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  • Published:

A systematic review of clinical trials of pharmacological interventions for acute ischaemic stroke (1955-2008) that were completed, but not published in full

Trialsvolume 11, Article number: 43 (2010) | Download Citation

Abstract

Background

We assessed the prevalence, and potential impact of, trials of pharmacological agents for acute stroke that were completed but not published in full. Failure to publish trial data is to be deprecated as it sets aside the altruism of participants' consent to be exposed to the risks of experimental interventions, potentially biases the assessment of the effects of therapies, and may lead to premature discontinuation of research into promising treatments.

Methods

We searched the Cochrane Stroke Group's Specialised Register of Trials in June 2008 for completed trials of pharmacological interventions for acute ischaemic stroke, and searched MEDLINE and EMBASE (January 2007 - March 2009) for references to recent full publications. We assessed trial completion status from trial reports, online trials registers and correspondence with experts.

Results

We identified 940 trials. Of these, 125 (19.6%, 95% confidence interval 16.5-22.6) were completed but not published in full by the point prevalence date. They included 16,058 participants (16 trials had over 300 participants each) and tested 89 different interventions. Twenty-two trials with a total of 4,251 participants reported the number of deaths. In these trials, 636/4251 (15.0%) died.

Conclusions

Our data suggest that, at the point prevalence date, a substantial body of evidence that was of relevance both to clinical practice in acute stroke and future research in the field was not published in full. Over 16,000 patients had given informed consent and were exposed to the risks of therapy. Responsibility for non-publication lies with investigators, but pharmaceutical companies, research ethics committees, journals and governments can all encourage the timely publication of trial data.

Open Peer Review reports

Background

Completing but not publishing clinical trials in full can be unethical[1]. Well designed clinical trials should be published because their results can benefit patients, justifying the risk to trial participants from experimental treatments[1]. Failing to publish clinical trials can bias the findings of systematic reviews and meta-analyses if their findings differ from published results[2] which may lead to inappropriate treatment decisions and health care policies[3].

Previous studies of unpublished clinical trials used small samples of clinical trials to estimate the prevalence of non-publication, including trial abstracts which were submitted to one conference over three years [4–6], trials submitted to a single research ethics committee[7, 8] or a single country's drug regulatory agency[9]. Limiting searches for published trials to databases[4, 8] may have missed full trial reports in non-indexed journals and books, leading such trials to be misclassified as unpublished. Also ongoing trials may have been misclassified as unpublished by failing to determine the status of clinical trials[4, 6, 9]. A systematic review which identified trials of acute ischaemic stroke only through reference lists of published Cochrane Stroke Group reviews found that 11% (19/178) had not been published in full as of December 31, 1999, although the trials had been reported in abstracts between two and 17 years before this date[10].

The Cochrane Stroke Group's Specialised Register of Trials is a very comprehensive database[11] which includes over 12,000 reports relating to around 6,000 stroke trials (Brenda Thomas, personal communication, June 2008). We used this register to perform a systematic review of clinical trials of pharmacological interventions for acute ischaemic stroke. We aimed to determine the prevalence of and characteristics of completed but unpublished trials.

Methods

Definition of 'unpublished'

We classified trials as unpublished if detailed methods and results were not reported in either a peer-reviewed journal article [8] or book chapter, i.e. not published in full. We considered forms of written information including abstracts, drug company reports, letters, literature reviews, and online trials registers to be less than full publications, which we term 'sources.' If it was unclear whether a trial had or had not been published from the titles of references, the trial source(s) were retrieved. We considered a study in the trials register to be unpublished if we could not match the details of study methods and results to any subsequent full publication.

Search strategy

One author (BT) searched the Cochrane Stroke Group's Specialised Register of Trials[12] on June 19th 2008 for trials of pharmacological interventions for acute ischaemic stroke. Another author (LG) screened the titles of references identified from the search of the register to select trials which appeared to be unpublished. We searched MEDLINE and EMBASE from January 2007 to March 2009 to check for recent publications of any trials which initially appeared to be unpublished. Duplicate trials were removed. There were no language restrictions.

Classification of trial completion status

We assigned a completion status of complete, ongoing, temporarily suspended, planned, never started or unclear to unpublished trials. We classified trials as complete if the most recent source reported results and gave no indication that these results were either interim or preliminary, or that patient recruitment or data analysis would continue. If the trial could not be classified as complete after reviewing the most recent source, we searched for the trial using the acronym or intervention on three online databases (Clinical trials.gov http://www.clinicaltrials.gov, The Internet Stroke Center http://www.strokecenter.org and Current Controlled Trials http://www.controlled-trials.com. Trials were classified as complete or ongoing depending on the status described by these databases. If completion status remained unknown, we attempted to contact investigators at least twice. If investigators did not reply by 31st December 2008, the trial completion status was classified as unclear.

Inclusion criteria

We included all completed randomised controlled trials (RCTs) and controlled clinical trials (CCTs) of pharmacological interventions for acute ischaemic stroke which were unpublished as of March 2009. Trials were labelled as RCTs if they stated that participants or groups of participants were randomly assigned to treatments. We assumed that trials that were described as either double-blind or placebo-controlled or both were randomised. Trials were labelled as CCTs if they stated that participants or groups of participants were allocated prospectively to different interventions using either a quasi-random method, or if no method was described[13]. We defined 'acute stroke' as a stroke assessed within 30 days of symptom onset. We excluded trials which included mixed populations of patients with acute and non-acute stroke unless they reported results for patients with acute stroke separately. Similarly, we excluded trials which included mixed populations of patients with ischaemic and haemorrhagic stroke unless they reported results for patients with ischaemic stroke separately. We excluded trials which did not describe a control group.

Data extraction

One author (LG) extracted data on trial designs, methods, and results. We recorded sample size, number of centres, type of intervention, comparison groups, method of randomisation, blinding procedures, and allocation concealment for each trial. If details were unclear, trial sources were referred to a second author (PS and/or MB). We classified trials as single or multi-centre according to descriptions provided by investigators. If such descriptions were not available, we noted investigators' institutional affiliations and arbitrarily classified trials with one affiliated hospital or clinic as single centre, and trials with more than one affiliated hospital or clinic as multi-centre, accepting that in rare instances, investigators from multiple hospitals or clinics would participate but only one centre would be responsible for recruiting patients.

We extracted all available data on treatment effects on clinical outcomes (e.g. death, death or dependency and adverse effects) and on non-clinical outcomes (e.g. physiological variables or laboratory measures of uncertain clinical significance). We classified results as qualitative or quantitative and noted whether statistical significance was reported. We extracted data on the most important clinical outcome reported, such as death or functional scales, from the most recent source. In the absence of data on death or dependency, we extracted data on the studies' pre-defined primary outcome. If no primary outcome was defined, we extracted data on the first outcome described in the methods.

We classified the reported effects of interventions as beneficial, harmful, or neutral based on statistical significance, or percentages of participants having a particular outcome if statistical data were not available. We defined trials as beneficial if the intervention was reported to have had a favourable effect compared with the control treatment; as harmful if the treatment effect was adverse; and neutral if no differences were reported between intervention and control groups. Where only quantitative results were available but statistical data were not provided, we classified trials as neutral only if the results were exactly the same for each intervention group. Where results were available for different time points, we recorded only the latest time point. We classified results as 'unable to analyse' if results were not reported separately for each intervention group.

We also extracted data on the number and type of sources reporting a trial, the investigators, country of origin, funding, and date of the latest source. If an investigator appeared to have been involved in multiple completed but unpublished trials, we cross-referenced their institutional affiliation in the sources for the different trials. We contacted investigators if it was still unclear whether they had been involved in multiple trials. We used the institutional affiliation of the first investigator of the latest source to determine the country of origin of each trial. We classified trials as receiving funding from pharmaceutical companies when this was explicitly stated in a source or if any of the investigators were affiliated to a pharmaceutical company.

If any of these data could not be extracted from the most recent source, we checked earlier sources. If data were still not available, they were classified as not reported.

Calculating the prevalence of unpublished studies

We did not have the resources to fully check the eligibility of each of the published studies. We therefore estimated the proportion that would not meet all our eligibility criteria by assessing in detail a random 20% sample of the published studies. We listed published studies by date of most recent publication, and used random.org [14] to select 20% of studies in each of the following date ranges: 1980-1984, 1985-1989, 1990-1994, 1995-1999, 2000-2004, 2005-2009, pre-1980 and unknown date. The percentage of published studies which otherwise met the inclusion criteria (which we term 'eligible published studies') was calculated and applied to the entire list of published studies. To calculate the point prevalence of unpublished studies, we divided the number of unpublished studies by the sum of the number of unpublished studies and the number of eligible published studies. We used the normal approximation method to calculate 95% confidence intervals (CI) [15].

Results

The prevalence of completed but unpublished trials

The search identified 940 trials of pharmacological interventions for acute ischaemic stroke of which 125 [16–130] (Castillo J: Cooling therapy for acute stroke, unpublished, Chen O: Batroxobin (DF-521) in the treatment of acute cerebral infarction, unpublished, Egberts JFM, Sommer W: Multicentre, randomised, assessor-blind, dose-comparative study of org 10172 (orgaron (r)) in the treatment of acute ischaemic stroke, unpublished, Garcia Tigera J, Avarez LG, Hernandez MO: Treatment with calcium channels blockers (nifedipine) of patients with acute brain infarction, unpublished, Geeganage C, Bath PMW: An assessment of the effects of altering blood pressure on cerebral and systemic haemodynamics in patients with acute ischaemic stroke, unpublished, UCB Pharma: Piracetam vs placebo in the acute treatment of acute ischaemic supratentorial cerebrovascular accidents: pilot study, unpublished, Bath P: Dose escalation study of dobutamine in acute stroke patients, unpublished, Utsumi H: Evaluation of the use of ticlopidine, an antiplatelet agent, in acute cerebral infarction, unpublished) were complete but unpublished by March 23rd 2009 and were included in this review (Figure 1). Note that two of the references to the 125 included trials reported two trials each. Our sample of 20% of the published studies identified 21/124 (16.9%) which failed to meet inclusion criteria. Two studies did not test pharmacological interventions, three studies did not involve patients with acute stroke, four did not test interventions for stroke (one study was a secondary prevention trial and three investigated treatment for deep vein thrombosis in patients with stroke), and the remaining 12 studies did not appear to be either CCTs or RCTs. Assuming 16.9% of published studies were ineligible, we estimate that of the 618 published studies, 104 were ineligible published studies and 514 were eligible published studies. The point prevalence of unpublished studies was 19.6% (125/(125+514), 95% CI 16.5-22.6%).

Figure 1
figure1

Trials flowchart.

Full size image

Available data on design of unpublished trials

Of these 125 trials, 112 (89.6%) provided the number of enrolled patients with acute ischaemic stroke (16,058 patients) on whom 89 different pharmacological interventions were tested (Figure 2).

Figure 2
figure2

Actual sample sizes of completed but unpublished trials.

Full size image

Amongst the 112 trials that provided the number of participants, the mean sample size was 143.4. Two trials included fewer than 10 patients each, and the largest trial included 856 patients (See Additional file 1: Trials which included 100 or more patients). Seventy-two trials included 99 patients or fewer, and 40 trials included 100 patients or more, of which eight trials included over 500 patients. Seventy-three trials reported the number of patients in each treatment group, giving a mean of 60.6 participants per group, with a mode of 2 groups per trial. There were 50 (40.0%) multi-centre trials and 55 (44.0%) single centre trials. We could not determine the number of centres for 20 (16.0%) trials.

Each of the 89 different interventions was investigated by a mean of 1.4 trials (range 1-4, mode 1). Arundic acid, also known as ONO-2506, was investigated by four trials. Seven interventions were investigated by three trials each (cerebrolysin, emoxipin, GM1, insulin, low molecular weight heparin, piclozotan, and piracetam). The 40 trials which included over 100 patients investigated 34 different interventions, with five interventions being tested by two trials each (arundic acid/ONO-2506, eliprodil, GM1, heparin, and piracetam).

Sixty-seven (53.6%) trials were placebo-controlled, of which 23 recruited over 100 patients. The remaining trials used either open controls (n = 29, 23.2%), or the controls received another drug (n = 28, 22.4%). One trial initially stated that controls received placebo and later reported that they received 'conventional treatment' within the only available source.

Details on randomisation, blinding procedures, and allocation concealment methods were often insufficient. Only seven (5.6%) trials - three trials involving over 100 patients - reported the method of randomisation or the allocation to intervention groups. Sixty-eight (54.4%) trials reported their blinding procedures: 10 (8.0%) were single-blind and the remaining 58 (46.4%) were double-blind. Of the 40 trials which recruited over 100 patients, three (7.5%) were single-blind and 21 (52.5%) were double-blind. Just four (3.2%) trials, two of which recruited over 100 patients, reported the method of allocation concealment (See Additional file 1: Trials which included 100 or more patients). Only 29 (23.2%) trials reported the trial phase (mode phase II, range I-III).

Available data on results of unpublished trials

Of the 125 included trials, 98 (78.4%) trials reported some outcomes. Only 22 (17.6%) trials reported deaths, having recruited 4,251 patients of whom 636 (15.0%) died. Only 6 (4.8%) trials reported the number of patients who either died or became dependent, with a total of 663 dead or dependent patients.

Adverse effects were observed in 40 (32.0%) trials, in 11 (8.8%) trials no adverse effects were noted, and 54 (43.2%) did not provide information on adverse effects. The remaining 20 (16.0%) trials did not provide findings.

We were able to extract data on outcomes reported at the end of the study period for 101 (80.8%) trials. Four (3.2%) trials reported only interim results and 20 (16.0%) trials did not provide any outcome data. Five of the 105 trials which reported outcomes did not provide results according to intervention group, leaving 100 trials with potentially analysable results (Table 1) of which 99 provided information on outcome measures. The overall findings of the European Eliprodil trial were only reported in the medical press without details of the outcomes measured in the trial[131].

Table 1 Characteristics of available data in completed but unpublished trials*
Full size table

Available data on other characteristics of unpublished trials

Investigators

We noted 551 different investigators as authors of completed but unpublished trials. The mean number of investigators per trial was 5.3 (range 0-18, mode 1). Two trials were investigated by a named group, and the number of investigators for these two trials was classified as 0. Seventy-two different investigators were authors of multiple trials (three were authors of four separate unpublished trials each).

Country of origin

Completed but unpublished trials were performed by investigators based in 23 different countries (Figure 3).

Figure 3
figure3

Country of origin of completed but unpublished trials. Country of origin was determined from the institutional affiliation of the first investigators listed in the most recent source from each trial.

Full size image

Only 43 (34.4%) trials reported their source of funding. Thirty-nine trials were funded by pharmaceutical companies and four by other agencies.

Sources of information about unpublished trials

Data from unpublished trials was obtained from 238 sources, including 160 (67.2%) abstracts and 78 (32.8%) non-abstract sources such as press releases, letters to editors, protocols, correspondence with investigators, correspondence between investigators and ethics committees, online trials registers, pharmaceutical company reports, and university websites. The mean number of sources per trial was 1.9 (range 1-6, mode 1) with a mean of 1.3 (range 0-5, mode 1) abstracts per trial and a mean of 0.6 (range 0-4 mode 0) non-abstract sources per trial. Fifteen trials were not reported in abstracts. Five trials were identified through online trials registers alone.

Dates of most recent report from each unpublished trial

The number of completed but unpublished trials has increased steadily (Figure 4).

Figure 4
figure4

Year of most recent report from completed but unpublished trials. Only 123 trials are included in the figure as we were not able to determine the date of the most recent report for two trials.

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Discussion

Key findings

We have demonstrated that an important minority of completed clinical trials are not reported in full, several of which may be large enough to influence clinical practice and the findings of systematic reviews and meta-analyses.

Prevalence of completed but unpublished trials in other studies

Estimates of completed but unpublished trials in a range of medical fields are much higher than the estimate of this review of acute stroke trials (19.6%). It is difficult to judge if the results of this review of trials in acute stroke are representative of publication practices in other areas of the medical literature (other studies on this question are limited), but we are not aware of any reasons to expect that they would be substantially different. Blumle and colleagues[7] found that 47.6% (49/103) of trials submitted to a German research ethics committee (REC) in 2000 were not published by 2007[7]. Peinemann and colleagues[132] identified 13 trials of negative pressure wound therapy, a type of wound dressing, of which four (30.8%) were unpublished[132]. The difference between estimates may be explained by the small sampling frames used in these studies compared to our review. We used the Cochrane Stroke Group's Specialised Register of Trials, an extremely large collection of stroke trials[11] as the sampling frame. It is the result of a comprehensive search strategy which includes bibliographic databases, trial registry websites, hand-searching of journals, conference proceedings, press releases, correspondence with investigators and information from pharmaceutical companies[12]. There are no language restrictions in the Register which has minimised the risk of selection bias.

Our findings are further strengthened by the system we used to determine the completion status of trials. Previous studies failed to determine completion status of trials so ongoing trials may have been misclassified as unpublished[4, 6, 9]. Using trial sources, online registers, consultation with an expert and contacting investigators as a last resort, enabled us to determine the completion status of 165 of the 184 trials which met the inclusion criteria.

We identified 40 completed but unpublished trials which had each involved over 100 patients, with eight including over 500 patients each. Large trials are given more weight in meta-analyses, and have greater potential to change clinical practice[133]. The assessment of trial methodological features (e.g. sample size, methods of randomisation, blinding procedures, allocation concealment) is required to decide whether a trial is of sufficient quality for inclusion in a systematic review, meta-analysis, or clinical practice guideline[133, 134], but few trials reported sufficient study details to allow methodological quality to be assessed.

How can authors be encouraged to publish trials more fully? The implications of this review

Initiatives to encourage investigators to disclose unpublished trials have been unsuccessful. Only 165 brief reports of unpublished trials had been submitted to the Medical Editors' Trials Amnesty after one year[135]. A survey of over 40,000 obstetricians revealed just 18 unpublished trials which had been completed at least 2 years previously[136].

RECs, journals and government could help to encourage investigators to publish clinical trials [137–139]. In the UK, it is recommended that RECs require investigators to declare their intent to publish, but it is not yet mandatory (Hugh Davies, unpublished data, 2008). RECs could act at three different stages of clinical trials to encourage publication of the results. Firstly, RECs could require investigators to intend to publish the results[137] when the trial is submitted for ethical approval. Secondly, as RECs currently require investigators to outline a plan of research dissemination [140], they could also request regular updates on the progress of publication after trial completion. Finally, RECs could elicit investigators' reasons for failing to publish results[137] if trials have not reached the public domain within a reasonable time.

Journals have taken steps to encourage investigators to submit reports of trials. Cancer Epidemiology, Biomarkers and Prevention created a section entitled 'Null Results in Brief'[141]. The journal Pediatrics announced that publication of a trial protocol would come with a provisional acceptance of the complete trial report for publication[138]. Journals dedicated to publishing null results now exist, including the Journal of Negative Results in Biomedicine[142]. Established journals could create sections for short reports of trials with null results, and with the development of online publishing, creating space for additional publications has become less of an issue[139].

Prospective registration of clinical trials may help to hold investigators to account for publishing results[139]. Only five trials were identified using online registers alone, suggesting that currently, prospective registration can assist in indentifying unpublished trials, but should not be used as the primary method of locating unpublished trials. Although the CONSORT statement supports prospective trial registration[143], and many journals have become signatories to the statement[144], it is not clear how often journals use prior registration of a trial as a pre-requisite for publication of the results paper. Chalmers suggests that government regulation is also required to improve the reporting of clinical trials[145]. In March 2008, the National Research Ethics Committee, the James Lind Alliance, and the Department of Health announced a joint project called 'Mind the Gap' (Linda Burridge, unpublished data, 2008) with the International Standard Randomised Controlled Trials Number Register and clinicaltrials.gov to improve the completeness of clinical trial registration, and to improve the dissemination of trial results[146]. The project is due to be completed by the end of 2008[146]. Both Italy and America have made comprehensive information on clinical trials publicly accessible[146, 147]. Registration of clinical trials investigating drugs and devices subject to approval from the Food and Drug Administration and reporting of basic results online has been a legal requirement in the United States since 2007 [147], but the governments of other countries could follow suit in an international effort to reduce non-publication of clinical trials.

Limitations

We were unable to determine the status of 19 trials and some may be completed but not published. The status of some trials may have been misclassified if the online trials registers were not up to date. We used the online registers to classify the status of 8 included trials, so any misclassification through using these registers is minimal. Also, the number of centres of some trials may have been misclassified.

We may have overestimated the prevalence of unpublished trials by including trials which were completed within the last three years and trials with very small sample sizes (two trials included fewer than ten patients each). It may be unreasonable to expect such trials to be published. We included all trials completed up to March 2009, and reported point prevalence, as there are now opportunities simultaneously to present trials at conferences and publish them in a journal. The estimates of the proportion of patients who died, were dead or dependent and who suffered adverse effects are of interest, but may not be reliable as the sources available to us rarely reported these data.

Conclusions

In this review, 19.6% of the clinical trials identified from the register were completed but not published in full. These data represent a substantial body of evidence that is of relevance both to clinical practice in acute stroke and to future research in the field, yet is not fully publicly available. Responsibility for non-publication lies with investigators, but pharmaceutical companies, research ethics committees, journals and governments can all play a part in ensuring that the results of RCTs are made publicly available within a reasonable interval of trial completion.

Authors' Information

Lorna Gibson is a medical student at the University of Edinburgh, this work was undertaken as part of her curriculum. Miriam Brazzelli has a Research Training Fellowship in Health Services Research, University of Edinburgh, funded by the Scottish Executive Health Department Chief Scientist Office. Brenda Thomas is the Information Scientist and Trial Search Co-ordinator for the Cochrane Stroke Group. Peter Sandercock is a neurologist with an interest in stroke and is the Co-ordinating Editor of the Cochrane Stroke Group.

Abbreviations

BD:

Twice daily

CCT:

Controlled clinical trial

FISS-bis:

Fraxiparine in ischaemic stroke study

GM1:

Monosialotetrahexosylganglioside

IV:

Intravenous

LMWH:

Low molecular weight heparin

MRECT:

Modified randomized exposure controlled trial

MRS:

Modified Rankin Scale

NIHSS:

National Institutes of Health Stroke Scale

OD:

Once daily

PASS II:

Piracetam acute stroke study II

PRISTINE:

Praxilene in stroke treatment in northern Europe

RANTTAS II:

Randomized trial of high dose tirilazad in acute stroke

RCT:

Randomised controlled trial

REC:

Research ethics committee

RREACT:

Rapid response with an astrocyte modulator for the treatment of acute cortical stroke

SC:

Subcutaneous

SIST:

Sipatrigine in Stroke Trial

TNK-TPA:

Tenecteplase - tissue plasminogen activator

tPA:

Tissue plasminogen activator

UK:

United Kingdom

USA:

United States of America.

References

  1. 1.

    Moher D: Publication bias. Lancet. 1993, 342: 1116-

  2. 2.

    Egger M, Smith GD: Misleading meta-analysis. BMJ. 1995, 311: 753-754.

  3. 3.

    Easterbrook PJ, Berlin JA, Gopalan R, Matthews DR: Publication bias in clinical research. Lancet. 1991, 337: 867-872. 10.1016/0140-6736(91)90201-Y.

  4. 4.

    Klassen TP, Wiebe N, Russell K, Stevens K, Hartling L, Craig WR, Moher D: Abstracts of randomized controlled trials presented at the society for pediatric research meeting: an example of publication bias. Arch Pediatr Adolesc Med. 2002, 156: 474-479.

  5. 5.

    Timmer A, Hilsden RJ, Cole J, Hailey D, Sutherland LR: Publication bias in gastroenterological research - a retrospective cohort study based on abstracts submitted to a scientific meeting. BMC Med Res Methodol. 2002, 2: 7-10.1186/1471-2288-2-7.

  6. 6.

    Toma M, McAlister FA, Bialy L, Adams D, Vandermeer B, Armstrong PW: Transition from meeting abstract to full-length journal article for randomized controlled trials. JAMA. 2006, 295: 281-1287. 10.1001/jama.295.11.1281.

  7. 7.

    Blumle A, Antes G, Schumacher M, Just H, von Elm E: Clinical research projects at a German medical faculty: follow-up from ethical approval to publication and citation by others. J Med Ethics. 2008, 34: e20-10.1136/jme.2008.024521.

  8. 8.

    von Elm E, Rollin A, Blumle A, Huwiler K, Witschi M, Egger M: Publication and non-publication of clinical trials: longitudinal study of applications submitted to a research ethics committee. Swiss Med Wkly. 2008, 138: 197-203.

  9. 9.

    Melander H, Ahlqvist-Rastad J, Meijer G, Beermann B: Evidence b(i)ased medicine - selective reporting from studies sponsored by pharmaceutical industry: review of studies in new drug applications. BMJ. 2003, 326: 1171-1173. 10.1136/bmj.326.7400.1171.

  10. 10.

    Liebeskind DS, Kidwell CS, Sayre JW, Saver JL: Evidence of publication bias in reporting acute stroke clinical trials. Neurology. 2006, 67: 973-979. 10.1212/01.wnl.0000237331.16541.ac.

  11. 11.

    Thomas B, Mclnnes A: [O33] The Cochrane Stroke Group's Specialised Register of Trials: A Comprehensive and Unique Resource for Reviewers. Cochrane Colloquium Proceedings: 5-9. 1999, October ; Rome

  12. 12.

    Sandercock P, Algra A, Anderson C, Bereczki D, Berge E, Bowen A: Cochrane Stroke Group. About The Cochrane Collaboration (Cochrane Review Groups (CRGs)). 2009, Art. No.: STROKE, 2

  13. 13.

    Learning to identify and classify reports of controlled trials in healthcare journals. http://apps1.jhsph.edu/cochrane/srch.htm

  14. 14.

    True random number service. http://www.random.org

  15. 15.

    Gardner MJ, Altman DG: Calculating confidence intervals for proportions and their differences. Statistics with confidence: confidence intervals and statistical guidelines. Edited by: Gardner MJ, Altman DG. 1989, London: BMJ, 28-33. 1

  16. 16.

    TUCSON: Safety study of microbubbles with transcranial ultrasound and tPA in the management of acute ischemic stroke. http://www.strokecenter.org/trials/

  17. 17.

    Alvarez-Sabin J, Chacon P, Molina CA, Arenillas JF, Ribo M, Fernandez-Cadenas I, Rosall A, Penalba A, Pujadas F, Montaner J: Triflusal is superior to aspirin suppressing the inflammatory response that follows ischemic attack [abstract]. Cerebrovasc Dis. 2004, 17: s109-

  18. 18.

    ARTIST+. http://www.strokecenter.org/trials/

  19. 19.

    ARTIST MRI. http://www.strokecenter.org/trials/

  20. 20.

    Orgogozo JM, Massey D, Whitehead J, Lataste X: Prediction of functional recovery after middle cerebral artery infarction [abstract]. Cerebrovasc Dis. 1994, 4: 242-10.1016/S1052-3057(10)80099-0.

  21. 21.

    Awadh MMM, Ali S, Sherif MA, Afify H, Aref H, Moustafa R, Abdulghani O: Large-dose loading clopidogrel is well tolerated in ischaemic stroke up to 24 hours from onset. Proceedings of the UK Stroke Forum Conference: 4-6. 2007, December ; Harrogate

  22. 22.

    Schabitz WR, Laage R, Schwab S, Schneider D, Hamann G, Rosenkranz M: AX200 (G-CSF) for the treatment of acute ischemic stroke (AXIS) [abstract]. Stroke. 2008, 39: 561-

  23. 23.

    Balkuv-Ulutin S, Hacihanefioglu M, Ulutin ON: Clinical and laboratory results obtained with defibrotide in the cases of acute stroke [abstract]. Thromb Haemost. 1989, 62: 585-

  24. 24.

    Combined aspirin, clopidogrel and dipyridamole versus aspirin alone in acute stroke; a safety, tolerability and feasibility study. https://portal.nihr.ac.uk/Profiles/NRR.aspx?Publication_ID=N0170106720

  25. 25.

    Bergamasco B, Gentile S, Tarenzi L, Scarzella L: Cyticholine in acute ischemic stroke: results of a controlled multicentric double blind study [abstract]. Electroencephalogr Clin Neurophysiol. 1986, 64: 98P-

  26. 26.

    Bo W, Ming L, Song T: A randomized controlled trial of ligustrazine for acute ischemic stroke [abstract]. J Neurol Sci. 2005, 238: s415-

  27. 27.

    The SaTIS Investigators: Safety of tirofiban in acute ischemic stroke (SaTIS) [abstract]. Cerebrovasc Dis. 2006, 21: s60-10.1159/000090004.

  28. 28.

    Caille JM, Bidabe AM, Dartigues JF, Pere JJ, Orgogozo JM: Action of an anti-aldosterone agent on ischemic cerebral oedema. A randomised therapeutic trial [abstract]. Neuroradiology. 1982, 22: 272-

  29. 29.

    Chandra B: Neuroprotective drugs in the treatment of acute ischemic stroke. J Stroke Cerebrovasc Dis. 1997, 6: 453-10.1016/S1052-3057(97)80116-4.

  30. 30.

    ROSIE-CT: ReoPro retavase reperfusion of stroke safety study - imaging evaluation with computed tomography. http://www.strokecenter.org/trials/

  31. 31.

    Chen W-H, Lien L-M, Fang S-C, Chiu H-C: Low molecular weight heparin for acute ischemic stroke. Annual Meeting of Taiwan Stroke Society: 22-23. 2003, March ; Taipei

  32. 32.

    Clark WM, Coull BM: Randomised trial of CGS19755 a glutamate antagonist, in acute ischaemic stroke treatment [abstract]. Neurology. 1944, 44: A270-

  33. 33.

    Fiblast Phase 3: European-Australian Fiblast (Trafermin) in acute stroke. http://www.strokecenter.org/trials/

  34. 34.

    Block GA, 1102-003 Study Group: Final results from a dose-escalating safety and tolerance study of the non-competitive NMDA antagonist CNS 1102 in patients with acute cerebral ischemia [abstract]. Stroke. 1995, 26: 185-

  35. 35.

    Cuparnecu B: Efficacy of cerebrolysin in patients with ischaemic stroke of the middle cerebral artery [abstract]. Pharmacol Toxicol. 2001, 89: s136-

  36. 36.

    Dan G-A, Gonta A, Serbanescu A, Ionete C: Improvement of outcome in patients with acute ischaemic stroke treated with fragmin. Proceedings of the 7th International Symposium on Thromboembolic Diseases: 9-10 June 2000; Palma de Mallorca. Haemostasis. Edited by: Haas S, Marder VJ, Samama M-M. 2000, 30: 168-169.

  37. 37.

    Davalos EA, de Cendra E, Genis D, Teruel J, Ruibal A, Musoles S: Double blind controlled trial of nicardipine versus placebo in the treatment of the acute phase of cerebral infarction [abstract]. Neurologia. 1992, 7: 157-

  38. 38.

    Defer G, Cesaro P, Moretti JL, Cinotti L, Degos JD: The cerebral effect of one-week intravenous administration of nicergoline in stroke patients: a SPECT study [abstract]. J Neurol. 1988, 235: s84-

  39. 39.

    Delwaide PJ, de Pasqua V, Lehert P, D'Hooge R: Naftidrofuryl and quantified EEG of patients with ischemic stroke. A double-blind controlled trial [abstract]. J Stroke Cerebrovasc Dis. 1992, 2: s111-

  40. 40.

    Dib H, Horozoglu H, Afsar N, Ekinci G, Aktan S: The effect of statins on infarct size and prognosis [abstract]. Cerebrovasc Dis. 2006, 21: s146-

  41. 41.

    Mori E, Takakura K, Yamaguchi T, Terashi A, Saito I, Shinohara Y, Kikuchi H, Tanikawa T, Kobayashi S, Kobayashi N, Machida T: Multicenter trial of a novel modified t-PA, E6010 by iv bolus injection in patients with acute carotid artery territory stroke [abstract]. Cerebrovasc Dis. 1996, 6: 191-

  42. 42.

    Zimmerman TR, Kidwell CS, Fisher M, Fiebach JB, Davalos A, Cheung Y-K, Arima K: Piclozotan (SUN N4057) in patients with acute ischemic stroke and MRI penumbra: a double-blind placebo-controlled multicenter study - the EPIC trial. Proceedings of the 15th European Stroke Conference: 16-19. 2006, May ; Brussels

  43. 43.

    Fisher M: Eliprodil [abstract]. Cerebrovasc Dis. 1996, 6: 189-

  44. 44.

    ROSIE: ReoPro retevase reperfusion of stroke safety study - imaging evaluation. http://www.strokecenter.org/trials/

  45. 45.

    Fayad P, Caplik J, Culligan N, Edwards K, Maisel J, Moonis M, Newman G, Srinivas N, Wirkowski E, Bozik M: Safety, tolerability, and pharmacokinetics of intravenous BMS-204352: a novel maxi-K channel opener, in patients up to 48 hours after acute ischemic stroke [abstract]. Cerebrovasc Dis. 2000, 10: s71-

  46. 46.

    The FIBLAST Safety Study Group: Clinical safety trial of intravenous basic fibroblast growth factor (bFGF, FIBLAST) in acute stroke [abstract]. Stroke. 1998, 29: 287-

  47. 47.

    Hommel M: Fraxiparine in ischaemic stroke study (FISS bis) [abstract]. Cerebrovasc Dis. 1998, 8: s19-10.1159/000047514.

  48. 48.

    Fogari R, Pasotti C, Zoppi A, Corradi L, Mugellini A, Preti P, Derosa G, Rinaldi A: Effect of perindopril and atenolol on plasma PAI-1 in hypertensive patients with acute ischemic stroke [abstract]. Stroke. 2003, 34: 309-

  49. 49.

    Galeas T, Contos T, Exarhos P, Galea V, Valotasiou B: The role of magnesium (Mg) a natural calcium (Ca) antagonist in the treatment of acute ischemic stroke (AIS) (clinical study) [abstract]. Cerebrovasc Dis. 1999, 9: s102-10.1159/000015906.

  50. 50.

    Garcia Pastor A, Diaz OF, Gil Nunez AC, Villanueva Osorio JA: Tolerability and efficacy of the combination of piracetam and citicoline in acute ischemic stroke. A randomized comparative open study [abstract]. Stroke. 2004, 35: e286-

  51. 51.

    Garcia Tigera J, Martinez DR: Levamisol, a new treatment for cerebral infarction [abstract]. J Neurol. 1994, 241: s162-

  52. 52.

    Study of ONO-2506 in patients with acute ischemic stroke. http://www.clinicaltrials.gov/ct2/show/NCT00229177?term=ONO-2506%26rank=1

  53. 53.

    MITI-IV: Intravenous administration of microplasmin for treatment of acute ischemic stroke. http://www.strokecenter.org/trials/

  54. 54.

    Giroux C, Rosen P, Scatton B: Preclinical, pharmacology and clinical safety profile of eliprodil, an atypical NMDA receptor antagonist. Pharmacology of Cerebral Ischemia 1994. Edited by: Krieglstein J, Oberpichler-Schwenk H. 1994, Stuttgart: Wissenschaftliche Verglagsgesellschaft, 643-648.

  55. 55.

    Guillen F, Buendia C, Herrera J: CDP-choline in the treatment of acute ischaemic stroke [abstract]. J Neurol. 1995, 242: s76-

  56. 56.

    Gusev EI, Skvortsova VI, Komissarova IA: Glycine in therapy of acute ischemic stroke [abstract]. Eur J Neurol. 1997, 4: s78-

  57. 57.

    Cerebrolysin in acute ischemic stroke. http://www.strokecenter.org/trials/

  58. 58.

    HALT: Hu23F2G phase 3 stroke trial. http://www.strokecenter.org/trials/

  59. 59.

    Hamamoto M, Nagao T, Kanda A, Ichiseki H, Miyazaki T, Terashi A: Hypervolemic hemodilution therapy for the elderly patients with atherothrombotic and hemodynamic ischemic stroke [abstract]. J Stroke Cerebrovasc Dis. 1992, 2: s136-10.1016/S1052-3057(10)80222-8.

  60. 60.

    Oral aspirin vs intravenous heparin for acute ischemic stroke progression. http://www.strokecenter.org/trials/

  61. 61.

    Hernandez Fustes O, Macarini L, Munhoz R, Panfilio C, Moreira A, Arteaga C: Evaluation of the neuroprotection with citicolina in the treatment of the acute cerebral infarct [abstract]. J Neurol Sci. 2005, 238: s399-

  62. 62.

    Huang P, Li XH, Qiao LJ: A study on the changes in plasma coagulative, anticoagulative, fibrinolytic activities in patients with cerebral infarction treated with low molecular weight heparin [abstract]. Hong Kong Med J. 2001, 7: 24-

  63. 63.

    Iannuzzi NP, Liebeskind DS, Jacoby M, Arima K, Shimizu K, Zimmerman TR: Piclozotan (SUN N4057), a novel 5HT1A receptor antagonist, is well tolerated in patients with acute stroke [abstract]. Stroke. 2006, 37: 655-

  64. 64.

    Jamieson DG, Reivich M, Alves W, Fazekas F, Kushner M, Chawluk J, Blackman D, Silver F, Alavi A: The effect of ganglioside (GM1) treatment in acute ischemic infarction: a positron emission tomography study [abstract]. J Cereb Blood Flow Metab. 1989, 9: s602-

  65. 65.

    Ji S, Liu Y, Li T, Ma M: Effect observation of shuxuetong on nervous function defect of cerebral infarction. Chin J Clin Rehabil. 2003, 7: 866-867.

  66. 66.

    Khrapova E, Chukhrova V, Kistenev B: Antioxidant emoxypine in complex treatment of patients with acute ischemic stroke [abstract]. Eur J Neurol. 1998, 5: s40-

  67. 67.

    Kistenev B, Suslina Z, Maksimov M, Geraskina L: Clinical effects of antioxidant therapy in patients with acute cerebral infarction. III South American Conference on Cerebrovascular Diseases: 15-18. 1994, June ; Buenos Aires

  68. 68.

    Konta Y, Aizu K, Fuziwara K, Matsui T: Evaluation of intravenous urokinase, ozagrel sodium and low molecular dextran therapy in acute ischemic stroke - comparison of infusion methods of urokinase [abstract]. Cerebrovasc Dis. 1996, 6: 187-

  69. 69.

    Kopa J, Radai F: A new combination of neuroprotective drugs in the therapy of acute ischemic stroke (comparative study) [abstract]. Stroke. 2000, 31: 2840-

  70. 70.

    Staszewski J, Kotowicz J, Swistak J, Stepien A: Intravenous insulin therapy in maintenance of euglycemia in nondiabetic acute stroke patients [abstract]. Cerebrovasc Dis. 2005, 19: s66-

  71. 71.

    Kovacevic MS, Mrsulja BB, Bumbasirevic LJ, Jovanovic D, Zidverc J, Bugarski C, Dodic A, Pecic O: Acute nonhemorrhagic stroke: neurological and biochemical study [abstract]. J Stroke Cerebrovasc Dis. 1992, 2: s90-

  72. 72.

    Kwiecinski H, Pniewski J, Kaminska A, Szyluk B: A randomized trial of fraxiparine in acute ischemic stroke [abstract]. Cerebrovasc Dis. 1995, 5: 234-

  73. 73.

    Lee JH, Seo DC, Kim JS, Lee MC: Therapeutic efficacy of urokinase and heparin in acute ischaemic stroke [abstract]. Stroke. 1994, 25: 268-

  74. 74.

    Li CY: Influence of ligustrazine in acute cerebral thrombosis [abstract]. Chinese Journal of Neurology & Psychiatry. 1986, 19: 386-

  75. 75.

    Li BXY, Lang S, Zhang Z, Dong Q, Zhu K, Zhang Z: Defibrase for the treatment of acute ischemic stroke [abstract]. Circulation. 1999, 100: sI-36.

  76. 76.

    Li C, Wang L, Dong W, Hu C: Fractal dimension of heart rate variability: a useful marker to predict the sudden unexpected death in patients with stroke. Proceedings of the 4th International Conference on Research Advances in Cerebrovascular Disease: 13-15. 2003, October ; Chengdu

  77. 77.

    Dong Q, Lu C-Z, Zhen H-M: Low-molecular-weight heparin for the treatment of acute ischemic stroke: a randomized controlled trial [abstract]. Neurology. 2003, 60: A228-

  78. 78.

    Lu XR, Mi ZZ, Yuan XD: Study of correlation between times of a disease and plasma fibrinogen molecular reactivity in patients with acute cerebral infarction [abstract]. Hong Kong Med J. 2001, 7: s42-

  79. 79.

    Luo ZM, Yang L: A randomized controlled clinical trial of MgSO4 plus cyclophophamide and colchicine in patients suffered from acute cerebral infarction [abstract]. Hong Kong Med J. 2001, 7: 23-

  80. 80.

    Luo Z, Zeng X, Chen H, Liu L, He L, Yuan G: Anti-inflammatory cell therapy for cerebral ischemic stroke in rats and patients. Proceedings of the 4th International Conference on Research Advances in Cerebrovascular Disease: 13-15. 2003, October ; Chengdu

  81. 81.

    Maksimova M, Kistenev B, Khrapova E, Geraskina L, Smirnova I: Comparative analysis of the clinical efficiency of ischaemic stroke therapy [abstract]. Int Angiol. 1995, 14: s181-

  82. 82.

    Mazagri R, Shuaib A, McPherson M, Deighton M: Amphetamine failed to improve motor function in acute stroke [abstract]. Can J Neurol Sci. 1995, 22: s25-

  83. 83.

    McCormick M, McLean JR, Condon B, Hadley D, Muir KW: Randomized controlled trial of insulin in hyperglycemia: lesion volume progression depends on vessel recanalization [abstract]. Stroke. 2007, 38: 505-

  84. 84.

    Metoki N, Konta Y, Baba Y, Okuguchi T, Matsui T, Fukuda M, Satoh K, Okumura K: Efficacy of combined therapy with ozagrel sodium and edaravone in patients with acute cerebral thrombosis [abstract]. Stroke. 2004, 35: e214-

  85. 85.

    Mihout B, Malberin M, Salzman V, Guez D, Bogousslavsky J: Effect of almitrine-raubasine combination on functional recovery in patients with ischemic stroke [abstract]. J Neurol. 1994, 241: s78-

  86. 86.

    Monaco P, Pastore L, Cottone A, Conti S: Effect of treatment with monosialotetraesosil-ganglioside (GM1) on neurological impairment in the acute and post-acute phases of the ischemic stroke [abstract]. J Stroke Cerebrovasc Dis. 1992, 2: s119-10.1016/S1052-3057(10)80333-7.

  87. 87.

    Moriwaki H, Nagatsuka K, Miyashita K, Yamagami H, Yamawaki T, Naritomi H: Antipyretic therapy prevents the development of cerebral edema in acute embolic stroke: a pilot study using serial CT examinations [abstract]. Stroke. 2000, 31: 313-

  88. 88.

    Crepin-Leblond T, Moulin T, Ziegler F, Bataillard M, Chopard JL, Chavot D, Rumbach L, Bonneville JF, Bogousslavsky J: A randomised trial of heparin therapy in acute ischemic stroke: first results [abstract]. Cerebrovasc Dis. 1994, 4: 259-

  89. 89.

    Teal P, Lyden P, Kaste M, Davis S, Hacke W, Fierus M: Effects of repinotan in patients with acute ischemic stroke: phase IIb modified randomized exposure controlled trial (MRECT) [abstract]. Cerebrovasc Dis. 2005, 19: s68-

  90. 90.

    Nakamura T, Uchiyama S, Tsutsumi Y, Shimizu Y, Iwata M: Renin-angiotensin system blockade safely reduces blood pressure without affecting cerebral blood flow in patients with acute ischemic stroke [abstract]. Stroke. 2007, 38: 517-10.1161/STROKEAHA.107.486522.

  91. 91.

    PASS II: Piracetam in acute stroke study II. http://www.strokecenter.org/trials/

  92. 92.

    Effect of MK-0724 on the improvement of neurological damage and recovery from ischemic stroke. http://www.strokecenter.org/trials/

  93. 93.

    GRASP: glucose regulation in acute stroke patients. http://www.strokecenter.org/trials/

  94. 94.

    Peng XS: Antioxidant treatment in high-altitude ischaemic stroke [abstract]. Chinese Journal of Neurology & Psychiatry. 1994, 27: 303-

  95. 95.

    Saltarelli MD, Weaver JJ, Hsu C, Bednar MM: Randomized double-blind, placebo-controlled study to evaluate the safety and efficacy of CP101,606 (Traxoprodil), an NR2B-selective N-methyl D-aspartate receptor antagonist, in subjects with acute ischemic stroke [abstract]. Stroke. 2004, 35: 241-

  96. 96.

    Piradov MA, Suslina ZA, Lebedeva NV, Altunina MN, Shchukin JD: Piracetam in acute ischemic stroke [abstract]. Cerebrovasc Dis. 1992, 2: 235-

  97. 97.

    Pokrupa R, Hakim A, Villanueva J, Francis G, Wolfe L: Clinical study of prostacyclin infusion after acute ischemic stroke [abstract]. Can J Neurol Sci. 1986, 13: 165-

  98. 98.

    Steiner TJ: Naftidrofuryl in the treatment of acute cerebral hemisphere infarction (ACHI). Stroke. 1996, 27: 195-

  99. 99.

    Fosphenytoin Phase 3: Multicenter study to evaluate the safety of intravenous fosphenytoin in patients with acute ischemic stroke. http://www.strokecenter.org/trials/

  100. 100.

    Qiang D: The dynamic study of stroke MRI in hyperacute stroke patients with thrombolysis [abstract]. Hong Kong Med J. 2001, 7: 16-

  101. 101.

    Haley EC: High-dose tirilazad for acute stroke (RANTTAS II) [letter]. Stroke. 1998, 29: 1256-1257.

  102. 102.

    RECT: Repinotan - randomized exposure controlled trial. http://www.strokecenter.org/trials/

  103. 103.

    Ricci S, Ricciotti E, Celani MG, Righetti E, Stragliotto E, Stracci F, Patrignani P: Differential suppression of thromboxane biosynthesis by indobufen and ASA in patients with ischaemic stroke [abstract]. Cerebrovasc Dis. 2003, 16: s114-10.1159/000070590.

  104. 104.

    Rosenberg G, Angel I, Kozak A, Schneider D: Evaluation of safety and changes in the NIH Stroke Scale, Rankin, and Barthel scores following DP-b99 administration to acute stroke patients [abstract]. Stroke. 2004, 35: 338-10.1161/01.STR.0000135294.08862.5d.

  105. 105.

    Teal PA, Sherman DG, Selchen DH, Grotta JC, Albers GW, Due BR: Arundic acid (ONO-2506 MK-0724) in acute ischemic stroke: results of RREACT study [abstract]. Stroke. 2007, 38: 472-

  106. 106.

    The rt-PA/acute Stroke Study Group: An open safety/efficacy trial of rt-PA in acute thromboembolic stroke: final report [abstract]. Stroke. 1991, 22: 153-

  107. 107.

    Rubiera M, Ribo M, Santamarina E, Delgado-Mederos R, Delgado P, Alvarez-Sabin J, Molina CA: Effects of blood pressure on the efficacy of microbubbles-enhanced sonothrombolysis in acute stroke [abstract]. Stroke. 2007, 38: 507-

  108. 108.

    Sansone A, Gulotta G, Sparacia B, Alongi A, Savoia G, Sparacia GV: Effect of hyperbaric oxygen therapy on neurologic recovery after focal cerebral ischaemia [abstract]. Br J Anaesth. 1997, 78: s73-74.

  109. 109.

    Overell J, Nazir F, Hilditch T, Lowe G, Lees KR: Vascular effects of statins in acute cerebral ischemia: the statins in acute stroke (SAS) trial [abstract]. Stroke. 2003, 34: 308-

  110. 110.

    Shamalov NA, Stakhovskaya LV, Gubsky LV, Tikhonova IV, Smichkov AS, Skvortsova VI: Effects of the neuroprotective drug cerebrolysin on the infarct volume after acute ischemic stroke [abstract]. Cerebrovasc Dis. 2005, 19: s107-

  111. 111.

    SIS: Sipatrigine in stroke. http://www.strokecenter.org/trials/

  112. 112.

    Staedt U, Heene DL, Bayerl JR, Schwarz M, Schwarz M: Comparative study with HAS and dextran of patients with cerebral ischemia. Neurological findings and a daily profile of rheological and hemostatic parameters [abstract]. Klin Wochenschr. 1985, 63: s18-

  113. 113.

    Szczepanska-Szerej A, Wojczal , Stelmasiak Z: Anti-aggregating effect of indobufen (IB) in acute ischemic stroke [abstract]. Eur J Neurol. 1998, 5: s109-10.1046/j.1468-1331.1998.510109.x.

  114. 114.

    Szczepanska-Szerej A, Kurzepa J, Wojczal J, Stelmasiak Z, Stryjecka-Zimmer M: Simvastatin prevents increasing MMP-9 activity in acute phase of ischemic stroke. J Neurol Sci. 2005, 238: s445-

  115. 115.

    Tamura A, Amano T, Sherman DG, Houkin K, Asano T, Fukuuchi Y: Arundic acid (ONO-2506 MK-0724) for the treatment of acute ischemic stroke: phase II clinical trial in Japan [abstract]. Stroke. 2007, 38: s511-512.

  116. 116.

    TEST: Tolerability of enecadin (INN) in acute ischemic stroke trial. http://www.strokecenter.org/trials/

  117. 117.

    Tietjen GE, Dombi T, Pulsinelli WA, Beckse T, Kulger AR, Mann ME: A double-blind, safety, and tolerance study of single intravenous doses of fosphenytoin in patients with acute ischemic stroke [abstract]. Neurology. 1996, 46: s424-

  118. 118.

    Azzimondi G, Casmiro M, D'Alessandro R, Fiorani L, Nonino F: Italian trial on glycerol in ischemic stroke (trial Italiano sul glicerolo nell'ictus: TIGI) [abstract]. Stroke. 1994, 25: 2113-

  119. 119.

    Molina CA, Ribo M, Rubiera M, Santamarina E, Delgado-Mederos R, Maisterra O: TNK induces faster MCA recanalization and leads to better short- and long-term clinical outcomes than native tPA. The TNK-TPA reperfusion stroke study [abstract]. Stroke. 2008, 39: 563-

  120. 120.

    Toso V, D'Agnolo B, Feruglio FS, Basaglia N, Donati G, Falezza G, Bruno R, Salvato G: GM1 therapy of acute stroke. A multicentre trial [abstract]. Cerebrovasc Dis. 1992, 2: 210-

  121. 121.

    Treib J, Behnke S, Seltmann A, Fischer C, Windisch F, Grauer MT, Schenk JF, Wenzel E, Haass A: Effects of a high-dose hypervolemic volume therapy using HES 200/0.5 or HES 70/0.5 on hemodynamics, hemorheology and coagulation in patients suffering from acute stroke. Results of a randomised double-blind study [abstract]. Cerebrovasc Dis. 1999, 9: s101-

  122. 122.

    Edaravone and argatroban stroke therapy for acute ischemic stroke. http://www.strokecenter.org/trials/

  123. 123.

    Wardlaw JM, Lindley RI, Warlow CP, Sandercock PAG: A pilot study of intra-arterial thrombolysis for acute ischaemic stroke [abstract]. JNNP. 1994, 57: 251-

  124. 124.

    Wester PO, Asplund K, Eriksson S, Hagg E, Lithner F, Strand T: Infusion of magnesium in patients with acute brain infarction [abstract]. Acta Neurol Scand. 1984, 70: 143-

  125. 125.

    Sprigg N, Willmot MR, Gray LJ, Walker MF, Sunderland A, Bath PM: The effect of dexamphetamine on motor recovery and systemic and cerebral hemodynamics in subacute ichemic stroke [abstract]. Stroke. 2007, 38: 520-10.1161/STROKEAHA.107.482877.

  126. 126.

    Wojczal J, Szczepanska-Szerej A, Stelmasiak Z: Pentoxifylline (PTX) and indobufen (IB) reduce platelet activation in the acute phase of ischemic stroke (IS) [abstract]. Eur J Neurol. 1998, 5: s108-

  127. 127.

    Standardized evaluation of Chinese medicine injection for cerebral infarction. http://dlib.edu.cnki.net/kns50/Navigator.aspx?ID=9

  128. 128.

    Zeng X, Li Y: Effects of pravastatin on the function of dendritic cells and high sensitive C-reactive protein and clinical effects in patients with acute ischemic stroke [abstract]. Stroke. 2005, 36: 495-

  129. 129.

    Zhang JJ, Deng M, Zhang Y, Sui W, Wang L, Sun A: A short-term assessment of recombinant human granulocyte colony-stimulating factor (RHG-CSF) in treatment of acute cerebral infarction [abstract]. Cerebrovasc Dis. 2006, 21: s143-144.

  130. 130.

    Edwards K, CNS 1102-008 Study Group: Cerestat (aptiganel hydrochloride) in the treatment of acute ischemic stroke: results of a phase II trial [abstract]. Neurology. 1996, 46: s424-

  131. 131.

    Anonymous: Eliprodil stroke trial halted. SCRIP. 1996, 2102: 20-

  132. 132.

    Peinemann F, McGauran N, Sauerland S, Lange S: Negative pressure wound therapy: potential publication bias caused by lack of access to unpublished study results data. BMC Med Res Methodol. 2008, 8: 4-10.1186/1471-2288-8-4.

  133. 133.

    Fletcher RW, Fletcher SW: Clinical epidemiology: the essentials. 2005, Baltimore: Lippincott Williams and Wilkins

  134. 134.

    Cochrane Handbook for Systematic Reviews of Interventions Version 5.0.0. http://www.cochrane-handbook.org

  135. 135.

    Roberts I: An amnesty for unpublished trials. One year on, many trials are unregistered and the amnesty remains open. BMJ. 1998, 317: 763-764.

  136. 136.

    Hetherington J, Dickersin K, Chalmers I, Meinert CL: Retrospective and prospective identification of unpublished controlled trials: lessons from a survey of obstetricians and pediatricians. Pediatrics. 1989, 84: 374-380.

  137. 137.

    Pearn J: Publication: an ethical imperative. BMJ. 1995, 310: 1313-1315.

  138. 138.

    Chalmers I: Underreporting research is scientific misconduct. JAMA. 1990, 263: 1405-1408. 10.1001/jama.263.10.1405.

  139. 139.

    Tumber MB, Dickersin K: Publication of clinical trials: accountability and accessibility. J Intern Med. 2004, 256: 271-283. 10.1111/j.1365-2796.2004.01392.x.

  140. 140.

    Standard operating procedures for research ethics committees. http://www.nres.npsa.nhs.uk/news-and-publications/publications/standard-operating-procedures/

  141. 141.

    Shields PG: Publication bias is a scientific problem with adverse ethical outcomes: the case for a section for null results. Cancer Epidemiol Biomarkers Prev. 2000, 9: 771-772.

  142. 142.

    Random samples. Science. 2002, 296: 2137-

  143. 143.

    Hopewell S, Clarke M, Moher D, Wager E, Middleton P, Altman DG, Schultz KF, the CONSORT Group: CONSORT for reporting randomized controlled trials in journal and conference abstracts: explanation and elaboration. PLoS Med. 2008, 5: e20-10.1371/journal.pmed.0050020.

  144. 144.

    Hopewell S, Altman DG, Moher D, Schultz 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: 20-10.1186/1745-6215-9-20.

  145. 145.

    Chalmers I: In the dark. New Scientist. 2004, 6: 9-

  146. 146.

    Project to improve public reporting of clinical trials underway. http://www.nres.npsa.nhs.uk/news-and-publications/news/project-to-improve-public-reporting-of-clinical-trials-underway/

  147. 147.

    PRS Information: U.S. Public Law 110-85. http://prsinfo.clinicaltrials.gov/fdaaa.html

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Acknowledgements

We would like to thank Naomi Newman and Mei-Chiun Tseng for translation, Dr Hugh Davies for discussions on research ethics, Richard Wilson for our discussion on prima facie principles, Alison McInnes for help with searching for trials, and all of the investigators who responded to our emails.

Funding for authors or those mentioned in Acknowledgements: None

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Affiliations

  1. College of Medicine and Veterinary Medicine, University of Edinburgh, UK

    • Lorna M Gibson

  2. Department of Clinical Neurosciences, University of Edinburgh, Western General Hospital, Edinburgh, UK

    • Miriam Brazzelli
    • , Brenda M Thomas
    •  & Peter AG Sandercock

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Correspondence to Peter AG Sandercock.

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Competing interests

The authors declare that they have no competing interests.

Authors' contributions

LG, MB and PS were responsible for the overall planning and conducting of the systematic review. BT contributed to the literature searches and identification of unpublished evidence. LG screened the search findings, assessed studies for inclusion, extracted and analysed data. LG, MB and PS contributed to interpret results. LG wrote the first draft of the manuscript with additional input from MB and PS. All authors have seen and approved the final version of the manuscript.

Electronic supplementary material

Additional file 1: Trials which included 100 or more patients. This data file contains data on trial design, sample size, interventions, number of deaths, number of patients dead or dependent, main outcomes and funding sources of trials which included 100 or more patients. (XLS 50 KB)

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Keywords

  • Acute Stroke
  • Acute Ischaemic Stroke
  • Piracetam
  • Negative Pressure Wound Therapy
  • Completion Status

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