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Clinical Trial Participation and Placebo: The Unsung Heroes During Consent Discussions

From the perspective of a patient or a patient’s family during the time of a medical crisis the idea of consenting to an investigational trial can be very stressful. Most will focus on the risks of the investigational therapy and will find it difficult to realize the inherent benefits of participating in a clinical trial and the possible benefits of receiving a placebo. Historically the mortality rate of a patient suffering an intraventricular hemorrhage can be as high as 80% per the literature. In comparison, a review of the IVH thrombolysis safety (Safety) trial unblinded data shows that participation in a clinical trial reduced mortality to about 20% in both treatment groups. Although the treatment assignments remain blinded, this appears to be holding true for the current CLEAR III trial as well with 30-day mortality below 40% in both treatment groups. An assessment of A/B mortality is done by a blinded statistician at the time of each death to ensure that survival is occurring at the expected rate in both groups. This trend of survival in subjects enrolled in the trials is attributed to the stringent stability protocols required by the protocol which include optimal catheter placement, daily CT scans to monitor for bleeding, and strict blood pressure and intracranial pressure management.

 

It is unclear if the administration of rt-PA to quickly remove the IVH is mitigating the survival rate. The Safety trial showed a 19% 30-day mortality rate in the treatment group and a 22% in the placebo group. The difference was not statistically significant. However, the important message here is that more subjects are surviving and we are now able to assess functional outcome up to one year following the ictus. Placebo may be playing a part in this survival rate. The administration of placebo (normal saline) followed by flush does not appear to be affecting the clot resolution rate as compared to historical controls or to the treatment group. Alternatively, the administration of placebo also does not appear to be harmful to the subjects either. Symptomatic bleeding was lower in the placebo group in the safety trial. Blinded analyses in the ongoing CLEAR III trial show that the symptomatic bleeding rate is low and remains balanced between the two groups.

When consenting a potential patient or when talking to their family emphasis should be placed on more than just the potential, unproven benefits and risks of the investigational therapy. The benefits of being in a controlled, clinical trial along with the as yet unknown benefits and certainly lack of significant risk of receiving a placebo should be conveyed as compared to conventional medical management. Randomization to receive placebo should no longer be considered ineffectual. It’s better to be in CLEAR and get the placebo than to not be in the study at all.

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