Overcoming the Placebo Effect in Fragile X Clinical Trials

In a placebo-controlled trial, one group of participants is given an experimental treatment, while another group takes a placebo. Participants do not know to which group they are assigned. The reason for this trial design is so that researchers can rule out the placebo effect by comparing outcomes between the two groups.

The placebo effect has been a particular pitfall in Fragile X clinical trials. Most of these studies have relied on subjective measures, such how happy or anxious someone feels. In addition, these measures are usually rated by caregivers, rather than the individuals who have Fragile X. In a new study, Response to Placebo in Fragile X Syndrome Clinical Trials: An Initial Analysis, Luu et al. (2020) examined data from participants given a placebo in eight recent Fragile X clinical trials. The results of their analysis “raise substantial concerns about outcome measures commonly used in randomized-controlled trials in FXS.” If a parent of a child with Fragile X thinks their child got a new treatment to reduce a specific behavior, they may believe changes are happening even if objective measures show otherwise.

FRAXA is working with pharmaceutical and biotech partners to develop and test new clinical trial designs that include objective measures to evaluate treatments. A few examples are:

• EEG: An electroencephalogram is a non-invasive test that can identify differences in the patterns of brain activity. EEG-based neural markers may also predict specific challenges, like speech delay or behavioral outbursts. Once neural markers are found for particular challenges, those markers can be measured during clinical trials to see if a child is improving based on objective biological readouts. Objective measures like EEG could be enormously helpful in determining whether or not a treatment is truly working. Another bonus of EEG is that it works well in Fragile X mice, so can be used to evaluate treatments in mice first.
• fNIRS: Functional near-infrared spectroscopy is another safe, non-invasive way to measure brain activity. This remarkable new technique uses light sources and sensors on the scalp to build a heat map of the brain in action. This technique is portable (and in the near future, likely, wireless), making it possible to use at home. It is less likely to be bothersome or frightening to babies and children and other individuals with sensory sensitivities or high levels of anxiety. In addition, it is not necessary that participants be still or sleeping, as can be true with EEGs or MRIs. It too can be used in mouse studies.
• Home based measures: Many individuals with Fragile X syndrome cannot tolerate visiting clinics at all, and so they have been left out of clinical trials. Other individuals actually become more and more comfortable with clinic visits, enjoying the attention and showing improvements regardless of whether they are taking medication or placebo. To sidestep these challenges, FRAXA is working with pharmaceutical and biotech partners to design outcome measures which can be performed in the comfort of home. These come in two flavors:
  • Wearable devices and monitors which can report objective measures like heart rate, skin responses, or movement.
  • Tablet and computer-based learning and memory and attention tests. These can often be designed as fun games.

  Home-based measures have heightened appeal now in our covid-challenged world, so we hope to see more of them in upcoming clinical trials.

To be sure you have a good outcome measure, you need to have an effective drug to test that measure. But to be sure you have an effective drug, you need to have a good measure to use to test it. This problem is the Catch 22 of Fragile X clinical trials, and this is why we have to invest so much time, money and effort to solve it.