Wide Spectrum Micronutrients Supplementation in Patients With Cancer Related Fatigue During Adjuvant Chemotherapy

Study Overview
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Brief Summary
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The goal of this clinical trial is to test the effect of the administration of APPORTAL® in addition to the SoC (recommended physical exercise), in patients with breast cancer, suffering from fatigue during adjuvant chemotherapy. The main questions it aims to answer are: if the food supplement APPORTAL® can be of help in supporting the physiological energy level, against the fatigue symptom in cancer patients undergoing adjuvant chemotherapy; if the supplementation with APPORTAL® can optimize the nutritional status, the muscular strength, the quality of life of the patient. Also, the patients' satisfaction on the product received, the adherence to treatment will be evaluated and the overall safety and tolerability of the study product. The patients will be asked to perform 3 study visits from baseline to the end of treatment (at 4 and 8 weeks after baseline) and a follow-up visit after 12 weeks from baseline. The main assessments at each visit will be: physical examination, weight, Body Mass Index (BMI), body temperature (°C), heart rate, respiratory frequency, and systolic and diastolic blood pressure; previous and concomitant treatments; fatigue assessment through BFI questionnaire; quality of life through questionnaire SF-12; muscular strength (dynamometer) Adverse Event check (from Visit 2) Moreover, at visit 1 (baseline) and at visit 3 (end of treatment) a blood sample will be collected to evaluate the blood metabolites. Telephonic follow-up will be done at 2 weeks, 6 weeks, 10 weeks to assess compliance and to recommendations on physical activity and to study treatment (only at 2 and 6 weeks) and tolerability/safety. Participants will receive the nutrition supplement or the placebo, in addition to the SoC (recommended physical exercise), for 8 weeks. Researchers will compare Apportal® and Placebo groups to see if the physiological energy level against the fatigue symptom, the nutritional status, the muscular strength, the quality of life of the patient improve after 8 weeks of treatment with APPORTAL® in addition to SoC (recommended physical exercise).

Detailed Description
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SAMPLE SIZE DETERMINATION Considering the average of the BFI 5 in the placebo group and the average 3 in the treated group, with standard deviation of 3, power at 80% and alpha 0.05, we obtain 37 patients per group, thus a total of 74 patients. If a drop-out rate of 20% is fixed, 92 patients in total are obtained. So, a sample of 92 subjects would be sufficient. DATA SAFETY MONITORING BOARD / DATA MONITORING COMMITTEE No Data Safety Monitoring Board (DSMB) or Data Monitoring Committee (DMC) will be convened for the evaluation of safety data during the study. However, the Network Italiano Cure di Supporto in Oncologia (NICSO) society will be in charge of the evaluation of safety information. In fact, a Scientific Committee, composed by NICSO members, has been established to support the Sponsor in the continuous evaluation of safety data emerging from the study. MONITORING AND QUALITY ASSURANCE The study will be monitored by adequately qualified and trained clinical monitors. Before the start of the study, the CRO (Contract Research Organization) responsible for the study site has the task to assess the adequacy of the study site and the staff involved. After start, the study will be monitored to ensure the proper conduct of the clinical study. DATA COLLECTION An Electronic Case Report Form (e-CRF) will be used for recording patient's study data. The Investigator will maintain a list of all persons authorized to make entries and/or corrections on the CRFs. Each authorized person will be provided with a user-specific ID (Identification) protected by a renewable password. Data entries and corrections will be made only by the authorized persons. The e-CRF system will record date and time of any entry and /or correction and the user ID of the person making the entry/correction. The system will keep track of all old and new values (audit trail).

Official Title
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Clinical Study on Wide Spectrum Micronutrients Supplementation in Patients With Cancer Related Fatigue During Adjuvant Chemotherapy

Conditions
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Fatigue, Breast Cancer

Intervention / Treatment
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* Dietary Supplement: APPOPRTAL®
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Females aged 18 or higher. Patients diagnosed with histologically confirmed breast cancer. Patients having done at least one cycle of adjuvant chemotherapy (independently from type of chemotherapy) (*). Patients with ECOG (Eastern Cooperative Oncology Group) performance status ≤1 at screening. Patients with cancer related fatigue of moderate-severe intensity (Numerical Rating Scale NRS > 4). Patients able to follow the recommendations on the physical exercise to do. Patients who accept to use adequate contraceptive methods, if they are of child-bearing potential. Patients willing and able to give signed informed consent and, in the opinion of the Investigator, to comply with the protocol tests and procedures. (*) The chemotherapy used and standard therapeutic regimens in the adjuvant phase in breast cancer and on the basis of the biological characteristics of the neoplasm are as follows: Epirubicin + Cyclophosphamide, 4 cycles, every 21 days -> Taxol weekly for 12 weeks Epirubicin + Cyclophosphamide, 4 cycles, every 14 days -> Taxol, 4 cycles every 14 days Epirubicin + Cyclophosphamide, 4 cycles every 21 days -> Taxol weekly + Trastuzumab with or without Pertuzumab for 1 year Taxotere + Cyclophosphamide, 4 cycles, every 21 days. Exclusion Criteria: Women who are pregnant or breast-feeding. Neoplastic disease other than primary breast cancer. Had major surgery other than breast cancer surgery (central venous access placement and tumor biopsies are not considered major surgery) within 4 weeks prior to randomization. Patients must be well recovered from acute effects of surgery prior to screening. Patients should not have plans to undergo major surgical procedures during the treatment period. Patients with known or symptomatic metastases. Patients unable to readily swallow. Patients with severe gastrointestinal disease (including esophagitis, gastritis, malabsorption, or obstructive symptoms) or intractable or frequent vomiting are excluded. Patients with known or suspected allergy or hypersensitivity to the study products or any of their excipients. Patients with an active, uncontrolled infection. Patients with uncontrolled diabetes mellitus. Patients with untreated clinically relevant hypothyroidism. Patients with concomitant not-correctable alterations, present before chemotherapy, possible determinants of fatigue (NRS ≥ 4), such as anemia, not well controlled pain (NRS > 4), insomnia, electrolyte imbalance, dehydration, anorexia/cachexia, hepatic, renal or heart failure, adrenocortical failure, neurological deficit. Other clinical diagnosis, serious chronic diseases (renal failure with creatinine clearance <30 ml / min; liver failure, heart failure with NYHA -New York Heart Association- class> 2), ongoing or intercurrent illness that in the Investigator's opinion would prevent the patient's participation. Patients receiving opioids or corticosteroids (except as replacement therapy at physiological dose, in subjects with adrenal insufficiency or to prevent emesis on the chemotherapy day). Patients receiving parenteral nutrition (either total or partial). Use of other investigational drug(s) within 30 days before study entry or during the study.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: APPORTAL®<br>APPORTAL® sachet, 1 sachet per day dissolved in a glass of water. To be consumed in the morning, about 10 minutes after breakfast. Dosage form: powder Route: Oral Treatment duration: 8 weeks | Dietary Supplement: APPOPRTAL®<br>* 1 sachet of APPORTAL® contains: Vitamin C 37,5 mg; Vitamin E 30 mg; Vitamin PP 18 mg; Vitamin B1 1 mg; Vitamin D 25 μg; Vitamin H 25 μg; L-arginine 1000 mg; L-carnitine 500 mg; Taurine 25 mg; Ginseng e.s. 100 mg; Eleutherococcus e.s. 50 mg; Magnesium 187,5 mg; Iron 14 mg; Zinc 1,5 mg; Iodine 75 μg; Selenium 27,5 μg; Coenzyme Q10 100 mg; Lycopene 3,06 mg; Tocotrienols 2,5 mg; Coenzyme Q10 100 mg; Lycopene 3,06 mg; Tocotrienols 2,5 mg<br>|
| Placebo Comparator: PLACEBO<br>PLACEBO sachet, 1 sachet per day dissolved in a glass of water To be consumed in the morning, about 10 minutes after breakfast. Dosage form: powder Route: Oral Treatment duration: 8 weeks | Other: Placebo<br>* Ingredients: Maltodextrin, acidifying agent: citric acid, flavours, anticaking agent: tricalcium phosphate, beetroot juice powder; sweetener: sucralose, anti-caking agent: silicon dioxide, colouring agent: beta-carotene<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The change of fatigue perception by the patient through the BFI questionnaire | The Brief Fatigue Inventory (BFI) is a questionnaire specifically developed for rapid assessment of CRF. It is a simple, easily administered questionnaire and the fatigue scale (validated in different languages) consists in nine items anticipated by a flag question asking the patient whether she has felt unusually fatigued or tired during the last week. Three items are related to the intensity of fatigue right now, at its usual level and at its worst level during the past 24 h using a 0-10 numerical scale (0= no fatigue, 10= fatigue as bad as you can image). Six items measure the interference of fatigue with the patients' life during the past 24 h by a 0-10 numerical scale (0= does not interfere, 10= completely interferes). Higher scores represent to more severe fatigue | Change from baseline to 8 weeks of treatment (Visit 3), in active and placebo groups. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The change of fatigue perception by the patient through the BFI questionnaire | The Brief Fatigue Inventory (BFI) is a questionnaire specifically developed for rapid assessment of CRF. It is a simple, easily administered questionnaire and the fatigue scale (validated in different languages) consists in nine items anticipated by a flag question asking the patient whether she has felt unusually fatigued or tired during the last week. Three items are related to the intensity of fatigue right now, at its usual level and at its worst level during the past 24 h using a 0-10 numerical scale (0= no fatigue, 10= fatigue as bad as you can image). Six items measure the interference of fatigue with the patients' life during the past 24 h by a 0-10 numerical scale (0= does not interfere, 10= completely interferes). Higher scores represent to more severe fatigue | Change after 4, 8 and 12 weeks with respect to baseline in both the active and placebo groups | 
| Change in Iron status through hemoglobin assessment | Blood samples of about 5 mL will be collected for the assessment of iron status (hemoglobin, ferritin, transferrin saturation), nutritional markers (albumin, total cholesterol, HDL, LDL and triglycerides), oxidative markers (homocysteine, uric acid) and C-Reactive Protein, serum L-arginine levels. Blood samples will be analysed locally by each site laboratory. | Change after 8 weeks of study treatment with respect to baseline, in both the active and placebo groups | 
| Change in Iron status through ferritin assessment | Blood samples of about 5 mL will be collected for the assessment of iron status (hemoglobin, ferritin, transferrin saturation), nutritional markers (albumin, total cholesterol, HDL, LDL and triglycerides), oxidative markers (homocysteine, uric acid) and C-Reactive Protein, serum L-arginine levels. Blood samples will be analysed locally by each site laboratory. | Change after 8 weeks of study treatment with respect to baseline, in both the active and placebo groups | 
| Change in Iron status through transferrin saturation assessment | Blood samples of about 5 mL will be collected for the assessment of iron status (hemoglobin, ferritin, transferrin saturation), nutritional markers (albumin, total cholesterol, HDL, LDL and triglycerides), oxidative markers (homocysteine, uric acid) and C-Reactive Protein, serum L-arginine levels. Blood samples will be analysed locally by each site laboratory. | Change after 8 weeks of study treatment with respect to baseline in both the active and placebo groups | 
| Change in nutritional status through albumin assessment | Blood samples of about 5 mL will be collected for the assessment of iron status (hemoglobin, ferritin, transferrin saturation), nutritional markers (albumin, total cholesterol, HDL, LDL and triglycerides), oxidative markers (homocysteine, uric acid) and C-Reactive Protein, serum L-arginine levels. Blood samples will be analysed locally by each site laboratory. | Change after 8 weeks of study treatment with respect to baseline in both the active and placebo groups | 
| Change in nutritional status through assessment of total cholesterol, HDL, LDL and triglycerides | Blood samples of about 5 mL will be collected for the assessment of iron status (hemoglobin, ferritin, transferrin saturation), nutritional markers (albumin, total cholesterol, HDL, LDL and triglycerides), oxidative markers (homocysteine, uric acid) and C-Reactive Protein, serum L-arginine levels. Blood samples will be analysed locally by each site laboratory. | Change after 8 weeks of study treatment with respect to baseline in both the active and placebo groups | 
| Change in oxidative status through homocysteine assessment | Blood samples of about 5 mL will be collected for the assessment of iron status (hemoglobin, ferritin, transferrin saturation), nutritional markers (albumin, total cholesterol, HDL, LDL and triglycerides), oxidative markers (homocysteine, uric acid) and C-Reactive Protein, serum L-arginine levels. Blood samples will be analysed locally by each site laboratory. | Change after 8 weeks of study treatment with respect to baseline in both the active and placebo groups | 
| Change in oxidative status through uric acid assessment | Blood samples of about 5 mL will be collected for the assessment of iron status (hemoglobin, ferritin, transferrin saturation), nutritional markers (albumin, total cholesterol, HDL, LDL and triglycerides), oxidative markers (homocysteine, uric acid) and C-Reactive Protein, serum L-arginine levels. Blood samples will be analysed locally by each site laboratory. | Change after 8 weeks of study treatment with respect to baseline in both the active and placebo groups | 
| Change in oxidative status through C-Reactive Protein (CRP) assessment | Blood samples of about 5 mL will be collected for the assessment of iron status (hemoglobin, ferritin, transferrin saturation), nutritional markers (albumin, total cholesterol, HDL, LDL and triglycerides), oxidative markers (homocysteine, uric acid) and C-Reactive Protein, serum L-arginine levels. Blood samples will be analysed locally by each site laboratory. | Change after 8 weeks of study treatment with respect to baseline in CRP in both the active and placebo groups | 
| Change in serum L-arginina levels | Blood samples of about 5 mL will be collected for the assessment of iron status (hemoglobin, ferritin, transferrin saturation), nutritional markers (albumin, total cholesterol, HDL, LDL and triglycerides), oxidative markers (homocysteine, uric acid) and C-Reactive Protein, serum L-arginine levels. Blood samples will be analysed locally by each site laboratory. | Change after 8 weeks of study treatment with respect to baseline in both the active and placebo groups | 
| Changes in QoL through SF-12 Questionnaire | SF-12 is a self-reported outcome measure assessing the impact of health on an individual's everyday life. It is often used as a quality of life measure. The SF-12 is a shortened version of it's predecessor, the SF-36 and it was created to reduce the burden of response The SF-12 consists of twelve questions that measure the same eight domains as the SF-36, to assess physical and mental health. Physical health-related domains include General Health (GH), Physical Functioning (PF), Role Physical (RP), and Body Pain (BP). Mental health-related scales include Vitality (VT), Social Functioning (SF), Role Emotional (RE), and Mental Health (MH). | Change after 4, 8 and 12 weeks with respect to baseline in both the active and placebo groups | 
| Change in muscular strength (hand grip test), | Grip strength is a measure of muscular strength or the maximum force/tension generated by one's forearm muscles. It can be used as a screening tool for the measurement of upper body strength and overall strength. Within this clinical study an hand digital dynamometer will be used. | Change after 4, 8 and 12 weeks with respect to baseline in both the active and placebo groups | 
| Overall patient's satisfaction with the product received, through a 5-points Likert scale | 5-points Likert scale: 1=very satisfied, 2=satisfied, 3=not satisfied nor unsatisfied, 4=not satisfied, 5= not satisfied at all | End of treatment (after 8 weeks of study treatment), in both the active and placebo groups | 
| Adherence to treatment | The percentage of actual sachets taken by the patient in relation to the expected number of sachets, calculated as (number of real sachets taken / number of expected sachets) * 100 | After 4 weeks and after 8 weeks from baseline |