Abstract
Objective
Alpha lipoic acid (ALA) is a nutraceutical and potent antioxidant that has shown efficacy in the retina light damage mouse model and in humans for multiple sclerosis. Our objective was to evaluate the efficacy and safety of oral ALA for the treatment of geographic atrophy (GA).
Design
Randomized, controlled, double-masked, multicenter phase 2 clinical trial of ALA vs. placebo.
Participants
Participants with unilateral or bilateral GA from age-related macular degeneration.
Methods
Participants were randomized to 1200 mg daily of ALA or placebo. Fundus autofluorescence (FAF), fundus color photography, spectral-domain optical coherence tomography, and best-corrected visual acuity (BCVA) were obtained at baseline and every 6 months through month 18.
Main Outcome Measures
Annual rate of change over 18 months in square root transformed area of GA in study eyes as measured on FAF. Secondary outcomes include number of adverse events (AEs), change in BCVA, and annual rate of change in area of GA measured on color photos.
Results
Fifty-three participants (mean age 80 years) were randomized from April 2016 to August 2017. There were 27 participants (37 eyes) in the placebo group and 26 participants (36 eyes) in the ALA group. Unadjusted mean (SE) annual change in GA area (square root transformed) was 0.28 (0.02) mm and 0.31 (0.02) mm for the placebo and ALA groups, respectively (difference 0.04 mm; 95% confidence interval [−0.03, 0.11]; p=0.30). Adjusting for baseline GA area, number of GA lesions, and presence of subfoveal GA, the mean annual change in GA area was 0.27 (0.04) mm and 0.32 (0.05) mm for the placebo and ALA groups, respectively (difference 0.05; 95% confidence interval [−0.02, 0.12]; p=0.14). At 18 months, the percent of eyes losing 15 or more letters in BCVA was 22% (8 of 36) and 14% (5 of 36) in the placebo and ALA groups, respectively (p=0.54). There was no difference in the percentage of participants with nonserious AEs (p=0.96) or serious AEs (p=0.28) between the placebo and ALA groups.
Conclusions
Results do not support ALA having beneficial effects on GA or BCVA. This trial design may be useful for other GA re-purposing drug trials.
Precis
Lipoic acid is an antioxidant with efficacy seen in neurodegeneration animal models, the retinal light-damage mouse model, and humans with multiple sclerosis. Lipoic acid did not slow geographic atrophy growth in a phase II trial.
Introduction
There currently is an urgent need to find a treatment for geographic atrophy (GA). GA is an advanced stage of age-related macular degeneration (AMD) that is estimated to affect 5 million people worldwide.1 Oxidative stress, dysregulation of the complement pathway, and the accumulation of toxic metabolic byproducts are, among others, considered to be key pathophysiologic mechanisms for GA.2 Oxidative stress is considered an upstream mechanism that contributes to complement dysfunction.
Several facts support consideration of alpha lipoic acid (ALA) as a potential therapeutic for GA. ALA is a nutritional supplement that is a potent antioxidant.3 ALA is a scavenger of reactive oxygen species and is a co-factor for several mitochondrial enzymes. In addition to being an antioxidant itself, ALA regenerates other antioxidants including glutathione. In atrophic AMD, Nrf2 (nuclear factor erythroid 2-related factor) related signaling is considered critical to the protection of the retinal pigment epithelium from oxidative stress,4 and ALA increases nuclear Nrf2 levels.5 Further, iron overload in AMD eyes is a potential mediator of oxidative stress, and ALA is a weak iron chelator.6,7 ALA has known pharmacokinetics,8 and it has been approved for use in Germany as a therapy for diabetic peripheral neuropathy.9,10 ALA is also under continued investigation for secondary progressive multiple sclerosis based on a phase II trial suggesting that ALA slows the development of brain atrophy in this disease.11 There is ample safety data on the use of ALA in humans; it generally is considered safe at doses up to 1200 mg daily, and gastrointestinal distress is the most significant adverse event (AE).10–12 ALA is known to cross the blood-brain barrier, and systemic administration of ALA can affect the transcription of oxidative stress-related genes within the retina.13 Importantly, systemic administration of ALA has shown a significant protective effect for the retina in the light damage mouse model,14 as well as several other animal models of eurodegeneration.13,15,16 If ALA is found to be effective as a re-purposed therapy for GA, then this would have a large public health impact because ALA is inexpensive and widely available.
Here, we report the results of a pilot phase II trial evaluating the efficacy of ALA for slowing the growth of GA.
Methods
Study Design
This phase 2 trial was a multi-center, randomized, double-masked study. Participants recruited from 5 clinical sites were randomized (1:1) to placebo or 1200 mg of ALA once daily. Before proceeding to randomization, participants meeting study criteria were required to demonstrate the ability to comply with study procedures by completing a single-masked (patient masked) run-in phase. Successful completion of the run-in phase required at least 8 of 10 placebo capsules to be taken over a 10-day period. Random treatment allocation schedules were generated by the Coordinating Center (Center for Preventive Ophthalmology and Biostatistics, UPenn) with a randomized block design and stratified by clinical center. The trial was approved by an institutional review board for each clinical site and written informed consent was obtained from all participants. The research was in accordance with the tenets of the Declaration of Helsinki and was registered in clinicaltrials.gov (NCT02613572).
ALA was provided by Pure Encapsulations (Sudbury, MA) as capsules containing 600 mg of racemic ALA and 30 mg of ascorbyl palmitate. The dose of 1200 mg once daily of ALA was chosen based on studies demonstrating that this dose leads to a meaningful serum level of ALA and is the highest tolerable dose in the elderly population.8,12 The purity of these capsules was confirmed independently at the University of Pennsylvania (Metabolomic Core at Children’s Hospital of Philadelphia). Compliance was measured by capsule counts at each study visit. Further, all participants were asked to give a one-time urine sample at the month 12 study visit. Urine was analyzed by gas-chromatograph-mass spectrometry for 4,6-bis-methylthio-hexanoic acid (BMHA), a metabolite of ALA considered specific to ALA (for methods, see Appendix).17,18 After ingesting oral ALA, BMHA is detectable in the urine for 24 hours; in contrast, ALA is minimally present in the urine. Plasma is a less suitable fluid for compliance testing, as ALA and BMHA are difficult to detect in plasma 6 hours after ALA intake.18 The placebo consisted of pharmaceutical grade capsules containing microcrystalline cellulose plus trace amounts of coloring agents in order to mimic the appearance and contents of ALA capsules.
Participants (Eligibility Criteria)
A full listing of eligibility criteria is provided in Table 1 (supplementary material). Briefly, eligible participants were 55 – 90 years of age with GA from AMD that met the study criteria in one or both eyes. GA was defined on color photos as one or more well-defined patches of loss of the RPE, typically with exposure of underlying choroidal blood vessels. In addition, the protocol required at least some visible hyperfluorescence at the edge of the GA lesion on fundus autofluorescence (FAF) imaging. The largest GA lesion needed to be 0.5 – 6.0 DA (disc areas) in size. If the GA was multifocal and the largest lesion was < 0.5 DA, then there needed to be at least 3 lesions ≥ 250 microns in greatest linear diameter. This criterion was made to enable enrollment of patients with smaller lesions. Lesions ≥ 250 microns are considered gradable,19 and the presence of 3 small lesions was considered enough to be confident that there was GA that would demonstrate lesion growth. Best corrected visual acuity (BCVA) needed to be 20/20 – 20/400 in study eyes. Eligibility of eyes with respect to GA was confirmed by a reading center (Scheie Eye Institute Reading Center) based on imaging at a screening visit.
Exclusion criteria for an eye included: evidence of ocular disease other than AMD that may affect the study outcomes (e.g., history of myopic degeneration, choroidal neovascularization, central serous chorioretinopathy, severe diabetic retinopathy, macular edema); any history of intravitreal injection for AMD or choroidal neovascularization; history of laser treatment (including photodynamic therapy) to the macula; intraocular surgery within 90 days; media opacity (e.g., corneal scar, cataract) that would prevent adequate fundus imaging. Exclusion criteria for participants included: history of involvement in another therapeutic clinical trial for GA; prior use of ALA; history of gastric ulcer, irritable bowel syndrome, or severe, chronic gastric reflux. AREDS (Age Related Eye Disease Study) vitamins taken at standard doses were not considered an exclusion criterion. Taking antioxidant supplements other than a standard multivitamin (e.g., bilberry, vitamin C that is not part of a multivitamin or taken at higher doses than the AREDS formula, or other similar antioxidants) within one month of enrollment or during the study was not allowed.
Outcome Measures
All participants were evaluated at baseline and every 6 months with a full eye exam including BCVA testing with either an ETDRS (Early Treatment Diabetic Retinopathy Study) chart or EVA (electronic visual acuity),20 color fundus photos, spectral-domain optical coherence tomography (OCT) (Spectralis, Heidelberg Engineering, Heidelberg, Germany), and blue light scanning laser ophthalmoscopy autofluorescence (Spectralis) according to a standardized reading center protocol. The reading center and all research coordinators were masked to study drug assignment. The primary outcome was the annual rate of change over 18 months in square root transformed area of GA in study eyes as measured on FAF by the reading center.21 Secondary outcomes were the mean change in BCVA, worsening of BCVA by 15 or more letters compared to baseline, the growth of geographic atrophy as assessed by color fundus photography, and the adverse events in the placebo and ALA groups.
Statistical Methods
Sample size was estimated under the assumptions that ALA would warrant further evaluation only if the growth rate observed in this study for the ALA group was less than the growth rate in the placebo group, and that we would be 90% confident that the standardized difference (“effect size”) between groups was no larger than 0.4.22 An example of an effect size of 0.4 would be square-root transformed growth rates of 0.40 mm in the placebo group and 0.32 mm in the ALA group when the standard deviation of the rate is 0.20 mm, which is a 20% reduction in growth rate. Thus, the study “go/-no-go” is based on 90% confidence for a clinically relevant threshold for GA growth rate reduction. Under the additional assumptions of a 15% loss to follow-up and only 1 eligible eye per patient, the total sample size goal was 50 participants.
Patient-level characteristics at baseline and at specific visits were compared using linear regression for continuous variables, and chi-square tests for categorical variables. Eye-level characteristics at baseline and at specific visits were compared using linear regression for continuous variables with generalized estimating equations (GEE) to account for correlation between eyes, and logistic regression with GEE for categorical variables (except where noted that Fisher’s exact test was used for small cell counts).23 Adverse events were compared using Poisson regression for counts of events, or chi-square tests for the proportion with 1 or more events. To estimate average annual growth, linear mixed-effects models were used where the square root of area of GA was modeled as a function of time from baseline, treatment group, adjustment variables (baseline GA area, number of GA lesions, and subfoveal GA), and interaction terms between each of the 4 variables and time from baseline. Slopes and intercepts were modeled as random effects within subjects. All analyses were performed with SAS 9.4 (SAS Institute, Inc., Cary, NC).
Results
Research Participants and Compliance in Taking Study Medication
Between April 2016 and August 2017, 75 participants were screened and 53 eligible participants were randomized to either placebo (N=27) or ALA (N=26) (Figure 1). Treatment groups were well-balanced with regard to age, sex, and race (Table 2). Twenty participants had bilateral GA meeting study criteria, therefore the study included 73 eyes in total, 37 in the placebo group and 36 in the ALA group. Treatment groups were well-balanced on baseline visual acuity, phakic status, and presence of subfoveal GA (Table 2). However, there was an imbalance for total size of GA at baseline with a mean total size of 4.8 mm2 in the placebo group and 7.1 mm2 in the ALA group (p = 0.01). The mean number of GA lesions at baseline was 2.6 in the placebo group and 3.5 lesions in the ALA group (p = 0.11). Small, multifocal lesions (all lesions < 0.5 DA) were present in 16% (6 of 37) of placebo eyes and 8% (3 of 36) of ALA eyes (p = 0.32).
Figure 1. Clinical Trial Flowchart.
Table 2.
Baseline Characteristics of Subjects and Eyes
| Baseline Subjects Characteristics | Placebo | ALA | p | |
|---|---|---|---|---|
| Age | ≤75 | 8 (30%) | 5 (19%) | |
| 76–80 | 8 (30%) | 6 (23%) | ||
| 81–85 | 5 (19%) | 8 (31%) | ||
| >85 | 6 (22%) | 7 (27%) | ||
| Mean (SD) | 79.0 (7.0) | 80.6 (6.5) | 0.38 | |
| Sex | Female | 16 (59%) | 18 (69%) | 0.45 |
| Male | 11 (41%) | 8 (31%) | ||
| Race | Other/Multiple/Unknown | 1 (4%) | 2 (8%) | 0.53 |
| White only | 26 (96%) | 24 (92%) | ||
| Bilateral GA | No | 3 (11%) | 3 (12%) | 0.96 |
| Yes | 24 (89%) | 23 (88%) | ||
| Eligible eyes | 1 | 17 (63%) | 16 (62%) | 0.91 |
| 2 | 10 (37%) | 10 (38%) | ||
| Baseline Eye Characteristics | ||||
| Visual acuity (letters) | ≤52 letters, 20/100 or worse | 10 (27%) | 8 (22%) | |
| 53–67 letters, 20/50–80 | 8 (22%) | 10 (28%) | ||
| ≥68 letters, 20/40 or better | 19 (51%) | 18 (50%) | ||
| Mean (SD) | 65.8 (15.6) | 62.6 (18.0) | 0.39 | |
| Phakic | IOL | 23 (62%) | 26 (72%) | 0.36 |
| Phakic | 14 (38%) | 10 (28%) | ||
| Subfoveal GA | No | 19 (51%) | 15 (42%) | 0.41 |
| Yes | 18 (49%) | 21 (58%) | ||
| Number of GA lesions | 1 | 15 (41%) | 8 (22%) | |
| 2 | 10 (27%) | 6 (17%) | ||
| 3–4 | 5 (14%) | 12 (33%) | ||
| >4 | 7 (19%) | 10 (28%) | ||
| Mean (SD) | 2.6 (2.2) | 3.5 (2.2) | 0.11 | |
| Total area of GA (mm2) | <2 mm2 | 9 (24%) | 2 (6%) | |
| 2–<5 mm2 | 13 (35%) | 10 (28%) | ||
| 5–10 mm2 | 12 (32%) | 16 (44%) | ||
| >10 mm2 | 3 (8%) | 8 (22%) | ||
| Mean (SD) | 4.8 (3.3) | 7.1 (3.8) | 0.01 | |
| Square root of area of GA (mm) | Mean (SD) | 2.1 (0.7) | 2.6 (0.8) | 0.01 |
GA=geographic atrophy; SD=standard deviation.
Compliance with taking study medication was assessed by capsule counts every 6 months at study visits. The placebo group used 88% of scheduled capsules and the ALA group used 75% of scheduled capsules. A few participants took a reduced or split dose of the assigned study drug, a reduction allowed per protocol if there were adverse effects perceived to be related to study drug. At 18 months, this included: 5 participants taking 600 mg twice daily of which 2 were in the ALA group, and 4 participants taking 600 mg once daily of which 2 were in the ALA group. Twenty-one (78%) of 27 placebo participants and 19 (73%) of 26 ALA participants self-reported taking 1200 mg daily through the 18 months. Three participants in the ALA group discontinued the study capsules, and these participants remained under follow-up.
Efficacy
The mean area of GA increased steadily over time in both treatment groups (Table 3A). At 18 months the mean increase in the square root of area was 0.42 mm in the placebo group and 0.48 mm in the ALA group, yielding a mean difference of 0.06 mm (95% confidence interval (−0.05, 0.16)). After adjustment for the baseline number of GA lesions, subfoveal location, and baseline GA area, the mean difference was 0.07 mm (95% confidence interval (−0.02, 0.17)). (Figure 2). The mean annualized growth rate for the square root of GA area, the primary outcome measure, was 0.28 mm/year in the placebo group and 0.31 mm/year in the ALA group, yielding a mean difference of 0.04 mm/year (95% confidence interval (−0.03, 0.11) (Table 3B). After adjustment for the above baseline characteristics, the mean difference in GA growth rate was 0.05 mm/year (95% confidence interval (−0.02, 0.12)). Figure 3 shows examples of GA growth in 3 cases from this trial. When GA area was measured on color photos instead of fundus autofluorescence images, results were similar (Table 4A, 4B, supplemental material). In exploratory analyses, we also evaluated GA growth rates when excluding those eyes with total baseline GA < 0.5 DA or with GA > 4.5 DA; these additional analyses did not shift the direction of treatment effect in favor of ALA (data not shown).
Table 3A.
Change in Area of Geographic Atrophy at Each Visit Measured by Fundus Autofluorescence
| Unadjusted | Adjusted* | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Placebo | ALA | Difference | Placebo | ALA | Difference | ||||||
| Outcome | Month | n | Mean (SE) | n | Mean (SE) | Mean (95% CI) | p | Mean (SE) | Mean (SE) | Mean (95% CI) | p |
| Change in GA area (mm2) | 6 | 36 | 0.60 (0.09) | 36 | 0.98 (0.11) | 0.39 (0.12, 0.66) | 0.005 | 0.64 (0.09) | 0.94 (0.10) | 0.30 (0.03, 0.56) | 0.03 |
| 12 | 36 | 1.24 (0.13) | 33 | 1.78 (0.16) | 0.54 (0.13, 0.96) | 0.01 | 1.33 (0.13) | 1.68 (0.14) | 0.35 (−0.03, 0.73) | 0.07 | |
| 18 | 35 | 1.87 (0.19) | 36 | 2.63 (0.20) | 0.77 (0.22, 1.31) | 0.006 | 2.01 (0.18) | 2.49 (0.18) | 0.48 (−0.02, 0.98) | 0.06 | |
| Change in square root of GA area (mm) | 6 | 36 | 0.15 (0.02) | 36 | 0.19 (0.02) | 0.04 (−0.02, 0.10) | 0.18 | 0.14 (0.02) | 0.19 (0.02) | 0.05 (−0.00, 0.11) | 0.07 |
| 12 | 36 | 0.29 (0.03) | 33 | 0.33 (0.03) | 0.04 (−0.04, 0.13) | 0.32 | 0.28 (0.03) | 0.34 (0.03) | 0.06 (−0.01, 0.14) | 0.11 | |
| 18 | 35 | 0.42 (0.04) | 36 | 0.48 (0.03) | 0.06 (−0.05, 0.16) | 0.31 | 0.41 (0.04) | 0.49 (0.03) | 0.07 (−0.02, 0.17) | 0.11 | |
GA=geographic atrophy; ALA=alpha lipoic acid; CI=confidence interval; SE=standard error.
Adjusted for baseline area in mm2, number of GA lesions, and subfoveal GA.
Figure 2. Adjusted Growth of Geographic Atrophy from Baseline to 18 Months as Measured on Fundus Autofluorescence Imaging.
Adjusted for baseline area in mm2, number of GA lesions, and subfoveal GA. ALA = alpha lipoic acid; CI = confidence interval.
Table 3B.
Mean Annual Change in Geographic Atrophy Area Measured by Fundus Autofluorescence
| Outcome | Unadjusted | Adjusted* | ||||||
|---|---|---|---|---|---|---|---|---|
| Mean (SE) | Difference (95% CI) | p | Mean (SE) | Difference (95% CI) | p | |||
| Placebo | ALA | Placebo | ALA | |||||
| Area of GA (mm2) | 1.21 (0.13) | 1.71 (0.13) | 0.50 (0.12, 0.87) | 0.009 | 1.29 (0.23) | 1.63 (0.28) | 0.35 (−0.05, 0.74) | 0.09 |
| Square root of area of GA (mm) | 0.28 (0.02) | 0.31 (0.02) | 0.04 (−0.03, 0.11) | 0.30 | 0.27 (0.04) | 0.32 (0.05) | 0.05 (−0.02, 0.12) | 0.14 |
GA=geographic atrophy; ALA=alpha lipoic acid; CI=confidence interval
Adjusted for baseline area in mm2, number of GA lesions, and subfoveal GA.
Figure 3. Color Photos and Autofluorescence Images at Baseline and 18 months for Three Representative Cases.
Borders of geographic atrophy (GA) are outlined in red on the autofluorescence images. Participant A was randomized to alpha lipoic acid (ALA) and had multifocal GA with a total square root transformed area of 1.12 mm (1.25 mm2) at baseline (A1, A2). At 18 months, the total GA was 1.83 mm (3.35 mm2) (A3, A4); the square root transformed annualized growth rate was 0.47 mm (1.4 mm2). Participant B was randomized to placebo, and had multifocal GA with a total square root transformed area of 2.41 mm (5.80 mm2) at baseline (B1, B2). At 18 months, the total GA was 3.05 mm (9.31 mm2) (B3, B4); the square root transformed annualized growth rate was 0.43 mm (2.34 mm2). Participant C was randomized to ALA, and had unifocal GA with a total square root transformed area of 3.34 mm (11.15 mm2) at baseline (C1, C2). At 18 months, the total GA was 3.52 mm (12.38 mm2) (C3, C4); the square root transformed annualized growth rate was 0.12 mm (0.82 mm2).
Mean visual acuity score decreased over time in each treatment group (Table 4A). At 18 months, the mean change in letter scores was −6.4 letters in the placebo group and −4.9 letters in the ALA group, yielding a mean difference of 1.5 letters (95% confidence interval (−3.3, 6.2)). At 18 months, 8 of 36 (22%) placebo eyes and 5 of 36 (14%) ALA eyes lost 15 or more letters compared to baseline (p = 0.54) (Table 4B). The mean annualized change in visual acuity was −3.8 and −3.1 letters for the placebo and ALA groups, respectively (p = 0.69).
Safety
There were 5 serious adverse events (SAEs) among 4 (15%) of 27 participants in the placebo group and 10 SAEs among 7 (27%) of 26 participants in the ALA group (p=0.28). Most SAEs were related to non-ocular hospitalizations for reasons consistent with the elderly demographic of the study participants (Table 6A, supplementary material). No SAEs were related to the gastrointestinal system. Three ocular SAEs were related to vision loss (≥ 30 letters lost) including one in the ALA group for vision loss in a study eye from a conversion to exudative AMD, one in the placebo group for vision loss in a non-study eye with pre-existing exudative AMD, and one in the placebo group for vision loss measured at a non-study visit (Snellen acuity without refraction) that improved to near baseline at a subsequent research study visit with refracted BCVA. No SAEs were considered to be related to ALA. There were 121 non-serious adverse events (AEs) among 24 (89%) of 27 participants in the placebo group and 171 AEs among 23 (88%) of 26 participants in the ALA group (p=0.96) (Table 6B, supplementary material). The mean (SD) number of AEs per participant was 4.48 (4.12) in the placebo group and 6.58 (5.99) in the ALA group (p=0.12). The most common ocular nonserious AE was “visual acuity reduced,” and this was reported in 6 of 27 (22.2%) participants in the placebo group and 7 of 26 (26.9%) participants in the ALA group. There was an expected difference in the number of nonserious AEs related to the gastrointestinal system with means of 0.6 and 1.7 gastrointestinal AEs per person in the placebo and ALA groups, respectively (p=0.004). The most common gastrointestinal AEs in the ALA group were dyspepsia, nausea, and vomiting.
Urine Test
Fifty-one participants (26 placebo participants, 25 ALA participants) provided a one-time urine sample at the month 12 study visit that was qualitatively analyzed for the ALA specific metabolite bis-methylthio-hexanoic acid (BMHA).17,18 Six of 26 participants (23%) in the placebo group and 17 of 25 participants (68%) in the ALA group showed a significant amount of BMHA in their urine. After the study concluded, these 6 participants were contacted and their use of medications or supplements during the study was queried again; all 6 participants denied the use of ALA during the study. In an exploratory analysis, we also evaluated GA growth rates when excluding those 6 participants in the placebo group with BMHA in their urine and excluding the 3 participants in the ALA group that discontinued ALA. In this additional analysis, there was no significant difference in GA growth rates (data not shown).
Discussion
As there was excellent compliance24 and study retention, this trial effectively evaluated ALA as a treatment for GA. We believe there was a clear rationale to test ALA as a treatment for GA. However, in keeping with our study design specification, because no meaningful difference was found between study arms, we conclude that further investigation of ALA with the dosing used in this study is not warranted.
We purposely allowed smaller GA lesions into this trial as perhaps earlier treatment of GA is needed to allow an effect of therapy. The average total baseline lesion size of this trial was therefore smaller than that of many other trials.25–29 The observed annual growth rates with square root transformation in this study were within the lower end of the range of growth rates reported by other studies, but this is not likely related to our smaller baseline GA lesion areas.26,27,29,30 For example, the GA lesions in the recent study of palucorcel had a larger baseline area but a growth rate (square root transformed) similar to our study, as GA growth can be variable.30 Similarly, images A1-A4 of Figure 3 show a case with small GA lesions but a relatively fast growth rate. While there was an imbalance in baseline total GA size with larger lesions in the ALA group, this did not affect our ability to evaluate ALA’s effect on GA growth rates as we used the square root of GA area and adjusted for baseline total lesion size.20,31 Further, exploratory analyses excluding the smaller or the larger GA lesion sizes did not result in slower growth in the ALA group.
We primarily measured protocol compliance by capsule counts but also included a urine test at the one year study visit.17,18 Regarding capsule counts, compliance was on par with compliance in the Age Related Eye Disease Study.24 While further validation of the urine test is needed to differentiate supplemental use of ALA from normal diet-acquired ALA with high confidence, it is possible that 6 participants in the placebo arm were also taking ALA outside of the protocol. None of these 6 participants stated that they used ALA during the study when queried after the conclusion of the study. When excluding these participants from analysis, there was still no beneficial effect seen for ALA. Many participants fear legal blindness from GA, and future trials testing re-purposed therapeutics obtainable by participants should consider the possibility of participants acquiring investigational product outside of the trial.
GA is a complex neurodegenerative disease and many potential therapies have failed in clinical trials.32,33 There are several possibilities that could explain why ALA failed as a treatment for GA. The dose of 1200 mg daily was chosen as it is the highest tolerable oral dose of ALA in the elderly population and provides a significant serum concentration of ALA.8,12 Further, this dose showed efficacy in a phase II pilot trial for multiple sclerosis.11 However, it is not known if this dose would be sufficient for GA treatment. It is unknown if direct delivery of ALA to the eye could be an effective therapy. Secondly, while systemic administration of ALA was highly protective for the light damage mouse model, this animal model may not effectively represent the complexity of GA pathophysiology. The lack of a representative animal model continues to slow development of GA therapeutics. Thirdly, it is possible there are different pathophysiologic subtypes of GA;34 perhaps a therapy such as ALA is beneficial for only a subset of GA participants. Finally, while there have recently been two drugs with interesting, positive phase 2 results,27,35 there is still some lingering concern that slowing GA lesion growth may not be feasible and treating atrophic AMD at earlier stages may be needed.32 Thus, it is possible that ALA could be beneficial for AMD at earlier stages in ways that were not measured in this trial. Endpoints for stages of AMD that lead to GA, such as nascent GA, have potential and require further development.36
Drug re-purposing trials typically involve agents with known safety profiles and pharmacokinetics such that a phase II trial can readily be initiated. Drug re-purposing can also involve agents, such as ALA, where an absence of intellectual property will most likely prevent a large phase II trial sponsored by industry. This trial effectively tested ALA for GA with a budget of less than $500,000. With a pilot phase II trial design and limited sample size, the study pre-specified a “go / no-go” threshold with a one-sided confidence interval approach based on effect size.22 Cost savings were also possible as study visits and testing utilized standard-of-care procedures, and the trial was based at a location with a pre-existing image reading center. While the treatment effect was not in the direction of a benefit for GA, this trial did not require significant resources compared to other trials.
In summary, many potential therapeutics have shown an inability to slow down GA growth, and this trial has effectively shown that ALA also cannot slow down GA growth. There remains an urgent need to discover a treatment for GA, and further understanding of the mechanisms of both GA development and GA growth are needed. Importantly, this trial provides a cost-effective study design that is especially relevant to re-purposed drugs.
Supplementary Material
Table 5A.
Visual Acuity and Change of Visual Acuity from Baseline at Each Visit
| Placebo | ALA | Difference | |||||
|---|---|---|---|---|---|---|---|
| Outcome | Visit | n | Mean (SE) | n | Mean (SE) | Mean (95% CI) | p |
| Visual acuity (letters) | 0 | 37 | 65.8 (2.7) | 36 | 62.6 (2.5) | −3.2 (−10.5, 4.1) | 0.39 |
| 6 | 36 | 62.6 (3.8) | 36 | 60.4 (2.7) | −2.2 (−11.3, 6.9) | 0.63 | |
| 12 | 36 | 63.0 (3.2) | 33 | 58.4 (2.8) | −4.6 (−13.0, 3.8) | 0.28 | |
| 18 | 36 | 58.8 (3.9) | 36 | 57.7 (2.7) | −1.2 (−10.4, 8.0) | 0.80 | |
| Change in visual acuity (letters) from baseline | 6 | 36 | −2.7 (2.1) | 36 | −2.3 (1.0) | 0.4 (−4.2, 5.1) | 0.86 |
| 12 | 36 | −2.2 (1.5) | 33 | −2.8 (1.1) | −0.6 (−4.3, 3.2) | 0.77 | |
| 18 | 36 | −6.4 (2.2) | 36 | −4.9 (1.1) | 1.5 (−3.3, 6.2) | 0.54 | |
ALA=alpha lipoic acid; CI=confidence interval; SE=standard error.
Table 5B.
Percent of Eyes with Three or More Lines of Visual Acuity Lost from Baseline at Each Visit
| Outcome | Visit | 3-line loss | Placebo | ALA | p* |
|---|---|---|---|---|---|
| Change in visual acuity | 6 | Yes | 4 (11%) | 1 (3%) | 0.36 |
| No | 32 (89%) | 35 (97%) | |||
| 12 | Yes | 1 (3%) | 3 (9%) | 0.34 | |
| No | 35 (97%) | 30 (91%) | |||
| 18 | Yes | 8 (22%) | 5 (14%) | 0.54 | |
| No | 28 (78%) | 31 (86%) |
ALA=alpha lipoic acid
p-value calculated using Fisher’s exact test
Acknowledgements
We thank Pure Encapsulations (Sudbury, MA, USA) for providing the alpha lipoic acid. We thank Y. Daikhin, O. Horyn, and Ilana Nissim for performing the analysis of BMHA in the Metabolomics Core Facility, The Children’s Hospital of Philadelphia.
Funding
This study was supported by the BrightFocus Foundation (Clarksburg, MD), Cures Within Reach (Chicago, IL), and the Pennsylvania Lions Eye Research and Sight Conservation Foundation (Harrisburg, PA). Funding was also provided in the form of block grants to the Scheie Eye Institute from Research to Prevent Blindness (New York, NY, United States), National Institutes of Health (Bethesda, MD) P30 EY01583–26, and the Paul and Evanina Bell Mackall Foundation Trust (Chicago, IL, United States). The funding organizations had no role in the design or conduct of this research.
Footnotes
Conflicts of Interest
B.J.K. reports being a consultant to Synergy Research, Inc., Apellis Pharmaceuticals, and Allergan.
P.H. reports being a consultant for Alcon, Allergan, DORC, Genentech, and Zeiss; and is a speaker for Genentech.
M.G.M. reports payments from Genentech/Roche for membership on data monitoring committees.
R.N.K serves as a consultant for Allergan, Genentech, and Regeneron; and has grant support from Allergan, Chengdu Kanghong, Clearside Biomedical, Roche, and Santen.
G.S.Y. reports payment for being a biostatistical consultant to Chengdu Kanghong Biotech Ltd., and for being a member of Data Safety Monitoring Committee for Synergy Research Inc.
No conflicting relationship exists for any other authors.
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