Editors Selection IGR 22-3

Medical Treatment: A Phase 2 Neuroprotection Randomized Clinical Trial

Harry Quigley

Comment by Harry Quigley on:

96133 Nicotinamide and Pyruvate for Neuroenhancement in Open-Angle Glaucoma: A Phase 2 Randomized Clinical Trial, De Moraes CG; John SWM; Williams PA, JAMA ophthalmology, 2021; 0:

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Short-term outcomes that measure neuroprotective treatments additional to IOP-lowering would be welcome. Modestly improved visual field parameters have been documented with IOP-lowering (cf. Glaucoma Laser Trial and Wright et al (AJO 2015)). A randomized trial with oral nicotinamide/pyruvate assessed a stated primary endpoint: individual test point improvement during 3 months' observation. Pandemic conditions led to 28% loss to follow-up in treated patients. Analysis was said to be based on the Wright et al. method: change in mean test point total deviation value between 4 fields at baseline and 4 at study end. However, the criterion for worse/better was reduced from exceeding the >95%ile of variability (Wright) to >75%ile, without explanation or sensitivity analysis for the criterion. This less specific criterion would judge 25% of points to "improve" and 25% to "worsen", even if no true change occurred (equivalent to p<0.25, instead of <0.05). With 52 field points, this would randomly produce 13 points better, 13 worse. In study treated eyes, there were 15 better, 12 worse points. Placebo eyes had 7 better, 11 worse. Thus, the treated group was minimally different from random chance. The only difference resulted from the failure of placebo eyes to achieve the expected (random) rate of improvement. While the two groups were stated not to differ, the placebo group had worse MD, worse PSD (p=0.077 for difference from treated), more glaucoma medication, and fewer incisional glaucoma surgeries. One placebo subject was excluded due to "high IOP", yet no IOP measurements were given. Since IOP lowering produces short-term improvement in field parameters, comparative IOP data are needed.

The question remains whether short-term effects will simply revert or possibly contribute to long-term preservation of visual function

No information was given on how much pointwise "improvement" occurred in total deviation sensitivity; thus, one is left to wonder how much "better" was better. Secondary analysis showed that the PSD, but not MD or VFI improved in the treated compared to placebo group. Since VFI is heavily dependent on pattern deviation values, the failure to see a difference in VFI is curious. The question remains whether short-term effects will simply revert or possibly contribute to long-term preservation of visual function.

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