1. BACKGROUND AND RATIONALE. 1.1 BACKGROUND. Melanoma: overview of disease and management options Melanoma is one of the most
aggressive cancers and is responsible for the majority of skin cancer deaths (Miller,
2006; Potrony, 2015; Ryu, 2017), with the presence of metastases prognostic for poor
survival. In Europe, BRAF V600-positive mutations are present in 40%-60% of cases of
metastatic melanoma (Moreau, 2012; Rutkowsi, 2014; Arance Fernández, 2015; Picard, 2014;
Colombino, 2013), with the V600E variant being the most common (in up to 90% of BRAF
V600 mutation-positive melanomas). BRAF mutations are associated with a younger age at
onset, higher number of melanocytic nevi, melanoma location in the trunk region and
intermittently UV-exposed skin (Rutkowski, 2014; Colombino, 2013; Carlino, 2014;
Ekedahl, 2013; Long, 2011).
Although mortality from melanoma has decreased over last decades, survival rate varies
considerably based on the disease stage at diagnosis. The 5-year survival rate is above
90% for patients diagnosed localised tumours, 24 to 88% for stage III, and 10-25% for
stage IV (Svedman, 2016; Schoffer, 2016; Jochems, 1990; Gershenwald, 2017). This
together with a growing incidence of the disease and a substantial decline in patient
health-related quality of life (HRQoL) (Hinz, 2014) as disease advances, make the
management of metastatic melanoma a critical public health issue.
In Europe, the European Society for Medical Oncology (ESMO) guidelines are the most
important international treatment guidelines that guide the clinical management of
melanoma patients. They also form the basis for the development of local/
country-specific guidelines and treatment protocols. These guidelines have been updated
recently (Michielin, 2019). New therapeutic strategies, such as immunotherapy (cytotoxic
T-lymphocyte antigen 4 [CTLA-4] inhibitors and programmed cell death 1 [PD-1]
inhibitors) and selective BRAF inhibitors are deemed the backbone of systemic therapy in
melanoma. For BRAFV600 mutation-positive tumours, depending on patient characteristics,
immunotherapies or combination of BRAF/MEK inhibitors are recommended. In second-line,
selection depends on the strategy used for the first-line. BRAFis/MEKis is the main
option if not used in the first-line setting. There are no specific recommendations on
the use of one BRAF or MEK inhibitor over another.
Mobile health apps in cancer Complications of melanoma and its treatments are common.
Many patients will experience side effects following immunotherapies or targeted
therapies. These lead to morbidity and mortality as well as increased resource
utilization in the community or hospital setting. Complications of melanoma and its
treatments are often predictable (fever, gastrointestinal symptoms, skin reactions and
drug-specific effects). Education of patients might help to increase compliance with
care pathways especially if tailored to an individual's needs (Osborn, 2019). In the
context of an increasingly digital healthcare system, it is therefore worth considering
the role of mobile health applications (mHealth) for clinical care, patient education
and safety of treatment.
Mobile health (mHealth) is actually part of the wider "eHealth" movement, which is using
technology such as computers, mobile phones, mobile health apps and patient monitors for
health services and information. Both mobile health and eHealth help providers get the
information they need to improve health care outcomes and lower costs. Research on
interventions based on mHealth applications suggests that they can be used to alter
health related behaviors (McKay, 2018), such as medication adherence (Haase, 2017), but
economic evidence for their usage is limited (Iribarren, 2017).
1.2 STUDY RATIONAL. In order to support the patients with metastatic melanoma in their daily-life, Pierre
Fabre has developed a digital solution, called TavieSkin, which is dedicated to all
BRAF-mutant unresectable or metastatic melanoma patients who are treated with "any"
targeted therapies. This application is expected to be extended to other therapies
including immunotherapies.
The aim of the TavieSkin app is (i) to deliver the necessary information and education
support to the patient in regards with their disease and medications, through virtual
nurse coaching, (ii) to keep track of the medications taken throughout the days through
push notification, with the aim to improve compliance, (iii) to assist patients in
identifying side effects using the virtual nurse coaching and side effects library, and
(iv) to engage them towards sustainable healthy behaviors thanks to lifestyle
interventions, health trackers and real time coaching.
The TavieSkin app allows for the provision of a report for the healthcare provider (HCP)
summarizing clinical and lifestyle data collected in the app and generated prior to the
medical visit, if needed. The objective being to optimize the time spent at the clinic
by facilitating the patient follow-up.
As per the Medicines and Healthcare products Regulatory Agency (MHRA) guidance, this
mobile application could not be considered as a medical device. Health mobile apps
classified as medical device are defined as softwares that gather data from the person
or a diagnostic device, such as diet, heartbeat, or blood glucose levels and then
analyze and interpret the data to make a diagnosis, prescribe a medicine, or recommend
treatment. This is in any case the objective of TavieSkin app. The treating physician or
the HCP remains the only eligible person to manage the patient and its disease.
Finally, a patient survey will be incorporated into the TavieSkin app to assess the
health-related quality of life (HRQoL) under treatment and the patients' satisfaction
toward their medications prescribed for melanoma and toward the application. The
objective of this survey is to describe the profile of the users of TavieSkin app, their
quality of life and daily activity impairment under targeted therapy treatments.
2. STUDY OBJECTIVES. 2.1 PRIMARY OBJECTIVE. The primary objective of this survey is to describe the demographics and clinical
characteristics of patients with unresectable or metastatic BRAF-mutated melanoma
treated with targeted therapy (BRAFi/MEKi) and using the TavieSkin application.
2.2 SECONDARY OBJECTIVES. The secondary objectives of the survey include:
- - To assess the use of TavieSkin app in patients with unresectable or metastatic
BRAF-mutated melanoma treated with BRAFi/MEKi combination;
- To assess the treatment adherence of patients using TavieSkin app including
treatment interruption or permanent discontinuation;
- To assess the health-related quality of life of patients using TavieSkin app
(FACT-M);
- To assess work productivity and activity impairment over the treatment duration.
- - To assess the patient satisfaction toward the TavieSkin application;
- To assess the patient satisfaction toward the treatment.
3. RESEARCH METHODS. 3.1 STUDY DESIGN This prospective, longitudinal, survey will be conducted in Europe to
characterize BRAF-mutant unresectable or metastatic melanoma patients using TavieSkin
app designed for accompanying patients treated with targeted therapies.
To date, there are three combinations of BRAFi/MEKi available in routine practice for
the treatment of BRAF-mutant unresectable or metastatic melanoma. The survey does not
provide or recommend any treatment or procedure; all decisions regarding treatment are
made at the sole discretion of the treating physicians in accordance with their usual
practices.
Access to the TavieSkin app The patients initiating any BRAFi/MEKi combination will be
invited to use the TavieSkin app by their healthcare provider (HCP) (i.e. oncologist,
dermatologist, nurse…). The HCP will give the patient an activation code printed on a
flyer. The flyer will provide detailed information about the application and
installation procedure. The patient will be able then to install the app and to activate
it using the activation code provided on the flyer.
Access to the e-survey Once the patient has installed and started to use the
application, an e-survey will be proposed to the patient via the app. A detailed
information letter about the data collection, data privacy and analysis will be
displayed to the patient via the app along with an e-consent for data collection. The
patient will be able then to provide an e-signature, if he/she accepts to take part of
this survey. The survey will collect anonymized data about health status, QoL data and
satisfaction. These data will be collected by the patient only. The physician will not
be involved in this e-survey (including e-consent), nor in data collection. If the
patient declined the data collection, thus he/she will not take part of the survey,
however he/she still can have access to the TavieSkin app modules.
Only patients having given consent (e-consent) to data collection and analysis will be
included. The number of patients refusing to consent to data collection will be
collected along with the reason, in order to assess the representativeness of the study.
Data will be collected at baseline and at different subsequent timepoints during the
treatment. Only data reported by the patients in the application will be collected and
analyzed.
Data will be collected only during the BRAFi/MEKi treatment duration. The patient will
discontinue the study in case of definitive withdrawal of BRAFi/MEKi treatment, or if
he/she decides to withdraw the study and to stop data collection.
The target countries for patient enrollment will include Germany, Belgium, Portugal,
France, Spain, Italy and Sweden with the additional possibility of including patients
from other EU countries.
At least, 400 adult patients (≥18 years) will be enrolled. A descriptive interim
analysis may be performed when the number of patients reaches the 200 patients.
3.2 POPULATION. 3.2.1 Study population. (See section: Eligibility)
3.2.2 Participants recruitment and follow-up. As mentioned above in section 3.1, the access to the app will be provided by the HCP
through a flyer and an activation code. Patients with BRAF-mutant unresectable or
metastatic melanoma will be invited by its healthcare provider (i.e. oncologist,
dermatologist, nurse…) to use TavieSkin app during a routine visit. The physician will
communicate orally to the patients, all necessary information about the application. In
addition, a written letter of information (a flyer) and the procedure to access the
application will be provided to the patient at this visit. The treatment decision with
regard to BRAFi/MEKi must have been made prior to this visit.
3.2.2.1 Participant recruitment. The access to the e-survey will be provided through the application for patients having
read and signed the e-consent for data collection and analysis. No involvement from the
HCP is required for this step. The patient will be the sole actor involved in signing
the e-consent and in reporting data.
Of note, the patients will have the choice to use the TavieSkin app, without
participating to the e-survey.
3.2.2.2 Participant follow-up. The patient will be managed and followed as per routine clinical practice. No additional
visit or any follow-up is required for the sake of this study.
3.2.2.3 Study duration. Data will be collected after Apps installation and informed consent provided and at
different subsequent timepoints during the treatment.
Data will be collected only during the BRAFi/MEKi treatment duration. The patient will
discontinue the study in case of definitive withdrawal of BRAFi/MEKi treatment, or if
he/she decides to withdraw the study and to stop data collection.
3.3 STUDY OUTCOMES (see section: Outcome measures)
3.4 DATA SOURCES. The study will assess only self-reported measures. All the data will be completed and
collected by the patient itself through the application. No other data will be
abstracted using other existing sources such as medical records or hospital discharge
files.
The data collection schedule is presented in the section: Outcome measures (Time Frame).
3.5 DATA MANAGEMENT. Patients will enter manually their clinical data in the TAVIE application through an
application programming interface (API). MedClinik, the service provider responsible for
data managing will ensure that data are anonymized, encrypted and secured, and then
transferred from the TAVIE API to two databases: an Structured Query Language (SQL)
database and a no SQL database (MongoDB) located on dedicated servers, themselves
located in the region where data subjects are.
These anonymous databases will be transferred every 3 months to Pierre Fabre via a
secured channel for processing and analytics.
3.6 STATISTICAL CONSIDERATIONS. 3.6.1 Sample size. This survey is purely descriptive. The primary objective is to describe the patient
profile at inclusion.
Since there is no hypothesis to test, we calculate the sample size for the worst-case
estimate being 50% with a precision/accuracy of 5%. A sample size of at least 384
patients will be able to describe the patient profile with a precision of < 5%. This was
considered adequate to meet the descriptive objectives of this study.
3.6.2 General considerations. Statistical analyses will be fully described in a written statistical analysis plan
(SAP). The study endpoints will be analysed overall and by country. Analyses will be
descriptive in nature, as no hypothesis will be tested. In general, missing data will
not be imputed (except for dates) and the data will be analysed according to the
complete case approach.
The treatment patterns of patients, baseline demographics and clinical characteristics,
and reasons for treatment discontinuation will be described using summary statistics.
Categorical variables will be summarized by frequencies and percentages. Continuous
variables will be summarized by descriptive statistics (mean, and standard deviation,
median, 25th and 75th percentiles, minimum and maximum). The number of missing
observations for each variable will also be reported.
Change in health-related quality-of-life scores (i.e. (FACT-M) will be summarised at
baseline and at each timepoints. The change from baseline will be assessed using a mixed
model for repeated measures (MMRM). Baseline covariates will be described in the SAP.
Time to event data (i.e. time to treatment discontinuation, time QoL deterioration) will
be evaluated using Kaplan-Meier survival curves. Median survival estimates will be
reported along with the 25th and 75th percentiles and corresponding 95% CIs. Cox
regression analysis may be performed to adjust for predefined (baseline) covariates.
If the sample size is adequate, subgroup analyses using variables at baseline might be
conducted.
3.6.3 Missing data. Due to the nature of the study, missing data (i.e., data that are not reported by the
patient) may be observed for some variables. In general, missing data will not be
imputed (except for dates) and the data will be analysed according to the complete case
approach.
3.7 QUALITY CONTROL The data are self-reported and therefore is no way to describe the
extent of source data verification or data monitoring. However, the quality of data will
be ensured using auto-queries, i.e. a patient who enters an invalid data or an out of
range value, a pop-up or a will automatically append warning message to the invalid
data.
3.8 LIMITATIONS OF THE RESEARCH METHODS. The main limitation of this study is the response bias. It occurs when individuals offer
self-assessed measures of some phenomenon. There are many reasons individuals might
offer biased estimates of self-assessed behavior, ranging from a misunderstanding of
what a proper measurement is to social-desirability bias, where the respondent wants to
'look good' in the survey, even if the survey is anonymous.
Second limitation is the selection bias. Only patients having access to the TavieSkin
App could be included in the survey. Patients with no access to mobile or tablet could
not take part of this survey. The demographics and health status of patients having
access to the app may differ from those who do not have access or do not want to use the
TavieSkin App.
Other limitations include also the number of missing data or non-completed
questionnaires. Since the survey does not involve the HCP, the only possible reminders
for missing data could be handled via the application; however, reminders or
notifications must be sent in a respectful manner and might be deactivated at any time
by the patient.
3.9 STUDY MANAGEMENT. 3.9.1 Sponsor. Pierre Fabre Médicament will serve as the Sponsor of this study. It is the
responsibility of Pierre Fabre (as a data controller) to ensure proper oversight of the
company MedClinik (data processor) in conducting data management and compliance with all
applicable regulatory guidelines and laws.
It is the responsibility of Pierre Fabre to conduct the statistical analysis according
to the observational plan and to the SAP.
3.9.2 Service Provider responsible for data management. MedClinik is the digital solution provider that develops and maintains the TavieSkin
Service. As part of the service, Medclinik will collect through the TAVIE Platform the
necessary data for this survey. It is the responsibility of MedClinik to securely
collect and host the data according to the requested data by Pierre Fabre. MedClinik
will extract and send to Pierre Fabre anonymized data for analysis. Only data collected
in the patient questionnaire will be sent to Pierre Fabre.
4. PROTECTION OF HUMAN SUBJECTS AND LOCAL REGULATORY ASPECTS. 4.1 ETHICS. This study will be conducted under the guidelines of good pharmacoepidemiology practices
(GPPs) issued by the International Society for Pharmacoepidemiology (ISPE), the
Declaration of Helsinki and its amendments, the European Union General Data Protection
Regulation (EU GDPR) and any applicable national guidelines.
4.2 INDEPENDENT ETHICS COMMITTEE OR INSTITUTIONAL REVIEW BOARD (IEC/IRB)
Consistent with local regulations and prior to enrollment of patients at a given site,
the observational plan will be submitted together with its associated documents (e.g.,
informed consent form [ICF]) to the responsible IRB/IEC for its review. Before
implementation of any substantial changes to the observational plan, and amendments will
also be submitted to the relevant IRB/IEC in a manner consistent with local regulations.
Pertinent safety information will be submitted to the relevant IECs during the course of
the study in accordance with local regulations and requirements.
This study will be undertaken only after the IRB/IEC have given full approval of the
final observational plan, the ICF, and the Sponsor had received a copy of this approval.
An ICF (e-consent) must be signed by the patient before his or her participation to the
survey.
4.3 PRIVACY OF PERSONAL DATA. Confidentiality of patient records will be maintained at all times. All study reports
will contain aggregate data only and will not identify individual patients. At no time
during the study the Sponsor will receive patients identifying information.
In order to maintain patient confidentiality, each patient will be assigned a unique
patient identifier upon study enrollment. This patient identifier will be used in place
of the patient name for the purpose of data analysis and reporting. All parties will
ensure protection of patient personal data and will not include patient names or other
identifiers (i.e. initials, full date of birth, address etc.) on any study forms,
reports, publications or in any other disclosures, except where required by law. In
accordance with local regulations in each of the countries, patients will be informed
about data handling procedures and asked for their consent. Data protection and privacy
regulations will be observed in capturing, forwarding, processing, and storing patient
data.
Pierre Fabre Medicament (PFM) as Sponsor of the study and data controller is responsible
for the processing of personal data in accordance with the provisions of Regulation
2016/679/EU of the European Parliament and of the Council of 27 April 2016 on the
protection of natural persons with regard to the processing of personal data and the
free movement of such data (GDPR), the data collected being for research purposes in the
field of health, the legal basis of the processing being the legitimate interest of the
data controller.
Within the context of this research, we may collect and process personal data. MedClinik
will comply with all regulations regarding personal data
- - including European General
Data Protection Regulation (GDPR).
MedClinik will only collect personal data strictly needed for the research, will
implement appropriate technical and organizational measures to ensure the protection of
personal data against unauthorized disclosure or access, will only retain personal data
for a limited and fixed period after the end of the research.
Participant's rights towards personal data are:
- - the right of access to their personal data;
- the right to rectify their personal data in case of mistakes;
- the right of limitation to the processing;
- the right to object processing with their personal data;
The personal information collected will be saved in a computerized file kept by
MedClinik for the survey.
This information will be stored for 15years and is reserved
for use by PF for the purpose of conducting the analysis.
For any enquiry regarding the process of personal data, or to exercise rights,
participants can contact MedClinik by email:
[email protected] or the Data
Protection Officer of Pierre Fabre by email:
[email protected]. This survey is run via a secure server; all information held on this server is protected
from external sources.
5. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE REACTIONS. To note, this study has no objective of analysing the safety profile of the products.
The survey is based on secondary use of data collected from consumers via the application.
The submission of suspected adverse reactions in the form of individual case safety reports
to competent authorities is therefore not required.
7 PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS (IF APPLICABLE)
A final study report will be prepared within 12 months from end of data collection. Pierre
Fabre is responsible for any presentation and/or publication arising from this study.
Any publication of the results from this study must be consistent with the Pierre Fabre's
publication policy and guided by the Uniform Requirements for Manuscripts Submitted to
Biomedical Journals: Writing and Editing for Biomedical Publication of the International
Committee of Medical Journal Editors (ICMJE), updated April 2010.
All reporting will be consistent with the STROBE (STrengthening the Reporting of
OBservational studies in Epidemiology) Initiative checklist.
8 REGULATORY CONSIDERATIONS. 8.1 CONFIDENTIALITY. The aim of the study, all information, or data relating to the study or any product studied
provided to the contractor and/or their collaborators during the term of this agreement and
all results of the study (hereinafter collectively called the "Information") will be
maintained confidential for an unlimited time period by the contractor and/or their
collaborators.
In addition, all Information shall not be used by the contractor for any other purpose than
the one described in this Agreement.
The above obligations shall, however, not apply to:
- - Information which at the time of disclosure to the contractor is part of the public
knowledge,
- Information, which, after disclosure, becomes part of the public knowledge through no
fault of the contractor.
- - Information which the contractor can establish by competent proof was in its possession
prior to disclosure hereunder and was not acquired from PFM, directly or indirectly
under a secrecy obligation.
- - Information which is subsequently obtained lawfully from a third party without any
secrecy obligation and was not acquired by such third party from PFM, directly or
indirectly under a secrecy obligation.
No publication or communication relating to the study or the results thereof, in written or
oral form, shall be made by the contractor and/or their collaborators, without PFM's prior
written consent.
8.2 PROPERTY OF RESULTS. The results of the Study shall be PIERRE FABRE MEDICAMENT's exclusive ownership and PIERRE
FABRE MEDICAMENT, and/or any designee shall have free use of the same in France and
worldwide.
Such ownership shall apply to any data, patentable or non-patentable inventions, know-how and
any invention resulting from the Study.
8.3 ARCHIVING. It is the responsibility of the sponsor to archive the survey document for at least 15 years
after completion of the survey.
9 REFERENCES (See section: References)
