Impact of AferBio® on quality of life and chemotherapy toxicity in advanced lung cancer patients (AFERBIO study): protocol study for a phase II randomized controlled trial

The present study was developed according to the norms of Resolution CNS 466/12 (Brazilian National Health Council) and was approved by the Research Ethics Committee of the Barretos Cancer Hospital (n° 2.395.325). This trial is registered with ClinicalTrials.​gov, NCT03469063. All individuals complying with the inclusion criteria will be invited to participate in the study by a trained research coordinator from the Researcher Support Cencer of the Barretos Cancer Hospital. Each participant will voluntarily sign an Informed Consent Form (ICF). This study will be carried out in accordance with International Conference on Harmonization Good Clinical Practice (ICH-GCP). Every amendment in the research protocol will be first submitted to Research Ethics Committee approval. To avoid breaking data confidentiality only some of the authors (CEP, BSRP, and MAO) will have access to the final study database, which will be typed into online REDCap with restrictive access passwords.

This is a Phase II double-blind placebo-controlled randomized clinical trial with two arms, intervention and control group conducted in only one center (Barretos Cancer Hospital [BCH], Brazil). The first 10 patients initiating chemotherapy with docetaxel infused every 21 days will undergo toxicity-testing for AferBio® during the three months of treatment. Table 1 illustrates some reported toxicities in previous studies with docetaxel, as well as the maximum tolerated toxicity determined a priori for the non-randomized phase of the study. If no criteria of unacceptable toxicity are met, then the study will move to the randomized phase. Furthermore, indicators of toxicity of the experimental product will also be assessed during the randomized phase of the study.

Patients will be randomly assigned (1:1) by researchers, who will have no clinical contact with patients; researchers will use the online tool REDCap [19]. After assignment to interventions, trial participants, care providers, outcome assessors and data analysts will be blinded; only the professionals responsible for the randomization process and a pharmacist responsible for the control of research products (who will not have direct contact with the participants) will be unblinded. The status of the Eastern Cooperative Group Performance Status (ECOG-PS) will be used for stratification (0–1 versus 2). All patients will receive chemotherapy according to the Department of Thoracic Oncology and will comply with the institute protocols regarding dose and procedure in cases of toxicity.

The primary goal is to compare HRQOL scores between the arms of the study over time. Secondary goal is to assess AferBio® safety and adherence; compare between the arms of the study the incidence of any given toxicity ≥ grade 3 (jointly and individually); worsening-free survival of 20% of HRQOL scores: number of days that the treatment was delayed due to toxicity; infection or worse performance status; compare the dose intensity (in mg/m2/week); dose-reduction rates (≥20%) and calculate dose reduction-free survival; number of hospitalizations; number of infections (any grade), use of systemic anti-microbial, number of chemotherapy cycles with addition of granulocyte colony-stimulating factor (G-CSF) and the incidence of febrile neutropenia; compare worsening-free survival of the ECOG-PS (> 1 point); anthropometric measurements between the arms of the study; compare response rates and progression-free survival.

Eligible patients will be required to be at least 18 years old and less than 75 years, and to have a 0 to 2 ECOG-PS, with a pathologically confirmed TNM Stage IIIB or IV NSCLC beginning any line of palliative mono-chemotherapy from the second-line. They must have adequate hematological (total neutrophil count ≥1500/μL, platelet count ≥100.000/μL and hemoglobin ≥9 g/dL), liver (serum bilirubin ≤1.5 × ULN, aspartate aminotransferase (AST), alanine transaminase (ALT), alkaline phosphatase ≤1.5 × ULN), and kidney (serum creatinine ≤1.5 × ULN based on the Cockcroft−Gault equation) functions; absence of any emotional family-related, sociological, or geographic condition that can potentially hamper adherence to the study protocol and the follow-up schedule (as per investigator).

Patients will be excluded from the study at the researcher’s discretion if there is tube feeding, gastrostomy or jejunostomy; uncontrollable vomiting; sexually active women in reproductive age, except for those who underwent surgical sterilization; intestinal obstruction or sub-obstruction; known allergy to any of the components of the investigational product; malabsorption syndrome or other condition that could interfere with enteric absorption; history of inflammation of the small or large intestine, previous or currently active (such as Crohn’s disease or ulcerative colitis); chronic diarrhea of any cause; diagnosis of any chronic disease that, in the researcher’s opinion, will interfere in their participation in the study; known diagnosis of HIV infection; diagnosis of any chronic disease that changes the immune system and significantly increases the risk of infection; the need to use G-CSF already in the first chemotherapy cycle; severe neuropsychiatric disease that prevents the patient from completing the study questionnaires.

Before initiating chemotherapy, patients will receive sachets containing AferBio® or placebo. They will be instructed by a nutritionist or nurse concerning how to ingest the product.

The fermented powder supplement will be provided by the company AferBio Bioalimentos, Ltd. (Santa Barbara D’Oeste, São Paulo, Brazil, ANVISA No. 6.04980–1). Each sachet will contain 10 g of the investigational product or placebo. Patients will be instructed to dissolve the contents of the sachet in 150 mL to 200 mL of soy milk, fruit juice, or iced tea and to shake it until homogenization is complete. A measuring cup (with 150 mL and 200 mL marks) will be provided to study participants. Patients will drink the product once a day for seven days and then twice a day continuously (for a total of three months). Participants will also be instructed to not discard used sachets, which shall be handed back to the research team during the return visits in order to be counted. The use of another nutritional supplement will not be allowed during the study.

All participating patients, both in the non-randomized and in the randomized phase of the trial, will be evaluated at baseline and at each chemotherapy cycle (Fig. 1). All evaluations will be performed while patients are in the hospital for medical visits and/or anticancer treatment (chemotherapy). No patient will be called to the hospital exclusively for study-related procedures.

Researchers will apply 3 questionnaires to measure HRQOL: The European Organization for Research and Treatment of Cancer Quality of Life Core Questionnaire with 30 items (EORTC QLQ C30), composed of 30 items that comprise functional, symptom, global health scales and financial impacts [20], validated in 2010 in Brazil [21, 22]. The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Lung Cancer Module (EORTC LC13), Brazil by Brabo/Brazil by Brabo et al [23, 24] is a specific supplementary module for lung cancer patients receiving chemotherapy or radiotherapy, composed of 13 questions addressing typical symptoms of lung cancer and treatment-related side effects [25]. The Instrument of Evaluation of the Quality of Life with 24 items for evaluation of patients with lung cancer (IQualiV-Lung) is a version of IqualiV-OG-21, a generic instrument for the evaluation of HRQOL, developed at the Barretos Cancer Hospital and validated in a Brazilian multicenter study [26]. Three specific items were included in IqualiV-OG-21 to assess the HRQOL in lung cancer patients (dyspnea, cough and hemoptysis), totaling 24 items, which was renamed as IQualiV-Lung.

The ECOG-PS scale will assess how the disease affects the daily living abilities of patients [27].

The following Anthropometric measurements will be used to assess the patient nutritional status during the length of the study: body mass index (BMI) [28‐30], triceps skinfold (TSF) thickness, weight, height [31], adductor pollicis muscle thickness (APMT) on the dominant side [32, 33].

The clinical and laboratorial side effects will be classified according to its severity by the Common Terminology Criteria for Adverse Events (CTCAE), a grading scale ranging from 1 (mild) to 5 (death related to adverse event) [34].

Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, will guide the evaluation of the oncological status related to the response to chemotherapy as complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD) [35, 36].

In cases of PD and consequently modification in the anticancer treatment, the participant will be withdrawn from the study. In this case, a final assessment of HRQL and anthropometric measurements will be conducted.

Enrolment of 94 participants (47 in each arm) was planned to have a power (1– β error) of 80% and alpha error of 0.05, when estimating an effect size of 0.25. Sample-size calculations were estimated with Gpower software v.3.0 (Heinrich-Heine-Universität, Düsseldorf, Germany) [37], considering a 20% loss during the study.

Demographic and clinical characteristics prior to treatment will be compared between the arms of the study with the Student’s t test (for continuous variables) or chi-square test (for categorical variables). The normality of the data distribution will be assessed with the Shapiro-Wilk test [38] combined with an evaluation of data distribution patterns.

All HRQOL scores and anthropometric measurements will be compared over time using a linear mixed model, considering the treatment group and time as fixed effects and patients as a random effect. Thus, the effect of the interaction time versus arm and the effects of the arm alone or time alone will be assessed, and the variability will be controlled by the effect of the patient. Multiple imputation of missing data will be used.

The number of patients with toxicity ≥ grade 3, hospitalization, infections, use of antimicrobials, febrile neutropenia, adherence to the investigational product/placebo, dose reduction above 20%, and clinical benefit rates will be compared between groups by the chi-square test (or Fisher’s exact test). Clinical benefit rate will be considered the percentage of patients who have achieved CR, PR and SD.

The total days of treatment delay, dose intensity, anthropometric measurements, and the number of chemotherapy cycles with G-CSF will be compared between groups at the end of the study using the Student’s t test (or Mann-Whitney U test, depending on the data normality).

Event-free survival times (worsening of HRQOL > 20%, worsening by > 1 point in the ECOG-PS score, and ≥ 20% dose reduction) will be estimated by Kaplan-Meier curves, which will be compared with the log-rank test.

An independent monitoring committee that consists of staff from the Research Support Center of BCH will monitor the collection and analysis of the study data. Meetings of the Monitoring Committee were planned to occur at least every six months.

An interim analysis is planned to be conducted after the inclusion of the first 10 participants with complete data (non-randomized phase). If no criteria of unacceptable toxicity are met (as detailed in Table 1), then the study will move to the randomized phase. In case of doubts about the toxicity of the investigational product after 10 participants, an addendum will be sent to the Ethics Committee requesting approval for inclusion of another 10 patients in the non-randomized phase. The Monitoring Committee will participate in the interpretation of the results. The principal investigator (CEP) will be the main responsible for the decision to stop or continue the study. Sponsor will not participate in this decision process.