Heterogeneity of primary outcome measures used in clinical trials of treatments for intermediate, posterior, and panuveitis

Orphanet Journal of Rare Diseases

Andrew D. Dick⁶  James T. Rosenbaum³  Annabelle A. Okada²  Robert B. Nussenblatt⁵  Andrej Kidess¹  Gary N. Holland⁴  Alastair K. Denniston⁷ 

[1] Institute of Translational Medicine, Birmingham Health Partners, University of Birmingham, Birmingham, UK;Department of Ophthalmology, Kyorin University School of Medicine, Tokyo, Japan;Department of Ophthalmology, Casey Eye Institute, Oregon Health & Science University, USA Legacy Devers Eye Institute, Portland, Oregon, USA;UCLA Stein Eye Institute and the Department of Ophthalmology, Ocular Inflammatory Disease Center, David Geffen School of Medicine at UCLA, 100 Stein Plaza, UCLA, Los Angeles 90095-7000, CA, USA;National Eye Institute, National Institutes of Health, Bethesda, Maryland, USA;NIHR Biomedical Research Centre for Ophthalmology, Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London, UK;Department of Ophthalmology, Queen Elizabeth Hospital Birmingham, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK

关键词: Composite endpoints;    Endpoints;    Outcome measures;    Clinical trials;    Uveitis;   

Others  :  1224120
DOI  :  10.1186/s13023-015-0318-6

 received in 2015-03-18, accepted in 2015-08-06,  发布年份 2015

【 摘 要 】

Background

Uveitis describes a heterogeneous group of conditions characterized by intraocular inflammation. Since most of the sight-threatening forms of uveitis are individually rare, there has been an increasing tendency for clinical trials to group distinct uveitis syndromes together despite clear variations in phenotype which may reflect real aetiological and pathogenetic differences. Furthermore this grouping of distinct syndromes, and the range of manifestations within each uveitis syndrome, leads to a wide range of possible outcome measures. In this study we wished to review the degree of consensus or otherwise in the choice of primary outcome measures for registered clinical trials related to uveitis.

Methods

Systematic review of data provided in clinical trial registries describing clinical trials dealing with medical treatment of intermediate, posterior, or panuveitis through 01 October 2013. We reviewed 15 on-line clinical trial registries approved by the International Committee of Medical Journal Editors. We identified all that met the following inclusion criteria: prospective, interventional design; target populations with intermediate, posterior or panuveitis; and one or more pre-specified outcome measures that were related to uveitis. Primary outcome measures were classified in terms of type (efficacy or safety or both; single, composite, or multiple); dimension (disease activity, disease damage, measured or patient-reported visual function); and domain (the specific study variable being measured).

Results

Of 195 registered uveitis studies, we identified 104 clinical trials that met inclusion criteria. There were 14 different domains used as primary outcome measures. Among clinical trials that utilized primary outcome measures of treatment efficacy (n = 94), 70 (74 %) used a measure of disease activity (vitreous haze in 40/70 [57 %]; macular oedema in 19/70 [27 %]) and 49 (70 %) used a measure of visual function (visual acuity in all cases). Multiple primary outcome measures were used in 23 (22 %) of 104 clinical trials. With regard to quality, in 12 (12 %) of 104 clinical trials, outcome measures were poorly defined. No clinical trial utilized a patient-reported study variable as primary outcome measure.

Conclusions

This systematic review highlights the heterogeneity of outcome measures used in recent clinical trials for intermediate, posterior, and panuveitis. Current designs prioritize clinician-observed measures of disease activity and measurement of visual function as outcome measures. This apparent lack of consensus regarding outcome measures for the study of uveitis is a concern, as it prevents comparison of studies and meta-analyses, and weakens the evidence available to stake-holders, from patients to clinicians to regulators, regarding the efficacy and value of a given treatment.

【 授权许可】

   
2015 Denniston et al.

【 图 表 】

Fig. 1.

Fig. 2.

【 参考文献 】

• [1]Durrani OM, Meads CA, Murray PI. Uveitis: a potentially blinding disease. Ophthalmologica. 2004; 218(4):223-36.
• [2]Williams GJ, Brannan S, Forrester JV, Gavin MP, Paterson-Brown SP, Purdie AT, Virdi M, Olson JA. The prevalence of sight-threatening uveitis in Scotland. Br J Ophthalmol. 2007; 91(1):33-6.
• [3]Rothova A, Suttorp-van Schulten MS, Frits Treffers W, Kijlstra A. Causes and frequency of blindness in patients with intraocular inflammatory disease. Br J Ophthalmol. 1996; 80(4):332-6.
• [4]Gritz DC, Wong IG. Incidence and prevalence of uveitis in Northern California;the Northern California Epidemiology of Uveitis Study. Ophthalmology. 2004; 111(3):491-500.
• [5]Vadot E, Barth E, Billet P. Epdemiology of uveitis- preliminary results of a prospective study in Savoy. In: Uveitis update. Saari K, editor. Elsevier, Amsterdam; 1984: p.13-6.
• [6]Jones NP. The Manchester Uveitis Clinic: The First 3000 Patients-Epidemiology and Casemix. Ocul Immunol Inflamm. 2013 Dec 2. [Epub ahead of print] PubMed PMID: 24295124.
• [7]Jabs DA, Nussenblatt RB, Rosenbaum JT. Standardization of uveitis nomenclature for reporting clinical data. Results of the First International Workshop. Am J Ophthalmol. 2005; 140(3):509-16.
• [8]Denniston AK, Dick AD. Systemic therapies for inflammatory eye disease: past, present and future. BMC Ophthalmol. 2013; 13:18. BioMed Central Full Text
• [9]Sreekantam S, Denniston AK, Murray PI. Survey of expert practice and perceptions of the supporting clinical evidence for the management of uveitis-related cataract and cystoid macular oedema. Ocul Immunol Inflamm. 2011; 19(5):353-7.
• [10]Lowder C, Belfort R, Lightman S, Foster CS, Robinson MR, Schiffman RM, Li XY, Cui H, Whitcup SM. Ozurdex HURON Study Group. Dexamethasone intravitrealimplant for noninfectious intermediate or posterior uveitis. Arch Ophthalmol. 2011; 129(5):545-53.
• [11]Kempen JH, Altaweel MM, Holbrook JT, Jabs DA, Louis TA, Sugar EA, Thorne JE. Randomized comparison of systemic anti-inflammatory therapy versus fluocinolone acetonide implant for intermediate, posterior, and panuveitis: the multicenter uveitis steroid treatment trial. Ophthalmology. 2011; 118(10):1916-26.
• [12]Friedman DS, Holbrook JT, Ansari H, Alexander J, Burke A, Reed SB, Katz J, Thorne JE, Lightman SL, Kempen JH. Risk of elevated intraocular pressure and glaucoma in patients with uveitis: results of the multicenter uveitis steroid treatment trial. Ophthalmology. 2013; 120(8):1571-9.
• [13]Nussenblatt RB, Palestine AG, Chan CC, Roberge F. Standardization of vitreal inflammatory activity in intermediate and posterior uveitis. Ophthalmology. 1985; 92(4):467-71.
• [14]Kempen JH, Ganesh SK, Sangwan VS, Rathinam SR. Interobserver agreement in grading activity and site of inflammation in eyes of patients with uveitis. Am J Ophthalmol. 2008; 146(6):813-8.
• [15]Hornbeak DM, Payal A, Pistilli M, Biswas J, Ganesh SK, Gupta V, Rathinam SR, Davis JL, Kempen JH. Interobserver Agreement in Clinical Grading of Vitreous Haze Using Alternative Grading Scales. Ophthalmology. 2014.
• [16]Chan AW, Song F, Vickers A, Jefferson T, Dickersin K, Gøtzsche PC, Krumholz HM, Ghersi D, van der Worp HB. Increasing value and reducing waste: addressing inaccessible research. Lancet. 2014; 383(9913):257-66.
• [17]Suhler EB, Smith JR, Wertheim MS, Lauer AK, Kurz DE, Pickard TD, Rosenbaum JT. A prospective trial of infliximab therapy for refractory uveitis: preliminary safety and efficacy outcomes. Arch Ophthalmol. 2005; 123(7):903-12.
• [18]Schulz KF, Altman DG, Moher D, for the CONSORT Group.CONSORT Checklist. Available at http://www.consort-statement.org/checklists/view/32-consort/80-outcomes. [Last accessed 16 March 2015]
• [19]Sugar EA, Jabs DA, Altaweel MM, Lightman S, Acharya N, Vitale AT, Thorne JE. Multicenter Uveitis Steroid Treatment (MUST) Trial Research Group. Identifying a clinically meaningful threshold for change in uveitic macular edema evaluated by optical coherence tomography. Am J Ophthalmol. 2011; 152(6):1044-52.
• [20]Pelosini L, Hull CC, Boyce JF, McHugh D, Stanford MR, Marshall J. Optical coherence tomography may be used to predict visual acuity in patients with macular edema. Invest Ophthalmol Vis Sci. 2011; 52(5):2741-8.
• [21]Taylor SR, Lightman SL, Sugar EA, Jaffe GJ, Freeman WR, Altaweel MM, Kozak I, Holbrook JT, Jabs DA, Kempen JH. The impact of macular edema on visual function in intermediate, posterior, and panuveitis. Ocul Immunol Inflamm. 2012; 20(3):171-81.
• [22]Hee MR, Puliafito CA, Wong C, Duker JS, Reichel E, Rutledge B et al.. Quantitative assessment of macular edema with optical coherence tomography. Arch Ophthalmol. 1995; 113(8):1019-29.
• [23]Wolf-Schnurrbusch UE, Ceklic L, Brinkmann CK, Iliev ME, Frey M, Rothenbuehler SP, Enzmann V, Wolf S. Macular thickness measurements in healthy eyes using six different optical coherence tomography instruments. Invest Ophthalmol Vis Sci. 2009; 50(7):3432-7.
• [24]Keane PA, Karampelas M, Sim DA, FRCOphth, Sadda S, Tufail A, Sen HN, Nussenblatt RB, Dick AD, Lee RW, Murray PI, Pavesio CE, Denniston AK. Objective Measurement of Vitreous Inflammation using Optical Coherence Tomography Ophthalmology 2014 May 15. doi:. 10. 1016/j.ophtha.2014.03.006 webcite
• [25]Kiss CG, Barisani-Asenbauer T, Maca S, Richter-Mueksch S, Radner W. Reading performance of patients with uveitis-associated cystoid macular edema. Am J Ophthalmol. 2006; 142(4):620-4.
• [26]Munk M, Kiss C, Huf W, Sulzbacher F, Bolz M, Sayegh R, Eisenkölbl S, Simader C, Schmidt-Erfurth U. Therapeutic interventions for macular diseases show characteristic effects on near and distance visual function. Retina. 2013; 33(9):1915-22.
• [27]Denniston AK, Kyte D, Calvert M, Burr JM. An introduction to patient-reported outcome measures in ophthalmic research. Eye (Lond). 2014;28(6):637-45.
• [28]Mangione CM, Lee PP, Gutierrez PR, Spritzer K, Berry S, Hays RD. Development of the 25-list-item National Eye Institute Visual Function Questionnaire. Arch Ophthalmol. 2001; 119(7):1050-8.
• [29]Schiffman RM, Jacobsen G, Whitcup SM. Visual functioning and general health status in patients with uveitis. Arch Ophthalmol. 2001; 119(6):841-9.
• [30]Murphy CC, Greiner K, Plskova J, Frost NA, Forrester JV, Dick AD. Validity of using vision-related quality of life as a treatment end point in intermediate and posterior uveitis. Br J Ophthalmol. 2007; 91(2):154-6.
• [31]Frick KD, Drye LT, Kempen JH, Dunn JP, Holland GN, Latkany P, Rao NA, Sen HN, Sugar EA, Thorne JE, Wang RC, Holbrook JT. Multicenter Uveitis Steroid Treatment-MUST Trial Research Group. Associations among visual acuity and vision- and health-related quality of life among patients in the multicenter uveitis steroid treatment trial. Invest Ophthalmol Vis Sci. 2012; 53(3):1169-76.
• [32]Naik RK, Rentz AM, Foster CS, Lightman S, Belfort R, Lowder C, Whitcup SM, Kowalski JW, Revicki DA. Normative comparison of patient-reported outcomes in patients with noninfectious uveitis. JAMA Ophthalmol. 2013; 131(2):219-25.
• [33]Lightman S, Belfort R, Naik RK, Lowder C, Foster CS, Rentz AM, Cui H, Whitcup SM, Kowalski JW, Revicki DA. Vision-related functioning outcomes of dexamethasone intravitreal implant in noninfectious intermediate or posterioruveitis. Invest Ophthalmol Vis Sci. 2013; 54(7):4864-70.
• [34]Thornley B, Adams C. Content and quality of 2000 controlled trials in schizophrenia over 50 years. BMJ. 1998; 317:1181-4.
• [35]Williamson PR, Altman DG, Blazeby JM, Clarke M, Devane D, Gargon E, Tugwell P. Developing core outcome sets for clinical trials: issues to consider. Trials. 2012; 13:132. BioMed Central Full Text
• [36]Core Outcome Measure in Effectiveness Trials Initiative. Available at http://www.comet-initiative.org[Last accessed 16 March 2015].
• [37]U.S. Department of Health and Human Services Food and Drug Administration. Guidance for Industry Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims. Available at http://www.fda.gov/downloads/Drugs/Guidances/UCM193282.pdf [Last accessed 16 March 2015].