Low-Frequency rTMS for In-Hospital Sleep Disturbance in Advanced NSCLC

Overview

This randomized, double-blind, sham-controlled trial will evaluate whether low-frequency repetitive transcranial magnetic stimulation (rTMS) can improve in-hospital sleep quality in adults with advanced non-small cell lung cancer (NSCLC) and clinically significant in-hospital sleep disturbance. A total of 160 participants with unresectable stage IIIB-IIIC or stage IV NSCLC, or recurrent NSCLC not suitable for curative local treatment, will be randomly assigned in a 1:1 ratio to active rTMS or matched sham stimulation. Active rTMS will target the left dorsolateral prefrontal cortex and will be delivered once daily for 10 sessions completed within 10-14 days. The primary outcome is sleep quality measured using the Richards-Campbell Sleep Questionnaire during the nights following stimulation sessions 8, 9, and 10. The study will also evaluate wearable-device sleep measures, insomnia symptoms, pain and symptom burden, psychological symptoms, quality of life, safety, feasibility, and changes in brain activity measured by 64-channel electroencephalography.

This is an investigator-initiated, single-center, prospective, randomized, double-blind, parallel-group, sham-controlled trial in adults with advanced non-small cell lung cancer (NSCLC) and in-hospital sleep disturbance. Eligible participants will have pathologically or cytologically confirmed unresectable stage IIIB-IIIC or stage IVA-IVB NSCLC, or recurrent disease after curative-intent treatment that is considered unsuitable for further curative local therapy. In-hospital sleep disturbance is defined as a mean Richards-Campbell Sleep Questionnaire (RCSQ) score below 70 across two consecutive valid inpatient nights together with a baseline Insomnia Severity Index (ISI) score of at least 8. Participants will be randomized in a 1:1 ratio to active or sham stimulation. Active treatment will consist of 1-Hz repetitive transcranial magnetic stimulation over the left dorsolateral prefrontal cortex at the F3 position, delivered at 100% of the resting motor threshold with 1,800 pulses per session over approximately 30 minutes. One session will be administered daily for a total of 10 sessions completed within 10-14 days. Participants will continue to receive their clinically indicated anticancer treatment and supportive care, and study procedures will not delay or interfere with necessary clinical treatment. The sham group will undergo matched stimulation using a dedicated sham coil or validated active/sham masking module. Target location, participant positioning, stimulation rhythm, sound, session duration, and study interaction procedures will be matched to active treatment, but the sham procedure will not provide the intended therapeutic cortical stimulation. Participants and outcome assessors will remain blinded to treatment allocation. The stimulation operator cannot be blinded because of device-operation requirements but will not participate in participant recruitment, primary outcome assessment, data entry, or statistical analysis. The primary outcome is the participant-level mean RCSQ total score obtained on the mornings after the nights following stimulation sessions 8, 9, and 10. RCSQ scores range from 0 to 100, with higher scores indicating better sleep. The primary analysis will compare the active and sham groups using ANCOVA/linear regression adjusted for the mean RCSQ score from two consecutive valid baseline inpatient nights and prespecified randomization stratification factors. Secondary and exploratory outcomes include total sleep time measured using the Lifesense HR6 wearable device, other device-derived sleep measures when reliably available, ISI, pain and opioid exposure, lung cancer-related symptom burden, fatigue, anxiety, depressive symptoms, health-related quality of life, functional status, length of hospital stay, anticancer-treatment interruption, treatment feasibility, and adverse events. Resting-state 64-channel EEG and a prespecified TMS-EEG mechanistic substudy will explore changes in frequency-band power, alpha peak frequency, functional connectivity, network topology, and TMS-evoked cortical responses.