A Mobile Supportive Care App for Patients With Metastatic Lung Cancer: a Pilot Randomized Controlled Trial - The Lung Cancer App (LuCApp) Study
Phase: NA
Conditions: Nonsmall Cell Lung Cancer, Small Cell Lung Carcinoma
Sponsor: Bocconi University

 
 
A mobile supportive care app for patients with 
metastatic lung cancer: a pilot randomized 
controlled trial 
The Lung Cancer App (LuCApp) study 
Version 1.0 
Date 3 November 2017 
 
Coordinating investigator:  
 
Dr. Paolo Pedrazzoli 
Dipartimento Oncoematologico: Oncologia 
Fondazione IRCCS Policlinico S. Matteo – Pavia 
Viale Camillo Golgi 19, 27100 Pavia 
Ph: +39 0382/501659 
E-mail: p.pedrazzoli@smatteo.pv.it 
 
Signature of Coordinating Investigator  
 
 
 
Date 
                                            6 November 2017                                          

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TABLE OF CONTENTS 
TABLE OF CONTENTS ...................................................................................................................... 2 
INVESTIGATOR STATEMENT ........................................................................................................ 3 
ABBREVIATIONS ............................................................................................................................... 4 
INTRODUCTION ................................................................................................................................. 5 
BACKGROUND AND OBJECTIVES ..................................................................................................................... 5 
METHODS ............................................................................................................................................ 7 
TRIAL DESIGN.................................................................................................................................................... 7 
PARTICIPANTS .................................................................................................................................................. 8 
INTERVENTION (LUCAPP) .......................................................................................................................... 11 
STANDARD OF CARE ...................................................................................................................................... 17 
OUTCOMES ..................................................................................................................................................... 18 
SAMPLE SIZE ................................................................................................................................................... 24 
RANDOMIZATION .......................................................................................................................................... 26 
STATISTICAL METHODS ................................................................................................................................ 27 
ETHICS & INFORMED CONSENT .................................................................................................................. 28 
DISCUSSION.......................................................................................................................................29 
DISSEMINATION AND IMPACT ..................................................................................................................... 29 
REFERENCES .....................................................................................................................................30 
 
 
 

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Investigator Statement 
 
By my signature, I agree with the content of the clinical study and confirm the Clinical 
Investigation Plan in the latest version. I confirm to conduct the study in compliance 
with the approved protocol and will adhere to the GCP guidelines, and other regulatory 
requirements as amended. 
 
Study Center please print name 
 
 
 
 
 
(Principal) Investigator please print name 
 
 
 
 
 
 
 
Signature of (Principal) Investigator   
 
 
Date 
 
 
 
 
 
 
 

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ABBREVIATIONS 
CSUQ  
Computer system usability questionnaire 
CTCAE 
Common Terminology Criteria for Adverse Events 
ECOG  
Eastern Cooperative Oncology Group 
EQ5D  
Euro Quality of Life 5 Dimensions 
FACT-L 
Functional Assessment of Cancer Therapy - Lung 
HADS  
Hospital Anxiety and Depression Scale 
HRQOL 
Health-related quality of life 
LuCApp  
Lung Cancer App 
OS 
 
Overall survival 
PROMs 
Patient reported outcome measures 
QALY  
Quality-adjusted life year 
SCNS-SF 
Supportive Care Needs Survey Short Form 
ZBI 
 
Zarit Burden Interview 
 
 

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INTRODUCTION 
Background and objectives 
The substantial progress made in the treatment and diagnosis of cancer has entailed it 
can be managed as other chronic disease, where greater long-term active surveillance 
is needed. To enhance patients’ quality of life new models of care thus need to be 
thought through and the paternalistic view according to which patients are sited in the 
role of patient recipients and should just follow what they are told by providers needs 
to be overcome (1).  
To this end, self-management (SM) interventions can help patients and their families 
care for themselves along the cancer care continuum. SM is here defined as “the 
individual’s ability to manage the symptoms, treatment, physical and psychosocial 
consequences and life style changes inherent in living with a chronic condition” (2). 
With respect to cancer care, patient involvement can aim at enhancing symptom 
management. Although recent advances in cancer therapies have led to better clinical 
outcomes (3), treatment-related side effects still carry a great weight in affecting 
patients’ quality of life.  
This new need for self-care activities has coupled with the unsustainability of current 
healthcare spending thus leading to the need to acknowledge solutions that are 
disruptive, yet capable of controlling costs without diminishing quality of service and 
quality of life. 
This scenario has witnessed the rapid and ongoing growth in mobile technologies, 
including mobile health (mHealth), defined as “medical and public health practice 
supported by mobile devices, such as mobile phones, patient monitoring devices, 
personal digital assistants (PDAs), and other wireless devices” (4). 
As a booming technology, mHealth can be instrumental in supporting decision-making 
and strengthening the data generation process, by integrating data from several different 
sources.  
For such reasons, the case of mHealth represents a highly significant one, since mobile 
devices can greatly enhance the connection between the main stakeholders in the health 
process and provide validated, yet innovative, approaches for economic evaluation. On 
the other hand, however, mHealth also poses new and unexplored regulatory, 
organizational and technological challenges that need to be better tackled in order to 
ensure that such technologies are put to best use.  

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This recent hype has led to the development of mHealth applications in all major 
therapeutic areas: in 2016, there were over 259,000 mHealth applications (apps) with 
over 3 billion downloads, reflecting a growth rate of over 35% in 2015 (5, 6). However, 
the development and subsequent download process has by far outpaced the evaluation 
phase: whether mHealth leads to better overall health outcomes and reduced disease 
burden is still unknown and overall scientific evidence is scant.  
mHealth, here intended as a stand-alone technology, can also be incorporated in broader 
health care programs that aim at enhancing overall patient empowerment by providing 
him with greater continuity of care and centrality along the whole care continuum.   
mHealth applications are being developed and evaluated in a variety of chronic care 
domains, including diabetes (7), asthma (8), obesity (9), smoking cessation (10), stress 
management (11) and depression treatment (12). However, although oncology is 
among the therapeutic areas where mHealth could have a more disruptive impact on, 
fewer interventions are aimed at cancer patients, with some notable exceptions. Basch 
et al. tested symptom self-reporting during routine cancer treatment via STAR 
(Symptom Tracking and Reporting) against usual care (13), while Denis et al. compared 
an e-follow-up application (e-FAP) for detecting lung cancer relapse with standard 
surveillance, showing improved overall survival (OS) for the experimental compared 
with the control arm (median OS: 19.0 vs 12.5 months) (14). In 2016, instead, the 
University of Surrey launched the eSMART study, a 5-year RCT conducted across five 
countries that aims at testing the impact of the Advanced Symptom Management 
System (ASyMS), a system that enables the real-time monitoring of patients-reported 
outcome measures (PROMs) (15).  
A similar remote monitoring system available to manage therapy-induced side effects 
is LuCApp (Lung Cancer App), an application developed by researchers and lung 
cancer clinicians and specifically tailored to lung cancer patients’ needs. LuCApp 
allows to gather symptom data in real time and to share it with healthcare professionals. 
Whilst focusing on a specific type of cancer, LuCApp adapts to all potential therapies 
for its treatment and not only to chemotherapy. The evaluation of LuCApp will be 
tested against the current standard of care, where symptom management during 
chemotherapy and other therapies is mostly up to clinicians and therapeutic 
professional teams with little technology support. The primary objective will be to 
determine whether, by enhancing self-monitoring of therapy-induced side effects, this 
application can lead to increased health-related quality of life (HRQoL) and therefore 

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generate value from a patient and public health perspective. The study summary is 
available in both English and Italian as an attachment.  
METHODS 
Trial design  
This is a 24-week, two-arm, multicenter feasibility parallel randomized controlled trial 
designed to evaluate the usability and effectiveness of LuCApp to improve self-
management of symptoms and quality of life in lung cancer patients. The protocol has 
been developed in accordance with the CONSORT-EHEALTH checklist (16). The 
flow diagram for recruitment and randomization is shown in Figure 1. 
 
Figure 1 - Flow diagram for recruitment, randomization and data collection 
 

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Participants  
Adults of both sexes with lung cancer (small and non-small cell) will be assessed for 
eligibility at participating sites. Study inclusion criteria will be ( 
 

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Table 1):  
 over 18 years of age individuals of both sexes;  
 diagnosed with small or non-small cell lung cancer;  
 patients eligible for chemotherapy, immunotherapy or biological therapy; 
 patients diagnosed with non-resectable tumor and eligible for neoadjuvant 
therapies; 
 life expectancy of six months or more;  
 a performance status between 0 (asymptomatic) and 2 (symptomatic, <50% in bed 
during the day) according to the Eastern Cooperative Oncology Group (ECOG) 
score; 
 patients fluently speaking Italian;  
 patients able to provide informed consent to participate in the study; 
 patients who own a smartphone that can access either the iOS or the Android 
platform. 
Although internet literacy was not defined as an explicit eligibility criterion in this 
study, it works as a de facto selection criterion since only individuals that personally 
own a smartphone can be enrolled in the study. It was assumed that, if individuals 
owned a smartphone, they would be able to use it.  
Patients will be excluded if they: i) are unable to provide written informed consent, ii) 
are unable to use the app and all other materials (i.e. blind), iii) have received, are 
receiving or plan to receive radiotherapy or surgical resection as their management will 
likely be different from patients undergoing pharmacological therapy. Furthermore, 
patients that are already included or about to join other clinical trials and individuals 
who are already using another smartphone application to self-manage cancer will not 
be considered eligible for the trial.  
 
 
 

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Table 1 - Summary of inclusion and exclusion criteria 
Inclusion criteria 
Exclusion criteria 
 over 18 years of age individuals of both sexes;  
 diagnosed with small or non-small cell lung 
cancer;  
 patients 
eligible 
for 
chemotherapy, 
immunotherapy or biological therapy; 
 patients diagnosed with non-resectable tumor 
and eligible for neoadjuvant therapies; 
 life expectancy of six months or more;  
 a 
performance 
status 
between 
0 
(asymptomatic) and 2 (symptomatic, <50% in 
bed during the day) according to the Eastern 
Cooperative Oncology Group (ECOG) score; 
 patients fluently speaking Italian;  
 patients able to provide informed consent to 
participate in the study; 
 patients who own a smartphone that can 
access either the iOS or the Android platform. 
 individuals 
unable 
to 
provide 
written 
informed consent; 
 individuals unable to see the App and all other 
materials (i.e. are blind); 
 patients receiving or that plan to receive 
radiotherapy or surgical resection; 
 patients already included or about to join 
other clinical trials; 
 patients already using other smartphone 
applications to self-manage cancer symptoms. 
 
Once eligibility has been established, patients will be asked to join the study by the 
medical oncologists after diagnosis and a face-to-face assessment at the participating 
centers. Patients will receive an invitation letter, the study leaflet and the informed 
consent form. This will not be a purely web-based trial, since face-to-face components 
will still be present: data will be collected through questionnaires via the app for the 
intervention patients, while standard-of-care patients will complete paper 
questionnaires during clinic visits, or at home (having received paper questionnaires 
during the previous visit) or via telephonic interviews with the research team. Outcomes 
will be self-assessed through Patient Reported Outcome Measures (PROMs) (for 
further information, please look at the “Outcomes” section) at different points in time. 
Patients assigned to the intervention arm will be trained to use LuCApp (study staff 
will provide them with a 15-minute presentation on how to use the App) and will be 
assisted during the whole study period by a “helpdesk”.   
University and participating centers affiliations will be displayed on the invitation letter 
to obtain participants’ trust but no bias is expected to result from the display of such 
information.  

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Intervention (LuCApp) 
BIOMEdical Research Informatics Solutions (BIOMERIS), a laboratory accredited as 
an academic spin-off by University of Pavia, in collaboration with the oncologists of 
the cancer center “Fondazione IRCCS Istituto Nazionale dei Tumori” (Milan, Italy) 
initially developed a web-based intervention. The original application was specifically 
tailored to the needs of head and neck cancer patients. Cancer type later switched to 
lung cancer and CRO Advice Pharma Group was commissioned the adjustment of the 
app to the new pathology and to the iOS platform. LuCApp was first made available on 
Playstore (Android online store) and on iTunes (Apple online store) in November, 
2017.  
The original App (HeNeA) was developed in direct collaboration with the oncologists 
of the cancer center “Fondazione IRCCS Istituto Nazionale dei Tumori” (Milan, Italy) 
and was pilot-tested with a small number of clinicians of the same institute. The 
structure and the flow chart were later refined in accordance with present legislation 
and in collaboration with the clinical teams of the three participating centers. 
Satisfaction with LuCApp was further tested with healthcare professionals from 
recruiting sites and a small group of oncologists and specialists in palliative care from 
other Italian centers before the launch of the randomized control trial. The information 
gathered was used to further improve the App. After several revisions and updates the 
App is now at its 5th version and is released on the main apps stores (see above). We do 
not anticipate any updating on LuCApp during the evaluation process, hence the 
technology content will be frozen once the trial begins. It is projected that there will be 
no further revisions or updating of either the intervention or the comparator during the 
study period. 
With respect to data quality and accuracy, the system allows to collect data and to 
perform checks by using automated range and consistency checks set during the setup 
phase. The user will be lead throughout the compilation phase by alerts and 
notifications that will ensure completeness and consistency of data captured. 
The study was developed in close cooperation with an Advisory Board, composed of 
the Scientific Directors and some healthcare professionals of all participating centers, 
the researchers at Università Bocconi and representatives of the CRO. Healthcare 
professionals will be trained on several aspects of the study protocol and on the use of 
LuCApp before the study begins. A research coordinator from each center will be 
identified. 

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Data will be collected through an electronic data capture (EDC), ICE (Integrated 
Clinical Trial Environment) owned by Advice Pharma Group. This system is compliant 
with Title 21, Part 11 of the Code of Federal Regulations and with the EU GMP Annex 
11 about electronic records for patients. Figure 2 and  
Figure 3 show the ICE data collection mask and the mobile app (“LuCApp”) data 
collection mask respectively. Data will be anonymized and stored in a secure database 
for the study.  
 
Figure 2 - Integrated Clinical Trial Environment mask 
 
 
Figure 3 - LuCApp interface  
 
 
 
 
 
 
 
 
 
 
After informed consent and randomization, happening in hospital setting before the 
start of medical therapy for lung cancer, clinicians will access a secured web-based 
platform where they will register patients and their credentials. Clinicians will use a 
hospital PC or their own mobile device connected to internet. Upon activation of a 

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personal account, patients, with the help of the team, will download the app on their 
mobiles and log in by inserting their e-mail address and a self-chosen password. For 
the duration of the trial, the interaction with LuCApp will thus occur via the patient’s 
own mobile and rely on the usual network connectivity. Patients will be required to log 
in whenever they access the application: this will guarantee that validated data are 
included in the eCRF and that only patients can access to sensitive data. Patients will 
not be paid any cash or in-kind amount nor will they be asked to disburse any amount, 
as LuCApp will be free to download for them. 
The intervention presents several different and unique functionalities and components 
that were designed to aid symptom self-reporting and management. The intervention 
content is organized as follows:  
1) “How do I feel today?” – This component of the app allows participants to fill in a 
questionnaire every day to report their current situation with respect to 22 side 
effects that are commonly experienced during therapies for lung cancer and were 
identified from the literature. Symptoms will be rated on a scale from 0 to 4 (where 
0 is symptom not present, 4 is maximum degree of severity). Questions were 
adapted for patient use from the National Cancer Institute’s Common Terminology 
Criteria for Adverse Events (CTCAE) (final list is available as an attachment 
“4.2_LuCApp_Annex 2_Adverse event list”) (17). LuCApp will trigger alerts to 
healthcare professionals whenever a symptom of level 3 or above is inserted. 
Although the compilation is possible multiple times per day at will, patients will 
receive a reminder (as a mobile banner or email) to fill in this questionnaire every 
three days. Up to three different reminders will be sent at noon, 6 p.m. and 9 p.m. 
to encourage patients to self-report their symptoms using a recall period of the past 
24 hours. Symptom reports are available for clinicians only.  
In order to identify this comprehensive list of symptoms, first, a rapid review of the 
literature was conducted. References considered included:  
a. The Edmonton Symptom Assessment System (ESAS): 9 most common 
symptoms in cancer patients (first 9 symptoms) (25); 
b. Symptoms identified from a systematic review of studies in adults with lung 
cancer (26), another review the common symptoms in advanced NSCLC 
(27), and a third review of symptoms at initial evaluation of lung cancer 
patient (28). 

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This activity resulted in a list of 68 symptoms. From this list, lung cancer specialists 
who are investigators in this trial checked those symptoms that they consider 
relevant for the patient population under investigation. A second team of experts 
was then asked whether those symptoms not selected by the experts but identified 
in the literature would also be worth including. These included: anorexia, weight 
loss (clinical parameter), constipation, weakness, insomnia, dry mouth, 
remembering, and peripheral neuropathy. A final list was then circulated and 
validated amongst all experts and is available as an attachment to this protocol. 
 
2) “Temperature” and “Weight” – Patients in the intervention arm will be asked to 
enter their body temperature everyday and to report their weight once per week 
(again via mobile banners or emails). Whenever body temperature exceeds the 38 
degree Celsius threshold or a 5-percentage point reduction in body weight in the 
previous two weeks is reported, specific alerts will be generated to inform the 
clinical team in charge.  
 
3) “Tip of the day” – Whenever a patient logs into the app, this feature of the app 
shows a daily tip, a short suggestion to better manage the side effects of the 
therapies. The tip is selected randomly among those related to the therapy the 
patient is undergoing. Tips were drawn from clinical practice guidelines and 
discussed by a consensus group of experts including medical oncologists, radiation 
oncologists, surgeons, nutritionists, speech language pathologists, infectious 
disease specialists, dentists and nurses (18, 19). All tips were later validated with 
the healthcare professionals from the three sites participating in the trial (final list 
is available as an attachment “4.1_LuCApp_Annex 1_Tips of the day”).  
 
4) “Questionnaires” – A final section allows patients to fill-in several PROMs about 
their HRQoL and experience with supportive care needs and LuCApp: EuroQol 5D, 
Functional Assessment of Cancer Therapy (Lung), Hospital Anxiety and 
Depression scale, supportive care needs survey, usability and satisfaction with the 
app (see next section on outcomes). Data will be collected at several points in time, 
depending on the type of questionnaire considered (see next section on outcomes). 
Questionnaire completion is instrumental in evaluating several end-points and in 
determining whether LuCApp can improve patient-relevant outcomes compared to 

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the standard of care. To enable the comparison, patients in the standard of care arm 
will fill out the same questionnaires via paper at clinic visits or follow up.  
 
5) “Trend” – In the Trend component, available in the healthcare professional App 
only, clinicians can access the longitudinal trend of their patients’ clinical 
parameters. Side effects, temperature and weight are displayed in charts, and it is 
possible to select a specific timeframe. Clinicians can access the same graphs 
remotely and analyze the progress of each patient’s clinical parameters and side 
effects over time (Figure 4).  
 
Figure 4 - An example of how trends for different symptoms and parameters are visualized in the app  
 
 
6) “Info” – In this final section, in order to increase the overall awareness of the disease 
and its potential treatments, the most relevant educational material is collected. This 
section includes some general information on lung cancer, therapies, patients’ 
rights, up to a series of institutional useful links (such as nearest pharmacy, hospital 
contacts) that patients can browse if needed (Figure 5).  

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Figure 5 - An example of how information is visualized in the app 
 
 
Continuity in the utilization of the application will be strongly recommended.  
Participants will be advised to access the App daily to receive their daily tip and enter 
their temperature information. Questionnaires and other clinical parameters will have 
to be entered according to the schedule, but additional information can be added at 
discretion and alerts will activate whenever necessary. Patients will be advised to enter 
their daily body temperature at similar times each day and to use the same scale to 
measure their weight. To facilitate a greater use of the application, LuCApp provides 
for several rounds of banner reminders (better detailed above) scheduled on days when 
the input of a specific information is due according to study protocol. 
Patients in the standard of care will follow the routine procedures and will be assisted 
by a clinical team at their site. Such professionals will still provide frequent assistance 
related to the trial since they will administer questionnaires when due and will update 
the CRF for the standard of care patients. On the other hand, in order to deal with the 
intervention arm, healthcare professionals will be trained through dedicated sessions 
prior to the launch of the patient recruitment phase. Contact details of LuCApp 
developers and technicians will be provided for assistance. However, if the technology 
does not function properly and the clinician believes an action is urgently needed for a 
patient, the research team is advised that standard of care applies to the intervention 
arm, too. During weekends it is possible that clinicians will not be reachable or will not 
reply promptly to alerts. Also in this case patients are advised to use the standard of 
care approach (e.g. out-of-hours service doctor, emergency department). The clinical 
teams that will take care of the intervention patients will be different from the standard 

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of care arm ones, to ensure that behaviors and results will not be influenced. The 
research teams are also advised not to share feedback or comments for the duration of 
the trial in order to reduce performance bias as much as possible. Clinicians will receive 
alerts on their dedicated LuCApp device and will be responsible for managing them in 
a timely way. A single alert will be generated for each patient and clinical parameter 
monitored (i.e. temperature, weight, side effects). Healthcare professionals will then be 
able to gain more information on the symptoms that triggered the alert and to monitor 
the longitudinal trend of side effects both on their device and on the LuCApp website 
from a PC or laptop. Professionals will be able to access all other patient information 
on the secure LuCApp website, only. In response to an alert triggered for a specific 
patient, clinicians will be requested to act within 24 hours and to document the type of 
intervention performed among a list of possible alternatives derived from the literature: 
referral to the ER/hospital, telephone counselling about symptom management, dose 
modification, supportive medication initiation/change, visit anticipation (13). 
To guarantee a greater use of the application automated reminders will be sent to 
participants both via email and via push notification. Participants will be prompted, via 
an automated message to update their body temperature and their weight and to fill out 
the side effects questionnaires. Three rounds of alerts will be generated at 12, 6 and 9 
p.m. on the dates when the input of the relative data is scheduled (daily for body 
temperature, weekly for weight and every three days for the side effects questionnaire, 
see above). 
Both groups will have access to treatment as usual. However, additional training will 
be provided to intervention arm participants right after enrolment: LuCApp features 
will be better detailed and training sessions will be scheduled accordingly. Furthermore, 
during the trial, a support center (“helpdesk”) will be available to help participants with 
any technical issues that may occur. 
 
Standard of care 
Usual care will consist of standard procedures currently available at participating 
centers for monitoring and documenting symptoms. These therapeutical procedures are 
based on the guidelines developed by the National Comprehensive Cancer Network 
(NCCN) and the Associazione Italiana di Oncologia Medica (AIOM) (20). Symptoms 
for control arm patients will be discussed and registered during scheduled clinical visits 

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with the oncologists. Standard-of-care patients will fill out their PROMs following the 
same schedule identified for LuCApp patients with paper questionnaires during clinic 
visits, or at home (having received paper questionnaires during the previous visit) or 
via telephonic interviews with the research team. Patients are usually allowed to contact 
their relative sites for concerning symptoms that occur between scheduled visits or 
advised to see the out-of-hour doctor or the emergency department if needed. This 
option is also recommended for the intervention arm during weekends. 
Outcomes 
As discussed above, the overarching research question of this study is to explore and 
pilot the impact of using LuCApp on relevant outcomes in patients with lung cancer. 
LuCApp has several functionalities and this pilot explores whether these functionalities 
impact on the patients’ health-related quality of lives (HRQoL) and needs in cancer 
supportive care. It also aims to assess whether it improves the burden on caregivers and 
the satisfaction with the use of the app. Finally, the cost-effectiveness of LuCApp will 
be explored, based on the improvement in HRQoL and the resources being used to 
manage the disease throughout the study period.  
A number of outcome measures have been identified to allow the assessment of the 
above trial objectives. LuCApp will be evaluated in terms of: (1) impact on HRQoL, 
(2) impact on cancer supportive care needs, (3) impact on the burden for caregivers, (4) 
resource use, (5) usability and satisfaction with LuCApp. The rationale for selecting 
these measures and their characteristics are summarized in the next sections.  
 
(1) HRQoL  
The impact on HRQoL of using LuCApp will be measured with existing valid and 
reliable patient-reported outcome measures (PROMs). Their selection was based on the 
availability of a validated Italian version, for self-report use, that can be administered 
both on paper and via smartphones or tablets, and commonly used in lung cancer 
patients.  
Symptoms are subjective experiences self-reported by the patient, and are a subset of 
patient perceptions of health status and HRQoL (21). HRQoL is a multidimensional 
construct of diverse functional scales (e.g. physical function, psychological function, 
social role function) and symptom scales (e.g. disease-related or treatment-related 
symptoms) (21).  

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Three questionnaires were selected and are described in the next paragraphs. 
 
a) EQ-5D-5L  
The EQ-5D-5L is a generic preference-based measure of health status, which is the 
most commonly used tool used to derive utility values that can be utilized within an 
economic evaluation model (22). This tool is also commonly used in lung cancer trials 
(23). It includes questions covering five domains: mobility, self-care, usual activities, 
pain and discomfort, and anxiety and depression. For each domain, 5-level questions 
are posed. Additionally, patients are asked to fill in how they feel today on a vertical 
visual analogue scale (VAS). Validated versions are available for paper-based and via 
smartphones and tablet administration.  
The questionnaire will be administered at baseline, every 3 ± 1 weeks to take into 
account that visit intervals may vary between patients and across therapies (in this way 
the completion of the questionnaire will happen approximately 1 day before each cycle 
of treatment for chemotherapy patients), and at the end of the study period. This 
frequency of administration is in line with other trials involving lung cancer patients 
that administered the EQ-5D (24, 25). 
 
b) FACT-L (lung cancer module):  
The Functional Assessment of Cancer Therapy-Lung (FACT-L) questionnaire is a 
disease-specific measure capturing multidimensional aspects of lung cancer patients’ 
quality of lives (26). The symptoms covered are shortness of breath, weight loss, 
consciousness, cough, hair loss, appetite, tightness in chest, breathing. FACT-L is the 
result of the combination of FACT-G (general module and core instrument), which is a 
general quality of life questionnaire for use in a variety of chronic illness conditions, 
with a Lung Cancer subscale. It is validated in the Italian version. These questionnaires 
are extensively used in clinical research, health care delivery studies, symptom 
management studies, psychological intervention studies, and other treatment 
evaluations. Studied in various subgroups of lung cancer patients receiving different 
courses of treatment. The administration mode could be interviews (in-person or 
telephone), self-administration (in the clinic or by mail) or computer administered 
questionnaire. Available data suggest that while there are small differences in the way 
people respond based on mode of administration, these alternate formats are essentially 

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equivalent, particularly when reporting data at the group level (27). The questionnaire 
will be administered at baseline, at 12 weeks, and at the end of the study period. 
 
c) Hospital Anxiety and Depression scale (HADS)  
HADS is a self-assessment scale developed to detect states of depression, anxiety and 
emotional distress amongst patients treated for a variety of problems in the setting of 
out-patient clinics (28). It is composed of two 7-item scales for depression and anxiety 
respectively. All symptoms relating to physical disorders (e.g. dizziness, headaches) 
were excluded to avoid interference with other diagnoses (29). HADS was identified as 
one of the most commonly used PROMs in advanced-staged lung cancer clinical trials 
of pharmaceutical agents (30), and has been used to measure HRQoL in NSCLC 
patients (31). 
The Italian version of the HADS showed to be valid and reliable, similarly to those 
results obtained in other languages (32). Specifically, there was a high internal 
consistency of both anxiety and depression scales. Factor analysis confirmed the bi-
dimensionality of the HADS model. Results showed that the two scales are not 
sufficient to detect distinct cases of anxiety and depression, which is supported by other 
studies. This is likely because patients with one or the other disorder are likely to have 
a common area of emotional disturbance, which is not differentiated by the HADS. The 
use of the total scale has shown high internal consistency. HADS has been used in 
various clinical settings, in cross-section and longitudinal studies as an outcome 
measure. Results show that the scales and total scale are sensitive to change, but may 
be less likely to the smaller changes. 
Another study conducted an updated literature review to assesses the validity of HADS 
(29). They highlight that HADS is administrated mainly in patients with cancer or other 
somatic illnesses. They looked at the number of factors in HADS identified by factor 
analysis, the correlation between the subscales of HADS, and the internal consistency 
of the subscales (Cronbach’s alpha). They confirm the two-dimensionality of the 
model, as well as the fact that although depression and anxiety are very different, it is 
difficult to distinguish these constructs empirically. The reliability of this self-report 
instrument was confirmed in all translations (based on Cronbach’s alpha). Results also 
show that the HADS is a good tool to identify patient with emotional disorders. Its 
concurrent validity with other scales ranged between good and very good. The 

LuCApp Study protocol V1.0 Date 03/11/2017 
21
questionnaire will be administered at baseline, at 12 weeks, and at the end of the study 
period. 
 
(2) Cancer supportive care needs 
LuCApp is to be used in the context of cancer supportive care. Given its functionalities 
in terms of monitoring and providing support and information, it may be that some of 
the unmet needs of cancer patients surrounding their supportive care may be met. Lung 
cancer patients have greater unmet supportive care needs than other cancer patients 
(33).  
The supportive care needs survey, short form (SCNS-SF34) is a needs assessment 
questionnaire in cancer supportive care measuring the gap between patients' experience 
and their expectations (34, 35). It consists of 31 items covering four domains: 
psychological needs, health system and information needs, physical and daily living 
needs, and patient care and support needs. For each question, patients are asked to 
provide an indication of their level of need on a 5-point Likert scale (1: not applicable; 
2: satisfied; 3: low need; 4: moderate need; 5: high need) (36). It is applicable to 
research, clinical settings (36) and routine care (37). It is commonly used to identify 
priorities for action, to assess the adequacy of current practice in order to identify areas 
for improvement, and as an intervention tool to reduce patients' perceived needs.  
The SCNS-SF34 has been translated and culturally validated (38), and more recently 
validated in a multicenter study led by Dr Paolo Leombruni. Its construct validity and 
internal reliability have been demonstrated (36). Its administration as pen-and-paper 
has been successfully psychometrically tested. It has also been adapted for electronic 
administration (via touchscreen computer), where the data collected was shown to be 
equivalent to the data collected from the pen-and-paper version (39). 
The SCNS-SF34 will be administered at the end of study, to assess whether some of 
the supportive care needs were fulfilled in the different study arms. There is still not 
evidence that the SCNC-SF34 is responsive to change over time, however this is 
currently being tested in an ongoing longitudinal study assessing how perceived needs 
change over time over the course of the cancer journey (newly diagnosed cancer 
patients are being administered the survey four times over the first five years after 
diagnosis) (36).  
 
(3) Burden on caregivers 

LuCApp Study protocol V1.0 Date 03/11/2017 
22
The Zarit Burden Interview (ZBI) is a 22-item self-administered scale measuring 
caregiver burden in health, psychological well-being, finances, social life, and 
relationship with patient. Each item is measured on a 5-point Likert scale (0=never to 
4=nearly always). The total burden is obtained by adding the scores across all 22 items: 
the higher the score, the higher the burden. Shorter versions have been developed with 
18 and 12 items.  
The ZBI was selected on the basis that it has been used in cancer patients (40) and is 
one of the most widely referenced scales in studies measuring caregiver burden (41). 
The ZBI was developed for nervous system disorders and mental disorders, but has also 
been applied to cancer patients (42-45). In one study, the authors explore if caregiver 
burden was in agreement with patient ratings. Patients had different forms of advanced 
cancer and their carer’s Zarit scores were relatively low. They conclude that Zarit may 
not capture some important aspects of burden in cancer, given that it was initially 
developed for dementia patients (42). A second study used the ZBI to assess the impact 
of breathlessness in lung cancer patients on their caregivers, and found high levels of 
unmet needs and burden particularly in the more severe cases (43).  
Assessment timing of the ZBI will be at the end of the study, and will be administered 
in paper format. Its criterion validity, construct validity and internal consistency have 
been demonstrated (40). The Italian version of the questionnaire is valid, reliable and 
useful for use in clinical contexts and in future studies (46). 
 
(4) Usability and satisfaction of LuCApp 
At the end of the study, patients in the intervention arm will have an opportunity to 
provide feedback on strengths and shortcomings of the application, including 
unintended/unexpected effects. This session will be of interest also for those who did 
not use the application as intended by the developers. Use and adoption metrics are 
important process outcomes to understand the mechanism of action of such 
intervention. The mHealth application contains a tracking system. Frequency and 
duration of logins and the activity will be recorded and evaluated. To test user 
satisfaction with the App, a modified computer system usability questionnaire (CSUQ) 
will be utilized at the end of the study and will be administered to both patients and 
clinicians using LuCApp. The CSUQ is an overall satisfaction questionnaire that was 
developed together with other subjective usability measures at IBM in the nineties (47). 
The CSUQ is identical to the Post-Study System Usability Questionnaire (PSSUQ), 

LuCApp Study protocol V1.0 Date 03/11/2017 
23
except that the wording of the items does not refer to a usability-testing situation but is 
rather appropriate for a field-testing situation. The CSUQ was later adapted for mobile 
apps usability testing to elicit participant satisfaction with the PAediatric Risk 
Assessment (PARA) app, a mHealth tool developed to help health care professionals 
in resource-limited settings detect patients at high risk of both in-hospital and post-
discharge mortality (48). Based on this revised version, the questionnaire was further 
elaborated upon: the final version consists of 12 items evaluated on a Likert scale 
ranging from 1 (“Strongly agree”) to 7 (“Strongly Disagree”). In addition, three 
qualitative questions were added to draw further information on the application and on 
the generalizability of LuCApp in the current and other clinical contexts: 1) “What do 
you like the most about the App?”; 2) “What do you like the least about the App”; 3) 
“How could the App be changed to make it easier to use?”. No validated Italian version 
of the CSUQ was available, so the authors, in cooperation with healthcare professionals 
of the participating sites, developed the current version. The questionnaire will be 
administered at the end of the study. 
 
(5) Resource use 
The perspective taken for the evaluation of resource consumption will be that of the 
National Healthcare System. In order not to overload patients and the App design with 
additional modules, resource use will be captured through patients reports of symptoms 
and clinicians actions in response to those symptoms (e.g. prescriptions, 
hospitalization, change in therapy). Moreover, additional information will be obtained 
for both control and treatment group patients via a form administered by the physician 
during the clinics. Unitary costs will be expressed as euros 2018. Drug unitary costs 
will be derived from national price listings, laboratory and instrumental tests will be 
valued according to the outpatient procedures formulary in accordance with the 
ongoing policies of Lombardy Region as well as eventual hospitalizations.  
 
Figure 6 summarizes the data collection process throughout the study. 
 

LuCApp Study protocol V1.0 Date 03/11/2017 
24
Figure 6 - Time-points of outcomes assessment 
 
 
Sample size  
As described above, the FACT-L v.4 contains four general and one lung cancer 
symptom-specific subscales. General subscales include: Physical Well-Being (PWB), 
Social/family Well-Being (SWB), Emotional Well-Being (EWB), and Functional 
Well-Being (FWB).(49) The Lung Cancer Subscale (LCS) assesses symptoms 
commonly reported by lung cancer patients (e.g., shortness of breath; loss of weight; 
tightness in chest). The Trial Outcome Index (TOI) is derived by adding scores on the 
PWB and FWB subscales to the LCS. Because they contain the most relevant questions 
about symptoms and physical functioning, the LCS and TOI were selected as the 
primary focus of this analysis. All FACT-L questions are rated on five-point Likert-
type scales ranging from 0 (“not at all”) to 4 (“very much”). Therefore, because the 
seven-items PWB, FWB, and LCS subscales scores range from 0–28 for each subscale, 
TOI scores range from 0–84. Higher scores represent better QoL or fewer symptoms.  
The primary outcome is the change in the score on the TOI from baseline to 12 weeks. 
We estimated that with 120 patients (Figure 7), the study would have 80% power with 
a two-sided α of 0.05 to detect a significant between-group difference of 6 points in the 
change in the TOI score from baseline to 12 weeks, given a pooled standard deviation 
of 11.54 and change in the reference group score of 53.(50) After accounting for 30% 
attrition rate, the expected number of enrolled patients is 156 allocated 1:1 between 
LuCApp and usual care groups. This sample size will also allow the detection with 80% 
power with a two-sided α of 0.05 of 2-points difference in the LCS subscale, assuming 

LuCApp Study protocol V1.0 Date 03/11/2017 
25
a pooled standard deviation of 4.15 and change in the reference group score of 19.3 
(50) (Figure 8). The clinically meaningful changes on the TOI and LCS subscales of 
FACT-L were derived from Cella et al.(51) 
The FACT-L questionnaire will be administered electronically (via LuCApp) or via 
paper in the control group at baseline, 12 weeks and 24 weeks, with an understanding 
that in the routine care setting, lung cancer therapies administration intervals vary 
between patients. 
 
Figure 7 - Sample size estimation: 5 to 10 -point difference in change in TOI score at 12 weeks  
 
 
 

LuCApp Study protocol V1.0 Date 03/11/2017 
26
Figure 8 - Sample size estimation: 1 to 5-point difference in change in LCS score at 12 weeks 
 
 
Assuming a constant recruitment rate of 6 patients per week (2 patients per centre) the 
study is planned to recruit consecutively for 26 weeks (Figure 9). 
 
Figure 9 - Planned recruitment process 
 
Randomization 
Randomization services will be provided by AdvicePharma via a computer system 
using randomly permutated blocks and stratified by trial centers and therapy (i.e. 

LuCApp Study protocol V1.0 Date 03/11/2017 
27
chemotherapy, immunotherapy and biological therapy). Nurses or physicians involved 
in the study will take care of the enrollment phase. After signature of informed consent, 
a randomization code will be generated electronically and assigned to the patient. 
During the informed consent procedure, the team will go carefully through the different 
aspects of the study design and will present LuCApp as well as the usual care 
alternative. During this phase the patient will have an opportunity to discuss her level 
of experience with mobile technology.  
The study is nonblinded, in fact it is not possible to blind the participants when this type 
of intervention and these outcomes are under investigation.   
Participants will remain on study until discontinuation of cancer treatment, voluntary 
withdrawal, study termination or death. 
 
Statistical methods 
The baseline differences between the intervention and control groups will be assessed 
using the chi-square (χ2) test for binary demographic data and the independent sample 
t-test for continuous variables. We will summarize graphically and numerically the 
distributions of symptoms, outcomes as well as covariates.  
For the primary quality of life endpoint, two groups t-test will be used to compare 
changes from baseline in FACT-L in the experimental group and the control group 12 
weeks after randomization. A multivariable linear regression model, with change score 
as the dependent variable, adjusted for covariates will be fitted. The proportion of 
patients in each arm who experienced improved, unchanged, or worsened scores from 
baseline will be compared using χ2 or Fisher’s exact test. This analysis will be run for 
both any change and clinically meaningful changes for specific subscales (51). The 
analyses will be repeated at 24 weeks after randomization. 
For all other questionnaires, changes from baseline in the LuCApp group and the 
control group at 12 and 24 weeks after randomization will be computed using t-test 
comparison. The SCNS-SF34, usability and ZBI data results will be summarized 
graphically and numerically. 
As a secondary analysis, adjusting for possible confounding factors of demographic 
variables and clustering in centers, the repeated measures multivariate analysis of 
covariance will be conducted to determine whether LuCApp affects HRQoL and 
symptoms as measured via EQ-5D-5L, FACT-L and HADS at different time points of 

LuCApp Study protocol V1.0 Date 03/11/2017 
28
data collection. Additionally, mixed-effects models will be used to analyze the same 
subject-specific continuous outcomes with incorporation of terms for intervention, 
time, centers, and any identified covariates.  
Analysis of missing data will first determine how common a problem this is and 
whether it can be assumed to be missing at random or not missing at random. Multiple 
sensitivity imputation analyses will be conducted, including last observation carried 
forward, minimum observation values carried forward, average observation values 
carried forward, and multiple imputation. EQ-5D value will be set to zero if death 
occurs before 6 months. Survival time will be calculated from the date of enrollment to 
the date of death or censoring those alive at the last follow-up with the use of the 
Kaplan–Meier method. A Cox proportional-hazards model will be fitted to assess the 
effect of LuCApp on survival, with adjustment for demographic characteristics and 
baseline performance status. 
By combining EQ-5D derived utilities and survival quality-adjusted life years (QALY) 
for participants in both arms will be computed and compared using two group t-tests 
between LuCApp and standard care arm. A multivariable linear regression model with 
QALY as dependent variable will be used to adjust for other covariates. Resource 
consumption and related costs will be calculated and reported for each treatment group 
and compared by means of parametric and non-parametric tests (52).  
Two-sided P values of less than .05 were considered to indicate statistical significance. 
All statistical analyses will be performed using STATA® 14.2, StataCorp, Texas. 
 
Ethics & Informed Consent 
All procedures involved in the study were consistent with generally accepted standards 
of ethical practice. The protocol is submitted for ethical clearance to the ethical 
committees at the three sites involved in the RCT (full list of participating centers is 
available as an attachment).  
Patients will be informed about the study by their clinician during the enrollment visit. 
The oncologist will provide patients with a brief introduction of the trial content and 
will hand them over a leaflet where all relevant information is gathered. This will enable 
patients to make an informed decision about whether to take part in the study. The 
leaflet will better explain the App’s “terms and conditions”, will assure the 
confidentiality of the data collected and outline users’ rights and responsibilities. 

LuCApp Study protocol V1.0 Date 03/11/2017 
29
Safety, privacy and legality are guaranteed using a unique username with an associated 
password, firewalls, secured sites and the transfer of confidential information: 
whenever one of the previous is missing, the brochure will explain which procedures 
to follow during an emergency. Furthermore, a statement on how data will be stored 
and when they will be destroyed is included in the form.  
To further support patients during the trial and increase security, an email “helpdesk” 
will be activated to help participants manage any kind of unexpected trouble.  
Participant signature is required for informed consent. After signing it, patients will 
send the consent form both to the research team and to their clinician.  
DISCUSSION 
The electronic and mobile health revolution holds great potentials for improving 
symptom management strategies in chronic conditions. With spending review reforms 
under way, using web- and mobile-based technology to develop low cost and pragmatic 
patient-centered intervention is the key to lessening the health care cost and advancing 
the science of symptom management. In parallel with the development of new 
strategies and products, the evaluation of such interventions becomes important in order 
to bring to patients and to healthcare systems effective and cost-effective solutions. This 
clinical trial focuses on primary outcomes of health related quality of life and usability 
to test preliminarily the impact of LuCApp as a technology to improve self-reporting 
and self-management of symptoms in patients with lung cancer. The trial was designed 
with a pragmatic “attitude”, eligibility criteria were intentionally set wide to capture the 
lung cancer population seen in real practice. However, this trial is to be intended as a 
pilot one in order to understand the usability and feasibility of introducing a new mobile 
technology in the management of symptoms and side effects of patients undergoing 
pharmaceutical treatments for lung cancer in three centers in Northern Italy.  
Dissemination and impact 
The protocol will be registered on a public repository and possibly published on a peer 
reviewed journal. Once the study will be completed and the analyses will be performed, 
a report will be produced and shared with all participating centers for interpretation. A 
manuscript will be drafted by the team and submitted for publication at conferences 
and in scientific journals.  

LuCApp Study protocol V1.0 Date 03/11/2017 
30
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