Sleep and Immune Checkpoint Inhibitors

Study Overview
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Brief Summary
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Sleep disturbances are prevalent in cancer patients and linked to levels of fatigue and depressive symptoms with a major impact on quality of life. A growing body of evidence links sleep disturbances with various health outcomes, including increased risk of depression, cancer, and overall mortality. Inflammation is suggested to be an underlying mechanism both driving and maintaining the symptom cluster of sleep disturbance, fatigue and depressive symptoms, as well as being bi-directionally linked to sleep. The main purpose of the present study is to investigate the prevalence of sleep disturbance and its association with psychological and physical symptoms as well as the clinical response to ICI in non-small-cell lung cancer patients (NSCLC), with a secondary aim of exploring the role of inflammation.

Detailed Description
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A total of 240 cancer patients diagnosed with advanced NSCLC, referred to treatment with ICI will be enrolled in this prospective observational study. Patients will be assessed prior to initiation of treatment (baseline) and every third subsequent week, corresponding to each treatment cycle over a period of 18 weeks. Assessments will include questionnaires, sleep diaries, actigraphy, and blood and saliva samples to examine sleep, fatigue, psychological and physical symptoms, the sleep-wake-cycle, inflammation, and cortisol. Additionally, the patients will be asked to complete a reduced questionnaire every week within the 18 weeks period, to address weekly fluctuations in sleep quality, fatigue, and mood. Treatment response is assessed after 9 and 18 weeks. Aims: To explore possible associations between sleep and the clinical response to treatment with ICI. To investigate the prevalence of sleep disturbance in patients with NSCLC during treatment with ICI. To prospectively assess changes in sleep parameters over the course of treatment. To examine associations between sleep parameters and fatigue, depression, anxiety, and inflammation. To explore possible associations between sleep, fatigue, depression, inflammatory responses and the clinical response to treatment with ICIs. Hypotheses: Patients with high levels of sleep disturbance (insomnia severity) will experience 1) poorer clinical response to ICI, 2) more depressive symptoms, 3) higher levels of fatigue, 4) poorer overall health-related quality of life (HRQoL), 5) higher levels of inflammation.

Official Title
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Sleep Disturbance and Its Association With Fatigue, Depressive Symptoms, and Clinical Response to Immune Checkpoint Inhibitors (ICI) in Lung Cancer Patients

Conditions
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Lung Cancer

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: - Confirmed diagnosis of advanced non-small cell lung cancer Exclusion Criteria: Insufficient Danish proficiency Pre-existing confounding psychiatric illnesses

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical response to treatment | Radiological evaluation of the clinical response to treatment with ICI, according to RECIST criteria. | Changes from baseline to 9 and 18 weeks after treatment initiation, respectively. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Insomnia Severity | Changes in insomnia severity as measured with The Insomnia Severity Index (ISI). Total score ranges from 0 to 28. Interpreted as follows: absence of insomnia (0-7); sub-threshold insomnia (8-14); moderate insomnia (15-21); and severe insomnia (22-28). | Weekly from baseline to 18 weeks after treatment initiation, and follow-up 1, 2 and 3 years from baseline, respectively. | 
| Sleep diary | Changes in Standard sleep metrics (nightly sleep onset latency (SOL), wakefulness after initial sleep onset (WASO), total sleep time (TST), total time spent in bed (TIB), sleep efficiency (SE). | Baseline, and week 3, 6, 9, 12, 15 and 18, respectively. | 
| Fatigue | Changes in subjective fatigue as measured with the Multidimensional Fatigue Symptom Inventory - Short Form (MFSI-SF). Subscales (general, physical, emotional, and mental fatigue) are summed and the vigor scale subtracted to create a fatigue total score, with higher scores indicating higher levels of fatigue. | Baseline, and week 3, 6, 9, 12, 15 and 18, respectively, and follow-up 1, 2 and 3 years from baseline, respectively. | 
| Depressive symptoms | Changes in depressive symptoms as measured with the Patient-Reported Outcomes Measurement Information System (PROMIS®) Depression - Short Form 8a. Total raw score ranges from 8 to 40, with higher scores indicating greater severity of depression. | Baseline, and week 3, 6, 9, 12, 15 and 18, respectively, and follow-up 1, 2 and 3 years from baseline, respectively. | 
| Health-related quality of life | Changes in health-related quality of life as measured with The European Organization for Research and Treatment of Cancer, Quality of Life questionnaire for cancer patients (EORTC QLQ-C30). The standardized raw score, ranges from 0 to 100; a higher score represents a higher (better) level of functioning, or a higher (worse) level of symptoms. | Baseline, and week 3, 6, 9, 12, 15 and 18, respectively, and follow-up 1, 2 and 3 years from baseline, respectively. | 
| Disease specific health-related quality of life | Changes in disease specific health-related quality of life as measured with The European Organization for Research and Treatment of Cancer, Quality of Life Lung Cancer Module (EORTC QLQ-LC29). The standardized raw score, ranges from 0 to 100; a high score for the symptom scales / single items represents a high level of symptomatology or problems. | Baseline, and week 3, 6, 9, 12, 15 and 18, respectively, and follow-up 1, 2 and 3 years from baseline, respectively. | 
| Perceived Stress | Changes in perceived stress as measured with The Perceived Stress Scale (PSS). Total score ranges from 0 to 40, with higher scores indicating higher perceived stress. | Baseline, and week 3, 6, 9, 12, 15 and 18, respectively, and follow-up 1, 2 and 3 years from baseline, respectively. | 
| Sickness behavior | Changes in subjective sickness behavior as measured with the Sickness Questionnaire (SicknessQ). Total score ranges from 0 to 30, with higher scores indicating more sickness behaviour. | Baseline, and week 3, 6, 9, 12, 15 and 18, respectively, and follow-up 1, 2 and 3 years from baseline, respectively. | 
| Cortisol | Cortisol awakening response (CAR), and the diurnal cortisol slope (DCS) | Baseline, and week 3, 6, 9, 12, 15 and 18, respectively. | 
| Inflammatory response 1 | CRP | Baseline, and week 3, 6, 9, 12, 15 and 18, respectively. | 
| Inflammatory response 2 | IL-6 | Baseline, and week 3, 6, 9, 12, 15 and 18, respectively. | 
| Inflammatory response 3 | TNF-a | Baseline, and week 3, 6, 9, 12, 15 and 18, respectively. | 
| Inflammatory response 4 | Se-Cortisol | Baseline, and week 3, 6, 9, 12, 15 and 18, respectively. | 
| Inflammatory response 5 | White blood cell count. | Baseline, and week 3, 6, 9, 12, 15 and 18, respectively. | 
| Actigraphy 1 | Objective sleep outcome. Nightly sleep onset latency (SOL) | Baseline to 18 weeks after initiation of treatment. | 
| Actigraphy 2 | Objective sleep outcome: Wakefulness after initial sleep onset (WASO) | Baseline to 18 weeks after initiation of treatment. | 
| Actigraphy 3 | Objective sleep outcome: Total sleep time (TST) | Baseline to 18 weeks after initiation of treatment. | 
| Actigraphy 4 | Objective sleep outcome: Total time spent in bed (TIB) | Baseline to 18 weeks after initiation of treatment. | 
| Actigraphy 5 | Objective sleep outcome: Sleep efficiency (SE, i.e., the percent of the time asleep out of amount of time spent in bed) | Baseline to 18 weeks after initiation of treatment. | 
| Actigraphy 6 | Objective sleep outcome: Circadian activity rhythms. | Baseline to 18 weeks after initiation of treatment. | 
| Disease status | Changes in disease status after treatment initiation with ICI. Changes are evaluated according to RECIST criteria. | 1, 2 and 3 years from treatment initiation (baseline). | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Sleep, Fatigue, Depressive symptoms, Immune Checkpoint Inhibitors, Lung Cancer, Clinical response