Stibium Metallicum Praeparatum Versus Placebo in the Prevention of Paclitaxel- or Nab-paclitaxel-induced Peripheral Neuropathy: the StibTax RCT
Stibium Metallicum Praeparatum Versus Placebo in the Prevention of Paclitaxel- or Nab-paclitaxel-induced Peripheral Neuropathy: the StibTax RCT
Chemotherapy induced peripheral neuropathy (CIPN) is one of the most limiting side effects of
 chemotherapy and often leads to adaptations in the protocol of the chemotherapy including
 dose reduction or even discontinuation of treatment. In general, the symptoms of CIPN are
 sensory, often distributed in a "stocking and glove" manner, and include pain, tingling, and
 numbness. CIPN has a marked negative influence on quality of life of patients and their
 families. It may result in serious limitations in daily functioning and affect the enjoyment,
 social relationships, and ability to perform work. Current management of CIPN (i.e.
 prevention and treatment) includes dose reduction or delay of chemotherapy cycles and
 treatment discontinuation. Unfortunately, this reduces the chance of an effective cancer
 treatment. Current guidelines of the American Society of Clinical Oncology (ASCO) on the
 Prevention and Management of Chemotherapy-Induced Peripheral Neuropathy do not conclusively
 recommend any agent for the prevention of CIPN. Due to the scarcity of drugs that are
 effective for preventing and treating CIPN, the distress of patients who suffer from CIPN,
 and the major societal and economic costs, new approaches and effective treatment strategies
 are required.

 An observational study which started in January 2017 in the outpatient clinic of the
 Institute of Complementary and Integrative Medicine at the University of Bern showed
 promising results regarding the medical treatment of CIPN with Stibium metallicum praeparatum
 6x. Patients received Stibium metallicum praeparatum 6x for prevention or treatment of
 chemotherapy-induced peripheral sensory neuropathy, respectively. The study included 91
 patients, and patients indeed showed lower incidence rates of (20%, 2 months after they
 started with Stibium), as compared to the incidence of 57-83% reported by the NCCN task
 force.

 Building on this observational study, the current study investigates the efficacy and
 tolerance of Stibium metallicum praeparatum 6x (Weleda) to prevent paclitaxel- or
 nab-paclitaxel-induced peripheral neuropathy as reported by patients. As secondary outcomes,
 the influence on quality of life and chemotherapy treatment adherence of patients is
 assessed. As the clinical experience with Stibium metallicum praeparatum 6x suggests
 promising results for CIPN prevention, a double blind, bicentric, randomized controlled trial
 will be conducted to address the efficacy of Stibium metallicum praeparatum 6x with a sound
 scientific approach. Stibium metallicum praeparatum 6x has been used in adults and children
 for several decades and has demonstrated no harm. Consequently, no adverse events are
 expected.
Epidemiology

 Chemotherapy induced peripheral neuropathy (CIPN) is one of the most limiting side effects of
 chemotherapy and often leads to adaptations in the protocol of the chemotherapy including
 dose reduction or even discontinuation of treatment. In addition, patients treated with
 taxanes also may experience motor symptoms, which often present as distal or general
 weakness, and autonomic nervous system dysfunction (e.g. constipation or diarrhea,
 abnormalities of sweating, and lightheadedness and/or dizziness with positional changes).
 CIPN has a marked negative influence on quality of life of patients and their families. It
 may result in serious limitations in daily functioning and affect the enjoyment, social
 relationships, and ability to perform work. Because of the growing prevalence of cancer and
 of cancer survivors, the lack of adequate treatment or preventive strategies against CIPN, as
 well as the major societal and economic costs, CIPN is becoming a major societal issue.

 According to the National Comprehensive Cancer Network (NCCN) task force report, the overall
 incidence of taxane-induced peripheral neuropathy ranges from 57 up to 83% of patients
 treated with paclitaxel. The nanoparticle albumin-bound (nab) form of paclitaxel was
 formulated to enable lower doses and reduce toxicity, but neuropathy rates with
 nab-paclitaxel are similar (not significantly lower) to those with standard paclitaxel when
 the same cumulative dosage is administrated. The incidence and prevalence of CIPN vary among
 neurotoxic agents, dosing regimens, and preexisting neuropathy. Severe symptoms are likely to
 persist longer. In patients treated with paclitaxel, symptoms of peripheral neuropathy
 persisted in 41% of patient at 3 years, while 50% of patients recovered within 9 months.
 Persistent numbness one year after treatment with paclitaxel were reported in approximately
 67% to 80% of early-stage breast cancer patients.

 Mechanisms

 Taxanes bind to the beta-tubulin in the microtubules of the mitotic spindle, and thus inhibit
 the disassembly of microtubules. This results in the apoptosis of the cell. The most widely
 accepted theory on the mode of action of taxane-induced peripheral neuropathy states that the
 disruption of the microtubulin structure interferes with axonal transport resulting in a
 "dying back" process starting from distal nerve endings and disturbed Schwann cells and
 neuronal bodies.

 Research Aim

 Due to the scarcity of drugs that are effective for preventing and treating CIPN, the
 distress of patients who suffer from CIPN, and the major societal and economic costs, new
 approaches and effective treatment strategies are required. This study investigates the
 efficacy and tolerance of Stibium metallicum praeparatum 6x (Weleda) to prevent paclitaxel-
 or nab-paclitaxel-induced peripheral neuropathy as reported by patients. As secondary
 outcomes, the influence on quality of life and chemotherapy treatment adherence of patients
 is assessed.

 Investigational Product and Indication

 Stibium metallicum praeparatum 6x is authorized in Switzerland and is listed by Swissmedic as
 an authorized anthroposophic medicinal product.

 Stibium metallicum praeparatum 6x contains the agent Stibium metallicum praeparatum D6, which
 is a liquid dilution (6x) in 1 ml ampoules for subcutaneous or intravenous injection. Other
 components are sodium chloride and lactose. It is used to stimulate the healing process in
 inflammation. According to the concept of anthroposophically extended medicine, the fields of
 application include the stimulation of the form processes in processes with strong metabolic
 activity, e.g. with inflammatory processes in the mucosa of the gastrointestinal tract and on
 the skin as well as with bleeding, allergic and catarrhal conditions of the upper airways, as
 additional treatment for bronchial asthma, cardiac arrhythmias, as well as memory disorders.

 Study design

 This study is a parallel, double blind, placebo controlled, randomised, phase III superiority
 trial, aiming to determine whether treatment with Stibium metallicum praeparatum 6x reduces
 the severity of manifestation of paclitaxel- or nab-paclitaxel-induced peripheral neuropathy,
 as compared to placebo. The study is restricted to paclitaxel and nab-paclitaxel in order to
 limit variability in CIPN characteristics and severity and thus improve assay sensitivity.

 The study population consists of 166 (83 per treatment arm) male and female cancer patients,
 aged 18 years or older, starting a 12-week paclitaxel- or nab-paclitaxel-based adjuvant,
 neoadjuvant, or palliative chemotherapy. Stibium metallicum praeparatum 6x will be
 administrated via 3 subcutaneous injections at 1 ampoule at 1 mL 3 times per week during
 chemotherapy and will be continued for 18 weeks after end of chemotherapy. Placebo (saline
 subcutaneous injection) is chosen as comparator, as it is state of the art to compare against
 placebo when no "gold standard" treatment option is available.

 The first injection of study medication or placebo will be administered on the day of the
 first dose of chemotherapy, Assessments during the intervention period will be done before
 each administration of the chemotherapy (i.e. every 3 weeks) at at the end of treatment with
 Stibium metallicum praeparatum 6x (at 18 weeks). Follow-up assessments will be done at
 patients' regular oncological control visits, which take place every 3 months after the end
 of therapy, during 1 year. To accommodate standard scheduling practices for clinic visits and
 outpatient appointments, a 1-week margin for assessments during the intervention period and a
 4-week margin for assessments during the follow-up period will be allowed. The total duration
 of subject participation will be 16.5 months.

 Justification of choice of study population

 Given the lower incidence of peripheral neuropathy in patients treated with docetaxel as
 compared to those treated with paclitaxel or nab-paclitaxel, the study population is
 restricted to patients with cancer starting a 12-week paclitaxel-based or
 nab-paclitaxel-based adjuvant, neoadjuvant, or palliative chemotherapy. Paclitaxel and
 nab-paclitaxel are used for the treatment of breast, ovarian, cervical, endometrial, lung,
 esophageal, gastric cancer, as well as germ cell tumor. Patients with gastric cancer are
 excluded because this cancer type may lead to relatively high withdrawal.

 Known or potential problems and limitations of the design

 Considering feasibility and generalizability challenges, multiple cancer types are included,
 which can decrease the homogeneity of the study population.

 A challenging aspect is that if the patients in the control group should receive less
 chemotherapy due to early development of neuropathy than the patients in the group with
 Stibium metallicum praeparatum 6x, the overall neuropathy severity measured at the end of the
 trial may be lower in the control group than in the experimental group. In such a case, the
 trial may fail to demonstrate a true treatment effect that allows more cancer patients to
 receive a full course of chemotherapy and possibly obtain better outcomes. For this reason,
 secondary endpoints were sepcified to investigate this situation. Moreover, per-protocol and
 sensitivity analyses will be conducted, excluding patients who require dose
 reduction/treatment interruption due to early development of neuropathy.

 Informed consent process

 The oncologist will explain to each participant the nature of the study, its purpose, the
 procedures involved, the expected duration, the potential benefits and risks, as well as any
 discomfort it may entail. Each participant will be informed that the participation in the
 study is voluntary and that he/she may withdraw from the study at any time and that
 withdrawal of consent will not affect his/her subsequent medical assistance and treatment.
 The participant must be informed that his/her medical records may be examined by authorized
 individuals other than their treating physician.

 All participants for the study will be provided a participant information sheet and a consent
 form describing the study and providing sufficient information for participant to make an
 informed decision about their participation in the study. At the chemotherapy planning visit
 the patient is informed about the study and is given time to consider participation until the
 baseline assessment when chemotherapy starts (generally about 7 days, at least 24 hours). The
 formal consent of a participant, using the approved consent form, must be obtained before the
 participant is submitted to any study procedure. The consent form must also be signed and
 dated by the investigator (or designee), and it will be archived as part of the study
 records.

 Participant privacy and confidentiality

 The investigator affirms and upholds the principle of the participant's right to privacy and
 their compliance with applicable privacy laws. Importantly, anonymity of the participants
 shall be guaranteed when presenting the data at scientific meetings or publishing in
 scientific journals.

 Individual subject medical information obtained as a result of this study is considered
 confidential and disclosure to third parties is prohibited. Subject confidentiality will be
 further ensured by utilising subject identification code numbers to correspond to treatment
 data in the computer files.

 For data verification purposes, authorized representatives of the Sponsor, a competent
 authority (e.g. Swissmedic), or an ethics committee may require direct access to parts of the
 medical records relevant to the study, including participants' medical history.

 Early termination of the study

 The Sponsor may terminate the study prematurely according to certain circumstances, for
 example:

 -  ethical concerns,

 -  insufficient participant recruitment,

 -  when the safety of the participants is doubtful or at risk, respectively,

 -  alterations in accepted clinical practice that make the continuation of a clinical trial
 unwise,

 -  early evidence of benefit or harm of the experimental intervention

 Screening

 Patients will be screened and recruited consecutively. Screening will be conducted by the
 Department of Oncology at the University Hospital Bern, as well as the Department of Oncology
 at the Hospital of Thun, ensuring that all eligible cancer patients who are going to start a
 paclitaxel- or nab-paclitaxel-based adjuvant, neoadjuvant, or palliative chemotherapy will be
 offered participation in the study at the chemotherapy planning visit. If interested,
 patients will be fully informed about the trial using the patient information and informed
 consent form.

 Compensation / payments

 The participating patients receive no financial, or any other form of compensation.

 Assignment to study groups Allocation of patients will be carried out by the study nurse via
 a dedicated website within the clinical trial management system REDCap.

 Randomisation

 Participants will be randomly allocated to either the experimental or control group of the
 study with a 1:1 allocation using permuted blocks with random block sizes.

 Randomization will be implemented at the Clinical Trial Unit of the University of Bern (CTU
 Bern), according to dedicated standard operating procedures (SOP). Allocation will be done
 via a dedicated website within the clinical trial management system REDCap
 (https://www.project-redcap.org/), also containing the electronic case report forms. Only
 system administrators who are otherwise not involved in the trial will have access to the
 algorithm and stored lists during the recruitment period. The underlying randomization lists
 and details of the algorithm will not be disclosed but kept securely at CTU Bern. All these
 measures will help to ensure concealment of allocation.

 Compliance with study intervention

 In order to monitor adherence, the patients are requested to return used or unused ampoules
 at each visit. Returned ampoules will be stored for adherence monitoring purposes.

 Study Drug Accountability

 The investigator or designee must maintain an inventory record of IMP at the site level
 (received from the sponsor, returned to the sponsor) and at the patient level (dispensed to
 the patient, returned by the patient).

 Return or Destruction of Study Drug

 Upon completion or termination of the trial, all unused study drugs/ placebos must be
 destructed on site following the site's standard procedures for medication destruction and
 the destruction documented. Documentation on study drug destruction must be provided to the
 sponsor-investigator for filing in the trial master file.

 Reporting of serious adverse events (SAE) and other safety related events Reporting of SAEs:
 all SAEs must be reported immediately and within a maximum of 24 hours to the
 Sponsor-Investigator of the study. The Sponsor-Investigator will re-evaluate the SAE and
 return the form to the site. SAEs resulting in death are reported to the Ethics Committee via
 BASEC within 7 days. The SAEs that are a clear result of the underlying disease (e.g., events
 occurring due to breast cancer or metastasis) are events that will not be reported.

 Reporting of SUSARs: a SUSAR needs to be reported to the Ethics Committee (local event via
 local Investigator) via BASEC and to Swissmedic for category B and C studies (via
 Sponsor-Investigator) within 7 days, if the event is fatal, or within 15 days (all other
 events).

 Reporting of Safety Signals: all suspected new risks and relevant new aspects of known
 adverse reactions that require safety-related measures, i.e. so called safety signals, must
 be reported to the Sponsor-Investigator within 24 hours. The Sponsor-Investigator must report
 the safety signals within 7 days to the Ethics Committee (local event via local Investigator)
 via BASEC and to Swissmedic.

 Reporting and Handling of Pregnancies: pregnant participants must immediately be withdrawn
 from the clinical study. Any pregnancy during the treatment phase of the study and within 30
 days after discontinuation of study medication will be reported to the Sponsor-Investigator
 within 24 hours. The course and outcome of the pregnancy should be followed up carefully, and
 any abnormal outcome regarding the mother or the child should be documented and reported.

 Periodic reporting of safety: an annual safety report is submitted once a year to the local
 Ethics Committee via local Investigator and to Swissmedic via Sponsor-Investigator.

 Follow up of (Serious) Adverse Events

 SAEs that are ongoing at study end are followed up until resolution or stabilization.

 Statistical methods

 Hypothesis

 The following null hypothesis is tested: The treatment arm does not result in a change in the
 NTX-subscale from baseline to week 12 against a two-sided alternative.

 Determination of Sample Size

 Based on current recommendations that the minimal clinically important difference (MCID) for
 FACIT cancer-specific subscales is 0.3 to 0.4 point change per item, MCID for the 11-item
 NTX-subscale is defined as a change in score of 3.3-4.4 points. In this study, we defined the
 MCID as a change in the score of 3 points. Assuming a standard deviation of 7, a correlation
 between baseline and follow-up measurement of 0.5 and type I error rate (alpha) of 5%, we
 will need 132 patients (66 per arm) to detect a MCID of 3 with a power of 80% based on a
 linear regression with the baseline as covariate (ANCOVA). To account for a dropout rate of
 20%, 166 patients (83 per group) are recruited. This equals approx. 5000 ampoules of study
 medication, as well as 5000 ampoules of placebo.

 Planned Analyses

 After the start of the trial but before the recruitment ends, a statistical analysis plan
 (SAP) will be written. The SAP will determine all necessary data preparation steps (e.g.
 additional validations, generation of new variables), definitions (e.g. analysis sets), and
 statistical analyses (e.g. models, outputs such as tables and graphs).

 Primary Analysis

 The primary analysis will follow an intention-to-treat approach, i.e. all patients will be
 analysed according to the group they were randomized to. Baseline characteristics of patients
 in the two treatment arms will be reported using frequency distribution and descriptive
 statistics. The primary endpoint will be analysed using a linear regression with the score in
 the NTX-subscale at week 12 as outcome and the treatment arm and the NTX-subscale at baseline
 as covariates. The treatment effect will be presented as mean difference with 95% confidence
 interval (CI) and a p-value. Continuous secondary outcomes measured at baseline and one time
 point during chemotherapy (i.e. PHQ-9 and GAD-7at week 12) will be analysed in the same way.
 Continuous secondary outcomes measured at several time points (the change in the
 NTX-subscale, FACT-G total score, BPI, NCCN distress thermometer, PHQ-9, and GAD-7) will be
 analyzed using linear mixed-effects regression models with time point as a factor variable,
 treatment group, the interaction of time point and treatment group, and baseline value as
 fixed covariates and a random intercept and/or slope for the patient. At each time point the
 treatment effect will be presented with a mean difference and a 95% CI. A joint p-value over
 all time points will be calculated.

 Binary secondary outcomes measured over several time points (neuropathy) will be analyzed
 with logistic-mixed effects regression model with time point, treatment group, and the
 interaction of time point and treatment group as fixed covariates and a random intercept
 and/or slope for the patient. Binary and binomial secondary outcomes measured once (number of
 patients with full course of chemotherapy, number of unused drug packs) will be analyzed
 using logistic regression. Treatment effects will be presented as odds ratios with 95% CIs.

 Count data (number of planned chemotherapy dosages that a participant received before
 presenting with an increase ≥ 10% in the neurotoxicity subscale score) will be analyzed using
 Poisson or negative binomial regression. The treatment effect will be presented as incidence
 rate ratio with 95% confidence interval. The time to modification to the planned chemotherapy
 regimen because of CIPN will be presented using Kaplan-Meier curves. The treatment effect is
 estimated using a Cox proportional hazard model, adjusted for the stratification factors from
 randomization and presented as hazard ratio with 95% CI. Exploratory/ secondary endpoints
 will be analysed descriptively using frequency distribution and descriptive statistics.

 Secondary Analyses

 A per-protocol analysis will be conducted to examine the robustness of our primary estimates.
 Patients fulfilling any of the following criteria will be excluded from the per-protocol
 analysis:

 -  any major protocol deviations (e.g. intake of a concomitant medication affecting the
 primary endpoint)

 -  non-availability of measurements of the primary endpoint

 -  non-sufficient exposure to study treatment

 -  patients who did not receive a full course of chemotherapy at week 12

 Interim analyses

 A sample size re-estimation will be performed based on examination of data after inclusion of
 83 patients (i.e. half of the initial sample size estimation). Only nuisance parameters of
 blinded data will be assessed, which includes the assessment of standard deviation over both
 treatment arms and of correlation between baseline and week 12. The sample size will be
 increased if required, with an upper limit of 200 subjects.

 Safety analysis

 Safety outcomes will be reported using frequency distribution and descriptive statistics.

 Deviation(s) from the original statistical plan

 Any deviation from the original statistical plan will be described and justified in the final
 trial report.

 Handling of missing data and drop-outs

 Missing data will be reported for all outcomes. The reason for drop-outs will be listed.
 Drop-outs are not replaced. The total sample size accounts for a dropout rate of 20% which is
 appropriate and a general thumb rule in oncological trials. Participants who prematurely
 discontinue chemotherapy for reasons unrelated to neuropathy (e.g. nausea) present a missing
 data challenge. These participants may or may not have developed neuropathy if they had
 continued their chemotherapy treatment. If a large number of participants prematurely
 discontinue or decrease planned dosages of chemotherapy before developing neuropathy, the
 ability of the study to detect a treatment effect (i.e. assay sensitivity) could decrease.
 Sensitivity analyses that make various assumptions regarding whether the participants who
 prematurely terminated chemotherapy would have developed neuropathy if the planned
 chemotherapy regimen had been completed, will be performed.

 If the number of missing data is larger than 10%, we will carry out multiple imputations
 based on baseline values, treatment groups and the outcome at other time points.

 Data handling and record keeping / archiving

 Case Report Forms

 The CRFs in this trial are implemented electronically using a dedicated electronic data
 capturing (EDC) system (REDCap, https://www.project-redcap.org/). The eligibility form will
 be prepared in paper format for the investigators. The study nurse will complete the Study
 Nurse Questionnaires directly in REDCap. Questionnaires for patients during the chemotherapy
 period (i.e. Baseline questionnaire, FACT/GOG-NTX, BPI, NCCN Thermometer distress, PHQ-9,
 GAD-7) will be prepared in paper format and handed out by the study nurse before the
 administration of the chemotherapy. The questionnaires for patients will not contain any
 patient-identifying information. Data entry into REDCap from the paper questionnaires will be
 done by the study nurse. Questionnaires for patients during the follow-up period will be
 prepared in electronic format and will be accessible through a personal link. The personal
 link will be sent to the patient's email address. Patients' email address will be therefore
 collected into REDCap but this field will be tagged as "Identifier field" and thus will be
 automatically removed from data exports.

 Specification of source documents

 Source documents must be available at the site to document the existence of the study
 participant and must include the original documents relating to the study, as well as the
 medical treatment and medical history of the participant.

 As source documents are considered (list not conclusive):

 -  Patient information and informed consent form

 -  Electronic / Paper version of completed eligibility form, patient questionnaires, and
 study nurse questionnaires.

 Record keeping / archiving

 The sponsor will keep the Trial Master File, the extracted data, the meta data and interim/
 final reports for at least 10 years.

 Data Management System

 The CRFs in this trial are implemented electronically using a dedicated electronic data
 capturing (EDC) system (REDCap, https://www.project-redcap.org/). The EDC system is activated
 for the trial only after successfully passing a formal test procedure. All data entered in
 the CRFs are stored on a Linux server in a dedicated mySQL database. Responsibility for
 hosting the EDC system and the database lies with CTU Bern.

 Data security, access and back-up

 Trial and participant data will be handled with utmost discretion and are only accessible to
 authorized personnel who require the data to fulfill their duties within the scope of the
 study. On the CRFs and other study specific documents, participants are only identified by a
 unique participant number. The participant number (unique and consecutively numbered) will be
 attributed to each patient registered. The code list will be stored at the Institute of
 Complementary and Integrative Medicine, in a secure compartment lockable with a key.

 The server hosting the EDC system and the database is kept in a locked server-room. Only the
 system administrators have direct access to the server and back-up tapes. A role concept with
 personal passwords (site investigator, statistician, monitor, administrator etc.) regulates
 permission for each user to use the system and database as he/she requires.

 All data entered into the CRFs are transferred to the database using Transport Layer Security
 (TLS) encryption. Each data point has attributes attached to it identifying the user who
 entered it with the exact time and date. Retrospective alterations of data in the database
 are recorded in an audit table. Time, table, data field and altered value, and the person are
 recorded (audit trail).

 A multi-level back-up system is implemented. Back-ups of the whole system including the
 database are run internally several times per day and on external tapes once a day. The
 back-up tapes are stored in a secure place in a different building.

 Analysis and archiving

 For the final analyses, data files will be extracted from the database to be analysed with
 statistical packages. After database lock, the status of the database is recorded in special
 archive tables. The sponsor will keep the Trial Master File, the extracted data, the meta
 data and interim, final reports for at least 10 years.

 Electronic and central data validation

 Data is checked by the EDC system for completeness and plausibility. Furthermore, selected
 data points are cross-checked for plausibility with previously entered data for that
 participant. In addition, central data reviews will be performed on a regular basis to ensure
 completeness of the data collected and accuracy of the primary outcome data.

 Before database lock, the principal investigator will validate the collected data with her
 signature.

 Monitoring

 For quality control of the study and data retrieval, an on-site visit will be done by
 appropriately trained and qualified monitors. Any findings and comments will be documented in
 site visit reports and communicated to the local investigator and the sponsor as applicable.
 Prior to study start (first participant enrolled) a plan detailing all monitoring-related
 procedures will be developed. All source data and relevant documents will be accessible to
 monitors and questions of monitors are answered during site visits.

 Audits and Inspections

 The study documentation and the source data/documents will be accessible to
 auditors/inspectors (also CEC and CA) and questions will be answered during inspections. All
 involved parties must keep the participant data strictly confidential.

 Confidentiality, Data Protection

 Direct access to source documents will be permitted for purposes of monitoring, audits and
 inspections.

 Ethical Conduct of the Study

 The study will be carried out in accordance to the protocol and with principles enunciated in
 the current version of the Declaration of Helsinki, the guidelines of Good Clinical Practice
 (GCP) issued by ICH, in case of medical device: the European Regulation on medical devices
 2017/745 and the ISO Norm 14155 and ISO 14971, the Swiss Law and Swiss regulatory authority's
 requirements. The CEC and regulatory authorities will receive annual safety and interim
 reports and be informed about study stop/end in agreement with local requirements.
Inclusion Criteria:

 -  Age ≥ 18

 -  Cancer patients who are about to receive paclitaxel- or nab-paclitaxel-based adjuvant,
 neoadjuvant, or palliative chemotherapy

 -  Eastern Cooperative Oncology Group (ECOG) performance status ≥ 2

 -  Ability to provide informed consent as documented by signature

 -  Ability to read, write, and speak German

 Exclusion Criteria:

 -  Patients with pre-existing neuropathy

 -  Prior chemotherapy with taxanes or other neurotoxic agents

 -  Diabetes mellitus

 -  Gastric cancer

 -  Inpatients

 -  Concomitant medications that are known to cause neuropathy

 -  Pregnancy or lactation

 -  Lack of safe contraception, defined as: female participants of childbearing potential,
 not using and not willing to continue using a medically reliable method of
 contraception for the entire study duration, such as oral, injectable, or implantable
 contraceptives, or intrauterine contraceptive devices, or who are not using any other
 method considered sufficiently reliable by the investigator in individual cases.

 -  Significant uncontrolled cardiac disease (e.g. unstable angina)

 -  Patients with psychiatric, addictive or any disorder that prevents the patient from
 adhering to the protocol requirements, in the opinion of the investigator

 -  Lactose intolerance or glucose-galactose-malabsorption, as well as any other
 contraindications to the class of drugs under study, e.g. known hypersensitivity or
 allergy to class of drugs or the investigational product

 -  Participation in another study with investigational drug within 30 days preceding and
 during the present study

 -  Life expectancy < 3 months