Wide Spectrum Micronutrients Supplementation in Patients with Cancer Related Fatigue During Neoadjuvant and Adjuvant Chemotherapy

Not Applicable

Recruiting

• Conditions: Breast Cancer; Fatigue
• Interventions: Other: Placebo; Dietary Supplement: APPOPRTAL®

• Registration Number: NCT06137833
• Lead Sponsor: Pharmanutra S.p.a.

Brief Summary

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 neoadjuvant and 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

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).

Study Timeline

• Study First Submitted: 2023-07-16
• Study First Submitted QC: 2023-11-14
• Study First Posted: 2023-11-18
• Study Start: 2023-11-27
• Status Verified: 2024-12
• Last Update Submitted: 2024-12-09
• Last Update Posted: 2024-12-13
• Primary Completion: 2025-06
• Study Completion: 2025-06

Recruitment & Eligibility

• Status: RECRUITING
• Sex: Female
• Target Recruitment: 92

Inclusion Criteria

1. Females aged 18 or higher.
2. Patients diagnosed with histologically confirmed breast cancer.
3. Patients having done at least one cycle of neoadjuvant or adjuvant chemotherapy (independently from type of chemotherapy) and who are on active chemotherapy treatment throughout the duration of the study (*).
4. Patients with ECOG performance status ≤1 at screening.
5. Patients with cancer related fatigue of moderate-severe intensity (Numerical Rating Scale NRS > 4).
6. Patients able to follow the recommendations on the physical exercise to do.
7. Patients who accept to use adequate contraceptive methods, if they are of child-bearing potential.
8. Patients willing and able to give signed informed consent and, in the opinion of the Investigator, to comply with the protocol tests and procedures.

(*)Examples of chemotheraphy and standard therapeutic regimens in the neoadjuvant and adjuvant phase in breast cancer and on the basis of the biological characteristics of the neoplasm are as follows:

Neoadjuvant Chemotheraphy

• Epirubicin + Cyclophosphamide, 3 cycles -> Taxol* weekly for 12 weeks;

• Epirubicin + Cyclophosphamide -> Pertuzumab + Trastuzumab (or Phesgo) 3 cycles + Taxol weekly for 12 weeks;

• Carboplatin + Taxol* weekly for 12 weeks -> Epirubicin + Cyclophosphamide;

  • Taxol could be replaced by Taxotere

Adjuvant Chemotheraphy

• 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.

These lists are not to be considered exclusive

Exclusion Criteria

1. Women who are pregnant or breast-feeding.
2. Neoplastic disease other than primary breast cancer.
3. 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.
4. Patients with known or symptomatic metastases.
5. Patients unable to readily swallow. Patients with severe gastrointestinal disease (including esophagitis, gastritis, malabsorption, or obstructive symptoms) or intractable or frequent vomiting are excluded.
6. Patients with known or suspected allergy or hypersensitivity to the study products or any of their excipients.
7. Patients with an active, uncontrolled infection.
8. Patients with uncontrolled diabetes mellitus.
9. Patients with untreated clinically relevant hypothyroidism.
10. 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.
11. 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.
12. 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).
13. Patients receiving parenteral nutrition (either total or partial).
14. Use of other investigational drug(s) within 30 days before study entry or during the study.
15. Triple negative patients in neoadjuvant treatment with Pembrolizumab.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
PLACEBO	Placebo	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
APPORTAL®	APPOPRTAL®	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

Primary Outcome Measures

Name	Time	Method
The change of fatigue perception by the patient through the BFI questionnaire	Change from baseline to 8 weeks of treatment (Visit 3), in active and placebo groups.	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

Secondary Outcome Measures

Name	Time	Method
Change in oxidative status through homocysteine assessment	Change after 8 weeks of study treatment with respect to baseline in both the active and placebo groups	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 in nutritional status through albumin assessment	Change after 8 weeks of study treatment with respect to baseline in both the active and placebo groups	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 in nutritional status through assessment of total cholesterol, HDL, LDL and triglycerides	Change after 8 weeks of study treatment with respect to baseline in both the active and placebo groups	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 in muscular strength (hand grip test),	Change after 4, 8 and 12 weeks with respect to baseline in both the active and placebo groups	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 in Iron status through hemoglobin assessment	Change after 8 weeks of study treatment with respect to baseline, in both the active and placebo groups	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 in Iron status through ferritin assessment	Change after 8 weeks of study treatment with respect to baseline, in both the active and placebo groups	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.
Changes in QoL through SF-12 Questionnaire	Change after 4, 8 and 12 weeks with respect to baseline in both the active and placebo groups	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 in Iron status through transferrin saturation assessment	Change after 8 weeks of study treatment with respect to baseline in both the active and placebo groups	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 in oxidative status through C-Reactive Protein (CRP) assessment	Change after 8 weeks of study treatment with respect to baseline in CRP in both the active and placebo groups	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.
Overall patient's satisfaction with the product received, through a 5-points Likert scale	End of treatment (after 8 weeks of study treatment), in both the active and placebo groups	5-points Likert scale: 1=very satisfied, 2=satisfied, 3=not satisfied nor unsatisfied, 4=not satisfied, 5= not satisfied at all
The change of fatigue perception by the patient through the BFI questionnaire	Change after 4, 8 and 12 weeks with respect to baseline in both the active and placebo groups	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
Adherence to treatment	After 4 weeks and after 8 weeks from baseline	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
Change in oxidative status through uric acid assessment	Change after 8 weeks of study treatment with respect to baseline in both the active and placebo groups	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 in serum L-arginina levels	Change after 8 weeks of study treatment with respect to baseline in both the active and placebo groups	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.

Trial Locations

Locations (5)

Cancer Center U.O. Oncologia Medica ed Ematologia IRCCS Humanitas Research Hospital; 🇮🇹 Rozzano, Milano, Italy

U.O.C. Oncologia medica ASST Spedali Civili di Brescia; 🇮🇹 Brescia, Italy

U.O. Oncologia 2 Universitaria A.O.U. Pisana; 🇮🇹 Pisa, Italy

UOSD di Medicina di Precisione e Senologia, Policlinico Universitario A. Gemelli; 🇮🇹 Rome, Italy

Dipartimento di Oncologia Azienda Sanitaria Universitaria Integrata di Udine; 🇮🇹 Udine, Italy