Impact of a Physical Activity Program to Reduce Long-term Cancer-related Fatigue in Metastatic Testicular Germ Cell Tumor Patients

Study Overview
=================
Brief Summary
-----------------
Testicular germ cell tumor (TGCT) is the most common malignancy in men between 15 and 40 years. Although TCGT survivors have a good survival prognosis, they suffer from short- and long-term sequelae such as chronic fatigue, psychological disorders, cardiovascular toxicities and second malignancies. The benefits of physical activity (PA) during treatments have been demonstrated in cancer patients to improve quality of life (QoL) and physical fitness and to reduce fatigue. However, few PA programs have been proposed to TGCT patients and their effects on sequelae have not been assessed yet. A growing body of evidence links treatment-related alteration in the gut microbiota to sequelae of cancer survivors, including fatigue and cardiovascular toxicities. Also, PA has been known as a possible modulator of the gut microbiota composition. To date, no study has been conducted to examine how the gut microbiota and its metabolites moderate the effect of PA on fatigue and other late effects in TGCT survivors. The objectives will be to assess the impact of a PA program on fatigue and other sequelae and to investigate how the gut microbiota and its metabolites moderate the associations between PA and sequelae. We will conduct a prospective, multicenter, phase III, randomized controlled trial of a one-year supervised PA program. 236 men with metastatic TGCT and eligible for a first line of chemotherapy will be randomly assigned to either PA intervention or control arm. All patients will benefit from a connected activity tracker and PA recommendations. In the intervention arm, PA will be based on supervised sessions and motivational interviews. The primary endpoint (fatigue) will be assessed at 3 years. The trial will provide novel insights into the impact of PA on fatigue and other sequelae in TGCT survivors with understanding a potential underlying mechanism of gut microbiota. This evidence will support the development of targeted PA guidelines to improve QoL and reduce sequelae in TGCT survivors.

Official Title
-----------------
A National, Multicenter, Phase III Randomized Controlled Trial to Assess the Impact of a One-year Supervised Physical Activity Program to Reduce Long-term Cancer-related Fatigue in Metastatic Testicular Germ Cell Tumor Patients

Conditions
-----------------
Metastatic Testicular Cancer

Intervention / Treatment
-----------------
* Behavioral: Physical activity recommendations
* Behavioral: Connected activity tracker
* Behavioral: Physical Activity (PA) Intervention


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Men ≥18 years With a metastatic germ cell tumor histologically confirmed (seminoma and non-seminoma) Who have already undergone an orchidectomy Having a first line of chemotherapy planned with BEP, EP or VIP Having a smartphone (i.e. to connect the activity tracker) PS < or = 2 Whose ability to practice an adapted physical activity (APA) has been certified by a medical certificate issued by the referring oncologist or the investigating physician Available and willing to participate in the study for the duration of the intervention and follow-up, Able to understand, read and write French, Affiliated with a social security scheme, Having dated and signed an informed consent. Exclusion Criteria: Presence of symptomatic bone and/or brain metastases Central nervous system involvement with neurological deficits preventing walking History or coexistence of another primary cancer (apart from in situ cancer of any location and/or basal cell skin cancer and/or basal cell skin cancer and/or a cancer in complete remission for more than 3 years), Contraindication to physical activity (e.g. uncontrolled hypertension, uncontrolled heart disease) uncontrolled heart disease), Unable to be followed for medical, social, family, geographical or psychological reasons, during the entire study period, Deprived of liberty by judicial or administrative decision, or adults protected by law, Concurrent participation in another study in PA.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
Male

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Control group<br> | Behavioral: Physical activity recommendations<br>* At the baseline, all participants will receive the international recommendations in terms of physical activity for promoting health in the general population.<br>Behavioral: Connected activity tracker<br>* At baseline, all participants will receive a connected activity tracker to wear 24 hours a day during one year. Patients will be asked to download an application, dedicated to the study so that the physical activity data (ie. number of steps per day) will be synchronized in the application.<br>|
| Experimental: Intervention group<br> | Behavioral: Physical activity recommendations<br>* At the baseline, all participants will receive the international recommendations in terms of physical activity for promoting health in the general population.<br>Behavioral: Connected activity tracker<br>* At baseline, all participants will receive a connected activity tracker to wear 24 hours a day during one year. Patients will be asked to download an application, dedicated to the study so that the physical activity data (ie. number of steps per day) will be synchronized in the application.<br>Behavioral: Physical Activity (PA) Intervention<br>* The intervention will last 1 year and will have 2 phases. Phase 1: At each cycle of chemotherapy, patients will be proposed to perform 2-4 sessions per week. This program will be individual, supervised, performed at a moderate intensity. Between cycles, patients will be asked to perform 1-2 supervised collective live online physical activity sessions per week, proposed by a partner specialized in online PA. Phase 2: After chemotherapy, patients will be asked to perform 2-3 PA sessions per week at a moderate intensity. Patients will be offered 2 options of PA practice: in the supervised collective live online PA session (as already performed in the phase 1), and/or in a fitness center (this practice will take place in a classic environment with a 9-month free access for patients thanks to a partnership). In addition, patients will benefit from 4 individual motivational interviews, conducted by videoconference and/or by phone call with a professional.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| cancer-related fatigue, considering both physical and cognitive fatigue scores at 3 years after the start of first-line chemotherapy | Multidimensional aspects of fatigue will be assessed by the European Organization for Research and Treatment of Cancer (EORTC) QLQ-FA12 cancer related fatigue module. EORTC QLQ-FA12 consists of 12 items to evaluated physical, cognitive and emotional domains of cancer-related fatigue. Participants will answer to a 4-points Likert scale ranging from not at all to very much. All scores will be transformed to a 0 to 100 scale and higher scores will indicate greater degree of fatigue. The Primary Outcome Measure will be assessed with physical and cognitive items. | Year 3 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| other dimensions of fatigue | Multidimensional aspects of fatigue will be assessed by the European Organization for Research and Treatment of Cancer (EORTC) QLQ-FA12 cancer related fatigue module. EORTC QLQ-FA12 consists of 12 items to evaluated physical, cognitive and emotional domains of cancer-related fatigue. Participants will answer to a 4-points Likert scale ranging from not at all to very much. All scores will be transformed to a 0 to 100 scale and higher scores will indicate greater degree of fatigue. All of the secondary cancer related fatigue dimensions except the physical and cognitive items are evaluated (emotional fatigue, interference with daily life and social sequelae, assessed by the EORTC QLQ-FA12 questionnaire). | Inclusion, end of chemotherapy (Month 4), Month 6, Month 12, Year 2, Year 3, Year 4, Year 5, Year 6, Year 7, Year 8, Year 9, Year 10 | 
| Health-related quality of life (EORTC QLQ-C30) | Health-Related Quality of Life (HRQoL) and fatigue will be measured by the European Organization for Research and Treatment of Cancer (EORTC) Quality Of Life Questionnaire (QLQ-C30). QLQ-C30 questionnaire consists of 30 items to evaluate 5 functioning domains (physical, role, emotional, cognitive, and social), a global HRQoL domain, 3 symptom domains (pain, fatigue and nausea) and 6 single items (dyspnea, insomnia, anorexia, diarrhea, constipation and financial impact).Participants will answer to a Likert scale ranging from not at all to very much and from very bad to excellent only for the global HRQoL questions. All scores will be standardized to a 0 to 100 scale according to the EORTC scoring manual. Higher scores represent better functioning, better global HRQoL and greater symptom burden. | Inclusion, end of chemotherapy (Month 4), Month 6, Month 12, Year 2, Year 3, Year 4, Year 5, Year 6, Year 7, Year 8, Year 9, Year 10 | 
| Health-related quality of life specific for testicular cancer (EORTC QLQ-TC26) | The module Quality of Life Questionnaire specific to Testicular Cancer (QLQ-TC26) comprises seven multi-item scales (treatment side effects, treatment satisfaction, future perspective, communication, sexual activity, functioning and enjoyment) and six single items (job and education problems, physical limitations, family problems, infertility, body image problems, testicular transplant satisfaction).Participants will answer to a Likert scale ranging from not at all to very much. All scores will be standardized to a 0 to 100 scale according to the EORTC scoring manual. Higher scores represent better functioning, better global HRQoL and greater symptom burden. | Inclusion, end of chemotherapy (Month 4), Month 6, Month 12, Year 2, Year 3, Year 4, Year 5, Year 6, Year 7, Year 8, Year 9, Year 10 | 
| Proportion of patients who modify their cognition | The cancer-related cognitive impairment will be measured by the Functional Assessment of Cancer Therapy-Cognition (FACT-Cog). The FACT-Cog is a validated self-administrated questionnaire in order to assess memory, attention, concentration, language, and thinking abilities. The questionnaire is composed of 37 items with four subscales: patients' perceived cognitive impairments, perceived cognitive abilities, deficits observed or commented on by others, and impact of cognitive changes on HRQoL. Participant will answer how often this situation occurred during the last 7 days on a Likert-type scale ranging from never to several times a day. For both scales, higher scores indicated better perceived cognitive function. | Inclusion, end of chemotherapy (Month 4), Month 12, Year 2, Year 3 | 
| Proportion of patients who modify their anxiety and depression level | Hospital Anxiety and Depression scale (HADS) is an instrument used to screen for anxiety and depressive disorders. It has 14 rated items from 0 to 3. Seven questions relate to anxiety (total A) and seven others to the depressive dimension (total D), allowing thus obtaining two scores (maximum score for each score = 21). | Inclusion, end of chemotherapy (Month 4), Month 6, Month 12, Year 2, Year 3 | 
| Proportion of patients who change their anthropometry | Weight (in kilograms), Height (in meters), Body Mass Index (in kg/m^2) | Inclusion, end of chemotherapy (Month 4), Month 6, Month 12, Year 2, Year 3 | 
| Physical condition and muscular strength (6-minute walk test) | assessed by the 6-minute walk test (distance traveled in meters in 6 minutes) | Inclusion, end of chemotherapy (Month 4), Month 6, Month 12, Year 2, Year 3 | 
| Physical condition and muscular strength (hand-grip) | assessed by the hand-grip test (kg) | Inclusion, end of chemotherapy (Month 4), Month 6, Month 12, Year 2, Year 3 | 
| Physical condition and muscular strength (sit-to-stand test) | assessed by the sit-to-stand test (number of repetitions) | Inclusion, end of chemotherapy (Month 4), Month 6, Month 12, Year 2, Year 3 | 
| Proportion of patients who change their physical activity (PA) and sedentary levels | PA and sedentary levels will be measured by National Observatory of Physical Activity and Sedentary Lifestyle - Physical Activity questionnaire (ONAPS-PAQ) This questionnaire assesses the level of physical activity and sedentary lifestyle during a typical week for the adult population. It is divided into three parts and 21 questions: activities at work, travel for utilitarian purposes and leisure or home activities. This questionnaire also assesses physical inactivity at all times of life (travel, work, leisure). | Inclusion, end of chemotherapy (Month 4), Month 6, Month 12, Year 2, Year 3, Year 4, Year 5, Year 6, Year 7, Year 8, Year 9, Year 10 | 
| Physical activity level | number of days wearing the tracker | Every days during the first year | 
| Adherence to the physical activity tracker | number of days wearing the tracker | Month 12 | 
| Satisfaction with the intervention | self-administered questionnaire | Month 12 | 
| sleep quality and heart rate | assessed by the connected watch | continuously during the first year | 
| compliance with PA sessions | assessed by the number of sessions scheduled/performed during the different phases of the intervention | Month 12 | 
| Motivation | This questionnaire can be used on a daily basis, for all populations, with the aim of better understanding the motivation of individuals to practice physical activities from a health perspective. The challenge is to provide professionals with an appropriate questionnaire that can assess patient motivation at the start and end of PA care. Participants will answer to a 7-points Likert scale ranging from does not match at all to corresponds very strongly. This questionnaire assesses several items : intrinsic motivation, integrated regulation, identified regulation, introjected regulation, external regulation, amotivation. The results for each patient should be compared with the results of the validation population. | Inclusion, end of chemotherapy (Month 4), Month 12 | 
| pre-intervention PA practice environment | The association between the pre-intervention PA practice environment (type of activity, practice locations) and compliance with the intervention | Inclusion | 
| Number of participants with neuropathies and the neuropathies level | Neuropathies assessed by a visual analog scale. Participants will answer to a 0 (better outcome) to 10 (worst outcome) scale. | Inclusion, end of chemotherapy (Month 4), Month 6, Month 12, Year 2, Year 3, Year 4, Year 5, Year 6, Year 7, Year 8, Year 9, Year 10 | 
| Number of participants with pain and the pain level | Pain assessed by a visual analog scale. Participants will answer to a 0 (better outcome) to 10 (worst outcome) scale. | Inclusion, end of chemotherapy (Month 4), Month 6, Month 12, Year 2, Year 3, Year 4, Year 5, Year 6, Year 7, Year 8, Year 9, Year 10 | 
| TGCT relapse | CT scan/tumor-marker increase | Month 12, Year 2, Year 3, Year 4, Year 5, Year 6, Year 7, Year 8, Year 9, Year 10 | 
| Number of participants with treatment-related adverse events as assessed by CTCAE v5.0 | Occurrence of induced-treatment toxicity according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE) | end of chemotherapy (Month 4), Month 6, Month 12, Year 2, Year 3, Year 4, Year 5, Year 6, Year 7, Year 8, Year 9, Year 10 | 
| Second primary malignancy | The occurence of second primary malignancy | Inclusion, end of chemotherapy (Month 4), Month 6, Month 12, Year 2, Year 3, Year 4, Year 5, Year 6, Year 7, Year 8, Year 9, Year 10 | 
| Sustainable return to work | number of consecutive working days without sick leave | Month 12, Year 2, Year 3 | 
| Immune and inflammatory biomarkers | IL-1α/β, IL-6, IL-15, TNF-α, CRP | Inclusion, end of chemotherapy (Month 4), Month 12, Year 3 | 
| liver function biomarkers | ALT/AST, bilirubin | Inclusion, end of chemotherapy (Month 4), Month 12, Year 3 | 
| gut microbiota composition and diversity | measured using 16s rRNA Illumina sequencing | Inclusion, end of chemotherapy (Month 4), Month 12, Year 3 | 
| french validation of EORTC QLQ-TC26 | To validate the psychometric properties of the French version of the EORTC QLQ-TC26 questionnaire assessing the health-related health-related quality of life in patients with testicular cancer | Inclusion, end of chemotherapy (Month 4), Month 6, Month 12, Year 2, Year 3, Year 4, Year 5, Year 6, Year 7, Year 8, Year 9, Year 10 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
fatigue, sequelae, gut microbiota composition