⚠️ Partially source-audited on 2026-08-18 against the PubMed/publisher abstract, indexed publisher record, and current plus initial ClinicalTrials.gov records. The complete article, original protocol/statistical-analysis plan, and full texts of a published comment and reply were unavailable;
verified: falseis intentional. gap/no-fulltext-access
Kuboi et al. 2024 — EDTA eye drops for early age-related cataract
TL;DR
An exploratory subgroup analysis of a randomized, double-masked, placebo-controlled phase 1/2 trial reported nominally significant eye-level differences in mesopic contrast sensitivity after 120 days of 2.6% ethylenediaminetetraacetic acid (EDTA; C-KAD) eye drops.1 The report analyzed 41 eyes from 29 participants, not the full 111-participant parent trial. Randomization occurred at the participant level and both eyes received the assigned treatment, whereas the published efficacy estimates use eyes as the unit. The inaccessible full methods are therefore needed to determine how inter-eye correlation was handled. This small retrospective subgroup is not prospective confirmation and does not establish cataract reversal or an alternative to surgery. gap/needs-replication gap/no-fulltext-access
Design
- Parent trial: NCT06365762 (CK-0103) was a six-site US trial in 111 participants with bilateral, low-grade age-related nuclear cataract. Participants were randomized 1:1:1 to 2.6% C-KAD, 1.3% C-KAD, or saline placebo; the assigned drops were given to both eyes four times daily, at least three hours apart, for 120 days. The trial started in January 2006, reached primary completion in December 2006, and ended in April 2007.2
- Published subgroup: The article selected 41 of 222 intent-to-treat eyes from 29 of 111 participants: 21 eyes from 15 participants assigned to 2.6% C-KAD and 20 eyes from 14 participants assigned to placebo. The 1.3% arm was not part of this comparison. Eligible eyes had baseline mesopic contrast-sensitivity scores of 1–7 grating patches (0–9 range; 0.15 logCS per patch) at all five tested spatial frequencies (1.5, 3, 6, 12, and 18 cycles/degree).1
- Design classification:
study-design: rctrecords the randomized parent experiment and PubMed publication type. The article itself is an exploratory analysis of a selected subgroup, not a new independently randomized trial. - Registration history: The sponsor first submitted NCT06365762 on 2024-04-10 and it was first posted on 2024-04-15—about 17 years after study completion. Its initial posting already listed 111 actual participants and the contrast-sensitivity endpoint, but the registry was not a prospective public record of the 2006 trial.
preregistered: falseis intentional.2
The registry defines its primary responder outcome as the proportion of patients improving by at least two patches (0.30 logCS) at two or more spatial frequencies. The publication reports the corresponding endpoint as the proportion of eyes. The public registry does not state the article’s all-five-frequency 1–7-patch subgroup rule, and neither the accessible article record nor the retrospectively posted registry can establish that this subgroup definition or its analysis was prespecified.
Outcomes and reported results
All values below are day-120 eye-level results from the abstract; no confidence intervals were reported there.1
| Outcome | 2.6% C-KAD (21 eyes) | Placebo (20 eyes) | Reported comparison |
|---|---|---|---|
| Responder: at least 0.30-logCS improvement at two or more of five frequencies | 66.7% | 35.0% | P=0.043 |
| AULCSF responder: at least 0.30-logCS improvement | 42.9% | 15.0% | P=0.050 |
| Mean AULCSF change | +0.25 logCS | +0.06 logCS | P=0.020 |
The abstract additionally reports C-KAD mean improvements of 0.28 logCS at 3 cycles/degree (P=0.004 versus placebo) and 0.31 logCS at 6 cycles/degree (P=0.047 versus placebo), but does not give the placebo means or between-arm estimates for those two outcomes. It calls best-corrected visual acuity (BCVA) a positive trend and reports statistical significance for lens density in a smaller Scheimpflug-imaging subgroup, without giving that subgroup’s denominator or effect estimate. Those statements are insufficient to establish either a BCVA benefit or reversal of lens opacity.
Interpretation and limitations
- The trial’s public record was created retrospectively and posts no results. The original 2006 protocol and statistical-analysis plan were not publicly available, so subgroup prespecification, multiplicity control, missing-data handling, and the statistical model cannot be verified.
- Both eyes could contribute for one participant. Without the complete methods, it is unknown whether the analyses and reported P values accounted for within-participant correlation.
- Participants had early, low-grade nuclear cataracts below the threshold recommended for surgery, retained best-corrected distance acuity of at least 20/50 in both eyes, and had contrast-sensitivity loss. The findings do not establish benefit in surgery-eligible cataract.
- Livionex Inc. was the registered lead sponsor, and Kuboi, Bhushan, and Goswamy list Livionex affiliations. Complete funding, sponsor-role, and conflict-of-interest statements could not be checked without the article’s full text.
- A formal comment and author reply were published online in September 2024 and in print in January 2025.3 Their full texts were unavailable, so the criticism and response cannot be summarized reliably.
Supersession check
PubMed and Europe PMC searches on 2026-08-18 for (EDTA OR edetate OR "edetic acid" OR C-KAD) AND cataract*, restricted to 2024-08-03 through 2026-08-18, found the article, the comment/reply pair, and unrelated uses of EDTA; no later randomized trial or meta-analysis confirming topical EDTA efficacy for natural age-related cataract was found.4 PubMed showed no linked correction, retraction, or expression of concern. Two older C-KAD phase 2 registrations (NCT00793091 and NCT00825721) remain stale with unknown status and no posted results, so they do not provide confirmatory efficacy evidence.
Cited by wiki pages
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Footnotes
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Kuboi T, Chuck RS, Pineda R 2nd, Bhushan R, Goswamy A, Olson RJ. American Journal of Ophthalmology. 2024;268:155–164. doi:10.1016/j.ajo.2024.07.038. PMID:39098755. Source scope for this page: structured abstract and publisher abstract/highlights plus indexed publisher subject-disposition text; complete article unavailable. ↩ ↩2 ↩3
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ClinicalTrials.gov NCT06365762, including the initial 2024-04-10 submission and 2024-04-12 update in Record History; checked 2026-08-18. The record lists Livionex Inc. as sponsor, 111 actual participants, randomized parallel assignment, participant/investigator masking, bilateral dosing, and no posted results. ↩ ↩2
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Sinha Roy A. Comment on “Subgroup Analysis…” doi:10.1016/j.ajo.2024.09.015, PMID:39306317; Kuboi T et al. Reply to Comment… doi:10.1016/j.ajo.2024.09.016, PMID:39313086. Both records have no abstract; complete texts were unavailable. ↩
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Date-filtered PubMed and Europe PMC title/abstract searches run 2026-08-18. ClinicalTrials.gov was also searched for cataract studies using EDTA, edetate, or C-KAD. No later published confirmatory efficacy trial or meta-analysis was identified through that date. ↩