Common Design and Data Elements Reported on Idiopathic Intracranial Hypertension Trials: A Systematic Review

Background: There are an increasing number of controlled clinical trials and prospective studies, ongoing and recently completed, regarding management options for idiopathic intracranial hypertension (IIH). We present a Common Design and Data Element (CDDE) analysis of controlled and prospective IIH studies with the aim of aligning essential design and recommending data elements in future trials and enhancing data synthesis potential in IIH trials. Methods: We used PubMed and ClinicalTrials.gov to screen for ongoing and published trials assessing treatment modalities in people with IIH. After our search, we used the Nested Knowledge AutoLit platform to extract pertinent information regarding each study. We examined outputs from each study and synthesized the data elements to determine the degree of homogeneity between studies. Results: The most CDDE for inclusion criteria was the modified Dandy criteria for diagnosis of IIH, used in 9/14 studies (64%). The most CDDE for outcomes was change in visual function, reported in 12/14 studies (86%). Evaluation of surgical procedures (venous sinus stenting, cerebrospinal fluid shunt placement, and others) was more common, seen in 9/14 studies (64%) as compared with interventions with medical therapy 6/14 (43%). Conclusions: Although all studies have similar focus to improve patient care, there was a high degree of inconsistency among studies regarding inclusion criteria, exclusion criteria, and outcomes measures. Furthermore, studies used different time frames to assess outcome data elements. This heterogeneity will make it difficult to achieve a consistent standard, and thus, making secondary analyses and meta-analyses less effective in the future. Consensus on design of trials is an unmet research need for IIH.

Original Contribution Section Editors: Clare Fraser, MD Susan Mollan, MD Common Design and Data Elements Reported on Idiopathic Intracranial Hypertension Trials: A Systematic Review Hassan Kobeissi, BS, Cem Bilgin, MD, Sherief Ghozy, MD, Gautam Adusumilli, MD, Jade Thurnham, BS, Nicole Hardy, BS, Timothy Xu, MD, Ranita Tarchand, BS, Kevin M. Kallmes, MS, Waleed Brinjikji, MD, Ramanathan Kadirvel, PhD, John J. Chen, MD, PhD, Alexandra Sinclair, PhD, Susan P. Mollan, MBcHB, David F. Kallmes, MD Background: There are an increasing number of controlled clinical trials and prospective studies, ongoing and recently completed, regarding management options for idiopathic intracranial hypertension (IIH). We present a Common Design and Data Element (CDDE) analysis of controlled Departments of Radiology (HK, CB, SG, WB, RK, DFK), Ophthalmology (TX, JJC), and Neurologic Surgery (RK), Mayo Clinic, Rochester, Minnesota; Department of Radiology (GA), Massachusetts General Hospital, Boston, Massachusetts; Nested Knowledge (JT, NH, RT, KMK), St Paul, Minnesota; Department of Neurology (AS), University Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital, Birmingham, United Kingdom; Translational Brain Science (AS, SPM), Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom; and Birmingham Neuro-Ophthalmology (SPM), University Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital, Birmingham, United Kingdom. D. F. Kallmes holds equity in Nested Knowledge, Superior Medical Editors, and Conway Medical, Marblehead Medical, and Piraeus Medical. He receives grant support from MicroVention, Medtronic, Balt, and Insera Therapeutics; has served on the Data Safety Monitoring Board for Vesalio; and received royalties from Medtronic. S. P. Mollan has received royalties from Springer publishing; has received consulting fees from Invex therapeutics, Velux foundation, and Neurodiem. She has received honoria for educational speaking from Heidelberg Engineering, Chugai-Roche Ltd, Allergan, Santen, Chiesi, and Santhera. She has received honoria for advisory board work with Invex therapeutics, GenSight, and Janssen. A. Sinclair reports personal fees from Invex therapeutics as well as share option and shareholdings. She has received speaker fees (Novartis; Allergan; Teva UK, Amgen) and consulting fees (Allergan; Chiesi; Novartis; Lundbeck). W. Brinjikji holds equity in Nested Knowledge, Superior Medical Editors, Piraeus Medical, Sonoris Medical, and MIVI Neurovascular. He receives royalties from Medtronic and Balloon Guide Catheter Technology. He receives consulting fees from Medtronic, Stryker, Imperative Care, Microvention, MIVI Neurovascular, Cerenovus, Asahi, and Balt. He serves in a leadership or fiduciary role for MIVI Neurovascular, Marblehead Medical LLC, Interventional Neuroradiology (Editor in Chief), Piraeus Medical, and WFITN. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Web site (www. jneuro-ophthalmology.com). H. Kobeissi and C. Bilgin contributed equally. Address correspondence to Hassan Kobeissi, BS, Department of Radiology, Mayo Clinic, 200 First Street SW Rochester, MN 55905; E-mail: [e-mail] 66 and prospective IIH studies with the aim of aligning essential design and recommending data elements in future trials and enhancing data synthesis potential in IIH trials. Methods: We used PubMed and ClinicalTrials.gov to screen for ongoing and published trials assessing treatment modalities in people with IIH. After our search, we used the Nested Knowledge AutoLit platform to extract pertinent information regarding each study. We examined outputs from each study and synthesized the data elements to determine the degree of homogeneity between studies. Results: The most CDDE for inclusion criteria was the modified Dandy criteria for diagnosis of IIH, used in 9/14 studies (64%). The most CDDE for outcomes was change in visual function, reported in 12/14 studies (86%). Evaluation of surgical procedures (venous sinus stenting, cerebrospinal fluid shunt placement, and others) was more common, seen in 9/14 studies (64%) as compared with interventions with medical therapy 6/14 (43%). Conclusions: Although all studies have similar focus to improve patient care, there was a high degree of inconsistency among studies regarding inclusion criteria, exclusion criteria, and outcomes measures. Furthermore, studies used different time frames to assess outcome data elements. This heterogeneity will make it difficult to achieve a consistent standard, and thus, making secondary analyses and meta-analyses less effective in the future. Consensus on design of trials is an unmet research need for IIH. Journal of Neuro-Ophthalmology 2024;44:66–73 doi: 10.1097/WNO.0000000000001902 © 2023 by North American Neuro-Ophthalmology Society I diopathic intracranial hypertension (IIH), also known as pseudotumor cerebri, is the most common cause of increased intracranial pressure (ICP), especially among women of childbearing age. The incidence and prevalence of the disease is increasing, likely due to the obesity epidemic.1 Complications of IIH include chronic disabling headaches, vision loss, and a loss of quality of life.2,3 IIH is associated with cognitive impairment, obstructive sleep apnea, and reduced fertility.4 IIH increases the risk of cardiovascular disease, pre-eclampsia, and gestational diabeKobeissi et al: J Neuro-Ophthalmol 2024; 44: 66-73 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution tes.4,5 To date, a number of different treatment modalities have been used to treat IIH. Medications such as acetazolamide are usually used to decrease ICP.6 Lifestyle modifications and bariatric surgery have been used because there is a strong association between IIH and obesity.7,8 Finally, surgical interventions such as intracranial venous sinus stenting, optic nerve sheath fenestration, or insertion of a cerebrospinal fluid shunt are performed in people with vision-threatening disease or those who have failed medical management.9,10 Since 2011, there have been several randomized clinical trials and prospective studies, active and completed, that explored treatment for IIH. There are widely accepted criteria for the diagnosis of IIH with the “Revised diagnostic criteria for the pseudotumor cerebri syndrome in adults and children” being the most recently published framework.11 They include the clinical findings of papilledema, neuroimaging where no alternate cause is found, and increased cerebrospinal fluid (CSF) pressure.12 However, there are no accepted definitions for the determination of resolution of IIH, patientreported outcomes, time frames for follow-up, and several other disease-specific outcomes. Numerous agencies and stakeholders, including the National Institute of Health (NIH), have stressed the urgent need for commonality across research studies regarding key data elements to enhance the utility of clinical trials data. The NIH defines a common data element (CDE) as “a standardized, precisely defined question.used systematically across different sites, studies, or clinical trials to ensure consistent data collection.CDEs help researchers share and combine data sets, meet funding requirements, and save time (https://cde.nlm.nih.gov/ home).” We expand the concept of the CDE beyond patient-reported outcomes to analyze the comprehensive common design and data element (CDDE), which includes other key aspects of study design, including enrollment criteria, type of intervention, and timing of outcomes. This CDDE for IIH trials aims to provide clinicians and researchers with a comprehensive overview of the recently published and ongoing trials by examining the interventions being evaluated, the inclusion criteria, exclusion criteria, and outcomes of interest. The aim of this analysis was to identify those elements that are homogeneous to inform future trials, thereby increasing the ability for metaanalyses to subsequently inform disease guidelines. mation data collected. Our literature search was performed using the Nested Knowledge AutoLit platform on April 25, 2022. Screening of MEDLINE and Embase databases, as well as ClinicalTrials.gov, was performed for studies pertaining to active and recently completed trials regarding treatment for IIH. Key terms of our literature search included the following: “idiopathic intracranial hypertension,” “pseudotumor cerebri,” “prospective,” and “trial.” After our literature search, we also performed a manual search to identify any additional eligible studies. Study titles and abstracts were initially screened, followed by full-text review of potential studies. Two authors screened studies (H.K. and C.B.) with a third, senior author (D.F.K.) responsible for resolving any inconsistencies in screening. Inclusion and Exclusion Criteria Inclusion criteria consisted of published and ongoing randomized controlled trials and prospective studies that included patients with IIH undergoing treatment, regardless of the treatment they were receiving. Any studies that did not focus on IIH or were retrospective in nature were excluded from our final analysis. Tagging Common Data Elements Interventions, patient inclusion and exclusion criteria, and outcomes of interest were assessed using the Nested Knowledge AutoLit tagging tool. Individual tags were assigned in accordance with the aforementioned tags on a per-study basis. Initial tagging was performed by coauthor (J.T.), and quality control was performed by additional 2 authors (H.K. and C.B.). Data Synthesis The qualitative synthesis feature of the Nested Knowledge AutoLit platform was used to synthesize and visualize the results of our CDE tagging. Ultimately, a sunburst diagram was produced to visualize commonalities and differences between trials. Each slice of the sunburst diagram represents a tag among trials, and the frequency was determined based on the number of studies with a particular tag (see Supplemental Digital Content, Figure S1, http://links.lww.com/ WNO/A708). RESULTS Search Results METHODS Literature Search This qualitive synthesis was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.13 Our study did not require ethics committee approval because the data we analyzed are publicly available and there were no patient infor- Kobeissi et al: J Neuro-Ophthalmol 2024; 44: 66-73 Our initial search identified 109 potential studies for inclusion. After the initial search, an additional 27 studies were identified through expert recommendation to bring the total to 136. A total of 17 texts were retained for fulltext screening. Ultimately, 14 studies were deemed to meet our inclusion criteria and are included in this study (see Supplemental Digital Content, Figure S2, http://links. lww.com/WNO/A708). 67 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution Study Design and Enrollment Criteria The most common study design was randomized controlled trial, with 11 (79%) of the 14 studies using this study design. The remaining 3 studies (21%) were prospective, nonrandomized trials (Table 1). Key study elements such as design, inclusion criteria, outcomes, and others are summarized in Supplemental Digital Content (see Tables S1 and S2, http://links.lww.com/WNO/A708). The most common inclusion criteria was the modified Dandy criteria,12 which was documented as an inclusion criteria in 9 (64%) of the 14 trials. Changes in visual function as an inclusion criterion was documented in 6 (43%) of the 14 trials. However, there was significant heterogeneity in the definition of changes in visual function for the parameters chosen. In all studies that included change in visual function, assessment was conducted with 24-2 Automated Visual Field (AVF). CSF opening pressure was documented in 6 (43%) of included studies; however, there was heterogeneity in the cutoff used to satisfy this criterion, with 5 studies (36%) using a cutoff of .25 cm H2O and one study using a cutoff of .20 cm H2O (Fig. 1A). Eight studies (57%) excluded patients who presented with severe or sudden IIH and/or neurological signs suggesting a secondary cause IIH; however, definitions for these neurological signs varied among studies. Seven studies (50%) excluded patients who had the presence of any highrisk conditions (history of deep vein thrombosis or pulmonary embolism, exposure to drugs that increase ICP, or uncontrolled systemic hypertension) or recent treatment for IIH. Six studies (43%) excluded patients who underwent previous CSF shunt surgery or optic nerve sheath fenestration. Five studies (36%) excluded patients who had a history of neurovascular disease, trauma, or surgery. Five studies (36%) excluded patients who presented with severe concerns regarding visual acuity or headaches (Fig. 1B). Interventions Four studies (29%) included a placebo arm. Nine (64%) of the studies included surgical procedures as an intervention arm. Of the surgical interventions, the most common was venous sinus stent (7/14, 50%), followed by CSF shunt (4/ TABLE 1. Included studies Randomized controlled trials: Intervention to preserve vision in idiopathic intracranial hypertension: Evaluation of clinical effectiveness and cost-effectiveness (IIH: intervention) (Study directors: Alexandra Sinclair and Susan P. Mollan) A trial to determine the efficacy and safety of presendin in IIH (IIH EVOLVE) (Study director: Alexandra Sinclair) Outcome of cerebral venous sinuses stenting on idiopathic intracranial hypertension (Study director: Mohammed Ahmed Zaki) Surgical idiopathic intracranial hypertension treatment trial (SIGHT) (Study director: Michael Wall) Stenting vs neurosurgical treatment of idiopathic intracranial hypertension (HYDROPTIC) (Study director: Amélie Yavchitz) Operative procedures vs endovascular neurosurgery for untreated pseudotumor trial (OPEN-UP) (Study director: Felipe C Albuquerque) Quantitative D-dimer level and anticoagulant therapy in idiopathic intracranial hypertension (Study director: Sherine El Mously) An RCT of bariatric surgery vs a community weight loss programme for the sustained treatment of IIH (IIH:WT) (Study director: Alexandra Sinclair) A randomized controlled trial of treatment for idiopathic intracranial hypertension (Study director: Alexandra K. Ball) Idiopathic intracranial hypertension treatment trial (IIHTT) (Study director: Michael Wall) Safety and effectiveness of 11b-hydroxysteroid dehydrogenase type 1 inhibitor (AZD4017) to treat idiopathic intracranial hypertension. (IIH:DT) (Study director: Alexandra Sinclair) Prospective studies: Venous sinus stenting for idiopathic intracranial hypertension refractory to medical therapy (VSSIIH) (Study director: Athos Patsalides) Stenting of venous sinus stenosis for medically refractory idiopathic intracranial hypertension (Study director: Daniela Iancu) Venous sinus stenting with the river stent in IIH (Study director: Athos Patsalides) IIH, idiopathic intracranial hypertension; RCT, randomized controlled trial. 68 Kobeissi et al: J Neuro-Ophthalmol 2024; 44: 66-73 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 1. A. Frequency of inclusion criteria. B. Frequency of exclusion criteria. 14, 29%). Optic nerve sheath fenestration plus acetazolamide plus reduced diet was included in one trial (7%), and bariatric surgery was also included in 1 trial (7%). Six (43%) of the studies included medical therapies as an intervention arm (Fig. 2). Outcomes Every study reported neuro-ophthalmic–related clinical outcomes. These outcomes were largely broken down into improvement in visual function (12/14, 86%) and improvement in papilledema (12/14, 86%) (Fig. 3). Although these general outcomes were reported in most trials, the methods used for assessment differed between studies. For change in visual function, perimetric mean deviation was used in 10 trials (71%), assessed with the 24-2 Automated visual field test. Twelve studies (86%) included patient-reported outcomes. Change in headaches or associated disability was reported in 9 studies (64%), and 7 studies (50%) assessed this using the Headache Impact Test (HIT-6). Quality-oflife changes were reported in 7 studies (50%), with 5 studies Kobeissi et al: J Neuro-Ophthalmol 2024; 44: 66-73 (36%) measuring this through the 36-item short-form survey (SF-36). Several other measures were unique to individual studies: hospital anxiety and depression scale, satisfaction with intervention, time to return to work, and health care resource use questionnaire. Ten studies (71%) included clinical outcomes. Serious adverse events, including perforation of sinus or cerebral vein, neurological death, all-cause mortality, and others were reported in 4 studies (29%). Use or change in medication or dosage of medication was reported in 3 studies (21%) studies. Referral to other treatment (rescue therapy) was reported in 3 (21%). Recurrence rate or stent patency was reported in 2 studies (14%). The absence of procedure and device-related complications was reported in 2 studies (14%). Minor and major complications as measured by Dindo et al14 were reported in 1 study (7%). DISCUSSION There are an increasing number of trials in IIH; however, there is a high degree of heterogeneity among studies. 69 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 2. Frequency of intervention arms. Heterogeneity among studies makes it difficult to achieve a standard for ongoing future trials. In addition, with no unified standard between studies, secondary analyses and meta-analyses of studies may suffer from a higher degree of bias. We found that inclusion and exclusion criteria differed significantly between studies. Many studies focused on criteria such as threatened vision, papilledema, and intracranial pressure. The choice of primary outcome to determine success of an intervention has varied in studies between visual function and intracranial pressure. To date, there has been no randomized control trial evaluating treatment for headache attributed to IIH, which is surprising given the burden of headache within the disease. When assessing the outcomes of interest, time frame of outcome measurement and determination of outcomes were inconsistent between nearly all studies included in this analysis. There was a long list of inclusion criteria, exclusion criteria, and outcomes that were unique to individual studies (i.e., not replicated in other studies). Outcomes, specifically, experienced the highest degree of heterogeneity between all the data elements extracted. Broadly, the 4 outcome categories of neuro-ophthalmology–related clinical, patient-reported, and “other” outcomes were highly studydependent. Beyond this, there were several data points that were too heterogeneous and too uncommon to the point we were unable to report them collectively. Collecting data is regarded not only as one of the most important steps of a clinical trial but also as one of the most expensive.15 In this context, several initiatives have been created to highlight the need for CDDEs between trials across all disciplines.16–18 Interestingly, despite this awareness of a need for CDDEs, our present study highlights there is a lack of CDDEs between trials for IIH. Although there has been a call for common data elements and FIG. 3. Frequency of reported neuro-related outcomes. 70 Kobeissi et al: J Neuro-Ophthalmol 2024; 44: 66-73 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution TABLE 2. Summary table of potential outcomes for idiopathic intracranial hypertension interventional trials Target Underlying pathophysiology Intracranial pressure Weight measures Symptoms Headache Visual function Tinnitus Signs Papilledema Patient-reported outcomes Quality-of-life measurement tools Quality-of-life measurement tools Other targeted considerations Early phase trials Later phase trials for medicinal products Surgical and neurointerventional trials Outcome (Measure) Lumbar puncture opening pressure (cm or mm H20) Intracranial pressure by telemetric device (mm Hg) Body mass index Weight (kg) change Excess body weight change % weight change Monthly headache days Moderate-to-severe monthly headache days Headache responder rate ($50% reduction) Headache responder rate ($30% reduction) Monthly analgesic days Headache severity (numerical rating scale) Visual acuity Automated visual field perimetric mean deviation Tinnitus questionnaire (THI) OCT global peripapillary Retinal Nerve Fibre Layer (RNFL) OCT optic nerve head volume measures OCT macular ganglion cell analysis Frisén classification grade Short form (SF)-36 25-Item National Eye Institute Visual Function Questionnaire (NEI-VFQ-25) 10-Item Neuro-Ophthalmic Supplement to the NEI-VFQ-25 EuroQol—EQ5D Hospital anxiety and depression score Headache impact test-6 (HIT-6) Safety profile Tolerability Pharmacokinetics Maximum tolerated dose Recommended dose/dose regimen Adverse events (severity and number) Drug tolerability (compliance and rate of discontinuation) Rate of rescue therapy Adverse events (severity and number) Number of revisions Rate of rescue treatment Rate of technically successful procedures Time to 1st failure of the intervention Major complications identified according to the validated and widely used Clavien–Dindo classification Numbers of adverse events and serious adverse events Rate of rescue procedure Rate of cross over to other arm (in a trial with 2 interventions) Rate of failures (evidenced by recurrent disease activity) Frequency of revision Reintroduction of IIH medications 30-day readmission rate Number of IIH-related admissions IIH, idiopathic intracranial hypertension; OCT, optical coherence tomography. Kobeissi et al: J Neuro-Ophthalmol 2024; 44: 66-73 71 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution outcome measures in IIH, there is currently no consensus or society recommendations.19 Specifically, we noticed heterogeneity in both internal and external reporting. On a studyby-study basis, this may not seem to be a problem. However, when examined collectively, this high degree of inconsistency is problematic for several reasons. Systematic reviews and meta-analyses suffer unnecessary bias when data cannot be included due to different definitions, timing of measurements, and outcome measurements. In the setting of inconsistent measurements and definitions of data elements, outcomes between studies may differ simply because different studies use different parameters for diagnosis, treatment, and time frames. This lowers the degree of reproducibility a study has and limits future research in the area. Certainly, there have been steps taken to objectify the diagnosis of IIH. The modified Dandy criteria, which was used to diagnose IIH before 2013, was present as an inclusion criteria in most of the studies, reflecting this time point at which the studies would have been set up.12 Yet, not every study in our analysis used recognized diagnostic criteria to diagnose IIH. By including people who may not have IIH or indeed have secondary causes of raised intracranial pressure, the disease phenotype could be expectantly different and would significantly affect patient enrollment, bias in outcomes, and incorrect conclusions being applied to a typical IIH population. Heterogeneity in patient inclusion and exclusion criteria is particularly detrimental to external validity of results reported in these studies and further harms the success and validity of secondary analyses.20 The disease duration also varied among studies. For example, Idiopathic Intracranial Hypertension Weight Trial had a mean disease duration of 1.1 years where as the idiopathic intracranial hypertension treatment trial enrolled people who were diagnosed within 6 weeks as an inclusion criteria. In most studies included, the disease duration was not specified in the publicly available protocols. This data element would be essential to report because it may influence management of IIH. Another area in which a high degree of heterogeneity was observed was the time frame of data collection and followup between studies. For example, even when there was a commonly reported outcome such as visual acuity (9/14, 64%), there was, concurrently, low interstudy agreement in the time frame to measure the outcome. Response to any intervention should be measured at a consistent time because it is, by nature, a time-dependent outcome.21 The same can be said for other outcomes where time can play a dominant role, such as all-cause mortality and other adverse clinical events. Our present study suffered from the following key limitations. Chiefly, we only analyzed data that were available through ClinicalTrials.gov. This was necessary because we valued keeping a high degree of consistency between included trials so that we could report more reliable CDDEs. However, it is possible that some random72 ized clinical trials or prospective studies were not listed on this platform because of a number of different reasons, including institutional policy or targets set for keeping the information up-to-date. We included trials that have completed and those who are still yet to recruit. This meant that we would not necessarily have the most accurate study information, thus potentially introducing reporting bias. For example, the listings on the ClinicalTrials.gov web site did not specify which subtype of HVF was used. Despite this limitation, we extracted and included all data that were available. We acknowledge that it is unlikely that consensus could agree any specific primary outcome for all trials in IIH because of the different types of intervention that may target vision or headache. However, future work required in the field of IIH should include agreement by consensus for inclusion and exclusion criteria. Outcome measure selection should be clinically relevant and as objective as possible. Although there is a tendency for outcomes based on the type of intervention (surgical vs medical therapy) and possibly the disease severity, researchers should consider the condition as a whole and select secondary outcomes that may enable meta-analysis (Table 2). The development and validation of a disease-specific quality of life tool for IIH would allow for the elimination of the multiple tools used to measure changes in quality-of-life after interventions. Conclusion There is a high degree of heterogeneity and disagreement between ongoing and completed IIH trials regarding inclusion and exclusion criteria, outcome measurement, and time frame of data collection. It is imperative that future trial design focus on incorporating a greater amount of CDDEs so that higher-powered secondary analyses can be performed to validate results and determine their clinical significance. STATEMENT OF AUTHORSHIP Conception and design: H. Kobeissi, C. Bilgin, S. Ghozy, D. F. Kallmes, J. J. Chen; Acquisition of data: G. Adusumilli, J. Thurnham, N. Hardy, T. Xu, R. Tarchand; Analysis and interpretation of data: H. Kobeissi, S. Ghozy, D. F. Kallmes, A. Sinclair, S. P Mollan. Drafting the manuscript: H. Kobeissi, C. Bilgin, S. Ghozy, G. Adusumilli, J. Thurnham, N. Hardy, T. Xu, R. Tarchand, K. M. Kallmes, W. Brinjikji, R. Kadirvel, J. J. Chen, A. Sinclair, S. P. Mollan, D. F. Kallmes; Revising the manuscript for intellectual content: H. Kobeissi, C. Bilgin, S. Ghozy, G. Adusumilli, J. Thurnham, N. Hardy, T. Xu, R. Tarchand, K. M. Kallmes, W. Brinjikji, R. Kadirvel, J. J Chen, A. Sinclair, S. P Mollan, D. F Kallmes. Final approval of the completed manuscript: H. Kobeissi, J. J. Chen, S. P. Mollan, D. F Kallmes. ACKNOWLEDGMENT The authors acknowledge the Nested Knowledge metaanalytical software. Kobeissi et al: J Neuro-Ophthalmol 2024; 44: 66-73 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. 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