Patient Safety in Trials of Therapy for Acute Ischemic Stroke

To the Editor: In their Editorial accompanying the report of our trial of aptiganel for acute ischemic stroke,¹ Drs Becker and Tirschwell² make a number of important and valid points. However, several of their inferences about our study were based on incomplete information and thus require clarification.

First, the authors were concerned that patients enrolled in the study were not informed about the availability of thrombolytic therapy. After the US Food and Drug Administration approved intravenous tissue plasminogen activator (t-PA) for patients with ischemic stroke who could be treated within 3 hours of symptom onset, the informed consent of our study was modified to reflect this new information. There was no intent to deprive patients of any treatment (including intravenous t-PA) that their physicians deemed appropriate. Patients who were treated with t-PA were precluded from participation in the trial because of concern of untoward drug interactions. Treating physicians decided whether an individual patient was a candidate for intravenous t-PA or any other specific therapy.

Second, Becker and Tirschwell suggest that our study inappropriately combined elements of phase 2 and 3 trials. Our study was designed as a phase 2 trial nested within a phase 3 trial. This type of study design is not novel³ and helps provide a sample size large enough to avoid erroneous conclusions, either negative or positive. When our trial was initiated, data were available from 3 phase 2 trials involving more than 200 patients with acute stroke who had received aptiganel hydrochloride without any evidence of significant toxicity. Therefore, as with a typical phase 3 trial design, there was no anticipated need to suspend enrollment while a planned interim analysis was performed.

Third, they suggest that enrollment should have been stopped earlier. Our trial was intensively and independently monitored by both a data and safety monitoring board (DSMB) and the sponsor, and a formal interim analysis was carried out within 11 days of unblinding the available study data after well-founded concerns were raised. Study enrollment was then terminated within 3 days. This decision was based not only on the 7-day data from 300 patients but also on all patient data available when the interim analysis was conducted. Even with the entire available sample, the statistically significant differences between the groups were marginal but precluded any meaningful benefit of the drug. Patient safety was never compromised.

We believe that our clinical trial was carried out in accordance with the highest ethical and scientific standards. Publication of the details of studies with negative results is an important responsibility of the investigators and the sponsors to both the medical community and the patients who agree to participate under the assumption that the findings will be used to help others, even if they themselves derive no benefit.^{4 - 5} These are the standards to which all clinical trials should aspire.