NICSO National Study: Physician - Nurse Monitoring Project About Oncological Adverse Events
Phase: NA
Conditions: Cancer
Sponsor: Fondazione IRCCS Istituto Nazionale dei Tumori, Milano

NICSO- Italian Network of Supportive Care in Oncology
Pag. 1
PROMOTER:            NICSO
    Piazza Europa n. 5 
                                  05100 - Terni
SCIENTIFIC  COMMITTEE:  Carla  Ida  Ripamonti,  Fausto  Roila,  Paolo  Bossi,  Andrea
Antonuzzo, Marilena Romero.
PRINCIPAL INVESTIGATOR:  Dr Carla Ida Ripamonti
PROTOCOL
Version 2.0 – 31st August 2020
NICSO National Study: 
Project of Physician-Nurse 
Monitoring of Side Effects of 
Cancer Therapies

NICSO- Italian Network of Supportive Care in Oncology
Pag. 2
INVESTIGATOR’S AGREEMENT
NICSO National Study: Project of Physician-Nurse Monitoring of Side Effects of Cancer
Therapies
Approval by the Promoter and the Principal Investigators
The protocol has been revised and approved by
______________________
____/____/______
Dr Carla Ida Ripamonti
date (dd/mm/yyyy)
(Promoter Representative)
______________________
____/____/______
Dr Carla Ida Ripamonti
date (dd/mm/yyyy)
(Principal Investigator)
Local Principal Investigator
I have been revised and approved the trial
______________________
(Name and Surname)
______________________
____/____/______
date (dd/mm/yyyy)
(Local Principal Investigator)

NICSO- Italian Network of Supportive Care in Oncology
Pag. 3
INDEX
1. BACKGROUND ……………………………………………………………...4
2. OBJECTIVES--………………………………………………………………..8
3. STUDY DESIGN……………………………………………………………...9
3.1 Study population
 
3.2 Patients’classification and randomisation
 
3.3 Study Duration
4. OPERATIVE ASPECTS…………………………………………………….10
5. STATISTICS………………………………….………………………………12
 
5.1 Sample Size
 
5.2 Data management
 
5.3 Data analysis
6. PHARMACOVIGILANCE……………………………………………………13
6.1 Legislation 
6.2 Adverse event report: investigators’responsabilities
        
6.2.1 Adverse reaction (AR)
        
6.2.2 Severity evaluation
        
6.2.3 Casuality evaluation
7. ETHIC ASPECTS…………….…………………………………………….....15
8. DIRECT ACCESS TO DATA AND ORIGINAL DOCUMENTS ….............16
9. DATA PUBLISHING……..……………………………………………………16
10.REFERENCES……………………………………………………………......16

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Pag. 4
1. BACKGROUND
The development of cancer drug has been revolutionized in the last years, especially with
the  market  authorization  of  targeted  drugs  and  immunotherapy,  both  used  alone  or  in
combination with chemotherapy. The oncology pipeline has been enriched by 45 drugs from
2010 to 2014 for a total of 53 new indications (1). In a year, from November 2015 to October
2016, the Food and Drug Administration (FDA) approved 20 therapies for more than 12
different types of neoplasms (2). The use of supportive care therapies and growth factors
has been increasing as well (1, 2). The existing anti-cancer therapies have produced a
better and better clinical outcome for cancer patients, that is an increase in their 5-year
overall survival for most tumours. To date, 68% of adults with cancer are alive at 5 years,
compared to 50% in the 70s (1). In Italy, 5-year overall survival has been increasing when
compared with the cases diagnosed in the previous three years in both men (57% in 2005-
2007  vs  39%  in  1990-1992)  and  women  (63%  vs  53%).  This  can  be  related  to  the
improvement in overall survival of some of the most frequent tumours: colorectal (5-year
overall survival of 64% in men and 63% in women), breast in women (87%), and prostate
(91%). For some worse-prognosis tumours, the overall survival has not improved in the
recent years, for example for lung tumours (14% in men and 18% in women) and pancreas
tumours (7% and 9%, respectively) (3-5).
New cancer therapeutic options offer, then, better outcomes when compared with existing
options and better overall survival of these patients with a low toxicity profile.
Generally  speaking,  cancer-related  symptoms,  therapy-related  toxicities,  and  disease
complications should promptly be evaluated and treated, since they negatively impact on
mortality and morbidity of these patients, worsen their quality of life and increase the related
costs for the National Health System. Several studies offered data on the high number of
unplanned visits and/or hospital admissions due to toxicities from chemotherapy, especially
about  gastrointestinal  issues,  haematological  toxicities,  such  as  transfusion-requiring
anaemia  and  thrombocytopenia,  infections,  fever  and/or  febrile  neutropenia,  but  also
electrolyte disorders, dyspnoea and pain (12-13).
National  and  international  guidelines  suggest  the  best  management  algorithm  for  the
management and treatment of chemo-related toxicities, but a low adherence in everyday
clinical practice can be observed, with a possible increase in the incidence and duration of
adverse  events,  as  demonstrated  by  several  studies,  especially  those  on  the  use  of
antiemetics (14-16, 49).
The recent development of immunotherapy has introduced a new problem related to the
toxicities associated with CTLA4 and/or PD-1/PD-L1 blockade since these two pathways
are involved in the regulation of the peripheral immune tolerance and are fundamental for
the prevention of autoimmune problems.
To date, immune-related adverse events are graduated according to the CTCAE criteria
(Common Terminology Criteria for Adverse Events) and they include a series of problems
related to the immune activation, especially correlated to the activity of T lymphocytes, and
they are similar to autoimmune diseases.
The  most-reported  toxicities  are  fatigue,  skin  problems  (skin  rash  and  pruritus),
gastrointestinal  problems  (colitis,  diarrhoea),  liver  issues  (autoimmune  hepatitis),
endocrinological problems (thyroiditis, hypophysitis); less frequent the neurological issues.
However, this scenario is partially unknown and it requires the development of new tools for
the evaluation of the possible consequences of these treatments, to observe the benefits in
terms of overall survival, but also to evaluate the long-term effects (17-20). At the moment
there are no validated predictive biomarkers that can help to identify patients at higher risk of
immune-related  toxicity  and  there  is  no  evidence  of  a  correlation  between  the  toxicity
development and the treatment efficacy (21). 

NICSO- Italian Network of Supportive Care in Oncology
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It is fundamental that the clinician is trained about the diagnosis and the early treatment of
these  toxicities  since  an  early  medical  intervention  reduces  both  the  severity  and  the
duration of these problems (22).
Correct management should avail of: adequate knowledge of toxicities by the oncologists,
timely information of the patients through verbal language and appropriate pamphlets, a
good  physician-patient  communication,  an  appropriate  application  of  supportive  care
protocols. All these elements should be included within multidisciplinary cooperation and in
a  standardized  path  including  several  medical  professionals  (medical  oncologists,
gastroenterologists, endocrinologist, general practitioners) with the aim of a short- and long-
term evaluation of the oncological patients.
In Italy, some facilities have realized a multi-specialist dedicated team within the Oncology
Units  and  data  coming  from  these  experiences  highlight  that  this  kind  of  approach
determines  a  net  reduction  of  unplanned  hospitalizations  and  related  costs.  For  such
reasons in the last few years major attention has been drawn on this model, which is not
focused on the cancer treatment, but on the cancer patient care (25-27). 
Apart  from  the  physicians,  the  involved  health  professionals  are  psychologists,  spiritual
assistants, and specialized nurses: some literature data show a possible positive impact on
the  management  of  toxicities  through  an  ad  hoc  nurse  intervention  (28).  The  high
specialized nurse professionals can apply an evidence-based care model, thus positively
impacting the clinical outcome (29-31).
Integrated supportive care models that are proposed nowadays often deal with the most
common side effects, as reported above. Still, there is a lack of randomized clinical trials that
investigate the diverse supportive care modalities in the different new therapeutic settings,
such as in the immunotherapy and targeted therapy setting. Such models should investigate
how these new toxicities might determine a worsening of the quality of life and, then, an
increase in the number of unplanned visits and hospital admissions, but also of the morbidity
and the mortality.
All these things considered, major attention to the quality of life needs to have a higher offer
of diagnostic and therapeutic paths with the use of one of the following modalities: either a
closer hospital follow-up or the use of less invasive, home-based approaches. In the latter
case, this could be performed through home visits or home phone calls. Furthermore, with
major access to health information, the patient him- or herself might become a more active
partner in his/her care path (1).
Specialised  home  assistance  has  been  evaluated  in  patients  undergoing  oral
chemotherapy.  The  programme  consisted  in  home  visits,  24/7  phone  availability,  and  a
weekly  phone  call  and  it  has  shown  that  the  experimental  group  experienced  a  lower
incidence of toxicities than the control group, but also a lower number of accesses to the
reference hospital or other health facilities and a reduction of the number of days of hospital
stay (28). Though positive, the results of this trial also showed increased costs. For such
reasons, there are data that a phone-only nurse follow-up might be an alternative to answer
to the patients'need with lower costs and thus it might determine a toxicity reduction when
compared with standard monitoring (32-35).
The  studies  on  the  management  of  oral  therapies  show  how  fundamental  it  is  that  the
involved  nurses  are  highly  specialised  in  the  disease  and  trained  to  take  immediate
therapeutic decisions, such as the variation or the interruption of the treatment, through the
use  of  pre-established  and  agreed  protocols,  that  were  previously  shared  with  medical
professionals (34). An educational programme on oral therapies might have the final aim of
limiting the dose reductions and inadequate treatment withdrawals.
Another field of interest is the management of "acute events" that might happen between
therapy cycles. Waiting for the subsequent cycle might cause a lack of reporting of some
serious side event.

NICSO- Italian Network of Supportive Care in Oncology
Pag. 6
The  vast  majority  of  trials  based  on  electronic  monitoring  evaluate  the  toxicities  during
planned visits (36-40). Only a few studies also included home control between hospital visits
(through an interim phone call) (41-42). Even if data are contrasting, some data show that,
by intensifying the treatment of toxicities and symptoms, the application of supportive care
guidelines, as well as the training of the patient, might lead to a statistically and clinically
reduction of the toxicity severity (42). 
A systematic literature review on 50 studies showed that there are three types of distance
interventions: treatment and side effect monitoring, but also phone-based follow up (rather
than hospital follow up), and psycho-educational phone interventions (43).
In lots of studies there is a positive perception for this approach, which is not only effective
and feasible, both for clinicians and patients, but also is a good way to guarantee easier
access to care, especially for those patients who live far from the referral centres o in rural
areas, when supportive care services are limited (42-45).
However, Liptropp revision (43) highlights contrasting results: the positive perception was
reported in all three overmentioned settings, even if with higher magnitude in the field of
adverse event management and treatment and in the psycho-educational settings, where
phone calls are lived as an adjunct component to the standard care. The phone call is seen
as an immediate source of reassurance and information, but also a continuum of care and it
gives important support of emotional nature, whereas in the follow-up setting patients refer
an  important  reassurance  through  physical  examination  and  direct  physician-patient
relationship (43).
Another important aspect is to understand how much this method can influence medical
management. Some data suggest that home management can reduce the re-hospitalization
rate, since many health conditions could be treated at home, especially with good clinical
surveillance  (44);  minor  access  to  healthcare  facilities,  emergency  room  and  general
practitioners was observed (28; 34). Phone surveillance might also ease the passage from
hospitalization  to  the  outpatient  setting  and  reduce  the  number  of  acute  events  (6;  45).
However, further studies in this setting are needed. 
NICSO trial includes the accrual of patients on adjuvant chemotherapy for breast, colon, and
lung cancer, on targeted therapies or immunotherapy. It aims at evaluating the difference in
terms of toxicity (but also Quality of Life, number of accesses to the emergency room, numb
er of unplanned specialist visits, number of hospital admission and days of hospitalization)
in patients who undergo a standard evaluation for prevention and treatment of toxicities
compared  to  a  group  of  patients  who  receive,  apart  from  the  standard  evaluation,  a
periodical phone-based nurse monitoring.
To sum up, the lack of adherence to guidelines on prevention and treatment of the different
toxicities induced by chemotherapy, targeted therapies, and immunotherapies is a reason
for the possible increase in the incidence and duration of the same side effects.
There is a need for a precocious diagnosis of side effects in order to have better clinical
management and a reduction of the intensity and duration of these events.
Better toxicity management can impact on the correct administration of cancer drugs (dose
intensity).
It is still debated by the scientific community which is the best modality and evaluation tools
to be used. In particular, the main questions are:

Side effect reporting by physicians and/or patients;

Role of nurses in the evaluation of side effects;

The impact of the evaluation tools (frequency, executor) on the reduction of time
spent with toxicity, their severity and the adherence to cancer treatment.

NICSO- Italian Network of Supportive Care in Oncology
Pag. 7
The  recent  Basch  study  (52)  confirmed  that  patients  that  use  patient-reported  outcome
(PRO-CTCAE)  as  an  evaluation  tool  for  toxicity  rather  than  standard  monitoring  have  a
benefit  in  terms  of  overall  survival.  This  evaluation  has  been  conducted  on  a  setting  of
metastatic  patients  on  chemotherapy  (50-52).  There  is  then  the  need  for  randomized
multicentric clinical trials in different therapeutic settings (chemotherapy, targeted therapies,
immunotherapies)  to  evaluate  the  possible  impact  of  a  planned,  continuative  nurse
monitoring of these patients. 
Being proposed and sustained by the multidisciplinary NICSO (Italian Network of Supportive
Care  in  Oncology)  and  having  as  a  primary  objective  the  improvement  of  toxicity
management, based on the Italian law DM 17 December 2004, the study is a non-profit trial
and it is a part of the health assistance in order to better the clinical practice.
2. OBJECTIVES
Primary: To evaluate the number of days patients spend with a grade 3 or higher toxicity
(among those considered). The specific toxicities that are the object of evaluation are
chosen  among  those  that  are  clinically  relevant  and  are  more  likely  responsible  for  a
reduction  of  treatment  adherence  and,  then,  a  reduction  of  the  benefit  from  such
treatment.
Secondary: 
Incidence and duration of grade 1-2 toxicities;
Number of emergency room accesses and unplanned specialist visits;
Number of hospital admissions and days spent in the hospital because of treatment
-related toxicities
Evaluation of quality of life.
Exploratory:
Variation of the oncology treatment dosage (dose intensity).
3. STUDY DESIGN
Multicentric,  randomized,  open-label  trial  of  comparison  of  planned,  continuative  nurse
monitoring intervention together with an information sheet with advice about prevention and
treatment  of  treatment-related  toxicities  –  chemotherapy-,  targeted  therapy-  or
immunotherapy-related ones versus the exclusive use of the same information sheet.
3.1 Study population
Every patient with a solid tumour treated with adjuvant chemotherapy or targeted therapy
or immunotherapy for metastatic disease will be included.
In  the  second  and  third  group  patients  receiving  either  targeted  therapies  or
immunotherapies will be eligible.
The following inclusion and exclusion criteria are valid for all groups:
Inclusion criteria

Patients aged 18 or over.

Histological diagnosis of solid tumour treated with the following drugs (defined per
group):

NICSO- Italian Network of Supportive Care in Oncology
Pag. 8
o
Adjuvant chemotherapy:

anthracyclines and cyclophosphamide ± taxanes (breast cancer)

oxaliplatin and fluoropyrimidines (colon cancer)

combination of platinum or its derivatives (lung cancer)
o
Oral targeted therapy:

sunitinib, pazopanib (kidney cancer)

gefitinib, erlotinib,afatinib, crizotinib (lung cancer)

vemurafenib ± cobimetinib, dabrafenib ± trametinib (melanoma)

everolimus ± exemestane (breast cancer)

aromatase inhibitors + CDK4/6 inhibitors (breast cancer)

fulvestrant + CDK4/6 inhibitors (breast cancer)

vandetanib, lenvatinib (thyroid cancer)

vismodegib (cutaneous basal cell carcinoma) 

imatinib (GIST)
o
Immunotherapy:

anti-CTLA4 drugs,

anti-PD-1/PDL-1 drugs,

their combination.

Written consent signature;

Availability, and accessibility, for phone contact;

Life expectancy ≥ 6 months.
Exclusion criteria:

Presence of symptomatic brain metastases;

Presence of neurological and psychiatric diseases or other conditions that may
prevent patients from being compliant to protocol procedures;

Prior exposure to systemic oncological treatment. This criterium is justified by the fact
that having received a previous oncological treatment usually causes an alteration of
the toxicity profile and in these cases, the attention to toxicity is higher and patients
often receive other preventive treatments.

Participation in other clinical trials.

3.2 Patients’classification and randomisation
Eligible patients are split up into three subgroups according to the oncological treatment

Patients on adjuvant chemotherapy

Patients treated with oral targeted therapy for the first time

Patients treated with immunotherapy for the first time
Within each subgroup patients are randomised to receive:

a  periodical  nurse  monitoring  phone  call,  that  is  planned  and  agreed  with  the
patient, together with an information sheet with advice about prevention and treatment of
toxicities (Experimental group)

an  information  sheet  with  advice  about  prevention  and  treatment  of  toxicities
(Standard group).
1:1 randomisation will be performed via computer using the randomly permuted
blocks system.
All participants are to give their written informed consent.

NICSO- Italian Network of Supportive Care in Oncology
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3.3 Study duration
The study will last 24 months. Patients'accrual will have a duration of 18 months, from the
beginning of the trial. The study period will be 4 months for the immunotherapy and targeted
therapy groups and 6 months for the adjuvant chemotherapy group.
The  study  can  be  interrupted  earlier  in  case  of  oncological  treatment  discontinuation
because  of  disease  progression,  unacceptable  toxicity,  or  withdrawal  of  consent  by  the
patient, or patient's death. In case of temporary suspension of the oncological treatment,
patients will continue to be monitored according to the group they are assigned. The study
ends with the end of the monitoring period, that is with the last phone call to the last enrolled
patient.
4. OPERATIVE ASPECTS
The  realisation  of  the  study  was  preceded  by  a  programme  of  training  meetings  about
supportive  therapies  in  patients  receiving  oncological  treatments.  These  meetings  were
organized in the entire national territory. At least one oncologist in each of the 63 centres
that have joined the trial participated in these meetings.
During these meetings, an information dashboard has been developed and shared. This
dashboard,  that  is  useful  for  both  the  physician  and  the  patients,  contains  the  best
supportive therapy for every administered oncological treatment (according to the expected
toxicities).
This dashboard was developed with the help of several health professionals (physicians and
nurses)  and  the  support  of  a  board  of  specialists  (dermatologists,  gastroenterologists,
cardiologists,  endocrinologists).  It  is  formed  by  a  synthetic  sheet  that  is  customized
according to the oncological treatment, based on the expected treatments. 
This  intervention,  based  on  either  national  and  international  guidelines  (AIOM,  NCCN,
MASCC,  ASCO)  is  the  standard  for  the  prevention  and  treatment  of  therapy-related
toxicities.
The study provides the randomisation between the use of the information sheet and the
addition of a periodical nurse monitoring intervention that is planned and agreed with the
physician. The nurse team that is in charge of the monitoring interventions is centralized
(Nurse Operation Center) and is adequately trained about the potential toxicities that may
come out during the study. The team has a function of coaching and training and supports
the patient's empowerment (see Appendix 1 – Service guide). 
The nurse monitoring intervention consists of a weekly phone call throughout the entire
period of treatment and it follows a protocol of predefined and individualized questions in
order to evaluate the toxicities according to the treatment group. During the empowerment
phone call, the patient is encouraged to adopt the correct protocols for prevention and
cure according to the specific oncological treatment.
The possible actions that may arise during the phone call (codified in the nurse algorithm)
may be:
a)
advice on the use of drugs and therapeutic/preventive actions according to
the information dashboard;
b)
facilitation of the contact of the patient with the referral specialists and/or
general practitioner in case of toxicities that do not need an urgent intervention
(within 12 hours);
c)
in case of toxicities that need an urgent intervention (less than 12 hours):
facilitation of the contact with the referral physician or, if the contact is not possible,
suggestion to access to the hospital through the centre-specific modalities (access

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Pag. 10
to the emergency room, access to the supportive care service, and so on);
d)
in case of not deferrable urgencies: direct access to the emergency room
through the emergency services (118).
At the end of every phone call, the Nurse Operative Center gives a synthetic report of the
detection and sends an appropriate email to the reference physicians (identified at the
moment of randomisation).
During  the  evaluation  period,  according  to  the  PRO-CTCAE  (validated  in  Italian)  (53)
(Attachment 1, 2, 3), in both groups, a questionnaire for the monitoring of toxicities will be
administered to each patient.
This  questionnaire,  which  takes  into  consideration  the  previous  week,  monitors  the
frequency  (F),  severity  (S),  and  intensity  (I)  of  each  symptom.  A  question  about  the
number  of  days  spent  with  toxicity  will  be  performed.  The  administration  of  the
questionnaire  will  be  made  through  a  pre-registered  phone  call  (without  an  operator),
which is based on an electronic score coding. This phone call does not overlap with the
monitoring phone call in the specific randomisation group.
For the patients’privacy, every date coming from the project will be dealt with according to
the current laws.
In  each  group,  at  the  baseline  visit,  then  every  month,  the  EORTC  QLQ-C30
questionnaire (Attachment 4) will be administered.
In both groups, there will be a monitoring activity of the number of unplanned hospital
accesses (emergency room or specialist visits). An evaluation of the number of hospital
admissions and days of hospital stay (due to toxicities) will be performed.
Finally, the dose intensity of the oncological drugs throughout the period of treatment will
be monitored (it will be considered as the ratio between the administered dose and the
planned dose). This aspect is fundamental not only for the management of the oncological
therapy but also for the adherence to the recommendations of supportive care.
5. STATISTICS
5.1 Sample size
The recent events related to the COVID19 pandemics have slowed down the accrual of
the study. For this reason, a revision of the sample size has been necessary.
The revision only involves group B and C, since the accrual of group A was completed
according to the original version of the protocol.
Group A
Considering  the  lack  of  data  from  the  literature  about  the  duration  of  side  effects,
especially grade 3 and 4, but estimating a prevalence of about 15%, considering a power
of 0.9 and an alpha value of 0.05, it is then necessary to have 207 patients for each arm of
the study to show a reduction from 15% to 5% of the proportion of days spent with a grade
3 or higher toxicity.
Groups B and C
Considering the same lack of data, but estimating a prevalence of about 25%, considering
a power of 0.72 and an alpha value of 0.05, it is then necessary to have 50 patients per

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Pag. 11
arm per group to show a reduction from 25% to 5% of the proportion of days spent with a
grade 3 or higher toxicity.
The entire sample size is then formed by 614 patients, to be found among the 63 involved
centres.
5.2 Data management
The investigator of each centre, together with the designated personnel, is in charge of the
report of the required information through the specific electronic case report form (eCRF),
that is provided by the Promotor. Data collected in the eCRF are anonymous and the patient
will be identified only through a specific code. All the data are elaborated and analysed by
the  study  scientific  committee.  All  data  are  archived  anonymously  according  to  the
guidelines for the treatment of personal data in clinical trials (Italian law approved on 24th
July 2008, Official Gazette of 14th August 2008). Genetic data are treated according to the
authorization 8/2013 (general authorization on the treatment of genetic data). The access to
these data is protected by the investigator of each centre.
5.3 Data analysis
Qualitative variables are synthesized in absolute frequencies and percentages; quantitative
ones  through  mean  and  standard  deviation,  maximum  and  minimum,  median  and
interquartile range. The evaluation of the statistical significance of the differences between
two main groups (nurse monitoring vs standard monitoring) will be analyzed through the
Student's t-test for dependent groups in case of quantitative parameters. The chi-square
test  will  be  used  to  evaluate  the  statistical  significance  of  the  differences  in  qualitative
parameters. The comparisons among groups will be performed at the end of the study. The
statistical significance of the variations in time of quantitative variables will be performed
through the two-way analysis of variance (ANOVA). A secondary analysis will be performed,
aiming at evaluating the statistical significance of the differences in all the other parameters
between the two groups.
6. PHARMACOVIGILANCE
6.1 Legislation
Since this study aims at the evaluation and the improvement of the prevention and treatment
of toxicities of oncological treatments, here we present the main definitions according to the
European legislation on pharmacovigilance – that is a reference for the Italian legislation.
This legislation was modified by the entry into force of the EU Regulation n. 1235/2010,
whose  application  has  been  operative  since  the  2nd  of  July  2012,  and  the  Directive
2010/84/EU,  that  is  currently  being  implemented.  Based  on  these  legislations,
pharmacovigilance  is  defined  as  "the  complex  of  activities  that  aim  at  continuously
evaluating all the information related to drug safety and at ensuring a favourable benefit/risk
ratio for the population for all the drugs on the market". The definition of adverse reaction
has been changed and it is now considered as a "noxious and unintended effect related to
the use of a drug". This definition considered, all adverse events will be notified, also those
that are related to therapy error, abuse, misuse, off label use, overdose, or professional
exposure.
6.2 Adverse event report: investigators' responsibilities
During  the  study,  the  overmentioned  pharmacovigilance  legislation  will  be  respected.
Investigators in each centre will be then asked to respect the current legislation and will be

NICSO- Italian Network of Supportive Care in Oncology
Pag. 12
in charge of reporting all adverse events related to the use of the drugs that are monitored in
the study. The reporting will be notified to the local health authority, or the responsible for
pharmacovigilance of the healthcare facility, through the sending of a copy of the "Form for
the Reporting of Suspected Adverse Event".
It is important to specify that all adverse events happening in the subjects included in the
study during the study period will be recorded by the investigators in the eCFR.
We then report some definition and some evaluation criteria.
6.2.1 Adverse reaction (AR)
According to the current legislation, an AR is defined as every unintended medical event
that happens in a patient or subject included in the clinical trial who is receiving a drug; this
event is not necessarily in a causal relationship with the used drug. Examples of AR include
(but are not limited to):
- abnormal results of laboratory tests,
- clinically relevant signs and symptoms,
- hypersensitivity,
- progression/worsening of the disease.
Furthermore, they can include signs and symptoms that may come from:
- drug overdose;
- treatment discontinuation;
- drug abuse;
- incorrect use of drugs;
- drug interactions;
- drug addiction;
- uterine exposure.
6.2.2 Severity evaluation
AR  severity  will  be  evaluated  according  to  the  NCI-CTCAE  (National  Cancer  Institute-
Common Terminology Criteria for Adverse Events), version 4.03 (see Appendix 1 – Medical
Dashboard). 
A brief definition is reported to clarify the meaning of each term.
Grades: Grade refers to adverse event severity. CTCAE is based on a scale from 1 to 5:

Grade 1 – mild: asymptomatic or mild symptoms; only clinical or imaging follow up is
required; no need for specific intervention;

Grade 2 – moderate: minimal and non-invasive intervention is required; the event
determines a slight limitation in the instrumental daily activities;

Grade  3  –  severe:  clinically  significant,  but  not  immediately  dangerous  for  life;
hospitalisation  or  prolongation  of  hospital  stay  is  needed;  disabling;  it  causes  a
limitation of the daily activities that are related to the person's self-care;

Grade 4: potentially fatal consequences; urgent intervention is needed;

Grade 5: adverse event-related death.

Since not all the grades are appropriate for all the AR, in case of AR which does not relate to
an appropriate NCI-CTCAE grading, the usual severity classes are used: mild, moderate,
severe, potentially fatal, and fatal. These are defined as follows:
GRADE
Description

NICSO- Italian Network of Supportive Care in Oncology
Pag. 13
Mild
It does not interfere with the subject’s daily functional activities
Moderate
It interferes with some of the subject’s daily functional activities
Severe
It significantly interferes with the subject’s daily functional activities
Not 
evaluable
There is insufficient or incomplete evidence to perform a clinical evaluation
of the causal relationship
6.2.3 Casuality evaluation
The causality evaluation by the investigator should be performed for every adverse event.
The investigator's evaluation is the determination of whether there may be a reasonable
possibility that the monitored pharmacological treatments may have caused or contributed
to the adverse event. To give conformity of judgement, the evaluation should be defined as
follows:
CAUSALITY
Description
Not related
There is no evidence in support of the drug-event relation
Improbable
The  evidence  that  suggests  a  causality  relation  is  scarce  and  not  very
sustainable (e.g. the event does not happen with a reasonable time from the
drug administration). Other reasonable causes may explain the event (e.g.
the patient's clinical conditions; other concomitant treatments)
Possible
There is some evidence that suggests a causal relationship (e.g. the event
happens within a reasonable time from the drug administration). However,
the  presence  of  other  conditions  may  contribute  to  the  event  (e.g.  the
patient's clinical conditions; other concomitant treatments)
Probable
There is evidence that suggests a causal relationship and the influence of
other factors is improbable
Certain
There is evidence to support a causal relationship and the influence of other
factors can be excluded
Not 
evaluable
There is no adequate evidence or evidence is not complete to perform a
clinical evaluation of the causality relationship
All the adverse events happening during the study will be recorded in the eCRF.
 
7. ETHIC ASPECTS
The study will be conducted according to the protocol, following the principles of the Helsinki
Declaration (last revision of October 2013), the rules of the Good Clinical Practice (ICH
GCP),  the  laws  on  data  protection  and  other  applicable  regulations,  including  the
pharmacovigilance laws and the Good Pharmacovigilance Practice, which is a reference for
the realisation of this type of studies.
8. DIRECT ACCESS TO DATA AND ORIGINAL DOCUMENTS 
Unless requested by law, only the investigator and his/her staff, the Ethics Committees, the
Monitors,  the  Study  Coordinators,  the  Auditors  and  the  inspectors  from  governmental
bodies may directly access to the archives to connect the study data with the single patients.
In particular cases, such as the inspection by regulatory agencies, the information of each
patient, report anonymously in the eCRF, may be connected to his/her clinical data through

NICSO- Italian Network of Supportive Care in Oncology
Pag. 14
the appropriate key (which is kept by the investigators).
9. DATA PUBLISHING
There are no constraints to data publishing. The promoter takes the responsibility to share
the results with the investigators from the participating centres (see Appendix 2) and, on
behalf of the entire working group, to publish them or to make them public during scientific
congresses, symposia, and so on.
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