Sample Size Requirements of Glaucoma Clinical Trials When Using Combined Optical Coherence Tomography and Visual Field Endpoints

Wu, Zhichao; Medeiros, Felipe A.

doi:10.1038/s41598-019-55345-x

Cited by 17 publications

(9 citation statements)

References 36 publications

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“…26 To date, studies suggesting the usefulness of this approach, which recommends intense testing at the beginning and end of follow-up, have been limited to computerized simulations or longer periods of follow-up than the present investigation. 40,41 In the UKGTS, 5 clustering was performed at baseline, 18 months, and 24 months. The investigators were able to detect statistically significant changes even at 12 months of follow-up.…”

Section: Discussionmentioning

confidence: 99%

Nicotinamide and Pyruvate for Neuroenhancement in Open-Angle Glaucoma

et al. 2022

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IMPORTANCE Open-angle glaucoma may continue to progress despite significant lowering of intraocular pressure (IOP). Preclinical research has suggested that enhancing mitochondrial function and energy production may enhance retinal ganglion cell survival in animal models of glaucoma, but there is scant information on its effectiveness in a clinical setting.OBJECTIVE To test the hypothesis that a combination of nicotinamide and pyruvate can improve retinal ganglion cell function in human glaucoma as measured with standard automated perimetry.DESIGN, SETTING, AND PARTICIPANTS In this phase 2, randomized, double-blind, placebo-controlled clinical trial at a single academic institution, 197 patients were assessed for eligibility. Of these, 42 patients with treated open-angle glaucoma and moderate visual field loss in at least 1 eye were selected for inclusion and randomized. A total of 32 completed the study and were included in the final analysis. The mean (SD) age was 64.6 (9.8) years. Twenty-one participants (66%) were female. Participant race and ethnicity data were collected via self-report to ensure the distribution reflected that observed in clinical practice in the US but are not reported here to protect patient privacy. Recruitment took place in April 2019 and patients were monitored through December 2020. Data were analyzed from January to May 2021.INTERVENTIONS Ascending oral doses of nicotinamide (1000 to 3000 mg) and pyruvate (1500 to 3000 mg) vs placebo (2:1 randomization). MAIN OUTCOMES AND MEASURESNumber of visual field test locations improving beyond normal variability in the study eye. Secondary end points were the rates of change of visual field global indices (mean deviation [MD], pattern standard deviation [PSD], and visual field index [VFI]).RESULTS Twenty-two of 29 participants (76%) randomized to the intervention group and 12 of 13 participants (92%) randomized to placebo received their allocation, and 32 participants (32 eyes; ratio 21:11) completed the study (21 from the intervention group and 11 from the placebo group). Median (IQR) follow-up time was 2.2 (2.0-2.4) months. No serious adverse events were reported during the study. The number of improving test locations was significantly higher in the treatment group than in the placebo group (median [IQR], 15 [6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25] vs 7 [6-11]; P = .005). Rates of change of PSD suggested improvement with treatment compared with placebo (median, −0.06 vs 0.02 dB per week; 95% CI, 0.02 to 0.24; P = .02) but not MD (0.04 vs −0.002 dB per week; 95% CI, −0.27 to 0.09; P = .35) or VFI (0.09 vs −0.02% per week; 95% CI, −0.53 to 0.36; P = .71). CONCLUSIONS AND RELEVANCEA combination of nicotinamide and pyruvate yielded significant short-term improvement in visual function, supporting prior experimental research suggesting a role for these agents in neuroprotection for individuals with glaucoma and confirming the need for long-term studies to establish their usefulness in slowing progression.

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Section: Discussionmentioning

confidence: 99%

Nicotinamide and Pyruvate for Neuroenhancement in Open-Angle Glaucoma

et al. 2022

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“…The advantages of using MD slopes for reducing the sample size requirements in glaucoma trials have been recently discussed. [15][16][17][18][19] Wu at al. have shown that the feasibility of glaucoma clinical trials could be improved by evaluating differences in the rate of visual eld change (slopes) between randomization groups.…”

Section: Discussionmentioning

confidence: 99%

“…Per the committee's discussion, an alternative glaucoma endpoint for pivotal trials should have a strong correlation and predictability of either current or future visual function, such as that measured with the above cited acceptable endpoints. 12 Investigators have reported the advantages of using visual eld mean deviation (MD) slopes as an endpoint in glaucoma clinical trials because studies employing trend analysis of visual eld global indices would likely require a smaller sample size than event-based endpoints, [15][16][17][18][19] such as the ones currently acceptable by the FDA. The purpose of the present study is to evaluate the relationship between MD slope from visual eld tests collected over a short period of time (2 years) and the current FDA recommended endpoints.…”

Section: Introductionmentioning

confidence: 99%

Visual Field Mean Deviation Slopes: A Potential Primary Endpoint for Clinical Trials in Glaucoma Neuroprotection

Moraes

Lane²,

Wang³

et al. 2022

Preprint

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The purpose of this retrospective, longitudinal study is to evaluate the relationship between MD slope from visual field tests collected over a short period of time (2 years) and the current United States’ Food and Drug Administration (FDA) recommended endpoints for visual field outcomes. If this correlation is strong and highly predictive, clinical trials employing MD slopes as primary endpoints could be employed in neuroprotection clinical trials with shorter duration and help expedite the development of novel IOP-independent therapies. Visual field tests of patients with or suspected glaucoma were selected from an academic institution and evaluated based on two functional progression endpoints: 1) five or more locations worsening by at least 7 dB, and 2) at least 5 test locations based upon the GCP algorithm. A total of 467 (76.6%) and 472 (77.4%) eyes reached Endpoints A and B, respectively, at any point in time. 359 (58.8%) eyes progressed faster than 0 dB/year, 278 (45.5%) faster than -0.5 dB/year, and 200 (32.7%) faster than -1.0 dB/year. It was found that eyes experiencing rapid 24-2 visual field MD slopes over a 2-year period were more likely to reach one of the FDA accepted endpoints during or soon after that period.

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“…In glaucoma clinical research, not only the slow progression of the disease but also the considerable noise in perimetry-based functional endpoints historically necessitated very large sample sizes [ 40 ]. Adding a structural dimension to a functional endpoint has shown to improve predictive accuracy for short-term data, increase the statistical power of tests, and therefore allow for reduced sample sizes in clinical trials [ 41 , 42 ]. We will explore combined functional and structural endpoints in iAMD following this prescription from glaucoma clinical research.…”

Section: Discussionmentioning

confidence: 99%

Clinical study protocol for a low-interventional study in intermediate age-related macular degeneration developing novel clinical endpoints for interventional clinical trials with a regulatory and patient access intention—MACUSTAR

Terheyden

Holz

Schmitz-Valckenberg

et al. 2020

Trials

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Background: There is an unmet need for treatment options in intermediate age-related macular degeneration (iAMD). However, for any new interventions to be tested in clinical trials, novel currently unavailable clinical endpoints need to be developed. Thus, the MACUSTAR study aims to develop and evaluate functional, structural, and patient-reported candidate endpoints for use in future iAMD trials. Methods: The protocol describes a low-interventional clinical multicenter study employing a novel two-part design. The cross-sectional part (total duration, 1 month) and the longitudinal part (total duration, 36 months) include participants with iAMD and control groups with early/late/no AMD. The cross-sectional part's primary objective is a technical evaluation of functional, structural, and patient-reported candidate outcomes. The longitudinal part's primary objective is to assess the prognostic power of changes in functional, structural, and patient-reported outcomes for progression from iAMD to late AMD. All data will be used to support a biomarker qualification procedure by regulatory authorities. Discussion: The MACUSTAR study characterizes and evaluates much needed novel functional, structural, and patient-reported endpoints for future clinical trials in iAMD and will improve our understanding of the natural history and prognostic markers of this condition.

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Sample Size Requirements of Glaucoma Clinical Trials When Using Combined Optical Coherence Tomography and Visual Field Endpoints

Cited by 17 publications

References 36 publications

Nicotinamide and Pyruvate for Neuroenhancement in Open-Angle Glaucoma

Nicotinamide and Pyruvate for Neuroenhancement in Open-Angle Glaucoma

Visual Field Mean Deviation Slopes: A Potential Primary Endpoint for Clinical Trials in Glaucoma Neuroprotection

Clinical study protocol for a low-interventional study in intermediate age-related macular degeneration developing novel clinical endpoints for interventional clinical trials with a regulatory and patient access intention—MACUSTAR

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