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

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.

Inclusion criteria

Age 18-80 years and able to understand the study and provide written informed consent.

Pathologically or cytologically confirmed non-small cell lung cancer (NSCLC), classified according to the IASLC 9th edition TNM system as unresectable stage IIIB-IIIC, stage IVA-IVB, or recurrent disease after curative-intent treatment and considered by a multidisciplinary team to be unsuitable for further curative local therapy.

Receiving a stable first-line or later-line systemic anticancer treatment regimen, or receiving inpatient symptom/supportive care after anticancer treatment; the treatment plan must be established before randomization, with no planned initiation of new radiotherapy or change in systemic anticancer therapy before assessment of the primary outcome.

Mean Richards-Campbell Sleep Questionnaire (RCSQ) score <70 across two consecutive valid inpatient nights and baseline Insomnia Severity Index (ISI) score ≥8.

Eastern Cooperative Oncology Group (ECOG) performance status 0-2 and estimated life expectancy ≥3 months.

Hospitalized for anticancer treatment-related observation, symptom control, or supportive care, with an expected remaining hospital stay of at least 10 days from randomization and ability to complete 10 stimulation sessions and the primary outcome assessment within 14 days.

Able to complete the prespecified RCSQ assessments and brief sleep diary, continuous Lifesense HR6 monitoring, and 64-channel EEG assessment.

Exclusion criteria

Unable to provide valid informed consent, unwilling to participate, or unable to reliably complete the primary RCSQ assessment.

History of epilepsy or unexplained seizures, active intracranial hemorrhage, significant cerebral edema, elevated intracranial pressure, recent stroke, or severe traumatic brain injury.

Intracranial ferromagnetic metal, cochlear implant, deep brain stimulator, cardiac pacemaker/implantable cardioverter-defibrillator, or other TMS-incompatible implant.

Severe scalp infection, open wound, or inability to safely position the TMS coil or EEG cap.

Pregnancy or any condition considered by the investigator to pose unacceptable risk.

Active or uncontrolled brain metastases, or brain metastases associated with cerebral edema, hemorrhage, focal neurological symptoms, or a need for escalating corticosteroid treatment.

Untreated or unstable obstructive sleep apnea, or another primary sleep disorder requiring priority specialist management.

Initiation, discontinuation, or ≥50% dose change of sedative-hypnotic medication within 48 hours before randomization, or a planned initiation/discontinuation of medication expected to substantially affect sleep before assessment of the primary outcome.

Planned initiation of new whole-brain or local radiotherapy, first use of high-dose corticosteroids, or switching of systemic anticancer therapy before assessment of the primary outcome.

ECOG performance status ≥3, uncontrolled respiratory failure, delirium, or inability to reliably complete the prespecified sleep assessments.