Transpalpebral electrical stimulation for the treatment of retinitis pigmentosa: study protocol for a series of N-of-1 single-blind, randomised controlled trial

What is the main takeaway?

This study outlines a protocol for assessing the efficacy and safety of transpalpebral electrical stimulation (TpES) in treating retinitis pigmentosa (RP) through a series of N of 1 single-blind, randomised controlled trials. RP is an inherited retinal degenerative disease leading to progressive vision loss. TpES, a non-invasive technique delivering electrical stimulation through the eyelids, has shown potential in preserving retinal function. The researchers aim to determine the therapeutic value of TpES in RP patients by employing personalised N of 1 trials, where individual responses to TpES are compared against sham treatments.

What is the real-world impact?

Implementing N of 1 trials to evaluate TpES in RP treatment offers a personalised approach, directly assessing individual patient responses. For the pharmaceutical and MedTech industries, this methodology can expedite the development and validation of novel therapeutic devices, potentially leading to more targeted and effective interventions for RP and other rare diseases. In digital health, integrating TpES with monitoring platforms could enable real-time tracking of treatment efficacy, facilitating timely adjustments to therapy. Clinical research organisations and academic institutions couldan adopt this trial design to conduct rigorous, patient-centric studies, advancing the understanding of TpES's role in managing retinal degenerative diseases and informing clinical practice.

What do we think about it?

This is a fascinating ground-breaking study. However, there are a couple of flaws that the authors could address for greater validity of the results. There is an issue with the Study period of control (no TpES intervention) because the authors say that when the TpES device is applied to the eyelids, no electrical stimulation is given, and no pulsation is felt but everything else remains the same. Patients will be unblinded by not feeling any pulsation, which could lead to erroneous conclusions. Also, the authors comment that each patient’s paired trial is treated as an independent trial. For the in-group effects, the paired t-test will be used for the data with normal distribution, and the Wilcoxon rank sum test  for the data with non-normal distribution. For the intergroup effect, three pairs of data with normal distribution will be used with repeated measures ANOVA test, and a linear mixed-effects model will be used with non-normal distribution. However, these methods do not account for serial correlation in repeated observations coming from the same individual. Tang et al have developed serial t-tests that account for this. They used Monte Carlo simulation to evaluate the statistical properties of these serial t-tests, namely, Type I and II errors, and confidence interval widths, and compared these statistical properties to those of the usual t-test. The serial t-tests clearly outperformed the usual t-tests commonly used in reporting N of 1 results. Thus, the results of this study will need to be interpreted bearing in mind potential unblinding and use of standard t-tests. 

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Who are the authors & where can I read the paper?

The study was conducted by Wei Zhou, Ziyang Huang, Kai Xu, Yamin Li, Xiaoyu Li, Jiaxian Li, Yu Jin, Torkel Snellingen, and Lina Liang.  The paper can be read here.