Analysis of early phase and subsequent phase III stroke studies of neuroprotectants: outcomes and predictors for success

For identification of phase III clinical trials on neuroprotective treatments for acute ischemic stroke we systematically searched the databases Clinicaltrials.gov (searched in November 2012) and The Internet Stroke Center (searched in November 2012) [1, 3]. The search strategy for Clinicaltrials.gov used the terms “Closed Studies” for the search term ‘Recruitment’, “All studies” for the search term ‘Study Result’, “Interventional Studies” for the search term ‘Study Type’, and “Phase III” for the search term ‘Phase’. For search in The Internet Stroke Center we used the terms “Completed” and “Terminated” for the search term ‘Status’ and the term “Phase 3” for the search term ‘Phase’. In addition, review articles on clinical acute stroke studies were reviewed for phase III trials [2, 4‐6]. To include only studies on acute stroke, the search was limited to those studies with treatment initiation within 72 hours after stroke onset. Only studies on neuroprotection were included. Studies of thrombolytic, antithrombotic, or antihypertensive agents without neuroprotective properties were excluded. Publications of thus identified phase III studies were retrieved and data were extracted. Only articles in English were included. When studies were not published in full data were obtained from the Internet Stroke Center or from Cochrane Stroke Group reviews. Results of phase III studies were judged to be either “positive”, “neutral” or “negative”. A study was defined to be “positive” if the primary end points were reached or if the neuroprotective treatment was superior to the placebo treatment regarding functional recovery or mortality in cases the primary end point was not stated. Additional data that were retrieved include the maximum time of treatment initiation after symptom onset, the dose and route of administration of the neuroprotective treatment, and the number of patients included in the study.

Phase I and phase II studies of neuroprotective therapies of identified phase III studies were searched using the database Pubmed (searched at November 2012). This strategy included the words “stroke” or “ischemia” or “infarct” AND “drug name” or “abbreviated drug name”. In addition, articles of phase III studies were searched for preceding phase I and phase II studies. Except the terms “Phase I” and “Phase II” for the search term ‘Phase’ the same search strategy as described for phase III studies was used for searching the databases Clinicaltrials.gov (searched in November 2012) and The Internet Stroke Center (searched in November 2012). Only articles in English were included. In the absence of full publication abstracts were analyzed when all required data were available by the Internet Stroke Center or from Cochrane Stroke Group reviews. Studies were determined as “positive” or “neutral” or “negative” regarding treatment efficacy as judged by the authors in the publication [7]. Moreover, data on the following characteristics of phase I and phase II studies were extracted: Number of patients enrolled, trial setting (single-center or multicenter), randomization, blinded outcome assessment, industry sponsoring, dose–response investigation, time point of outcome assessment, use of imaging endpoints (e.g. infarct size), and use of the same therapeutical time window, the same dose and the same route of administration as in the corresponding phase III trial. The selection of considered study characteristics was based on previously published articles on the design of acute stroke studies [7, 8].

Early phase studies (phase I and II) were assigned to their corresponding phase III trial. As early clinical stroke studies were frequently not clearly specified as phase I or phase II studies we subsumed these in one category. For treatments of which more than one phase III trials exists, phase I and phase II studies were allocated to their immediately following phase III studies. Phase I and II studies were classified as “true neutral” or “false positive”. Those with positive results and subsequent negative phase III studies were classified as “false positive” and those with neutral results and subsequent negative phase III studies were classified as “true neutral”. No phase I or phase II studies with negative results could be identified. As conflicting results of phase III studies on the efficacy of NXY-059 exist, the larger (neutral) Stroke-Acute Ischemic NXY Treatment Trial (SAINT) II trial was used as reference for the classification of phase I and phase II studies on NXY-059. For comparison of study characteristics between “false positive” and “true neutral” phase I and II studies we applied unadjusted (crude) logistic regression analysis and a multivariable model that included all study characteristics simultaneously. The level of significance was defined as a two-tailed P < 0.05. The analyses were carried out using SAS 9.2 and the Statistical Package of Social Sciences (version 21).

The search strategy yielded 153 studies by searching the database Clinicaltrials.gov and 165 studies by searching the database The Internet Stroke Center. Seven further studies were identified by searching review articles on clinical acute stroke studies. Of the identified studies 46 phase III studies fulfilled the inclusion criteria (Table 1). In these studies 34 different neuroprotective treatments were investigated. The studies were published between 1988 and 2012. Four studies were not published (POST-010 and POST-011, Eliprodil Phase III, Fosphenytoin Phase III, and ARTIST+) and information on these studies was obtained from the Internet Stroke Center database. The median number of patients enrolled in the included studies was 670.5 (range 126 to 3306). Forty-three studies were neutral (active treatment and control not significantly different), two studies were negative (control superior to active treatment), and only one study was positive (active treatment superior to control). However, the only positive study (SAINT I) was followed by a larger negative study (SAINT II).

Fifty-nine early phase studies, investigating 26 neuroprotective treatments were identified. The characteristics of these studies are shown in Table 2. For 8 treatments (combination of Atenolol and Propanolol, BMS-204352, Diazepam, Eliprodil, Enlimomab, Fibroblast Growth Factor, Fosphenytoin, Israpidine) evaluated in phase III studies no preceding randomized phase I/II trials were identified. The median number of subjects enrolled in phase I/II studies was 92 (range 25 to 725). More than half (61.0%) of the studies were sponsored by industry. The majority of studies were multicenter studies (69.5%). Randomization was reported in 57 (96.6%) and blinded outcome assessment in 52 (88.1%) of the included phase I/II studies. In 16 (27.1%) studies the dose–response relationship was explored and in 15 (25.4%) studies an imaging endpoint in addition to clinical endpoints was used. The median duration of follow-up for endpoints was 87 days (range 3 to 365). Compared to corresponding phase III trials in phase I and phase II studies the same therapeutical time window, the same dose, and the same route of administration was used in 18 (32.2%), 29 (49.2%), and 50 (84.7%), respectively.

Twenty-two (37.2%) early phase studies were considered to be positive and 37 (62.7%) to be neutral. Characteristics of early phase studies and their associations with prediction of phase III study results are shown in Table 2. We found no study characteristic of early phase studies to be significantly associated with correct prediction of phase III results, neither in a univariate nor in multivariable logistic regression analysis.

In one study endpoints were determined at discharge and mean length of hospital stay was reported to be 9.5 days in verum treated patients and 11.2 days in the placebo group. Therefore duration to follow-up for endpoints in this study was estimated to be ten days (results of the regression model remained unchanged when duration to follow-up of this study was largely varied).