Orally Administered Alpha Lipoic Acid as a Treatment for Geographic Atrophy: A Randomized Clinical Trial
NCT02613572 | Not specified | Kim B et al. (2020)
Kim B, Hunter A, Brucker AJ, et al. Orally Administered Alpha Lipoic Acid as a Treatment for Geographic Atrophy: A Randomized Clinical Trial. Ophthalmol Retina, 2020; 4(9):889-898.
Locations
5 clinical sites in the United States
Study Period
April 2016 – August 2017
Study Design
Phase 2, randomized, double-masked, placebo-controlled trial
Study Population
Experimental Group
Control Group
Follow-up Time: 18 Months
Outcomes
Durability
Not reported
Vision
Best-Corrected Visual Acuity (BCVA) The mean change in BCVA (letters) at 6 months:
• Placebo: -2.7 (SE 2.1) letters
• ALA: -2.3 (SE 1.0) letters
• Difference: 0.4 letters (95% CI: -4.2 to 5.1; p = 0.86) The mean change in BCVA (letters) at 12 months:
• Placebo: -2.2 (SE 1.5) letters
• ALA: -2.8 (SE 1.1) letters
• Difference: -0.6 letters (95% CI: -4.3 to 3.2; p = 0.77) The mean change in BCVA (letters) at 18 months:
• Placebo: -6.4 (SE 2.2) letters
• ALA: -4.9 (SE 1.1) letters
• Difference: 1.5 letters (95% CI: -3.3 to 6.2; p = 0.54) Vision Maintaining The proportion of eyes with three or more lines of visual acuity lost at Month 6:
• Placebo: 11%
• ALA: 3%
• Fisher’s exact test: p = 0.36 The proportion of eyes with three or more lines of visual acuity lost at Month 12:
• Placebo: 3%
• ALA: 9%
• Fisher’s exact test: p = 0.34 The proportion of eyes with three or more lines of visual acuity lost at Month 18:
• Placebo: 22%
• ALA: 14%
• Fisher’s exact test: p = 0.54
Other
Efficacy: Progression Outcomes GA Mean adjusted change in GA area (mm²) at Month 6:
• Placebo: 0.64 (SE 0.09)
• ALA: 0.94 (SE 0.10)
• Difference: 0.30 mm² (95% CI: 0.03 to 0.56; p = 0.03) Mean adjusted annual change in GA area (mm²) (Primary Outcome):
• Placebo: 1.33 (SE 0.13)
• ALA: 1.68 (SE 0.14)
• Difference: 0.35 mm² (95% CI: -0.03 to 0.73; p = 0.07) Mean adjusted change in GA area (mm²) at Month 18:
• Placebo: 2.01 (SE 0.18)
• ALA: 2.49 (SE 0.18)
• Difference: 0.48 mm² (95% CI: -0.02 to 0.98; p = 0.06) Adjusted mean annual change in square root GA area (mm) (Primary Outcome):
• Placebo: 0.28 ± 0.03
• ALA: 0.34 ± 0.03
• Difference: 0.06 mm (95% CI, -0.01 to 0.14); p = 0.11 Urine test Patients with metabolite bis-methylthio-hexanoic acid (BMHA):
• Placebo: 23% (6/26)
• ALA: 68% (17/25)
Immunognicity
Not reported
Pharmokinetics
Not reported
Anatomic
Not reported
Safety
AEs The mean (SD) number of AEs per participant:
• Placebo: 4.48 (4.12)
• ALA: 6.58 (5.99)
• Difference: p = 0.12 Patients with AEs:
• Placebo: 89% (24/27) with 121 events in total
• ALA: 88% (23/26) with 171 events in total
• Difference: p = 0.96 Ocular AEs Patients with reduced visual acuity (most common ocular AE):
• Placebo: 22.2% (6/27)
• ALA: 26.9% (7/26) Non-ocular AEs Patients with gastrointestinal AEs:
• Placebo: 0.6 per person
• ALA: 1.7 per person
• p = 0.004 (The most common gastrointestinal AEs in the ALA group were dyspepsia, nausea, and vomiting) Serious AEs (SAEs) Patients with SAEs:
• Placebo: 15% (4/27) with 5 events in total
• ALA: 27% (7/26) with 20 events in total
• Difference: p = 0.28 Patients with ocular SAEs:
• Placebo: 2
• ALA: 1
• Difference: p = 0.28 No SAEs were related to the gastrointestinal system No SAEs were considered to be related to AL Study discontinuation
• Placebo: 1 due to death
• ALA: 3 (reasons was not reported) Death One in the placebo group
Conclusion
ALA did not significantly slow GA progression or improve BCVA compared to placebo. Increased gastrointestinal AEs were observed in the ALA group. The trial does not support ALA as a treatment for GA.
Risk of Bias Assessment for Primary Outcome
Randomization Process
Some concerns
Note: “Random treatment allocation schedules were generated by the Coordinating Center (Center for Preventive Ophthalmology and Biostatistics, UPenn) with a randomized block design…” However, there was an imbalance in the 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).
Missing Outcome Data
Low risk
Note: The evidence that the analysis of the primary outcome was not biased by the missing data (sensitivity analysis): “After adjustment for the above baseline characteristics, the mean difference in GA growth rate was…”
Selection of the Reported Results
Low risk Note: the registration with the protocol
Deviations from Intended Observations
Low risk Note: This is a double-masked study. “Analyze for primary outcome with ITT principle (Figure 1)”
Measurement of the Outcome
Low risk Note: “The reading center and all research coordinators were masked to study drug assignment.” “All participants were evaluated at baseline and every 6 months with a full eye exam, including BCVA testing, according to a standardized reading center protocol.”
Overall
Some concerns
Categories: Dry AMD Geographic Atrophy