Head injuries are a major health and IMPORTANCE OF SCREENING LOGS IN CLINICAL TRIALS FOR SEVERE TRAUMATIC BRAIN INJURY CLINICAL TRIAL

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1 CLINICAL TRIAL IMPORTANCE OF SCREENING LOGS IN CLINICAL TRIALS FOR SEVERE TRAUMATIC BRAIN INJURY Frnçois J.A. Slieker Deprtment of Neurosurgery, Ersmus Medicl Center, Rotterdm, The Netherlnds Erwin J.O. Kompnje, Ph.D. Deprtments of Neurosurgery nd Intensive Cre, Ersmus Medicl Center, Rotterdm, The Netherlnds Gordon D. Murry, Ph.D. Public Helth Sciences, University of Edinburgh Medicl School, Edinburgh, Scotlnd Juh Öhmn, M.D. Pirknm Hospitl District, Tmpere, Finlnd Nino Stocchetti, M.D. Ospedle Policlinico Istituto di Ricovero e Cur Crttere Scientifico, Miln University, Miln, Itly Sir Grhm Tesdle, F.R.C.S. University of Glsgow nd Royl College of Physicins nd Surgeons, Glsgow, Scotlnd Andrew I.R. Ms, M.D., Ph.D. Deprtment of Neurosurgery, Ersmus Medicl Center, Rotterdm, The Netherlnds, nd Deprtment of Neurosurgery, University Hospitl, Antwerp, Belgium OBJECTIVE: The primry intent for obtining screening logs in rndomized clinicl tril is to ssess selection bis in ptient recruitment. This is prticulrly relevnt to focused trils in heterogeneous popultions such s trumtic brin injury (TBI) ptients. We imed to investigte the benefits of collecting screening logs in two rndomized clinicl trils conducted in TBI. METHODS: Screening logs were collected s prt of the conduct of two multicenter trils of neuroprotective gents in TBI: the Slzburg Atherosclerosis Prevention Progrm in Subjects t High Individul Risk study (n 924) nd the dexnbinol study (n 861). Centers were requested to submit monthly informtion on ll ptients with TBI dmitted to the intensive cre unit, including demogrphics, time of injury nd dmission, injury severity, nd, if not recruited, the reson(s) for exclusion. RESULTS: In the Slzburg Atherosclerosis Prevention Progrm in Subjects t High Individul Risk study, 52 centers submitted dmission dt on 4166 ptients. In the dexnbinol tril, 96 centers submitted dt on 7052 ptients. On verge, only 20% of ptients screened for the Slzburg Atherosclerosis Prevention Progrm in Subjects t High Individul Risk study nd 10% for the dexnbinol tril were enrolled. The min resons for exclusion were neurologicl sttus (29 nd 26%, respectively), ge (24 nd 30%, respectively), nd dmission outside of the time window (17 nd 21%, respectively). Differences in ptient chrcteristics between screened nd enrolled ptients, with substntil country-specific vrition, were observed. CONCLUSION: The collection of screening logs is necessry to report tril results ccording to the Consolidted Stndrds of Reporting Trils guidelines nd to ssess the generlizbility of findings. Our experience shows the fesibility of collecting screening logs nd illustrtes how the potentil for selection bis my creep into well-designed rndomized clinicl trils s result of fctors outside the control of investigtors. Consistency nd ccurcy in screening log completion my further serve s n erly indictor of center performnce in tril. KEY WORDS: Clinicl trils, Consolidted Stndrds of Reporting Trils guidelines, Dexnbinol, Neuroprotection, N-methyl-D-sprtte glutmte ntgonists, Screening logs, Trumtic brin injury Neurosurgery 62: , 2008 DOI: /01.NEU F3 SAPHIR nd Phrmos TBI Investigtors (see Acknowledgments) Reprint requests: Andrew I.R. Ms, M.D., Ph.D., University Hospitl Antwerp, Deprtment of Neurosurgery, Wilrijkstrt 10, 2650 Edegem, Belgium. Emil: Andrew.Ms@uz.be Received, June 15, Accepted, Mrch 17, Hed injuries re mjor helth nd socioeconomic problem throughout the world nd re leding cuse of deth nd disbility, prticulrly in young dult men (2, 6). There re strong incentives to improve tretment, including the use of new phrmcologicl gents, nd rndomized clinicl trils re required to determine the benefit of new pproches. Reporting of clinicl trils should follow the Consolidted Stndrds of Reporting Trils (CONSORT) guidelines (15). These include the need to ssess whether selection bis hs occurred in the enrollment of ptients. This cn only be ccomplished by the collection of informtion on ll ptients screened for prticiption. Screening logs were routinely collected during two rndomized clinicl trils in severe trumtic brin injury (TBI). The min objective ws to investigte the possibility of selection bis during enrollment. Additionl objectives were to promote the qulity of the study in generl, to evlute the numbers of ptients potentilly vilble t different sites nd NEUROSURGERY VOLUME 62 NUMBER 6 JUNE

2 SLIEKER ET AL. cross countries, nd to investigte the effects of enrollment criteri on recruitment. We report how screening logs my be used s qulity mesure for site performnce nd lso how our findings rise some doubts concerning the generlizbility of focused clinicl trils in TBI. PATIENTS AND METHODS Screening logs were obtined in two multicenter plcebo-controlled Phse III trils investigting the efficcy nd sfety of neuroprotective gents: the Slzburg Atherosclerosis Prevention Progrm in Subjects t High Individul Risk (SAPHIR) study nd the recently completed dexnbinol (Phrmos Corp., Iselin, NJ) tril. SAPHIR Study The SAPHIR study ws conducted in 54 Europen centers from November 1995 to April The im of the study ws to determine the efficcy nd sfety of D-CPP-ene[3-(2-crboxy-piperzine-4-yl)-1- propenyl-1-phosphonic cid (d-cpp-ene), competitive N-methyl-Dsprtte ntgonist in ptients with severe TBI. Enrollment criteri re summrized in Tble 1. Ptients were rndomized in 1:1 rtio to tretment with plcebo or 200-mg dose of d-cpp-ene dministered over 5 minutes every 12 hours for 5 dys (for totl of 10 doses). The protocol stipulted dministrtion of the first dose of study drug within 12 hours fter injury. The study recruited 924 ptients with severe TBI. Source dt verifiction ws performed on ll cses enrolled, nd sites were closely monitored by routine site visits. No beneficil effect of d-cpp-ene ws found. Phrmos Dexnbinol Tril The dexnbinol tril ws conducted from Jnury 2001 to Mrch 2004 in Europe, Isrel, Austrli, nd the United Sttes. The objective of the study ws to investigte the efficcy nd sfety of single 150-mg dose of dexnbinol in ptients with severe TBI. Dexnbinol is synthetic cnnbinoid nlog with strong neuroprotective potentil nd is devoid of psychotropic ctivity. The protocol stipulted study drug dministrtion within 6 hours fter injury. Enrollment criteri for the study trgeted ptients with cute severe TBI nd ws imed t recruiting s homogeneous popultion s possible (Tble 1). The study recruited 861 ptients with severe TBI. Source dt verifiction ws performed on ll ptients enrolled, nd sites were closely monitored by routine visits. No beneficil effect of dexnbinol ws found. Full detils nd results of the study hve been reported (13). Screening Logs In both trils, the collection of screening logs ws performed off protocol s joint inititive between the Europen Brin Injury Consortium nd the respective sponsor. The submission of screening logs ws voluntry, nd no dditionl finncil compenstion ws provided. Source dt verifiction ws not performed on screening log dt. Sites were requested to submit screening log dt on ll ptients with TBI dmitted to their intensive cre units. The logs contined dt on ge, sex, dy nd time of injury nd dmission, nd emergency surgery. They lso contined clinicl dt, including Glsgow Com Scle (GCS) score, pupillry rectivity (summrized with the GCS s clinicl neuro sttus ), the occurrence of hypoxi nd/or hypotension, nd the findings of the first computed tomogrphic scn of the hed (computed tomogrphic clssifiction) fter dmission. If the ptient ws excluded, the logs contined the reson(s) for exclusion. Ptient outcomes were not recorded on the screening logs. All screening log dt were nonymous nd without ny ptient identifiers. In the SAPHIR study, 52 of the 54 prticipting centers submitted screening logs. This resulted in the collection of 768 logs over 994 study months (77%) with informtion on 4166 ptients. In the dexnbinol tril, 96 of 100 initited centers submitted 1587 logs over 2015 study months (79%) with informtion on 7052 ptients. All submitted screening logs were centrlly reviewed on n ongoing bsis during the study to monitor for correct ppliction of enrollment criteri. Resons for exclusion specified by investigtors were crosschecked ginst the chrcteristics recorded on the screening logs. RESULTS Submission of Screening Logs nd Center Performnce In the SAPHIR study, 768 monthly screening logs were submitted from 52 sites. Two sites did not submit ny logs, nd nother seven sites submitted fewer thn 50% of the required logs. The overll submission rte of screening logs over totl of 994 study months tht sites were open to enrollment ws 77%. In the dexnbinol tril, 1587 monthly screening logs were submitted from 96 sites. Four sites did not submit ny logs, nd 17 sites submitted fewer thn 50% of the required logs. The overll submission rte of screening logs over totl of 2015 study months ws 79%. Submission rtes were higher in centers in the United Sttes (88%) thn in Europen centers (76%), but dt were less complete. Dt from 113 (12%) of the 924 ptients enrolled into the SAPHIR tril nd from 112 (13%) of 861 ptients in the dexnbinol tril were not cptured on the screening logs. Screening logs for the SAPHIR study contined dt on 4166 ptients, nd those for the dexnbinol study contined dt on 7052 ptients. The verge rtio of number of ptients enrolled versus number screened ws 0.19 in the SAPHIR study nd 0.11 in the dexnbinol tril. A wide vribility ws noted between prticipting countries (Tble 2). A cler reltion ws found between complince in submission of screening logs nd the totl number of ptients recruited by center (Tble 3), with centers with good return rtes for screening logs rndomizing ptients t pproximtely double the rte of centers with poor return rtes. Poor return rtes were lso ssocited with more incomplete dt on ptient outcomes, but there ws no consistent ssocition with mortlity rtes. Enrollment Criteri nd Recruitment Of ll ptients screened, 2594 (73%) in the SAPHIR study nd 5972 (85%) in the dexnbinol tril did not meet the enrollment criteri. Furthermore, 207 ptients in the SAPHIR tril nd 174 in the dexnbinol tril were excluded becuse of inbility to obtin informed consent (i.e., inbility to contct reltives or refusl). Logistic spects (e.g., unvilbility of study personnel or of mediction) prevented inclusion of 191 ptients (5%) in the SAPHIR study nd of 137 (2%) of ptients in the dexnbinol tril. Owing to incomplete dt on screening logs, the resons for not rndomizing ptients could not be determined in 363 ptients (9%) in the SAPHIR tril nd in 20 ptients (0.3%) in the dexnbinol tril VOLUME 62 NUMBER 6 JUNE

3 CLINICAL TRIAL SCREENING LOGS FOR SEVERE TRAUMATIC BRAIN INJURY TABLE 1. Enrollment criteri for the Slzburg Atherosclerosis Prevention Progrm in Subjects t High Individul Risk nd dexnbinol trils in trumtic brin injury SAPHIR study Age yr (s per locl or ntionl regultions) Sustined hed trum within pst 12 h Ptients will be intubted nd ventilted GCS motor score 5 nd t lest one rective pupil CT scn showing intrcrnil bnormlity consistent with trum (CT clss 2) Hemodynmiclly stble fter resuscittion (systolic blood pressure 90 mmhg) Femle ptients should be of non-childbering potentil or must hve negtive pregnncy test Witnessed informed consent from leglly responsible representtive nd obtined ccording to ntionl or locl legisltion Dexnbinol study Inclusion criteri Age yr (s per locl or ntionl regultions) Sustined hed trum within pst 6 h Injury severity requires intrcrnil pressure monitoring GCS motor score of 2 5 with no eye-opening nd t lest one rective pupil CT scn showing intrcrnil bnormlity consistent with trum (CT clss 2) Hemodynmiclly stble fter resuscittion (systolic blood pressure 100 mmhg) Femle ptients should be of non-childbering potentil or must hve negtive pregnncy test Ptient hs n informed consent form signed by either next of kin or leglly cceptble representtive. Informed consent obtined ccording to ntionl or locl legisltion Exclusion criteri Hed injury owing to gunshot wound to the hed Severe injury to the cervicl spinl cord History of unstble crdic, pulmonry, or heptic disese, including n cute myocrdil infrction, within the pst 3 mo; history of cliniclly significnt renl impirment; pre-existing condition resulting from psychitric, neurologicl, or other medicl disorder Receipt of n experimentl drug within 4 wk before current injury Admission of study drug is not possible within 12 h of injury Hed injury owing to penetrting foreign object Any spinl cord injury Mjor extrcrnil injuries cusing continuous bleeding nd likely to require trnsfusion of more thn 5 blood units within the first 12 h fter injury Com owing to pure epidurl hemtom with n initil GCS score of 12 Known or CT evidence of previous mjor cerebrl dmge Any severe concomitnt condition (e.g., cncer, hemtologicl, renl, heptic, or coronry disese) or chronic disorder (e.g., psychitric disorder) tht cn be scertined t the time of dmission Com suspected to be primrily due to cuses other thn hed injury (e.g., drug overdose) Receipt of n experimentl drug within 4 wk before current injury Admission of study drug is not possible within 6 h of injury Suspected inbility to obtin complete 6 mo follow-up SAPHIR, Slzburg Atherosclerosis Prevention Progrm in Subjects t High Individul Risk; GCS, Glsgow Com Scle; CT, computed tomogrphic. The min resons for not meeting inclusion criteri in the SAPHIR study were clinicl neuro sttus (n 756; 29%), ge (n 610; 24%), nd dmission outside of time window (n 431; 17%); totl of 368 ptients were excluded becuse of young ge, nd 242 were excluded for being older thn ge 70 yers. An bsent motor score ws reported s the min reson for exclusion in 2%, nd bilterlly fixed pupils ws the reson in 9% of ptients. In the dexnbinol tril, the min resons for not meeting inclusion criteri were clinicl neuro sttus (n 1578; 26%), ge (n 1808; 30%), nd dmission outside of time window (n 1237, 21%). In totl, 1074 ptients were older thn 65 yers, nd 734 ptients were under the ge of 18 yers. An bsent motor score ws reported s the min reson for exclusion in 14%, nd bilterlly fixed pupils resulted in the exclusion of 4% of screened ptients. Other fctors were the presence of mjor extrcrnil injuries (n 443; 7%) or bsence of intrcrnil pthology on the dmission computed tomogrphic scn (n 573; 10%). The cumultive effects of different enrollment criteri on recruitment re summrized in Figure 1. These strict enrollment criteri resulted in low recruitment in both trils (0.93/mo for SAPHIR nd 0.43/mo for dexnbinol), with only one in five nd one in 10 ptients, respectively, being recruited. NEUROSURGERY VOLUME 62 NUMBER 6 JUNE

4 SLIEKER ET AL. TABLE 2. Overview of screened nd enrolled ptients per country SAPHIR study Dexnbinol study No. of enrol- No. of enrol- Country No. of Rtio of No. of Rtio No. of led ptients No. of led ptients ptients enrolled/ ptients enrolled/ centers cptured centers cptured screened screened screened screened on logs on logs Germny Itly Isrel Netherlnds Frnce United Sttes Finlnd Spin United Kingdom Austrli Austri Belgium Denmrk Turkey Polnd Sweden Switzerlnd Totl SAPHIR, Slzburg Atherosclerosis Prevention Progrm in Subjects t High Individul Risk. TABLE 3. Submission of screening logs nd site performnce SAPHIR study Dexnbinol study Sites sub- Sites sub- Sites sub- Sites submitting mitting mitting mitting 50% 50% 50% 50% of logs of logs of logs of logs (n 9) (n 45) (n 21) (n 79) No. enrolled Averge enroll ment/mo Missing outcome 3 (3%) 5 (1%) 3 (5%) 7 (1%) Mortlity 15 (18%) 197 (24%) 17 (30%) 128 (16%) SAPHIR, Slzburg Atherosclerosis Prevention Progrm in Subjects t High Individul Risk. Chrcteristics of Screened Ptients nd Comprison to Enrolled Ptients The ge distribution of the screened ptients in both trils ws remrkbly similr, with the highest incidence in the group ged 20 to 40 yers (Fig. 2). Comprisons between countries in the dexnbinol tril showed considerble differences in ptient chrcteristics (Tble 4). Differences were substntil for the percentge of indirect trnsfers nd for the severity of TBI. The percentge of indirect trnsfers vried from 19% in the Netherlnds to 71% in the United Kingdom. More mss lesions were reported in ptients indirectly trnsferred (48 versus 30%). In the United Sttes, more ptients (22%) were dmitted to n intensive cre unit (ICU) with mild TBI (GCS score, 13 15) thn in Europe (5%), Isrel (4%), nd Austrli (3%). The frequency of n bsence of motor response on dmission vried from 22% in the United Sttes to 66% in Austri. Overll, 2185 ptients (34%) were reported not to hve motor response. The bsence of motor response ws combined with bnormlities of pupillry rectivity in 45% of these ptients. In the SAPHIR study, 970 screened ptients (27%) did not hve motor response when dmitted to hospitl. Differences in the distribution of the chrcteristics between ll screened ptients nd the enrolled subpopultion re summrized in Tble 5. These differences cn lrgely be explined by effects of the enrollment criteri. However, we lso noted substntil difference for sex in both trils, with higher proportion of women in the screened popultion. In both trils, the recruitment rtes for men were significntly greter thn for women (odds rtio, 1.44 [95% confidence intervl, ] for SAPHIR nd 1.55 [95% confidence intervl, ] for dexnbinol) VOLUME 62 NUMBER 6 JUNE

5 CLINICAL TRIAL SCREENING LOGS FOR SEVERE TRAUMATIC BRAIN INJURY FIGURE 2. Age distribution for ptients screened for the SAPHIR nd dexnbinol studies. DISCUSSION FIGURE 1. Cumultive effects of different enrollment criteri on recruitment. SAPHIR, Slzburg Atherosclerosis Prevention Progrm in Subjects t High Individul Risk; CT, computed tomogrphy. Asterisks indicte the number of enrolled ptients cptured on screening logs. Full disclosure of the number of ptients considered for rndomiztion into tril nd resons for exclusion is dvocted in the CONSORT sttement (15). The intent is to permit full trnsprency regrding the possibility of selection bis in rndomiztion nd to provide insight into the generlizbility of findings. To meet these objectives in hed injury trils, the TABLE 4. Country-specific differences in chrcteristics of ptients screened for the dexnbinol tril Country Indirect Time Age Mle GCS GCS Mss Smple Age Age trnsfer inj-dm >50 yr sex 13 M 1 lesion size (medin) IQR (%) (medin) (%) (%) 15 (%) (%) (%) Germny h 55m Itly h 04m Isrel h 15m Netherlnds h 15m Frnce h 50m United Sttes h 19m Finlnd h 52m Spin h 29m United Kingdom h 00m Austrli h 01m Austri h 20m Belgium h 48m Denmrk h 30m Turkey h 00m Polnd h 30m Time inj-dm, time intervl between injury nd dmission; IQR, interqurtile rnge; GCS, Glsgow Com Scle; GCS M, GCS motor score. NEUROSURGERY VOLUME 62 NUMBER 6 JUNE

6 SLIEKER ET AL. TABLE 5. Comprison of screened nd enrolled ptients SAPHIR study Dexnbinol study Screened Enrolled Screened Enrolled (n 4166) (n 924) (n 7052) (n 861) Referrl (no.) Direct dmission 415 (45%) 4357 (64%) 675 (78%) Secondrily referred 508 (55%) 2454 (36%) 186 (22%) Sex (no.) Mle 2857 (77%) 738 (80%) 5310 (75%) 704 (82%) Age (no.) Medin Rnge Interqurtile rnge Admission GCS motor score (no.) : no response 970 (27%) 142 (16%) 2185 (34%) 3 ( 1%) 2: bnorml extension 315 (9%) 123 (13%) 686 (11%) 109 (13%) 3: bnorml flexion 365 (11%) 144 (16%) 656 (10%) 191 (23%) 4: flexion withdrwl 565 (16%) 224 (24%) 1008 (16%) 271 (32%) 5: loclizing 884 (25%) 287 (31%) 1368 (21%) 272 (32%) 6: obeying commnds 384 (11%) (8%) 0 CT clssifiction (no.) : no bnormlities 426 (15%) 39 (4%) 607 (10%) 14 (2%) 2: diffuse injury 678 (23%) 355 (38%) 2287 (37%) 409 (49%) 3: diffuse injury + oblitertion 325 (11%) 143 (16%) 704 (11%) 200 (24%) bsl cisterns 4: shift, no mss lesion 107 (4%) 23 (3%) 285 (5%) 55 (6%) 5: ny mss lesion 1378 (47%) 358 (39%) 2259 (37%) 161 (19%) Pre-enrollment hypoxi (no.) Present 842 (25%) 110 (13%) 1306 (21%) 210 (25%) Pre-enrollment hypotension (no.) Present 695 (21%) 128 (15%) 1212 (19%) 127 (15%) SAPHIR, Slzburg Atherosclerosis Prevention Progrm in Subjects t High Individul Risk; GCS, Glsgow Com Scle; CT, computed tomogrphic. Europen Brin Injury Consortium developed screening logs to id in the collection nd reporting of dt from ll hed injury ptients screened for recruitment to tril. In the two trils reported, screening logs were submitted on voluntry bsis to the Europen Brin Injury Consortium coordinting center. The dt were collected off protocol becuse the inclusion of collection of screening logs within the tril protocol would, ccording to good clinicl prctice guidelines, necessitte request for informed consent from ll screened ptients. Dt were fully nonymized without ny specific ptient identifiers nd only pertined to observtionl dt to prevent violtion of ethicl principles or conflict with privcy regultions. As voluntry effort, the submission rtes of 77 nd 79% in the trils re extremely plesing. Nevertheless, the bsence of 21 to 23% of the required logs is limittion of the study. In the dexnbinol tril, we observed higher rte of submission of logs in the centers in the United Sttes (88%) thn in Europen sites (76%), but dt were less complete, reporting, for exmple, only ge rnges nd omitting the dte or time of dmission. The United Sttes centers joined the study in June 2003, fter the institution of the Helth Insurnce Portbility nd Accountbility Act regultions, nd mny United Sttes investigtors thought tht reporting full dt on the screening logs would violte the principles of privcy legisltion s outlined in the Helth Insurnce Portbility nd Accountbility Act regultions (12). Other investigtors hve lso stressed this unintended dverse effect of Helth Insurnce Portbility nd Accountbility Act regultions (4). We noted cler ssocition between low submission rte of screening logs nd low recruitment rte. Monitoring site 1326 VOLUME 62 NUMBER 6 JUNE

7 CLINICAL TRIAL SCREENING LOGS FOR SEVERE TRAUMATIC BRAIN INJURY performnce is routine procedure during clinicl trils, but the reltively low enrollment rte in TBI trils, resulting from the strict enrollment criteri, impedes ssessment of center. The ssocition observed between low submission rte of screening logs nd performnce could be useful in pointing to the need for close monitoring of site. Detiled nlysis of the ptients excluded from rndomiztion showed tht over 98% of ptients in both trils hd been excluded ppropritely, nd few ptients (191 in the SAPHIR study nd 137 in the dexnbinol tril) were identified who hd potentilly been missed for enrollment mostly owing to logisticl resons (e.g., filure to contct study personnel). These ptients represent only 5 nd 2% of screened ptients, respectively; t the sme time, they equte to 21 nd 16%, respectively, of the totl number of ptients enrolled. The inclusion of these ptients would hve shortened the durtion of the trils by t lest 4 months nd probbly even more if we tke into ccount tht pproximtely 21% of the required logs were not submitted. From n economic perspective, efforts to improve locl study orgniztion in order to further reduce the number of ptients missed for enrollment could be very cost-effective. Effects of Enrollment Criteri Clinicl trils in hed injury ptients generlly pply strict enrollment criteri to trget homogeneous popultion of ptients who re judged to hve strong potentil to benefit from the intervention under evlution. This pproch enhnces the prospect of detecting ny difference consequent upon the new tretment, but it limits recruitment nd compromises the generlizibility of findings. The effect of strict enrollment criteri on recruitment nd on the resulting selection of ptients hs not been reported previously. We observed substntil effects of the enrollment criteri on recruitment. The enrollment rte nd the rtio of enrolled to screened ptients ws considerbly lower in the dexnbinol study thn in the SAPHIR tril, reflecting more restrictive enrollment criteri. Although we confirmed tht enrollment criteri were used ppropritely, we observed differences in chrcteristics between screened nd enrolled ptients. In generl, enrolled ptients were dmitted sooner nd were younger, with mle ptients overrepresented, nd mss lesions were noted less frequently. In TBI trils, ptients over the ge of 65 yers nd those with n bsent motor score re generlly excluded from the tril popultion becuse they constitute only minority of TBI ptients nd their prognosis is worse. Our dt, however, indicte tht substntil proportion of smple of ptients dmitted to the ICU with neurotrum is over 65 yers of ge (15%). Other studies hve demonstrted n incresed incidence of TBI nd dmission to the ICU in elderly ptients (8 11). We noted higher incidence of n bsent motor score in screened ptients thn hs been observed in previous series, nd we suspect tht the current policy of erly sedtion nd prlysis induced during resuscittion t the scene of the ccident by emergency medicl tems cused flsely bsent motor score in mny cses. Other studies hve likewise emphsized the importnce of the effects of sedtion nd prlysis on ssessments of the motor score (1, 3, 16, 18), nd recent metnlysis hs shown less poor outcome in ptients with n bsent motor score compred with those with n extensor response (14). These observtions cst doubts on the vlidity of n bsent motor score s n exclusion criterion in TBI trils. The difference in sex rtio between screened nd enrolled ptients ws surprising nd very similr in both trils. The observed difference my prtilly be explined by differences in ge distribution, s the mle prepondernce decreses with incresing ge. Alterntively, some reluctnce of investigtors to enroll femle ptients of childbering potentil into trils my hve contributed to this difference. We observed greter number of ptients with mss lesions in the screened popultion compred with enrolled ptients in both trils. Detiled nlysis of ptients screened for prticiption in the dexnbinol tril showed cler reltion between the prevlence of mss lesions nd greter proportion of ptients indirectly trnsferred. These differences reflect spects of locl trum orgniztion with much more selective dmission policy in countries with high rtes of indirect trnsfers, such s in the United Kingdom (Tble 4). Generlizbility of Findings The reltively low rtio of enrolled to screened ptients csts some doubts on the generliztion of findings towrd the overll popultion of TBI ptients dmitted to ICUs in prticipting centers. Wht is the vlue of new tretment if it hs only been tested in 10 to 20% of the popultion, in prticulr if this is not rndom selection, or not trgeting specific mechnism known to be ctive in n individul ptient? To the contrry, it my be rgued tht it would mke little sense to use n invsive nd possibly risky tretment in ptients with n excellent prognosis or to test the efficcy of new tretment in ptients considered nerly unslvgeble. The principle of the concept to decrese heterogeneity nd to exclude ptients with n extreme prognosis from trils remins, in our opinion, vlid. Defining n pproprite trget popultion by prognostic risk my, however, be better performed on combintions of predictors (prognostic models) thn on individul chrcteristics. Of prticulr concern is the observtion tht the selective dmission policy used in some centers induces different constitution of the ptient popultion, with lrger percentge of ptients with mss lesions requiring intrcrnil surgery. From tril perspective, this mens tht the selection of countries nd sites prticipting in tril will influence the constitution of the ptient popultion; diffuse injuries will be more common in countries with high rtes of primry referrls, nd focl pthology will be more frequent in countries with more ptients indirectly trnsferred. These observtions illustrte how the potentil for selection bis my creep into even well-designed clinicl tril s the result of fctors outside the control of investigtors, nd they highlight the importnce of the CONSORT sttement. The observtions re lso highly relevnt to the issue of the reltive merit of focused Phse III tril versus meg-tril in TBI. The concept of meg-tril is tht the presence of considerble het- NEUROSURGERY VOLUME 62 NUMBER 6 JUNE

8 SLIEKER ET AL. erogeneity, in both ptient chrcteristics nd ptient mngement, is inevitble nd dopts the simple strtegy of recruiting such lrge smple size tht tretment signl cn still be detected reltive to the bckground noise. In contrst, conventionl TBI trils control nd djust for bckground noise s much s possible, either by pplying strict enrollment criteri or by using covrite djustment (7). Some investigtors hve doubted the prcticbility of meg-tril in TBI, but the Corticosteroid Rndomistion After Significnt Hed Injury tril hs demonstrted the fesibility of this pproch (5, 17). It should, however, be recognized tht the Corticosteroid Rndomistion After Significnt Hed Injury tril investigted the efficcy of drug (methylprednisolone) tht ws believed, on the bsis of long nd widespred use, to hve well-estblished sfety profile. Whether meg-tril is fesible for newer neuroprotective gents for which insufficient sfety dt re vilble remins questionble. Further methodologicl reserch is required to determine the reltive merits of megtril versus conventionl focused trils in TBI. By definition, meg-tril will hve greter generlizbility thn conventionl focused trils. CONCLUSIONS We conclude tht screening logs form n importnt tool in rndomized clinicl trils nd re essentil to reporting dt ccording to the CONSORT guidelines. Complince in submitting screening logs is relted to other spects of center performnce. Informtion collected in the screening logs should be limited to the most importnt chrcteristics to minimize the burden on tril stff collecting dt, but it should provide dequte dt for nlysis of pproprite exclusions, including ccurte documenttion of ge, time of injury, referrl, time of dmission, nd bsic clinicl nd rdiologicl chrcteristics. The strict enrollment criteri for TBI trils my hve hd n dverse effect on recruitment. Chrcteristics of ptient popultions in different centers nd countries re influenced by spects of locl trum orgniztion. The differences in ptient chrcteristics between screened nd enrolled ptients nd the observed differences between countries ffect the generlizbility of results of focused trils in TBI. DISCLOSURE The collection of screening logs ws finncilly supported by the sponsors of the trils (Sndoz, Inc., Broomfield, CO, nd Phrmos Corp., Iselin, NJ). REFERENCES 1. Blestreri M, Czosnyk M, Chtfield DA, Steiner LA, Schmidt EA, Smielewski P, Mtt B, Pickrd JD: Predictive vlue of Glsgow Com Scle fter brin trum: Chnge in trend over the pst ten yers. J Neurol Neurosurg Psychitry 75: , Bruns J Jr, Huser WA: The epidemiology of trumtic brin injury: A review. Epilepsi 44:2 10, Buechler CM, Blostein PA, Koestner A, Hurt K, Schrs M, McKernn J: Vrition mong trum centers clcultion of Glsgow Com Scle score: Results of ntionl survey. J Trum 45: , Dimond K: The impct of privcy regultions on clinicl reserch. J Biolw Bus 5:50 53, Edwrds P, Arngo M, Blic L, Cottinghm R, El-Syed H, Frrell B, Fernndes J, Gogichisvili T, Golden N, Hrtzenberg B, Husin M, Ullo MI, Jerbi Z, Khmis H, Komolfe E, Lloë V, Loms G, Ludwig S, Mzirc G, Muñoz Snchéz Mde L, Nsi L, Olldshi F, Plunkett P, Roberts I, Sndercock P, Shkur H, Soler C, Stocker R, Svobod P, Trenkler S, Venktrmn NK, Wsserberg J, Ytes D, Yutthksemsunt S; CRASH tril collbortors: Finl results of MRC CRASH, rndomised plcebo-controlled tril of intrvenous corticosteroid in dults with hed injury: Outcomes t 6 months. Lncet 365: , Ghjr J: Trumtic brin injury. Lncet 356: , Hernández AV, Steyerberg EW, Butcher I, Mushkudini N, Tylor GS, Murry GD, Mrmrou A, Choi SC, Lu J, Hbbem JD, Ms AI: Adjustment for strong predictors of outcome in trumtic brin injury trils: 25% reduction in smple size requirements in the IMPACT study. J Neurotrum 23: , Knnus P, Niemi S, Plvnen M, Prkkri J: Fll-induced injuries mong elderly people. Lncet 350:1174, Knnus P, Plvnen M, Niemi S, Prkkri J, Ntri A, Vuori I, Järvinen M: Incresing number nd incidence of fll-induced severe hed injuries in older dults: Ntionwide sttistics in Finlnd in nd prediction for the future. Am J Epidemiol 149: , Knnus P, Plvnen M, Niemi S: Time trends in severe hed injuries mong elderly Finns. JAMA 286: , Luukinen H, Herl M, Koski K, Kivelä SL, Honknen R: Rpid increse of fll-relted severe hed injuries with ge mong older people: A popultionbsed study. J Am Geritr Soc 47: , Ms AI, Kompnje EJ, Slieker FJ, Stocchetti N: Differences in completion of screening logs between Europe nd the United Sttes in n emergency phse III tril resulting from HIPAA requirements. Ann Surg 239: , Ms AI, Murry G, Henney H III, Kssem N, Legrnd V, Mngelus M, Muizelr JP, Stocchetti N, Knoller N, Phrmos TBI investigtors: Efficcy nd sfety of dexnbinol in severe trumtic brin injury: Results of phse III rndomized, plcebo controlled, clinicl tril. Lncet Neurol 5:38 45, Mrmrou A, Lu J, Butcher I, McHugh GS, Murry GD, Steyerberg EW, Mushkudini NA, Choi S, Ms AI: Prognostic vlue of the Glsgow Com Scle nd pupil rectivity in trumtic brin injury ssessed pre-hospitl nd on enrollment: An IMPACT nlysis. J Neurotrum 24: , Moher D, Schulz KF, Altmn DG: The CONSORT sttement: Revised recommendtions for improving the qulity of reports of prllel group rndomized trils. Lncet 357: , Moskopp D, Stähle C, Wssmnn H: Problems of the Glsgow Com Scle with erly intubted ptients. Neurosurg Rev 18: , Roberts I, Ytes D, Sndercock P, Frrell B, Wsserberg J, Loms G, Cottinghm R, Svobod P, Bryley N, Mzirc G, Lloë V, Muñoz-Sánchez A, Arngo M, Hrtzenberg B, Khmis H, Yutthksemsunt S, Komolfe E, Olldshi F, Ydv Y, Murillo-Cbezs F, Shkur H, Edwrds P; CRASH tril collbortors: Effect of intrvenous corticosteroids on deth within 14 dys in dults with cliniclly significnt hed injury (MRC CRASH tril): Rndomised plcebo-controlled tril. Lncet 364: , Stocchetti N, Pgn F, Clppi E, Cnvesi K, Berett L, Citerio G, Cormio M, Colombo A: Inccurte erly ssessment of neurologicl severity in hed injury. J Neurotrum 21: , Acknowledgments We re very grteful to the investigtors in the centers prticipting in the SAPHIR nd dexnbinol trils for their coopertion in the collection of the dt reported. A full listing of ll investigtors prticipting in the SAPHIR nd dexnbinol trils is locted on the EBIC web site ( We lso thnk Mrj vn Gemerden for the dministrtive support provided in the preprtion of the mnuscript. COMMENTS Slieker et l. continue to provide vluble insights into the mens nd mechnisms of improving trumtic brin injury (TBI) clinicl 1328 VOLUME 62 NUMBER 6 JUNE

9 CLINICAL TRIAL SCREENING LOGS FOR SEVERE TRAUMATIC BRAIN INJURY trils through their meticulous exmintion of the dt nd methodology of pst trils. Screening logs hve generlly been used before the initition of TBI studies to ssess center volume for the pthology in question, thereby identifying likely high volume centers for potentil ptient enrollment nd estblishing study ccrul timeline. The informtion presented in this study indictes tht such logs cn be very useful s study qulity ssessment nd vlidity tool. It is very interesting tht there ws two-fold increse in ptient enrollment in centers most complint with screening log submission. One certinly hs to wonder if such ttention to detil crried over to the clinicl cre of TBI in these centers, yet nother re of unintentionl bis potentilly ffecting outcome. Although the informtion presented is importnt to consider in future tril designs, there re severl cvets. There ws no source verifiction of the screening dt. Although such is understndble given the sheer volume nd the resources vilble for conducting these trils, unfortuntely we hve no wy of ssessing the potentil for significnt noise to signl rtio in this dt. In ddition, both of the clinicl trils exmined in this study were undertken before the enhnced protection of n individul ptient s helthcre dt. Given current constrints in this regrd, subsequent screening logs will be ble to cpture significntly less informtion, which my mke them significntly less useful. Jck E. Wilberger Pittsburgh, Pennsylvni These highly respected neurotrum reserchers hve done nice job in conducting nd reporting this investigtion. A relted issue is the growing interest in including only specific types of trumtic brin injury ptients in some trils. For exmple, ptient with lrge cute subdurl hemtom nd nother ptient with diffuse xonl injury who both hve Glsgow Com Scle score of 7 might be enrolled in the sme clinicl tril, but their underlying pthophysiology nd tretment might be very different. An investigtionl tretment designed to help one of these ptients my not help the other, thus mking it counterproductive to enroll the other ptient. If future TBI trils become more nd more specific bout the types of ptients they enroll, the lessons of this rticle will become even more importnt. Alex B. Vldk Houston, Texs This rticle represents distilltion of dt from two lrge hed injury trils in which 10 nd 20% of the ptients screened, respectively, were ctully enrolled into the tril. It is creful technicl nlysis of the vribles collected which shows substntil intercountry nd intercenter vribility. The conclusions of the dt re very importnt for construction of clinicl trils in severe TBI, nd the uthors nd the IMPACT group s whole should be congrtulted. The bility of the IMPACT group, Ntionl Institutes of Helth- Ntionl Institutes of Neurologicl Disorders nd Stroke-funded interntionl group of neurotrils specilists nd sttisticins, to obtin the originl dt sets, from pproximtely eight mjor neurotrum trils, both industry- nd Ntionl Institutes of Helth-funded, is unique chievement. (For n overview of the chievements of the IMPACT group, the reder should review J Neurotrum:24, 2007, in which multiple studies from the group re presented.) In this study, it is especilly impressive tht only 5 nd 2% of the ptients in the Slzburg d-cpp-ene nd dexnbinol trils, respectively, were lost to enrollment due to logisticl fctors such s unvilbility of the drug or coordintors. As the uthors point out, the country-specific referrl bises seen in these lrge trils provide dt bse upon which to ssess neurotrum cre. For exmple, in the United Kingdom, most ptients re secondrily referred to neurosurgicl centers, so tht focl mss lesions re more common in the tril ptients nd referrl times were much longer (6 hr versus 2 hr 19 min) in the United Sttes, wheres only 28% of ptients were secondrily referred. Contributions from this lrge Ntionl Institutes of Neurologicl Disorders nd Stroke-funded meg dtbse, with more thn 10,000 ptient records vilble, if judiciously nlyzed, could yield one of the most powerful sources of leverge to lter ptterns of neurotrum cre worldwide nd could lso yield better clinicl tril design. Ross M. Bullock Mimi, Florid NEUROSURGERY VOLUME 62 NUMBER 6 JUNE