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Table 2 Objectives and hypotheses of the study

From: Protocol for the “Chemobrain in Motion – study” (CIM – study): a randomized placebo-controlled trial of the impact of a high-intensity interval endurance training on cancer related cognitive impairments in women with breast cancer receiving first-line chemotherapy

Objectives Hypotheses
Main objective
• To evaluate the effects of a HIIT versus placebo, conducted simultaneously with first-line chemotherapy regimen on CRCI, in women with breast cancer
Main hypothesis
• In women with breast cancer, the decline in HVLT-R-, TMT-A/B- and COWAT test performance from baseline to completion of the exercise-intervention, is significantly smaller in the HIIT group compared to the control group (hypothesis A)
Secondary objective
• To evaluate the effects of a HIIT versus placebo, conducted simultaneously with first-line chemotherapy regimen on self-perceived cognitive performance, in women with breast cancer
Secondary hypotheses
• In women with breast cancer, the decline of FACT-COG scores from baseline to completion of the exercise-intervention/to 6-months follow-upa, is significantly smaller in the HIIT group compared to the control group (hypothesis B)
• To evaluate the effects of a HIIT versus placebo, conducted simultaneously with first-line chemotherapy regimen on executive functioning subdomain response inhibition, in women with breast cancer • In women with breast cancer, the decline of INHIB performance from baseline to completion of the exercise-intervention/to 6-months follow up, is significantly smaller in the HIIT group compared to the control group (hypothesis C)
• To evaluate the effects of a HIIT versus placebo, conducted simultaneously with first-line chemotherapy regimen on proinflammatory marker expression, in women with breast cancer • In women with breast cancer, the increase of serum levels of TNF-α, IL-6, IL-1α, IL-1β, CRP from baseline to completion of the exercise-intervention/to 6-months follow up, is significantly smaller in the HIIT group compared to the control group (hypothesis D)
• To evaluate the effects of a HIIT versus placebo, conducted simultaneously with first-line chemotherapy regimen on antiinflammatory marker expression, in women with breast cancer • In women with breast cancer, the decrease of serum levels of IL-1RA, IL-10 from baseline to completion of the exercise-intervention/to 6-months follow up, is significantly smaller in the HIIT group compared to the control group (hypothesis E)
• To evaluate the effects of a HIIT versus placebo, conducted simultaneously with first-line chemotherapy regimen on neurotrophin expression, in women with breast cancer • In women with breast cancer, the decrease of BDNF serum level from baseline to completion of the exercise-intervention/to 6-months follow up, is significantly smaller in the HIIT group compared to the control group (hypothesis F)
• To evaluate the effects of a HIIT versus placebo, conducted simultaneously with first-line chemotherapy regimen on growth factor expression, in women with breast cancer • In women with breast cancer, the decrease of VEGF and IGF-1 serum levels from baseline to completion of the exercise-intervention/to 6-months follow up, is significantly smaller in the HIIT group compared to the control group (hypothesis G)
• To evaluate the effects of a HIIT versus placebo, conducted simultaneously with first-line chemotherapy regimen on physical fitness, in women with breast cancer • In women with breast cancer, the decrease of watts per kilogram and VO2peak measured during IXT from baseline to completion of the exercise-intervention/to 6-months follow up, is significantly smaller in the HIIT group compared to the control group (hypothesis H)
• To evaluate the effects of a HIIT versus placebo, conducted simultaneously with first-line chemotherapy regimen on anxiety, fatigue, quality of life, sleep disturbances and chemotherapy compliance, in women with breast cancer • In women with breast cancer, the change of HADS-D, MFI-20, EORTC-QLQ-C30, QOL-BR23 and PSQI scores from baseline to completion of the exercise-intervention/to 6-months follow up, is significantly more favorable in the HIIT group compared to the control group (hypothesis I)
• To evaluate the sustainability of the effects of a HIIT versus placebo conducted simultaneously with first-line chemotherapy regimen on CRCI in women with breast cancer • In women with breast cancer, the decline in HVLT-R-, TMT-A/B- and COWAT test performance from baseline to 6-months follow up is significantly smaller in the HIIT group compared to the control group (hypothesis J)
Exploratory mediation analysis
 • To evaluate if the change in proinflammatory marker expression, from baseline to completion of the exercise-intervention, partially mediates the effect of the exercise intervention on the change of cognitive performance, from baseline to completion of the exercise-intervention, in women with breast cancer. • In women with breast cancer, there is a significant indirect effect of exercise intervention on the change of HVLT-R−/TMT-A/B-/COWAT test performance, from baseline to completion of the exercise-intervention, through the change of TNF-α/IL-6/IL-1α/IL-1β/CRP serum level, from baseline to completion of the exercise-intervention (hypothesis K)
 • To evaluate if the change in antiinflammatory marker expression, from baseline to completion of the exercise-intervention, partially mediates the effect of the exercise intervention on the change of cognitive performance, from baseline to completion of the exercise-intervention, in women with breast cancer. • In women with breast cancer, there is a significant indirect effect of exercise intervention on the change of HVLT-R−/TMT-A/B-/COWAT test performance, from baseline to completion of the exercise-intervention, through the change of IL-1RA/IL-10 serum level, from baseline to completion of the exercise-intervention (hypothesis L)
 • To evaluate if the change in neurotrophin marker expression, from baseline to completion of the exercise-intervention, partially mediates the effect of the exercise intervention on the change of cognitive performance, from baseline to completion of the exercise-intervention, in women with breast cancer. • In women with breast cancer, there is a significant indirect effect of exercise intervention on the change of HVLT-R−/TMT-A/B-/COWAT test performance, from baseline to completion of the exercise-intervention, through the change of BDNF serum level, from baseline to completion of the exercise-intervention (hypothesis M)
 • To evaluate if the change in growth factor marker expression, from baseline to completion of the exercise-intervention, partially mediates the effect of the exercise intervention on the change of cognitive performance, from baseline to completion of the exercise-intervention, in women with breast cancer. • In women with breast cancer, there is a significant indirect effect of exercise intervention on the change of HVLT-R−/TMT-A/B-/COWAT test performance, from baseline to completion of the exercise-intervention, through the change of VEGF/IGF-1 serum level, from baseline to completion of the exercise-intervention (hypothesis N)
  1. a 6-month follow up will be conducted 6 months after completion of the exercise intervention
  2. HIIT high-intensity interval endurance training, HVLT-R Hopkins Verbal Learning Test - Revised, COWAT Controlled Oral Word Association Test, TMT-A/B Trail Making Test part A/part B, INHIB Response Inhibition Test, FACT-COG Functional Assessment of Cancer Therapy – Cognitive function, TNF-α tumor necrosis factor alpha, IL-6 Interleukin-6, IL-1α Interleukin-1 Alpha, IL-1β Interleukin-1 Beta, CRP C-reactive protein, IL-1RA Interleukin-1 receptor antagonist, IL-10 Interleukin-10, BDNF brain-derived neurotrophic factor, VEGF vascular endothelial growth factor, IGF-1 insulin-like growth factor 1, VO2peak peak of oxygen uptake in milliliter oxygen uptake per kilogram bodyweight per minute, IXT incremental exercise test, HADS-D German version of the Hospital Anxiety and Depression Scale MFI-20 The multidimensional Fatigue Inventory, EORTC-QLQ-C30 core questionnaire 30 items of the European Organization for Research and Treatment of Cancer, QOL-BR23 the breast cancer specific quality of life questionnaire of the EORTC PSQI Pittsburgh Sleeping Quality Index