Reporting of noninferiority and equivalence randomized trials for major prostaglandins: A systematic survey of the ophthalmology literature

doi:10.1186/1745-6215-9-69

Trials. 2008; 9: 69.

Published online 2008 December 3. doi: 10.1186/1745-6215-9-69

PMCID: PMC2621118

Reporting of noninferiority and equivalence randomized trials for major prostaglandins: A systematic survey of the ophthalmology literature

Oghenowede Eyawo,¹ Chia-Wen Lee,² Beth Rachlis,³ and Edward J Mills⁴

¹Faculty of Health Sciences, Simon Fraser University, Burnaby, Canada

²Department of Outcomes Research and Evidence Based Medicine, Pfizer Ltd., Surrey, UK

³Department of Public Health, University of Toronto, Toronto, Canada

⁴Department of Clinical Epidemiology & Biostatistics, McMaster University, Hamilton, Canada

Corresponding author.

Oghenowede Eyawo: edeyawo/at/yahoo.com; Chia-Wen Lee: chia-Wen.Lee/at/pfizer.com; Beth Rachlis: brachlis/at/hotmail.com; Edward J Mills: millsej/at/mcmaster.ca

Received May 10, 2008; Accepted December 3, 2008.

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

This article has been cited by other articles in PMC.

Abstract

Background

Standards for reporting clinical trials have improved the transparency of patient-important research. The Consolidated Standards of Reporting Trials (CONSORT) published an extension to address noninferiority and equivalence trials. We aimed to determine the reporting quality of prostaglandin noninferiority and equivalence trials in the treatment of glaucoma.

Methods

We searched, independently and in duplicate, 6 electronic databases for eligible trials evaluating prostaglandins. We abstracted data on reporting of methodological criteria, including reporting of per-protocol [PP] and intention-to-treat [ITT] analysis, sample size estimation with margins, type of statistical analysis conducted, efficacy summaries, and use of hyperemia measures.

Results

Trials involving the four major prostaglandin groups (latanoprost, travoprost, bimatoprost, unoprostone) were analyzed. We included 36 noninferiority and 11 equivalence trials. Seventeen out of the included 47 trials (36%, 95% Confidence Intervals [CI]: 24–51) were crossover designs. Only 3 studies (6%, 95% CI: 2–17) reported a presented results of both ITT and PP populations. Twelve studies (26%, 95% CI: 15–39) presented only ITT results but mentioned that PP population had similar results. Thirteen trials (28%, 95% CI: 17–42) presented only PP results with no mention of ITT population results while 17 studies (36%, 95% CI: 24–51) presented only ITT results with no mention of PP population results. Thirty-four (72%, 95% CI: 58–83) of studies adequately described their margin of noninferiority/equivalence. Sequence generation was reported in 22/47 trials (47%, 95% CI: 33–61). Allocation concealment was reported in only 10/47 (21%, 95% CI: 12–35) of the trials. Thirty-five studies (74%, 95% CI: 60–85) employed masking of at least two groups, 4/47 (9%, 95% CI: 3–20) masked only patients and 8/47 (17%, 95% CI: 9–30) were open label studies. Eight (17%, 95% CI: 9–30) of the 47 trials employed a combined test of noninferiority and superiority. We also found 6 differing methods of evaluating hyperemia.

Conclusion

The quality of reporting noninferiority/equivalency trials in the field of glaucoma is markedly heterogeneous. The adoption of the extended CONSORT statement by journals will potentially improve the transparency of this field.

Background

There is emerging debate about the adherence to standards or recommendations made by regulatory bodies in the design, statistical analysis, description, and reporting of randomised clinical trials (RCT) intended to show noninferiority or equivalence [1]. The recent extension of the Consolidated Standards of Reporting Trials (CONSORT) statement to noninferiority and equivalence trials [1], the U. S. Food and Drug Administration (FDA) guidelines [2], as well as statements from other regulatory authorities, have updated recommendations to guide the conduct and reporting of RCTs investigating noninferiority or equivalence [3].

Noninferiority and equivalence studies aim to demonstrate that a new experimental treatment is not statistically worse than the active control intervention by more than a pre-specified amount (Δ), the noninferiority or equivalence margin. There are now a large number of studies intending to demonstrate noninferiority or equivalence. However, only very few of them have been designed, described, and reported as such [4]. In designs intending to show noninferiority (i.e. that a new treatment is at least as good as or no worse than an existing treatment) or equivalence (i.e. show that a new treatment has equal or comparable efficacy effects), one area of debate has been the application of the intent-to-treat (ITT) principle versus the per-protocol (PP) analysis [5]. There has been an expectation that ITT analyses are less conservative, tending to reduce the observed treatment difference in noninferiority trials, thus permitting wider confidence intervals; a factor that has increased the dependence on per-protocol analysis. The International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) E9 guideline on 'statistical principles for clinical trials' unequivocally states that the use of the ITT analysis in equivalence and noninferiority trials is 'generally not conservative and its role should be considered very carefully' [6]. However, the Committee for Proprietary Medicinal Products (CPMP) consider both analyses to be equally important [7] and simulation studies have not demonstrated the anticonservative approach of ITT versus PP [8]. In the extension of the CONSORT statement, conducting and reporting PP analyses alongside ITT has been suggested as a means of increasing confidence in the study finding particularly when both methods produce similar results.

In order to determine the methodological quality and reporting standards for those trials designed to show noninferiority or therapeutic equivalence, we conducted a systematic survey of the literature to identify noninferiority and equivalence randomised clinical trials involving glaucoma drugs of prostaglandin origin. We applied the extended CONSORT statement for non-inferiority and equivalence trials as methodological criteria of minimum reporting standards [1].

Methods

Eligibility Criteria

Noninferiority and equivalence randomized clinical trials that involved the application of any of the four major drugs of the prostaglandin analogues (latanoprost, travoprost, bimatoprost, and unoprostone) in the treatment of patients with open angle glaucoma (POAG) or ocular hypertension (OH) were eligible for the study. We defined noninferiority trials as 1-sided trials aiming to demonstrate effectiveness not lower than Δ. Whereas, equivalence studies were defined as 2-sided trials wherein the difference between treatments is between -Δ and +Δ margins of equivalence. We further determined a trial to be eligible for inclusion if 'equivalence' or 'noninferiority' was mentioned as the intent anywhere in the methods sections of the manuscripts. We excluded bioequivalence (pharmacokinetic and pharmacodynamic) trials and trials designed to show superiority.

Search Strategy

Using independent and duplicate searchers (OE, EM), we searched the following 6 databases from inception to March 2008: MEDLINE via PubMed, CinAhl, AMED, Toxnet, Cochrane CENTRAL and E-Psyche. Our MEDLINE search strategy identified the exact MeSH terms for the following expressions: open angle glaucoma, ocular hypertension and prostaglandin* (latanoprost, bimatoprost, travoprost aand unoprostone). We conducted 3 main searches. First we collated all articles with the MeSH key terms "glaucoma, open angle OR ocular hypertension" [see Additional file 1]. We then extracted articles containing the MeSH terms "prostaglandin* OR latanoprost OR travoprost OR bimatoprost OR unoprostone." We then pooled these two searches to produce a third list, representing all articles that had as its key terms, "POAG or OH or prostaglandin* OR latanoprost OR travoprost OR bimatoprost OR unoprostone." We also searched multiple databases including CinAhl, AMED, Toxnet, Cochrane CENTRAL and E-Psyche using key search terms like latanoprost, bimatoprost, travoprost, unoprostone, open angle glaucoma, ocular hypertension and prostaglandin*. Simultaneous review of these databases was possible through the use of the Ovid interdisciplinary database that permits the checking of multiple databases. Where full text was unavailable, we searched Google Scholar and also used interlibrary loans to order full text articles. We supplemented this search by reviewing the bibliographies of key papers.

Study selection

Working independently and in duplicate OE and EM reviewed all abstracts and full articles, where available, of our search results. We excluded articles at this stage that were not randomized trials or were reviews and/or comments. All full text articles of identified RCT studies that examined treatment with prostaglandin drugs were sought. Eligibility was determined in consensus. Only comparisons containing at least one study drug of interest (i.e., bimatoprost, latanoprost, travoprost or unoprostone) were eligible for inclusion. When comparisons involved several different dosages (e.g., 0.005% or 0.03%), we included only those that met FDA-approved standards. Where we were unsure of specific intentions of noninferiority/equivalence compared to superiority, we contacted one author via email.

Data Collection

We collected information about the type of interventions tested, study design and purpose. We also obtained data on sample size estimation with margins, type of statistical analysis conducted, population analyzed [ITT or/and PP], efficacy summaries, and use of hyperemia measures. Our study evaluation included an assessment of the following general methodological quality features: allocation concealment, sequence generation, masking status, and the handling of losses to follow-up. We also recorded sample size (recruited, randomized and completed) and the use of a combined test of noninferiority and superiority. Finally, we noted whether there was a clear objective/hypothesis relating to noninferiority or equivalence, a tabular presentation of baseline data (demographic and clinical), and a predetermined noninferiority/equivalence margin.

Data Analysis

In order to assess inter-rater reliability on inclusion of articles, we calculated the Phi statistic, which provides a measure of inter-observer agreement independent of chance [9]. In order to determine the proportion reporting the specific item with appropriate confidence intervals, we first stabilized the variances of the raw proportions (r/n) using a Freeman-Tukey type arcsine square root transformation: y = arcsine (square root(r/(n+1))+arcsine(square root(r+1)/(n+1))), with a variance of 1/(n+1), where n is the denominator overall size [10]. We used StatsDirect (version 2.5.2, http://www.statsdirect.com for all calculations.

Results

Results of literature search

Our first and second search produced 35,207 and 97,523 abstracts respectively. The third and final search (search #1 AND #2 pooled) produced 1144 abstracts. After thorough assessment, 215 abstracts were excluded since they were review articles. Another 549 abstracts were excluded as they were not relevant to present study. Overall, 380 full text papers were retrieved for possible inclusion. Upon careful review of the 380 full text articles, we included 47 full text articles in our analysis (Phi = 0.88). Figure Figure11 presents details of the exclusion criteria at the various stages during the study selection process.

Figure 1

Flow diagram of included studies

Trial interventions

Table Table11 outlines the characteristics of all 47 included publications. Of these, 31 reported conducting comparisons of treatments (e.g., travoprost vs. latanoprost) that were duplicated in at least one other included study. More specifically, five trials compared bimatoprost to latanoprost [11-15]. Four trials compared bimatoprost and timolol [16-19]. Three trials compared bimatoprost to a fixed combination (FC) treatment that contained timolol [20-22].

Table 1

Characteristics of included publications

Six trials compared latanoprost to timolol [13,23-27]. Three studies compared latanoprost to brimonidine (or brimonidine-containing fixed combination) [28-30]. Two studies compared FC latanoprost/timolol vs FC dorzolamide/timolol [31,32]. Two studies compared FC latanoprost/timolol versus its individual components (i.e. latanoprost and timolol) [33,34]. Two studies compared FC latanoprost/timolol versus latanoprost and timolol administered concomitantly [35,36].

Four studies compared travoprost and latanoprost [12,13,23,37]. Two studies compared travoprost and timolol [23,38]. Two studies compared travoprost or FC-containing travoprost versus latanoprost (or FC-containing latanoprost) [39,40] and three studies compared travoprost or FC-containing travoprost versus timolol (or FC-containing timolol) [39-41]. Finally, 16 publications contained other comparisons of treatment types that were not duplicated with any other included study. [42-57]

Characteristics of trials

Table Table22 shows the characteristics of the trials as well as the quality of reporting. The average sample size was 311 (SD 33), although on average, only 86% of patients were included in the final analyses. Seventeen out of the included 47 trials (36%, 95% CI: 24–51) were crossover designs.

Table 2

Methodological quality and reporting

Of the 47 trials, 36 were noninferiority trials (77%, 95% CI: 63–86) and 11 (23%, 95% CI: 14–37) were designed for equivalence. In the final interpretations of the studies, 16/47 (34%, 95% CI: 22–48) trials claimed noninferiority, 14/47 (30%, 95% CI: 19–44) claimed equivalence and 17/47 (36%, 95% CI: 24–51) claimed superiority. For the trials claiming noninferiority, 33/36 (92%, 95% CI: 78–92) were accurate within their noninferiority margin. For those claiming equivalency, 10/11 (90%, 95% CI: 62–98) were accurate within their a priori margins. Seventeen percent of trials (8/47, 95% CI: 9–30) employed a combined test of noninferiority and superiority.

Sequence generation was reported in 22/47 trials (47%, 95% CI: 33–61). Allocation concealment was reported in only 10/47 (21%, 95% CI: 12–35) of the trials. Thirty-five studies (74%, 95% CI: 60–85) employed masking of at least two groups, 4/47 (9%, 95% CI: 3–20) masked only patients and 8/47 (17%, 95% CI: 9–30) were open label studies.

Only 6 of the 47 (13%, 95% CI: 6–25) studies specified that the trial was a noninferiority or equivalence trial in the title or abstract. The background or introduction section of 5/47 (11%, 95% CI: 5–23) articles contained a rationale for using a noninferiority or equivalence trial design. Thirteen articles (28%, 95% CI: 17–42) had a clear objective or hypothesis pertaining to noninferiority or equivalence. Thirty-four trials (72%, 95% CI: 58–83) properly described the method applied in the sample size determination and set appropriate boundaries on noninferiority or equivalence. The pre-stated noninferiority/equivalence in all the trials lied between the ranges of -1 to 2.5. Primary outcome measure was the mean intraocular pressure which was mostly measured as a mean difference or as a mean reduction from baseline.

Only 3/47 (6%, 95% CI: 2–17) studies reported and presented results of both ITT and PP populations. Two studies (4%, 95% CI: 1–14) presented only PP results but mentioned that ITT population had similar results. Twelve studies (26%, 95% CI: 15–39) presented only ITT results but mentioned that PP population had similar results. Thirteen trials (28%, 95% CI: 17–42) presented only PP results with no mention of ITT population results while 17/47 (36%, 95% CI: 24–51) studies presented only ITT results with no mention of PP population results.

From the 47 trials reported in this study, only one (2%, 95% CI: 0.5–11) diagrammatically presented its results by use of a figure showing the confidence intervals and pre-specified margins of equivalence or noninferiority. Handling of losses to follow-up was not addressed in 33 of the 47 trials (70%, 95% CI: 56–81). Loss to follow-up was mentioned but unaddressed in 10 trials (21%, 95% CI: 12–35), while 3/47 (6%, 95% CI: 2–17) were addressed in the statistics and 1/47 (2%, 95% CI: 0–11) had a zero loss to follow-up.

Measurement of hyperemia

We found large heterogeneity of measuring hyperemia. Two of the 47 (4%, 95% CI: 1–14) included studies used a severity scale based on non-serious, mild, moderate, and serious. Six studies (13%, 95% CI: 6–25) used a severity scale based on none, mild, moderate, and serious. Five (11%, 95% CI: 5–23) used a scale that recorded only mild, moderate, and severe. One (2%, 95% CI: 0.5–11) used a scale that included only non-serious and serious. One (2%, 95% CI: 0.5–11) used a four-point scale from 1–4 stating minimum and maximum as the scale endpoints. Six (13%, 95% CI:6–25) studies used a 5 point scale with 0 = none, 0.5 = trace, 1 = mild, 2 = moderate, and 3 severe. A further 26/47 (55%, 95% CI: 41–69) did not report their method of measuring hyperemia, of which 5/26 (19%, 95% CI: 9–38) did not report on hyperemia outcomes.

Discussion

To our knowledge, this is the first study that has attempted to look into the methodological quality and reporting of any ophthalmology RCTs designed to show noninferiority or equivalence for glaucoma treatments. These findings reinforce the gaps that exist in the methodological quality and reporting of these trials in general. We additionally found that within ophthalmology trials, a substantial heterogeneity exists in terms of measuring clinical outcomes, such as hyperemia. It is clear that further efforts at improving the reporting and analyses of clinical trials in this field are needed. Recent work by Hopewell and colleagues [58] highlighted the need for journals to endorse the CONSORT Statement and its extensions, and also make its application a condition for authors wishing to publish in the journal. Journals in the ophthalmology field should consider such an endorsement as well as promoting a strict adherence to the extended CONSORT statement in order to potentially improve manuscript reporting.

There are several strengths and limitations to consider in interpreting our study. Strengths include our extensive searching of the literature to identify a representative sample of a field that commonly utilizes noninferiority and equivalence trials. Our data abstraction methods aimed to reduce investigator driven bias with duplicate data abstraction. Limitations to consider include that we solely relied upon the reporting of specific items rather than inquiring about any missing items through contact with each individual trial investigator. As outlined in the methods, study authors were only contacted when we were unclear whether the trial itself included a non-inferiority or equivalence study design. It is possible that some of the specific methodological items were conducted but not reported. Indeed, this issue has been highlighted by investigators [59]. However, our study aimed to determine reporting quality in order to make specific recommendations on transparent reporting. We did not determine changes pre- versus post-publication of the extended CONSORT statement in 2006. Previous research has found that the quality of reports improved after publication of the original 1996 CONSORT publication [60]. Per-protocol analyses have traditionally been preferred over ITT approaches despite current consensus of displaying both [1,4,7]. In our study we were unable to determine if one is superior to the other as we found too few examples where both outcomes are reported.

The findings of our study are consistent with other studies investigating reporting quality in general medicine journals and specialist journals [61]. General medicine journals tend to report important methodological recommendations more frequently than specialist journals. This may be due to the encouragement of journals to utilize the CONSORT recommendations through editorials and letters [62]. Providing editorials or guidelines in the instructions to authors is a potential option for improving the reporting of these RCTs. An option that may be considered is a checklist submitted with clinical trials indicating where in the manuscript specific details are reported, as required by many current journals.

An important methodological issue that has been raised by this review is the use of a combined test of noninferiority and superiority. The purpose of conducting noninferiority and equivalence trials is not to evaluate superiority, as that would require far more power than would be expected in this type of trial and would maintain the need for ITT analysis [63]. In our study, 8 trials employed the combined test for noninferiority and superiority. This allows a trial to claim its original intent of noninferiority if superiority is not identified, but can claim superiority if the arbitrary threshold, upper-limit of noninferiority, is surpassed [64].

Given the heated market of the prostaglandin field, we found that several (n = 17) noninferiority and equivalence trials claimed superiority of the test intervention over competitors products, regardless of overall findings and the study intent. For example, in a randomized trial evaluating travoprost to latanoprost on 408 patients' daily intraocular pressure at 9 am, 11 am and 4 pm, the authors found noninferiority, but report on statistical superiority at the 9 am measurement [40]. Given the lack of ITT analysis, the multiple testing and initial intention of a noninferiority analysis, such findings provide misleading evaluations of superiority. Indeed, this phenomenon exists across a range of medical fields [65-70].

Pre-specifying the noninferiority or equivalence margin is necessary to provide strong inferences about the suitability of one treatment compared to another. If the margin employed is too wide, risk for type 1 error exists. Similarly, although unlikely, if one were to establish the margin too narrow, a type 2 error is possible. Margins should be established based on clinical justification and not statistical rule [71].

Conclusion

In conclusion, based on the analysis of the study reports that we have examined, our findings demonstrate deficiencies in the design, planning, and reporting of noninferiority and equivalence trials in the ophthalmology literature. Many studies of clinical noninferiority and equivalence do not set boundaries for equivalence. Claims of "superiority" and "similarity" are often displayed despite the use of improper analysis. These methodologic deficiencies appear to lead to false claims, unrepeatable experiments, and possible costs or harms to patients.

Competing interests

Over the past 5 years, Edward Mills has consulted to Pfizer Ltd. Edward Mills is the recipient of an industry partnered New Investigator award from The Canadian Institutes of Health Research to conduct methodological research. Chia-Wen Lee has been an employee of Pfizer Ltd. No other authors have any competing interests. We can think of no way that the declared competing interests can benefit from this manuscript.

Authors' contributions

OE, BR, CWL, and EM conceptualized the study. OE, BR, CWL, and EM acquired the data. OE, BR, CWL, and EM analyzed the data. OE, BR, CWL, and EM wrote the manuscript. OE, BR, CWL, and EM approved the final manuscript.

Supplementary Material

Additional file 1

Example search strategy, MedLine. Search Strategy for MEDLINE via PubMed Search.

Click here for file^{(20K, doc)}

Acknowledgements

Funding for this study was provided by Pfizer Ltd in the form of an educational grant.

References

Piaggio G, Elbourne DR, Altman DG, Pocock SJ, Evans SJW. Reporting of noninferiority and equivalence randomized trials. JAMA. 2006;295:1152–1160. doi: 10.1001/jama.295.10.1152. [PubMed] [Cross Ref]
United States Food and Drug Administration (FDA) Guidance for Industry, E 10, Choice of control group and related issues in clinical trials. 2001. http://www.fda.gov/cder/guidance/4155fnl.pdf
Gøtzsche PC. Lessons from and cautions about noninferiority and equivalence randomized trials. JAMA. 2006;295:1172–1174. doi: 10.1001/jama.295.10.1172. [PubMed] [Cross Ref]
Le Henanff A, Giraudeau B, Baron G, Ravaud P. Quality of reporting of noninferiority and equivalence randomized trials. JAMA. 2006;295:1147–1151. doi: 10.1001/jama.295.10.1147. [PubMed] [Cross Ref]
Brittain E, Lin D. A comparison of intent-to-treat and per-protocol results in antibiotic non-inferiority trials. Statist Med. 2005;24:1–10. doi: 10.1002/sim.1934. [PubMed] [Cross Ref]
The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) Statistical principles for clinical trials. 1998. p. E9.http://www.ich.org/LOB/media/MEDIA485.pdf
Committee for Proprietary Medicinal Products (CPMP) Points to consider on switching between superiority and non-inferiority. 2000. http://www.emea.europa.eu/pdfs/human/ewp/048299en.pdf [PubMed]
Ebbutt AF, Frith L. Practical issues in equivalence trials. Statist Med. 1998;17:1691–1701. doi: 10.1002/(SICI)1097-0258(19980815/30)17:15/16<1691::AID-SIM971>3.0.CO;2-J. [PubMed] [Cross Ref]
Meade MO, Guyatt GH, Cook RJ, Groll R, Kachura JR, Wigg M, Cook DJ, Stutsky AS, Stewart TE. Agreement between alternative classifications of acute respiratory distress syndrome. Am J Respir Crit Care Med. 2001;163:490–493. [PubMed]
Jaynes ET. Confidence intervals vs. Bayesian intervals. In: Harper WL, Hooker CA, editor. Foundations of Probability Theory, Statistical Inference, and Statistical Theories of Science. Dordrecht: D. Reidel; 1976.
Gandolfi S, Simmons ST, Sturm R, Chen K, Van Denburgh AM., for the Bimatoprost Study Group Three-month comparison of bimatoprost and latanoprost in patients with glaucoma and ocular hypertension. Adv Ther. 2001;18:110–121. doi: 10.1007/BF02850299. [PubMed] [Cross Ref]
Parrish RK, Palmberg P, Sheu WP., for the XLT Study Group A comparison of latanoprost, bimatroprost, and travoprost in patients with elevated intraocular pressure: a 12-week, randomized, masked-evaluator multicenter study. Am J Ophthalmol. 2003;135:688–703. doi: 10.1016/S0002-9394(03)00098-9. [PubMed] [Cross Ref]
Zimmerman T, Stewart WC., for the Latanoprost Axis Study Group Intraocular pressure, safety, and quality of life in glaucoma patients switching to latanoprost from monotherapy treatments. J Ocul Pharmacol Ther. 2003;19:405–15. doi: 10.1089/108076803322472971. [PubMed] [Cross Ref]
Noecker RS, Dirks MS, Choplin NT, Berstein P, Batoosingh AL, Whitcup SM., for the Bimatoprost/Latanoprost Study Group A six-month randomized clinical trial comparing the intraocular pressure-lowering efficacy of bimatoprost and latanoprost in patients with ocular hypertension or glaucoma. Am J Ophthalmol. 2003;135:55–63. doi: 10.1016/S0002-9394(02)01827-5. [PubMed] [Cross Ref]
DuBiner H, Cooke D, Dirks M, Stewart WC, Van Denburgh AM, Felix C. Efficacy and safety of bimatoprost in patients with elevated intraocular pressure: a 30-day comparison with latanoprost. Surv Ophthalmol. 2001;44:S353–360. doi: 10.1016/S0039-6257(01)00212-0. [PubMed] [Cross Ref]
Whitcup SM, Cantor LB, Van Denburgh AM, Chen K. A randomized, double-masked, multicentre clinical trial comparing bimatoprost and timolol for the treatment of glaucoma and ocular hypertension. Br J Ophthalmol. 2003;87:57–62. doi: 10.1136/bjo.87.1.57. [PMC free article] [PubMed] [Cross Ref]
Cohen JS, Gross RL, Cheetham J, Van Denburgh AM, Bernstein P, Whitcup SM. Two-year double-masked comparison of bimatoprost with timolol in patients with glaucoma or ocular hypertension. Surv Opthalmol. 2004;49:S45–52. doi: 10.1016/j.survophthal.2003.12.019. [PubMed] [Cross Ref]
Higginbotham EJ, Schuman JS, Goldberg I, Gross RL, Van Denburgh AM, Chen K, Whitcup SM., for the Bimatoprost Study Groups 1 and 2 One-year randomized study comparing bimatoprost and timolol in glaucoma and ocular hypertension. Arch Ophthalmol. 2002;120:1286–1293. [PubMed]
Brandt JD, Van Denburgh AM, Chen K, Whitcup SM., for the Bimatoprost Study Group Comparison of once- or twice-daily bimatoprost with twice-daily timolol in patients with elevated IOP: a 3-month clinical trial. Ophthalmology. 2001;108:1023–1031. doi: 10.1016/S0161-6420(01)00584-X. [PubMed] [Cross Ref]
Brittain CJ, Saxena R, Waldock A. Prospective comparative switch study from timolol 0.5% and latanoprost 0.005% to bimatoprost 0.03% Adv Ther. 2006;23:68–73. doi: 10.1007/BF02850348. [PubMed] [Cross Ref]
Day DG, Sharpe ED, Beischel CJ, Jenkins JN, Stewart JA, Stewart WC. Safety and efficacy of bimatoprost 0.03% versus timolol maleate 0.5%/dorzolamide 2% fixed combination. Eur J Ophthalmol. 2005;15:336–342. [PubMed]
Coleman AL, Lerner F, Bernstein P, Whitcup SM. A 3-month randomized controlled trial of bimatoprost (LUMIGAN) versus combined timolol and dorzolamide (COSOPT) in patients with glaucoma or ocular hypertension. Ophthalmol. 2003;110:2362–2368. [PubMed]
Netland PA, Landry T, Sullivan EK, Andrew R, Silver L, Weiner A, Mallick S, Dickerson J, Bergamini MV, Robertson SM, Davis SS., for the Travoprost Study Group Travoprost compared with latanoprost and timolol in patients with open-angle glaucoma or ocular hypertension. Am J Ophthalmol. 2001;132:472–484. doi: 10.1016/S0002-9394(01)01177-1. [PubMed] [Cross Ref]
Larsson LI. Intraocular pressure of 24 hours after repeated administration of latanoprost 0.0055 or timolol gel-forming solution 0.5% in patients with ocular hypertension. Ophthalmology. 2001;108:1439–1444. doi: 10.1016/S0161-6420(01)00605-4. [PubMed] [Cross Ref]
Tomita G, Araie M, Ktazawa Y, Tsukhara S. A three-year prospective, randomized and open comparison between latanoprost and timolol in Japanese normal-tension glaucoma patients. Eye. 2004;18:984–989. doi: 10.1038/sj.eye.6701373. [PubMed] [Cross Ref]
Watson P, Stjernschantz J. A six-month, randomized, double-masked study comparing latanoprost with timolol in open-angle glaucoma and ocular hypertension. Ophthalmology. 1996;103:126–137. [PubMed]
Konstas AG, Maltezos AC, Gandi S, Hudgins AC, Stewart WC. Comparison of 24-hour intraocular pressure reduction with two dosing regimens of latanoprost and timolol maleate in patients with primary open-angle glaucoma. Am J Ophthalmol. 1999;128:15–20. doi: 10.1016/S0002-9394(99)00073-2. [PubMed] [Cross Ref]
Thomas R, Parikh R, Muliyil J, George R, Paul P, Abraham LM. Comparison between latanoprost and brimonidine efficacy and safety in Indian eyes. Indian J Ophthalmol. 2003;51:123–128. [PubMed]
Konstas AG, Karabatsas CH, Lallos N, Georgiadis N, Kotsimpou A, Stewart JA, Stewart WC. 24-hour intraocular pressures with brmonidine purite versus dorzomalide added to latanoprost in primary open-angle glaucoma subjects. Ophthalmology. 2005;112:603–608. doi: 10.1016/j.ophtha.2004.11.032. [PubMed] [Cross Ref]
Simmons ST, Earl ML., for the Alphagan/Xalatan Study Group Three-month comparison of brimonidine and latanoprost as adjunctive therapy in glaucoma and ocular hypertension patients uncontrolled on beta-blockers; tolerance and peak intraocular pressure lowering. Ophthalmology. 2002;109:307–314. doi: 10.1016/S0161-6420(01)00936-8. [PubMed] [Cross Ref]
Shin DH, Feldman RM, Sheu WP., for the Fixed Combination Latanoprost/Timolol Study Group Efficacy and safety of the fixed combinations latanoprost/timolol versus drozolamide/timolol in patients with elevated intraocular pressure. Ophthalmology. 2004;111:276–282. doi: 10.1016/j.ophtha.2003.05.019. [PubMed] [Cross Ref]
Konstas AG, Kozobolis VP, Lallos N, Christodoulakis E, Stewart JA, Stewart WC. Daytime diurnal curve comparison between the fixed combinations of latanoprost 0.005%/timolol maleate 0.5% and dorzomalide 2%/timolol maleate 0.5% Eye. 2004;18:1264–1269. doi: 10.1038/sj.eye.6701446. [PubMed] [Cross Ref]
Pfeiffer N., for the European Latanoprost Fixed Combination Study Group A comparison of the fixed combination of latanoprost and timolol with its individual components. Graefes Arch Clin Exp Ophthalmol. 2002;240:893–899. doi: 10.1007/s00417-002-0553-0. [PubMed] [Cross Ref]
Higginbotham EJ, Feldman RJ, Stiles M, Dubiner H., for the Fixed Combination Investigative Group Latanaprost and timolol combination therapy vs. monotherapy: one year randomized trial. Arch Ophthalmol. 2002;120:915–922. [PubMed]
Diestelhorst M, Larsson LI., for the European-Canadian Latanoprost Fixed Combination Study Group A 12-week, randomized, double-masked, multicenter study of the fixed combination of latanoprost and timolol in the evening versus individual components. Ophthalmology. 2006;113:70–76. doi: 10.1016/j.ophtha.2005.06.027. [PubMed] [Cross Ref]
Diestelhorst M, Larrson LI., for the European Latanoprost Fixed Combination Study Group A 12 week study comparing the fixed combination of latanprost and timolol with the concomitant use of the individual components in patients with open angle glaucoma and ocular hypertension. Br J Ophthalmol. 2004;88:199–203. doi: 10.1136/bjo.2003.018234. [PMC free article] [PubMed] [Cross Ref]
Konstas AG, Kozobolis VP, Katsimpris IE, Boboridis K, Koukoula S, Jenkins JN, Stewart WC. Efficacy and safety of latanoprost versus travoprost in exfoliative glaucoma patients. Ophthalmology. 2007;114:653–657. doi: 10.1016/j.ophtha.2006.07.064. [PubMed] [Cross Ref]
Goldberg I, Cunha-Vaz J, Jakobsen JE, Nordmann JP, Trost E, Sullivan EK., for the International Travoprost Study Group Comparison of topical travoprost eye drops given once daily and timolol 0.5% given twice daily in patients with open-angle glaucoma or ocular hypertension. J Glaucoma. 2001;10:414–422. doi: 10.1097/00061198-200110000-00010. [PubMed] [Cross Ref]
Franks WA, Renard JP, Cunlife IA, Rojanapongpun P. A 6-week, double-masked, parallel-group study of the efficacy and safety of travoprost 0.004% compared with latanoprost 0.005%/timolol 0.5% in patients with primary open-angle glaucoma or ocular hypertension. Clin Ther. 2006;28:332–339. doi: 10.1016/j.clinthera.2006.03.001. [PubMed] [Cross Ref]
Topouzis F, Melamed S, Danesh-Meyer H, Wells AP, Kozobolis V, Wieland H, Andrew R, Wells D. A 1-year study to compare the efficacy and safety of once-daily travoprost 0.004%/timolol 0.5% to once-daily latanoprost 0.005%/timolol 0.5% in patients with open-angle glaucoma or ocular hypertension. Eur J Ophthalmol. 2007;17:183–190. [PubMed]
Hughes BA, Bacharach J, Craven ER, Kaback MB, Mallick S, Landry TA, Bergamini MV. A three-month, multicenter, double-masked study of the safety and efficacy of travoprost 0.004%/timolol 0.5% ophthalmic solution compared to travoprost 0.004% ophthalmic solution and timolol 0.5% dosed concomitantly in subjects with open-angle glaucoma or ocular hypertension. J Glaucoma. 2005;14:392–299. doi: 10.1097/01.ijg.0000176935.08392.14. [PubMed] [Cross Ref]
Fechtner RD, Airaksinen PJ, Getson AJ, Lines CR, Adamsons IA., for the COSOPT versus XALATAN Study Groups Efficacy and tolerability of the dorzolamide 2%/timolol 0.5% combination (COSOPT) versus 0.005% (XALATAN) in the treatment of ocular hypertension or glaucoma: results from two randomized clinical trials. Acta Ophthalmol Scand. 2004;82:42–48. doi: 10.1046/j.1600-0420.2004.0205.x. [PubMed] [Cross Ref]
Hommer A. A double-masked randomized parallel comparison of a fixed combination of bimatoprost 0.03%/timolol 0.5% with non-fixed. Eur J Ophthalmol. 2007;17:53–62. [PubMed]
Holló G, Chiselita D, Petkova N, Cvenkel B, Liehneova I, Izgi B, Berta A, Szaflik J, Turacli E, Stewart WC. The efficacy and safety of timolol maleate versus brinzolamide each given twice daily added to travoprost in patients with ocular hypertension or primary open-angle glaucoma. Eur J Ophthalmol. 2006;16:816–823. [PubMed]
Netland PA, Mroz M, Rosner SA, Katzman B, Macy JI. Brimonidine purite and bimatoprost compared with timolol and latanoprost in patients with glaucoma and ocular hypertension. Adv Ther. 2003;20:20–30. doi: 10.1007/BF02850116. [PubMed] [Cross Ref]
Stewart WC, Stewart JA, Day DG, Sharpe ED, Jenkins JN. Efficacy and safety of the latanoprost/timolol maleate fixed combination vs concomitant brimonidine and latanoprost therapy. Eye. 2004;18:990–995. doi: 10.1038/sj.eye.6701375. [PubMed] [Cross Ref]
Day DG, Schacknow PN, Wand M, Sharpe ED, Stewart JA, Leech J, Stewart WC. Timolol 0.5%/dorzolamide 2% fixed combination vs timolol maleate 0.5% and unoprostone 0.15% given twice daily to patients with primary open-angle glaucoma or ocular hypertension. Am J Ophthalmol. 2003;135:138–143. doi: 10.1016/S0002-9394(02)01887-1. [PubMed] [Cross Ref]
Sharpe ED, Henry CJ, Mundorf TK, Day DG, Stewart JA, Jenkins JN, Stewart WC. Brimonidine 0.2% vs unoprostone 0.15% both added to timolol maleate 0.5% given twice daily to patients with primary open-angle glaucoma or ocular hypertension. Eye. 2005;19:35–40. doi: 10.1038/sj.eye.6701392. [PubMed] [Cross Ref]
Konstas AGP, Kozobolis VP, Tsironi S, Makridaki I, Efremova R, Stewart WC. Comparison of the 24-hour intraocular pressure-lowering effects of latanorpost and dorzolamide/timolol fixed combination after 2 and 6 months of treatment. Ophthalmology. 2008;115:99–103. doi: 10.1016/j.ophtha.2007.03.007. [PubMed] [Cross Ref]
Schuman JS, Katz GJ, Lewis RA, Henry JC, Mallick S, Wells DT, Sullivan EK, Landry TA, Bergamini MVW, Robertson SM. Efficacy and safety of a fixed combination of travoprost 0.004%/timolol 0.5% ophthalmic solution once daily for open-angle glaucoma or ocular hypertension. Am J Ophthalmol. 2005;140:242–250. [PubMed]
Stewart WC, Stewart JA, Day D, Sharpe ED. Efficacy and safety of timolol maleate/latanoprost fixed combination versus timolol maleate and brimonidine given twice daily. Acta Ophthalmol Scand. 2003;81:242–246. doi: 10.1034/j.1600-0420.2003.00065.x. [PubMed] [Cross Ref]
Honrubia FM, Larsson LI, Spiegel D., the European Latanoprost Study Group A comparison of the effects on intraocular pressure of latanoprost 0.005% and the fixed combination of dorzolamide 2% and timolol 0.5% in patients with open-angle glaucoma. Acta Ophthalmol Scand. 2002;80:635–641. doi: 10.1034/j.1600-0420.2002.800615.x. [PubMed] [Cross Ref]
Susanna R, Jr, Giampani J, Borges AS, Vessani RM, Jordao MLS. A double-masked, randomized clinical trial comparing latanoprost with unoprostone in patients with open-angle glaucoma or ocular hypertension. Ophthalmol. 2001;108:259–263. [PubMed]
Diestelhorst M., for the German Latanoprost Study Group The additive intraocular pressure-lowering effect of latanoprost 0.005% daily once and pilocarpine 2% t.i.d. in patients with open-angle glaucoma or ocular hypertension. A 6-month, randomized, multicenter study. Graef Arch Clin Exp Ophthalmol. 2000;238:433–439. doi: 10.1007/s004170050375. [PubMed] [Cross Ref]
Stewart WC, Day DG, Sharpe ED, Dubiner HB, Holmes KT, Stewart JA. Efficacy and safety of timolol solution once daily vs timolol gel added to latanoprost. Am J Ophthalmol. 1999;128:692–696. doi: 10.1016/S0002-9394(99)00237-8. [PubMed] [Cross Ref]
Petounis A, Mylopoulos N, Kandarakis A, Andreanos D, Dimitrakoulias N. Comparison of the additive intraocular pressure-lowering effect of latanoprost and dorzolamide when added to timolol in patients with open-angle glaucoma or ocular hypertension: a randomized, open-label, multicenter study in Greece. J Glaucoma. 2001;10:316–324. doi: 10.1097/00061198-200108000-00012. [PubMed] [Cross Ref]
Konstas AGP, Nakos E, Tersis I, Lallos NA, Leech JN, Stewart WC. A comparison of once-daily morning vs evening dosing of concomitant latanoprost/timolol. Am J Ophthalmol. 2002;133:753–757. doi: 10.1016/S0002-9394(02)01460-5. [PubMed] [Cross Ref]
Hopewell S, Altman DG, Moher D, Schulz KF. Endorsement of the CONSORT Statement by high impact factor medical journals: a survey of journal editors and journal 'Instructions to Authors'. Trials. 2008;9:20. doi: 10.1186/1745-6215-9-20. [PMC free article] [PubMed] [Cross Ref]
Devereaux PJ, Choi PT, El-Dika S, Bhandari M, Montori VM, Schünemann HJ, Garg AX, Busse JW, Heels-Ansdell D, Ghali WA, Manns BJ, Guyatt GH. An observational study found that authors of randomized controlled trials frequently use concealment of randomization and blinding, despite the failure to report these methods. J Clin Epidemiol. 2004;57:1232–1236. doi: 10.1016/j.jclinepi.2004.03.017. [PubMed] [Cross Ref]
Plint AC, Moher D, Morrison A, Schulz KF, Altman DG, Hill C, Gaboury I. Does the CONSORT checklist improve the quality of reports of randomized controlled trials: a systematic review. Medical Journal of Australia. 2006;185:263–267. [PubMed]
Wiens BL, Zhao W. The role of intention-to-treat in analysis of noninferiority studies. Clin Trials. 2007;4:286–291. doi: 10.1177/1740774507079443. [PubMed] [Cross Ref]
Mills E, Wu P, Gagnier J, Heels-Ansdell D, Montori VM. An analysis of general medical and specialist journals that endorse CONSORT found that reporting was not enforced consistently. J Clin Epidemol. 2005;58:662–667. doi: 10.1016/j.jclinepi.2005.01.004. [PubMed] [Cross Ref]
McNamee D, Horton R. Lies, damn lies, and reports of RCTs. Lancet. 1996;348:562. doi: 10.1016/S0140-6736(05)64795-2. [PubMed] [Cross Ref]
Kaufman R. The prostaglandin wars. Am J Ophthalmol. 2003;136:727–728. doi: 10.1016/S0002-9394(03)00658-5. [PubMed] [Cross Ref]
Eisenberg D. Randomized clinical trial comparing intraocular pressure-lowering efficacy of bimatoprost and latanoprost in patients with ocular hypertension or glaucoma. Am J Ophthalmol. 2003;136:217. doi: 10.1016/S0002-9394(03)00195-8. [PubMed] [Cross Ref]
Tinmouth JM, Steele LS, Tomlinson G, Glazier RH. Are claims of equivalency in digestive diseases trials supported by the evidence? Gastroenterol. 2004;126:1700–1710. doi: 10.1053/j.gastro.2004.03.005. [PubMed] [Cross Ref]
Krysan DJ, Kemper AR. Claims of equivalence in randomized controlled trials of the treatment of bacterial meningitis in children. Pediatr Infect Dis J. 2002;21:753–758. doi: 10.1097/00006454-200208000-00011. [PubMed] [Cross Ref]
Greene WL, Concato J, Feinstein AR. Claims of equivalence in medical research: are they supported by the evidence? Ann Intern Med. 2000;132:715–722. [PubMed]
McAlister FA, Sackett DL. Active-control equivalence trials and antihypertensive agents. Am J Med. 2001;111:553–558. doi: 10.1016/S0002-9343(01)00900-7. [PubMed] [Cross Ref]
Parienti JJ, Verdon R, Massari V. Methodological standards in non-inferiority AIDS trials: moving from adherence to compliance. BMC Med Res Methodol. 2006;6:46. doi: 10.1186/1471-2288-6-46. [PMC free article] [PubMed] [Cross Ref]
Weins BL. Choosing an equivalence limit for non-inferiority or equivalence studies. Control Clin Trials. 2002;23:2–14. doi: 10.1016/S0197-2456(01)00196-9. [PubMed] [Cross Ref]

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