Protocol violation

ECASS-II was designed to test a lower dose of rt-PA (0.9 mg/kg) during the same 0-6-hours time period after stroke onset, using similar inclusion criteria as in ECASS-I. ° The primary endpoint was the proportion with a favorable outcome on the mRS scale (defined as a score of 0 or 1). There was no difference in this outcome between rt-PA-treated and placebo controls (40% vs. 37%, p = 0.28). A separate analysis of the 158 subjects enrolled within 3 hours of stroke onset also showed no difference in the proportion with a favorable outcome (42% vs. 38%, p = 0.63) this result, however, must be treated with caution because in ECASS-II there was a substantially lower number of patients treated within 3 hours of stroke onset, compared to the 1995 NINDS rt-PA study. Parenchymal hematoma on post-treatment CT was seen in 12% of rt-PA-treated and 3% of placebo patients (p < 0.001). The 90-day mortality rate was 11 % for the rt-PA group and 11 % for the placebo group (p = 0.54). Protocol violations were much less frequent in ECASS-II compared to ECASS-I (9% vs. 18%), probably because of standardized training in CT interpretation at the study sites. 

Per-protocol All patients who did not experience a subjectively defined serious protocol violation during the study. 

The budget must be set, the means of payment agreed and contractual arrangements for premature trial termination decided. In addition, the legal contract should include payments, if any, when a study subject drops out or when it is impossible to evaluate an individual subject (e.g. protocol violations by an investigator, such as recruitment of subjects who do not meet the inclusion criteria - which are an indication for extra clarification of protocol requirements). There should be a clear understanding of the costs and expenses that the site s institution or hospital will absorb and what the sponsor will pay for either directly or indirectly. 

In explanatory trials, we are hkely to exclude both protocol violators and treatment non-compliers. The objective behind these exclusions is to increase the efficiency. However the exclusions may give rise to bias and hence to compromise the results if too many patients are excluded. Such an analysis population is termed as completers, or per protocol, population. In pragmatic trials, we generally include all patients using the intention-to-treat (ITT) principle. 

It can provide a check that the patient about to be entered satisfies certain inclusion/exclusion criteria thus reducing the number of protocol violations. 

If the categorical outcome was Main Reason for Discontinuation which was classified as Adverse Event, Withdrawal of Consent, Protocol Violation, Other, there may be interest in expressing an OR in relation to Adverse Event, in which case we would collapse the other three categories and proceed as in the binary case. 

These omissions will not cause bias only under some circumstances. In particular, subjects in each of the treatment groups should receive equal scrutiny for protocol violations and all such violators should be excluded, in relation to the first point. For the second and third points, the fact that patients do not take study medication or do not provide any post-baseline data should be unrelated to the treatments to which such subjects were assigned. Any potential bias arising from these exclusions should be fully investigated. 

Rates of recruitment, ineligibility, non-compliance, protocol violations and dropouts, overall and by study site ... 

As investigators create files on enrolled (and excluded) patients, CRAs are probably making periodic checks of the completeness and internal consistency of these notations of patients visits, checking also for protocol violations. This is the first step in what should be an ongoing effort to ensure adherence to the protocol and accurate and complete documentation of all selected variables. Visual and computerized reviews by data managers are the next checks. Records are gathered from the various clinicians and checked again in these interim reviews of the raw data, the most important objectives are as follows ... 

In the case of protocol violations, a team member must determine whether this resulted from the clinician s misunderstanding or misinterpretation of the protocol, indifference and sloppiness, inability to communicate necessary information to the patient, or, as happens in rare cases, fraudulent practices. It is very likely that when there have been serious violations or a substantial number of dropouts, the study will have to enroll more patients and be extended beyond the originally projected time frame. 

The number of annual inspections has been growing steadily, and in 2004, reached a total of 242 for US clinical investigators and 82 for foreign clinical investigators (2004 Report to Nation). The top five deficiencies, led by protocol violations, appear in Figure 11.9. 

Serious and/or unexpected AEs, if any occur during the study, including the follow-up period Protocol amendments, if any, and reasons for amendments Protocol violations which impact on subject safety, if any... 

The monitor will be ever-vigilant for protocol violations which can occur during a study and which can have a serious impact on eligibility and evaluability. Many researchers confuse the... 

Visit dates. All visit dates should be recorded in the medical file. Interim visit dates recorded in the medical file, but not in the CRF, should be noted by the monitor in case they signify occurrence of AEs or protocol violations. The final visit date should be so indicated, for example study finished or withdrew from study AEs. All AEs noted in the medical file during the time period specified by the protocol must be recorded in the CRF. The monitor must also carefully check other documents (e.g. diary cards, quality of life forms) for sources of information about AEs. Occurrence of out-of-range laboratory values, which are considered to be clinically significant by the investigator, must be reported and assessed as AEs... 

Were a lot of participants removed for the same protocol violation ... 

Were many of the participants with protocol violations enrolled at the same investigative site ... 

Einally, a series of pnblications [57-67] have described the nse of rt-PA in rontine clinical practice. The resnlts in general have been favorable. However, strict adherence to protocols and the experience of the individnals providing thrombolytic care were clearly important. Indeed, an increased rate of symptomatic intracerebral hemorrhage was docnmented with protocol violations by several gronps [60, 64, 65, 67]. In a stndy of 29 Cleveland area hospitals, a 15.7% rate of symptomatic ICH was found [62]. However, 50% of these patients had protocol deviations from treatment gnidehnes. 

Lopez-Yunez, A.M., et al., Protocol violations in community-based rTPA stroke treatment are associated with symptomatic intracerebral hemorrhage. Stroke, 2001. 32(1) p. 12-6. 

The data for the use of GP Ilb/IIIa inhibitors in conjunction with lAT are even more scant and are limited to case reports [18-23]. Deshmukh et al reported on 21 patients with large vessel occlusion refractory to lAT with rt-PA who were treated with IV and/or lA abcix-imab, eptifibatide, or tirofiban [20]. Twelve patients received IV rt-PA and 18 underwent balloon angioplasty. Complete or partial recanalization was achieved in 17/21 patients. Three patients (14%) had asymptomatic ICH, but there were no cases of sICH. Mangiafico et al described 21 stroke patients treated with IV tirofiban and heparin followed by lA urokinase. Nineteen of these patients also underwent balloon angioplasty. TIMI 2-3 flow was achieved in 17/21 patients. ICH occurred in 5/21 patients (3 sICH and 2 SAH) and was fatal in three patients [23]. Qureshi et al described the use of IA reteplase and intravenous abciximab on 20 stroke patients [22]. There was one sICH. Partial or complete recanalization occurred in 13/20 patients. Conversely, the use of abciximab was predictive of asymptomatic SAH (OR 19.2) in nine patients who received this drug as a study protocol violation in the Multi-MERCI Part 1 trial [24]. 

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