluorescence) - Square Root of Area of GA (mm) - Unadjusted | 0.31 mm/year | Standard Deviation 0.02 |
p-value: 0.3Mixed Models Analysis
Primary
Phase II: Mean Annual Growth of Geographic Atrophy (Fundus Autofluorescence) - Total Area of GA (mm2) - Adjusted
The rate of change over time in area of Geographic Atrophy (GA) in the study eye. This is determined by masked grading of Fundus Autofluorescence by an image reading center, in participants randomized to placebo or 1200 mg once daily of ALA. The values represent the annualized change from baseline to 18 months. Mean annual geographic atrophy growth rate was calculated by taking the total atrophy area at 18 months minus the baseline area. This value was then divided by 18 months and then multiplied by 12 months to get the annual growth rate. Timepoints for the study were baseline, 0, 6, 12, and 18 months. The baseline and 18 month timepoints were used for the annualized calculations as noted below.
Time frame: 18 months
Population: Phase II: 52 subjects randomized to placebo or 1200mg ALA. 1 subject died due to unrelated event and was replaced in study; thus, 53 total subjects were enrolled, but 52 subjects were analyzed in this outcome.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Alpha Lipoic Acid (ALA) 600 mg | Phase II: Mean Annual Growth of Geographic Atrophy (Fundus Autofluorescence) - Total Area of GA (mm2) - Adjusted | 1.29 mm^2/year | Standard Deviation 0.23 |
| Alpha Lipoic Acid (ALA) 800 mg | Phase II: Mean Annual Growth of Geographic Atrophy (Fundus Autofluorescence) - Total Area of GA (mm2) - Adjusted | 1.63 mm^2/year | Standard Deviation 0.28 |
p-value: 0.09Mixed Models Analysis
Primary
Phase II: Mean Annual Growth of Geographic Atrophy (Fundus Autofluorescence) - Total Area of Geographic Atrophy (mm2) - Unadjusted
The rate of change over time in area of Geographic Atrophy (GA) in the study eye. This is determined by masked grading of Fundus Autofluorescence by an image reading center, in participants randomized to placebo or 1200 mg once daily of ALA. The values represent the annualized change from baseline to 18 months. Mean annual geographic atrophy growth rate was calculated by taking the total atrophy area at 18 months minus the baseline area. This value was then divided by 18 months and then multiplied by 12 months to get the annual growth rate. Timepoints for the study were baseline, 0, 6, 12, and 18 months. The baseline and 18 month timepoints were used for the annualized calculations as noted below.
Time frame: 18 months
Population: Phase II: 52 subjects randomized to placebo or 1200mg ALA. 1 subject died due to unrelated event and was replaced in study; thus, 53 total subjects were enrolled, but 52 subjects were analyzed in this outcome.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Alpha Lipoic Acid (ALA) 600 mg | Phase II: Mean Annual Growth of Geographic Atrophy (Fundus Autofluorescence) - Total Area of Geographic Atrophy (mm2) - Unadjusted | 1.21 mm^2/year | Standard Deviation 0.13 |
| Alpha Lipoic Acid (ALA) 800 mg | Phase II: Mean Annual Growth of Geographic Atrophy (Fundus Autofluorescence) - Total Area of Geographic Atrophy (mm2) - Unadjusted | 1.71 mm^2/year | Standard Deviation 0.13 |
p-value: 0.009Mixed Models Analysis
Primary
Phase I: Percentage of Participants With Adverse Events
The percent of adverse events that develop will be stratified by the alpha lipoic acid dose.
Time frame: 15 days
Population: Phase I: 15 subjects took escalating ALA doses (600mg, 800mg, 1200mg). 1 subject withdrew after 800mg due to wanting to delay start of 1200mg dose beyond planned completion date.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Alpha Lipoic Acid (ALA) 600 mg | Phase I: Percentage of Participants With Adverse Events | 11 Participants |
| Alpha Lipoic Acid (ALA) 800 mg | Phase I: Percentage of Participants With Adverse Events | 10 Participants |
| Alpha Lipoic Acid (ALA) 1200 mg | Phase I: Percentage of Participants With Adverse Events | 10 Participants |
p-value: 1Fisher Exact
Secondary
Phase II: Mean Annual Change in Best-Corrected Visual Acuity (BCVA)
Unit of Measure. Mean annual change in best-corrected visual acuity was calculated by taking the letter score at 18 months minus the baseline letter score. This value was then divided by 18 months and then multiplied by 12 months to get the mean annual change in visual acuity. Timepoints for the study were baseline, 0, 6, 12, and 18 months. The baseline and 18 month timepoints were used for the annualized calculations as noted below.
Time frame: 18 months
Population: Phase II: 52 subjects randomized to placebo or 1200mg ALA. 1 subject died due to unrelated event and was replaced in study; thus, 53 total subjects were enrolled, but 52 subjects were analyzed in this outcome.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Alpha Lipoic Acid (ALA) 600 mg | Phase II: Mean Annual Change in Best-Corrected Visual Acuity (BCVA) | -3.8 letters/year | Standard Deviation 1.1 |
| Alpha Lipoic Acid (ALA) 800 mg | Phase II: Mean Annual Change in Best-Corrected Visual Acuity (BCVA) | -3.1 letters/year | Standard Deviation 1.12 |
p-value: 0.69Mixed Models Analysis