Protocol of Interim Analysis Study for Repeated Transcranial Magnetic Stimulation for improving cognition in Alzheimer’s Disease (Preprint)

BACKGROUND Many clinical trials investigating treatment efficacy require an interim analysis. Recently we have been running a large multi-site randomized placebo controlled double-blind clinical trial investigating the effect of repetitive transcranial magnetic stimulation (rTMS) treatment for improving or stabilizing the cognition of patients diagnosed with Alzheimer’s disease (AD). OBJECTIVE The objectives of this paper are to report on recruitment, adherence, and adverse events to date, and to describe in detail the protocol for interim analysis of the clinical trial data. The protocol will investigate whether the trial is likely to reach its objectives if continued to the planned maximum sample size. METHODS The specific requirements of the analytic protocol are to: 1) Ensure the double-blind nature of the data while doing the analysis, 2) re-estimate the predictive probabilities of success, 3) re-estimate the numbers needed to evaluate treatment given the so-far standard deviations for each of the output variables. The initial estimate of sample size was 208. The interim analysis will be based on 150 patients who will be enrolled in the study and finish at least 8 weeks of the study. Our protocol for interim analysis, at the very first stage, is to determine the response rate for each participant to the treatment (either sham or active), while ensuring the double-blind nature of the data. The blinded data will be analyzed by a statistician to investigate the treatment efficacy. We will use Bayesian predictive probabilities of success (PPOS) to predict the success rate and determine whether the study should continue. RESULTS The enrollment has been slowed significantly due to COVID-19 pandemic and lockdown. Nevertheless, so far 133 participants have been enrolled, while 22 of these have been withdrawn or dropped out for various reasons. In general, rTMS has been found tolerable with no serious adverse event. Only two patients dropped out of the study due to their intolerability to rTMS pulses. CONCLUSIONS Overall the study with the same protocol is going as expected with no serious adverse event or any major protocol deviation. CLINICALTRIAL https://clinicaltrials.gov/ct2/show/NCT02908815