Evaluation of the Impact of a Nurse-led Telephone Follow-up on Treatment Compliance of Patients Treated From a Locally Advanced or Metastatic Non-small-cell Lung Cancer (NSCLC) With Activating Epidermal Growth Factor Receptor (EGFR) Mutation(s).The PARTAGE Study.
Conditions: Carcinoma, Non-Small-Cell Lung
Sponsor: Boehringer Ingelheim

Study Protocol 
 
BI Study Number: 
1200.227 
 
BI Investigational 
Product 
Non applicable 
 
ANSM reference 
number:  
2014-A00721-46 
 
Title: 
Evaluation of the impact of a nurse-led telephone follow-
up on treatment compliance of patients treated from a 
locally advanced or metastatic non-small-cell lung cancer 
(NSCLC) with activating epidermal growth factor receptor 
(EGFR) mutation(s). The PARTAGE study 
 
Clinical Phase: 
Routine clinical practice study 
 
Trial Clinical Monitor: 
 
  
 
 
Principal Investigator : 
  
 
 
Status: 
Protocol final 
 
Version and Date: 
Version:  1.2 
Date: 19-May-2014 
Page 1 of 51 
Proprietary confidential information 
© 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved. 
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission 
 

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Confidential Information © 2017 Boehringer Ingelheim International GmbH or one or several affiliates 
 
 
 
PRINCIPAL INVESTIGATOR SIGNATURE 
 
Study Title: Evaluation of the impact of a nurse-led telephone follow-up on treatment 
compliance of patients treated from a locally advanced or metastatic non-small-cell lung 
cancer (NSCLC) with activating epidermal growth factor receptor (EGFR) mutation(s). The 
PARTAGE study 
 
 
 
 
 
Study Number: 1200.227 
 
 
 
 
I herewith certify that I agree to adhere to the trial protocol  
and to all documents referenced in the trial protocol. 
 
 
 
 
 Name:________________________       Signature:__________________________ 
 
Signed signature page is located in the electronic Clinical Trial Master File 
 
 
 Affiliation:  
 
 Date:  
___________________________ 
 
 
 

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LOCAL SIGNATURES 
(PRINCIPAL INVESTIGATOR OF SITE) 
 
Study Title: Evaluation of the impact of a nurse-led telephone follow-up on treatment 
compliance of patients treated from a locally advanced or metastatic non-small-cell lung 
cancer (NSCLC) with activating epidermal growth factor receptor (EGFR) mutation(s). The 
PARTAGE study. 
Trial Number: 1200.227 
Protocol Version: 1.1 dated on 19-May-2014 
 
I herewith certify that I agree to adhere to the protocol of the routine clinical 
practice trial and to all documents referenced in the trial protocol. 
 
 
 
Principal Investigator (site): 
 
 
 
 
 
 
 
 
Date 
 
Name 
 
 
 
Full name 
 
 
 
Organization/Department 
Signed signature page is located in the electronic Clinical Trial Master File 

Boehringer Ingelheim 
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Study Protocol
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Confidential Information © 2017 Boehringer Ingelheim International GmbH or one or several affiliates 
PROTOCOL SYNOPSIS 
Name of company/Marketing Authorisation 
Holder: 
Tabulated 
Study Protocol 
Boehringer Ingelheim 
Name of finished product: N/A 
Name of active ingredient: N/A 
Protocol date: 
Trial number: 
ANSM reference number: 
Revision date: N/A 
19 May 2014 
Title of study: 
Evaluation of the impact of a nurse-led telephone follow-up on treatment 
compliance of patients treated from a locally advanced or metastatic non-small-cell 
lung cancer (NSCLC) with activating epidermal growth factor receptor (EGFR) 
mutation(s). The PARTAGE study 
Principal Investigator: 
 
Study site(s): 
Approximately 75 centres in metropolitan France 
Clinical phase: 
Routine clinical practice study 
Study rational: 
The current management of patients with stage IIIb/IV non-small-cell lung cancer 
(NSCLC) uses targeted therapy as first, second and third-line therapy. These 
treatments belong to the group of oral cancer therapies, which are being increasingly 
developed and used in oncology. However, because patients become responsible for 
taking their treatment and managing the related toxicity, this practice raises the 
question of compliance. The literature shows that compliance rates range from less 
than 20 % to 100% during the treatment of cancer with oral therapies, with low 
compliance being mainly due to problems of cost, adverse reactions and dose 
schedule (e.g., relative to meals). To increase compliance during treatment with oral 
cancer therapies, several specific surveillance strategies have been implemented e.g. 
customised follow-up, education sessions for patients and caregivers (doctor, 
pharmacist, nurse), and telephone follow-up. In particular, the nurse-led telephone 
follow-up is recommended by the ‘Plan Cancer 3’ and is gradually being 
implemented in routine practice. In France, some institutions have established a 
nurse-led telephone follow-up with the patient, at least weekly for 4-8 weeks, and 
after discussion with the patient and, if possible, with his entourage. This follow-up 
should reassure patients, permit them to have their questions answered, help in the 
management of targeted therapy related adverse events (AEs) (e.g. by facilitating 
their reporting by the patient or their identification by the nurse) and may therefore 
improve patient treatment compliance or rectify certain situations of poor 
compliance. 
The objective of this study is to evaluate the impact of a personalised nurse-led 
telephone follow-up on treatment compliance of patients with stage IIIb/IV NSCLC 
with activated epidermal growth factor receptor (EGFR) mutation(s) who are treated 
with oral targeted therapy in routine clinical practice. 
Objectives: 
Primary objective 

To evaluate, during routine clinical practice, the impact of nurse-led telephone
follow-up on overall patient treatment compliance with oral targeted therapy 
(cumulated dose* during the 3-month follow-up). 
* The cumulated dose (mg) of oral targeted therapy taken between 2 visits is the sum of the
doses (mg) of the tablets taken by the patient. The cumulated dose (mg) of the oral targeted 
therapy taken during the 3-month follow-up is the sum of the doses (mg) cumulated taken 

Boehringer Ingelheim 
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Confidential Information © 2017 Boehringer Ingelheim International GmbH or one or several affiliates 
 
Name of company/Marketing Authorisation 
Holder: 
Tabulated 
Study Protocol 
 
Boehringer Ingelheim 
 
Name of finished product: N/A 
Name of active ingredient: N/A 
 
Protocol date: 
Trial number: 
ANSM reference number: 
Revision date: N/A 
19 May 2014 
 
between 2 visits during the 3 months follow-up.  
Secondary objectives 
To evaluate: 
 
The impact of an additional nurse-led telephone follow-up on patient treatment 
compliance (Girerd questionnaire). 
 
To evaluate, during routine clinical practice, the impact of nurse-led telephone 
follow-up on overall patient treatment non-compliance with oral targeted 
therapy, following decision of the medical team (cumulated dose not taken* 
during the 3-month follow-up). 
 
To evaluate, during routine clinical practice, the impact of nurse-led telephone 
follow-up on overall patient treatment non-compliance with oral targeted 
therapy, following decision of the patient (cumulated dose not taken* during the 
3-month follow-up). 
* The cumulated dose (mg) of oral targeted therapy not taken between 2 visits is the sum of 
the doses (mg) of tablets not taken by the patient. The cumulated dose (mg) of oral targeted 
therapy not taken during the 3-month follow-up is the sum of the cumulated doses (mg) not 
taken between 2 visits during the 3-month follow-up. 
 
Overall patient satisfaction with the level of care provided (Visual Analogue 
Scale [VAS]). 
 
Evolution of patient quality of life during the study (Functional Assessment of 
Cancer Therapy [FACT] Lung questionnaire). 
 
Use of healthcare such as emergency department visits/admissions, number and 
duration of unplanned hospitalisations, number of unplanned visits during the 3-
month follow-up (visits to the investigator, to any other specialist or to the 
general practitioner). 
 
Overall satisfaction of the investigator (pneumologist/oncologist) and for the 
patients included in the group with a remote additional personalised nurse-led 
follow-up, the overall satisfaction of their pharmacist and general practitioner 
(VAS). 
 
Safety (data collected according to the Common Terminology Criteria for 
Adverse Events [CTCAE] version 4.03). 
 
Impact of the additional nurse-led follow-up on the frequency of calls to the 
general practitioners/specialists by the patient. 
Methodology: 
Routine clinical practice, randomised, multicentre study. 
Up to 450 specialised doctors will be contacted in order to recruit 130 participating 
medical team (investigators) in 75 centres. These centres should enrol around 
400 patients in the study. 
In order to extrapolate the study results to the rest of the target population, the 
participating investigators will be selected by stratified random sampling of the 
PMSI 2011 file, which includes a list of all French hospitals providing healthcare for 
NSCLC patients. Stratification factors will be geographical breakdown and the size 
of the patient base. 

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Study Protocol
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Confidential Information © 2017 Boehringer Ingelheim International GmbH or one or several affiliates 
Name of company/Marketing Authorisation 
Holder: 
Tabulated 
Study Protocol 
Boehringer Ingelheim 
Name of finished product: N/A 
Name of active ingredient: N/A 
Protocol date: 
Trial number: 
ANSM reference number: 
Revision date: N/A 
19 May 2014 
The study will take place over a period of 27 months. The recruitment phase will 
last approximately 24 months and each patient will participate for approximately 
3 months. 
At the inclusion visit (D0), the investigator will ask the patient whether he would 
like to participate in the study and will obtain his written consent. Refusal to 
participate including the reason if available will be collected in a register specific to 
this study (study register). The collected data will allow any selection bias to be 
identified.  
Patients agreeing to participate will be randomised (3:1 ratio) and included in one of 
the following 2 groups: 

Group without ‘remote additional personalised nurse-led follow-up’: patients
will receive the healthcare given routinely by their medical team (100 patients). 

Group with ‘remote additional personalised nurse-led follow-up’: patients will
receive telephone calls from a nurse in addition to the healthcare given 
routinely by their medical team (300 patients). 
All the patients will be seen according to normal practice by the study medical team. 
In this study, 3 data collection time points at monthly intervals are defined (D30, 
D60, D90); however, the frequency of visits should not be adjusted and the medical 
team should maintain his routine practice (example: if the investigator is used to see 
the patient on D15, the visit will still take place, but no information, except 
pharmacovigilance data, will be collected). As such, the data from the closest 
defined visit will be reported in the case report form (CRF) at each time-point. 
The telephone calls will be made by a nurse from a company specialised in patients 
support called Patientys. Patients in the group with ‘remote additional personalised 
nurse-led follow-up’ will be contacted 8 times during the study (at D1, D7, D14, 
D21, D28, D44, D59 and D89). The nurse will make sure that the treatment takes 
place in good conditions; she cannot intervene in the medical care of the patient, nor 
give answer to the questions relative to the disease or to the treatment of the patient. 
The medical team remains the privileged contact of the patient.  
During the first telephone call at D1, the nurse will confirm the enrolment of the 
patient 
in 
the 
study 
and 
will 
then 
inform 
the 
patient’s 
general 
practitioner/pharmacist by letter or telephone call. 
During the following telephone calls, the nurse will perform an evaluation with the 
help of a questionnaire and will collect treatment related AEs. After each telephone 
call, the nurse will establish a report. These reports will be sent to the investigators 
on the same day of the nurse follow-up phone call. 
On arrival for the consultations (D0, D30, D60 et D90) with the investigator, the 
patient will be asked to complete questionnaires regarding treatment compliance, 
satisfaction and/or quality of life before the start of consultation, in the doctor’s 
office or any other available private place. 
No. of patients: 
Around 400 patients. 
Diagnosis: 
Adult patients diagnosed with NSCLC locally advanced or metastatic, with 
activating mutation(s) of EGFR and who are EGFR-TKI naïve. 

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Confidential Information © 2017 Boehringer Ingelheim International GmbH or one or several affiliates 
 
Name of company/Marketing Authorisation 
Holder: 
Tabulated 
Study Protocol 
 
Boehringer Ingelheim 
 
Name of finished product: N/A 
Name of active ingredient: N/A 
 
Protocol date: 
Trial number: 
ANSM reference number: 
Revision date: N/A 
19 May 2014 
 
Main criteria for 
inclusion: 
 
Male or female patient older than 18 years. 
 
Adult patient diagnosed with stage IIIb/IV NSCLC locally advanced or 
metastatic, with activating mutation(s) of EGFR and who is EGFR-TKI naïve. 
 
Patient for whom a decision of treatment with afatinib monotherapy has been 
taken in the frame of its marketing authorization. 
 
Out-patient. 
 
Patient having given written consent for participation in the study. 
 
Patient who is able to participate in the investigator’s opinion. 
 
Patient affiliated with the French social security. 
Test product(s): 
NA 
Comparator product(s): NA 
Study duration: 
Approximately 27 months (September 2014-December 2016) 
 
Recruitment: approximately 24 months. 
 
Patient follow-up: approximately 3 months. 
Criteria for efficacy: 
Primary criterion 
 
Cumulated dose of oral targeted therapy during the 3-month follow-up. 
The cumulated dose (mg) of oral targeted therapy taken between 2 visits is the sum 
of the doses (mg) of the tablets taken by the patient. The cumulated dose (mg) of the 
oral targeted therapy taken during the 3-month follow-up is the sum of the doses 
(mg) cumulated taken between 2 visits during the 3-month follow-up. 
Secondary criteria 
 
Score (0–6) obtained with the Girerd questionnaire at D30, D60 and D90. 
 
Cumulated dose of oral targeted therapy not taken (all categories) following 
decision of the medical team.  
 
Cumulated dose of oral targeted therapy not taken due to dose reduction
following decision of the medical team. 
 
Cumulated dose of oral targeted therapy not taken due to temporary or definitive 
interruption following the medical team decision. 
 
Cumulated dose of oral targeted therapy not taken (all categories) following 
patient decision. 
 
Cumulated dose of oral targeted therapy not taken due to dose reduction 
following patient decision. 
 
Cumulated dose of oral targeted therapy not taken due to temporary or definitive 
interruption following patient decision. 
Cumulated dose (mg) of oral targeted therapy not taken between 2 visits is the sum 
of the doses (mg) of the tablets not taken by the patient. The cumulated dose (mg) of 
the oral targeted therapy not taken during the 3-month follow-up is the sum of the 
doses (mg) cumulated not taken between 2 visits during the 3-month follow-up. This 
dose can be calculated overall and by reason for not taking the prescribed dose: 

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Study Protocol 
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Confidential Information © 2017 Boehringer Ingelheim International GmbH or one or several affiliates 
 
Name of company/Marketing Authorisation 
Holder: 
Tabulated 
Study Protocol 
 
Boehringer Ingelheim 
 
Name of finished product: N/A 
Name of active ingredient: N/A 
 
Protocol date: 
Trial number: 
ANSM reference number: 
Revision date: N/A 
19 May 2014 
 
dose reduction, temporary or definitive discontinuation following decision of the 
medical team / patient decision.  
 
VAS score (0–10) for overall patient satisfaction with the level of care 
(information, advice) at D90. 
 
Absolute variation observed for the quality of life questionnaire FACT Lung 
score between D30 and D0, between D90 and D30 and between D90 and D0. 
 
Number of emergency admissions (related to the treatment) during the 
3-month follow-up. 
 
Number and duration of unplanned hospitalizations (related to the treatment) 
during the 3-month follow-up. 
 
Number of unplanned visits to the investigator during the 3-month follow-up. 
 
Number of unplanned visits to a specialist, whatever is his specialty, other than 
the investigator during the 3-month follow-up.  
 
Number of unplanned visits to the general practitioner during the 3-month follow-
up. 
 
VAS score (0–10) for overall investigator satisfaction with the level of patient 
care at D90. 
 
VAS score (0–10) for overall general practitioner satisfaction with the level of 
patient care at D90 (only for the patients with ‘remote additional personalised
nurse-led follow-up) 
 
VAS score (0–10) for overall pharmacist satisfaction with the level of patient care 
at D90 (only for the patients with ‘remote additional personalised nurse-led
follow-up). 
 
Number of calls made by the patients to their general practitioner during the 3-
month follow-up. 
 
Number of calls made by the general practitioner to the patient during the 3-
month follow-up. 
 
Number of calls made by the patients to their medical team during the 3-month 
follow-up. 
 
Number of calls made by the medical team to their patient during the 3-month 
follow-up.  
 
Number of calls between the general practitioners and the medical team during 
the 3-month follow-up. 
 
Number of AEs related to the oral biological therapy. 
 
Number of AEs of grade ≥ 3 related to the oral biological therapy. 
 
Number of serious adverse events (SAEs) related to the oral targeted therapy. 
 
Number of AEs related to the oral targeted therapy which causes temporary or 
definitive discontinuation of the treatment or dose reduction. 
Statistical methods: 
Analysis population 
The primary analysis population will be the population of randomised patients who 

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Name of company/Marketing Authorisation 
Holder: 
Tabulated 
Study Protocol 
 
Boehringer Ingelheim 
 
Name of finished product: N/A 
Name of active ingredient: N/A 
 
Protocol date: 
Trial number: 
ANSM reference number: 
Revision date: N/A 
19 May 2014 
 
satisfy the essential inclusion and exclusion criteria, and for whom information is 
available for the major evaluation criteria (in particular the primary criterion). 
Statistical methods 
The statistical analysis will be performed using SAS (version 9.1 or a more recent 
version). All tests will be performed 2-sided with a cut-off of 5%. 
Analysis of the primary criterion 
The primary objective of the study is to evaluate overall treatment compliance after 
3-months and to compare this compliance between the 2 study groups: the group 
with nurse-led follow-up and the group without nurse-led follow-up. 
The cumulated dose (mg) of oral targeted therapy taken between 2 visits will be 
calculated as follows: sum of the doses (mg) of the tablets taken by the patient. The 
count of taken tablets by the patient between visit Vi-1 and visit Vi will be done by 
the medical team investigator during visit Vi based on the tablet boxes returned by 
the patient. The physician will indicate in the Case Report Form (CRF) for each 
dosage (20 mg, 30 mg, 40 mg and 50 mg [only in 2nd intent dose if the treatment is 
well tolerated and according to the recommendations of the patient leaflet]), the 
number of tablets taken by the patient. The cumulated dose between visit Vi-1 and 
visit Vi will then be calculated as follows: 
[Cumulated dose (mg)]i= 
[Dosage x Number of tablets(Dosage)] 
                                Dosages in 20, 30, 40, 50 
where Number of tablets is the number of tablets of 20mg, 30 mg, 40mg or 50mg 
taken. 
The cumulated dose (mg) of oral targeted therapy taken during the 3-month follow-
up will be the sum of the cumulated doses (mg) used between 2 visits during the  
3-month follow-up. The total cumulated dose (mg) in 3 months will be calculated as 
follows:  
Cumulated dose (mg) = 
[Cumulated Dose (mg)]i 
                                        i 
As such, the cumulated dose (mg) of the oral targeted therapy over the 3-month 
follow-up will be described for each groups (number of observed values, mean, 
standard deviation, median, lower quartile, upper quartile, minimum, maximum, 
two-sided 95% confidence interval of the mean). 
The mean cumulated dose will be compared between groups by Student test, or 
Wilcoxon rank sum test in case of non-normal data or non-homeogeneity of 
variance. 
A complementary analysis using a Kaplan-Meier curve will also be performed on 
the principal criteria, to evaluate the time between start of treatment and the first 
dose modification or interruption of the targeted oral therapy. 
The main analysis will also be completed by a descriptive analysis of the reasons for 
non-compliance. The numbers of the temporary and/or definitive stops due to the 
patient and/or to the investigator will be tabulated. Reasons will be listed. 
Sample size 

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Confidential Information © 2017 Boehringer Ingelheim International GmbH or one or several affiliates 
 
Name of company/Marketing Authorisation 
Holder: 
Tabulated 
Study Protocol 
 
Boehringer Ingelheim 
 
Name of finished product: N/A 
Name of active ingredient: N/A 
 
Protocol date: 
Trial number: 
ANSM reference number: 
Revision date: N/A 
19 May 2014 
 
In the absence of dose discontinuation or reduction, the cumulated dose of oral 
targeted therapy should be 3600 mg of afatinib, which corresponds to a daily dose 
of 40 mg for 90 days. 
Clinical trials performed with afatinib before its marketing authorisation showed 
that over the first 3-month follow-up the mean dose of 3000 mg was taken (which 
corresponds to a dose intensity of 83%) (Boehringer Ingelheim First Interim Study 
Report 1200.32). 
It was estimated that the mean dose observed in the group ‘without remote 
additional personalised nurse-led follow-up’ will be similar to the mean dose 
observed in the afatinib clinical trials and that adding an additional nurse-led follow-
up will increase the mean dose by 6% (3180 mg, dose intensity of 88%). 
As such, the number of patients to be included in the study has been calculated on 
the basis of a t-test for 2 unmatched samples with the following hypotheses: 
 
Mean cumulated dose of oral targeted therapy taken during the 3-month 
follow-up in the group without ‘remote additional personalised nurse-led 
follow-up’: 3000 mg (dose intensity of 83%). 
 
Mean cumulated dose of oral targeted therapy taken during the 3-month 
study in the group with ‘remote additional personalised nurse-led follow-
up’: 3180 mg (dose intensity of 88%). 
 
Standard deviation of the cumulated dose of oral targeted therapy taken 
during the 3-month follow-up in both groups: 500. 
 
Type I error: α = 0.05. 
 
Type II error: β = 0.20 (power = 80%). 
 
Ratio 
‘with 
remote 
additional personalised 
nurse-led follow-up’ 
group/‘without remote additional personalised nurse-led follow-up’ group 
= 3. 
Using these hypotheses, in order to show an increase in the cumulated dose with the 
addition of 3-month nurse-led follow-up, it is necessary to have 82 patients in the 
group ‘without remote additional personalised nurse-led follow-up’ and 246 patients 
in the group ‘with remote additional personalised nurse-led follow-up ’. 
If it is considered that 20% of included patients will be non-evaluable for the 
primary criterion, it is necessary to include 99 patients in the group without ‘remote 
additional personalised nurse-led follow-up’ and 297 patients in the group with 
‘remote additional personalised nurse-led follow-up’, i.e. 396 patients in total which 
can be rounded up to 400. 

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FLOW CHART 
Table 1 
Visit schedule and data collection 
 
D0 
D1a 
D7a 
D14a 
D21a 
D28a 
D30 
M1 
D45a D59a 
D60 
M2 
DJ89a D90b 
M3 
 
MV Incl NFPC 
1 
NFPC 
2 
NFPC 
3 
NFPC 
4 
NFPC 
5 
MV1 NFPC 
6 
NFPC 
7 
MV2 NFPC
8 
MV3 
Written consent   
X 
 
 
 
 
 
 
 
 
 
 
 
Verification of eligibility 
X 
 
 
 
 
 
 
 
 
 
 
 
Documentation of patient’s 
acceptance or rejection of 
participation in the study file 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographic information c 
X 
 
 
 
 
 
 
 
 
 
 
 
Physical exam d 
X 
 
 
 
 
 
 
 
 
 
 
 
NSCLC characteristics e 
X 
 
 
 
 
 
 
 
 
 
 
 
Past medical history, past 
treatments  
X 
 
 
 
 
 
 
 
 
 
 
 
Concomitant diseases, 
concomitant medications 
X 
 
 
 
 
 
X 
 
 
X 
 
X 
Randomisation 
X 
 
 
 
 
 
 
 
 
 
 
 
Patient diary delivery 
X 
 
 
 
 
 
 
 
 
 
 
 
Clinical evaluation by 
Patientys nurse 
 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
 
Collection of AEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Patient compliance 
(returned tablets and Girerd 
questionnaire) 
 
 
 
 
 
 
X 
 
 
X 
 
X 
Patient quality of life 
questionnaire 
X 
 
 
 
 
 
X 
 
 
 
 
X 
Patient global satisfaction 
questionnaires 
 
 
 
 
 
 
 
 
 
 
 
X 
Data collection on use of 
healthcare services 
 
 
 
 
 
 
X 
 
 
X 
 
X 
General practitioner and/or 
pharmacist global 
satisfaction questionnaires 
 
 
 
 
 
 
 
 
 
 
 
X 
Investigator global 
satisfaction questionnaires 
 
 
 
 
 
 
 
 
 
 
 
X 
a Only for patients ‘With nurse-led follow-up’ group 
b Or end of study visit if the patient withdraws prematurely from the study 
c Including age, gender, weight, height 
d Complete physical exam at inclusion visit including: Vital signs (Heart & respiratory rate, blood pressure, temperature), 
and collection of the cutaneous, gastro-intestinal, respiratory, eye, cardiovascular and allergic symptoms  
e Diagnosis date, disease stage, performance status (ECOG), biopsy date, type of mutation(s), method of mutation typing, 
previous treatments of NSCLC 
f The drug accountability of taken and not taken tablets will be made by the medical team in the Case Report Form 
D = day ; M = month ; MV = medical visit according to the routine practice of the centre, NFPC= nurse follow-up phone call, 
Incl.= inclusion, NSCLC = non-small-cell lung cancer ;  
AE= adverse event. 
 

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TABLE OF CONTENTS 
TITLE PAGE ............................................................................................................................ 1 
PROTOCOL SYNOPSIS ........................................................................................................ 4 
FLOW CHART ...................................................................................................................... 11 
TABLE OF CONTENTS ....................................................................................................... 12 
ABBREVIATIONS ................................................................................................................ 14 
1. 
INTRODUCTION ............................................................................................... 15 
2. 
RATIONALE AND OBJECTIVES ................................................................... 17 
2.1 
RATIONALE FOR PERFORMING THE STUDY ......................................... 17 
2.2 
OBJECTIVES ...................................................................................................... 17 
2.2.1 
Primary objective ................................................................................................ 17 
2.2.2 
Secondary objectives ........................................................................................... 17 
3. 
DESCRIPTION OF DESIGN AND STUDY POPULATION ........................ 19 
3.1 
OVERALL DESIGN AND PLAN ..................................................................... 19 
3.1.1 
Administrative structure of the study................................................................ 21 
3.2 
DISCUSSION OF STUDY DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP ........................................................................................... 22 
3.3 
SELECTION OF STUDY POPULATION ....................................................... 22 
3.3.1 
Main diagnosis for study entry ........................................................................... 22 
3.3.2 
Inclusion criteria .................................................................................................. 22 
3.3.3 
Exclusion criteria ................................................................................................. 23 
3.3.4 
Removal of patients from therapy or assessments ........................................... 23 
4. 
TREATMENTS ................................................................................................... 23 
5. 
EVALUATION CRITERIA ............................................................................... 24 
5.1 
PRIMARY ENDPOINT ...................................................................................... 24 
5.1.1 
Primary endpoint ................................................................................................ 24 
5.1.2 
Assessment methods ............................................................................................ 24 
5.2 
SECONDARY ENDPOINTS ............................................................................. 24 
5.2.1 
Secondary endpoints ........................................................................................... 24 
5.2.2 
Assessment methods d’évaluation ...................................................................... 25 
5.3 
SAFETY DATA TOLERANCE ......................................................................... 26 
5.3.1 
Safety endpoints ................................................................................................... 26 
5.3.2 
Assessment of adverse events ............................................................................. 26 
5.3.2.1 
Definition of adverse events .................................................................................. 27 
5.3.2.2 
Adverse event and reporting .................................................................................. 28 
5.3.3 
Assessment of other safety parameters.............................................................. 28 
5.4 
APPROPRIATENESS OF MEASUREMENTS .............................................. 29 
6. 
INVESTIGATIONAL PLAN ............................................................................. 30 
6.1 
VISIT SCHEDULE ............................................................................................. 30 
6.2 
DETAILS OF DATA COLLECTION AT EACH  VISIT/ PHONE CALL .. 31 

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6.2.1 
Inclusion (Incl. MV) ............................................................................................ 31 
6.2.2 
Other visits (MV1, MV2, MV3) ......................................................................... 31 
6.2.3 
Remote additional nurse-led follow-up ............................................................. 32 
7. 
STATISTICAL METHODS AND DETERMINATION OF PATIENTS 
SAMPLE SIZE .................................................................................................... 34 
7.1 
STATISTICAL DESIGN .................................................................................... 34 
7.2 
NULL AND ALTERNATIVE HYPOTHESES ................................................ 34 
7.3 
PLANNED ANALYSES ..................................................................................... 34 
7.3.1 
Demographic information and baseline characteristics .................................. 35 
7.3.2 
Primary analyses ................................................................................................. 35 
7.3.3 
Secondary analyses .............................................................................................. 36 
7.3.4 
Safety analyses ..................................................................................................... 37 
7.3.5 
Interim analyses ................................................................................................... 38 
7.4 
HANDLING OF MISSING DATA .................................................................... 38 
7.5 
RANDOMISATION ............................................................................................ 38 
7.6 
DETERMINATION OF SAMPLE SIZE .......................................................... 39 
8. 
INFORMED CONSENT, DATA PROTECTION, STUDY RECORDS ....... 40 
8.1 
STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT ............................................................................................................ 40 
8.2 
QUALITY CONTROL ....................................................................................... 41 
8.3 
RECORDS MANAGEMENT ............................................................................ 41 
8.3.1 
Data management ................................................................................................ 41 
8.3.2 
Source documents ................................................................................................ 41 
8.3.3 
Access to source documents ................................................................................ 42 
8.3.4 
Storage of records ................................................................................................ 42 
8.4 
PROCEDURES FOR REPORTING ADVERSE EVENTS ............................ 43 
8.5 
STATEMENT OF CONFIDENTIALITY ........................................................ 44 
8.6 
COMPLETION OF STUDY .............................................................................. 44 
8.7 
SCIENTIFIC COMMITTEE ............................................................................. 44 
8.8 
RESULTS PUBLISHING ................................................................................... 44 
9. 
RÉFÉRENCES .................................................................................................... 45 
10. 
APPENDICES ..................................................................................................... 47 
10.1 
INFORMED CONSENT FORM ....................................................................... 47 
10.2 
GIRERD QUESTIONNAIRE ............................................................................ 47 
10.3 
FACT-LUNG QUESTIONNAIRE .................................................................... 47 
11. 
SUMMARY OF NON-INTERVENTIONAL STUDY PROTOCOL 
MODIFICATIONS ............................................................................................. 48 
 

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ABBREVIATIONS 
AE 
Adverse Event 
AUC 
Area under the Curve 
CI 
Confidence Interval 
CML 
Clinical Monitor Local 
CRA 
Clinical Research Associate 
CRF 
Case Report Form 
CTMF 
Clinical Trial Master File 
CTP 
Clinical Trial Protocol 
CTR 
Clinical Trial Report 
DMC 
Data Monitoring Committee 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
EMEA 
European Medicines Agency 
EU 
European Union 
EudraCT 
European Clinical Trials Database 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HPC 
Human Pharmacology Centre 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
ISF 
Investigator Site File 
i.v. 
intravenous 
IVRS 
Interactive Voice Response System 
IWRS 
Interactive Web-based Response System 
MedDRA 
Medical Dictionary for Drug Regulatory Activities 
MST 
Medical Subteam 
OPU 
Operative Unit 
p.o. 
per os (oral) 
PCC 
Protocol Challenge Committee 
PV 
Pharmacovigilance 
q.d. 
quaque die (once a day) 
SAE 
Serious Adverse Event 
s.c. 
subcutaneous 
SmPC 
Summary of Product Characteristics 
TCM 
Trial Clinical Monitor 
TDMAP 
Trial Data Management and Analysis Plan 
t.i.d. 
ter in die (3 times a day) 
TMM 
Team Member Medicine 
TMW 
Trial Medical Writer 
TSAP 
Trial Statistical Analysis Plan 
 

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1. 
INTRODUCTION 
In recent years, changes have occurred in the management of oncology patients. This 
evolution is the result of increased chemotherapy in day hospitals which allows faster return 
home but with increase in the day hospital consultations, longer survival of patients, and 
development of new molecules and strategies of therapy. Implementing an individualized 
therapeutic strategy, during and after treatment, proves reassuring for the patient and 
improves overall care (APM news, Cancer Plan 2, measures 18 and 24). In this context, and 
with the introduction of nurse coordinators and follow-up visits conducted by specialized 
nurses, nurses have become key players in the management and support of oncology patients. 
These practices were developed around the world (Canada, England, and France) for different 
types of cancer (Allard 2008, Moore 2002, Cancer Plan 2, measures 18-24, Cancer Plan 2. 
Results of studies on individualized programs on patients during and after cancer). Similarly, 
a telephone follow-up conducted by specialized nurses to prepare chemotherapy sessions 
(Berhoune 2010) or to monitor patients after treatment was considered and evaluated in 
several countries such as Canada, the United Kingdom, Netherlands and Australia (Cox 2003, 
Barbu 2009, Kimman 2011, Beaver 2011, Beaver 2012, Harisson 2013). Studies involving 
telephone follow-up in the follow-up of oncology patients have demonstrated that such 
intervention was economically feasible and well accepted by the majority of patients (Lewis 
2009). It can reassure patients and manage treatment related adverse events and recurrent 
symptoms (Cusack 2010). A recent study in France evaluated the impact of the 
implementation of a pilot program for remote follow-up involving a call centre specialised in 
follow-up of patients (Scotté 2013, Berhoune 2010). Nurses of this centre contacted patients 2 
days before their chemotherapy to collect adverse events encountered during their treatment. 
These data combined with the results of routine blood tests have allowed confirming or 
adjusting chemotherapy regimens and improving the management of patients during the 
chemotherapy session. Compared to a control group retrospectively evaluated, this program 
has helped to optimize the utilization of healthcare services (reduction of hospital stays, 
increase in rates of bed occupancy and reduction in waste of chemotherapy preparations). In 
addition, the program has allowed adjusting and individualising the strategies of prevention of 
adverse events which may occur during chemotherapy and improving the overall management 
of side effects, resulting in better management of patients. 
 
Telephone follow-up is part of the recommendations of the ‘Cancer Plan 3’ to develop the 
tools that facilitate patient information and treatment compliance. This comes in the context 
of both patient management and support. In France, some institutions have established a 
nurse-led telephone follow-up with the patient, at least weekly for 4-8 weeks, and after 
discussion with the patient and, if possible, with his entourage (Recommendations of Cancer 
Plan 3. Section 2.4.7). The use of this particular form of surveillance is not yet widespread 
and, to our knowledge, its impact on patient compliance to treatment and management of side 
effects has not yet been evaluated.  
 
Non-small-cell lung cancer (NSCLC) accounts for approximately 80-85% of all cases of lung 
cancer (ESMO 2012). The therapeutic strategy varies depending on the stage and combines 
local treatments (surgery, radiotherapy) and systemic treatments (chemotherapy and targeted 
therapy). In patients with stage IIIb/IV (unresectable cancers), systemic therapies represent 
the mainstay of treatment including chemotherapy, vascular endothelial growth factor (VEGF) inhibitor, and 

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epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). Treatment with an 
EGFR-TKI is the preferred option for patients with EGFR gene mutation (in France 9.4% of 
NSCLC, Barlési 2013). This treatment belongs to the group of oral anticancer therapies, 
which are being increasingly developed and used in oncology. Indeed, about 25% of 
anticancer molecules under development are oral therapies. In addition, when comparing 
equally effective therapies, patients generally prefer an oral anticancer treatment (Liu 1997). 
However, the use of oral home treatment brings changes to the doctor-patient relationship. 
Because patients become responsible for taking their treatment and managing the related 
toxicity, this practice raises the question of compliance. The literature shows that compliance 
rates range from less than 20% to 100% during the treatment of cancer with oral therapies 
(Ruddy, 2009; Geynisman 2013), with low compliance being mainly due to problems of cost, 
adverse events and dose schedule (e.g., relative to meals) (Ruddy, 2009; Geynisman 2013). 
To increase compliance during treatment with oral cancer therapies, several specific 
surveillance strategies have been implemented e.g. customized follow-up, education sessions 
for patients and caregivers (doctor, pharmacist, nurse), and telephone follow-up. This nurse-
led follow-up should reassure patients, permit them to have their questions answered, help in 
the management of targeted therapy related toxicity (e.g. by facilitating the adverse events 
reporting by the patient or their identification by the nurse) and may therefore increase patient 
treatment compliance or rectify certain situations of poor compliance. 
 
The objective of this study is to evaluate the impact of personalised nurse-led follow-up 
phone call on treatment compliance of patients with stage IIIb/IV NSCLC with EGFR-
activating mutation(s) being treated with oral targeted therapy in routine clinical practice. 

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2. 
RATIONALE AND OBJECTIVES 
2.1 
RATIONALE FOR PERFORMING THE STUDY 
The current management of patients with stage IIIb/IV NSCLC uses targeted therapy (ESMO 
2012) as first, second and third-line therapy. Targeted therapies are generally oral treatments 
which makes the patient responsible of the treatment intake. This approach affects patient 
compliance to treatment and management of AEs. In routine clinical practice, patients are 
regularly seen by their oncologists and a support program can be established following the 
recommendations of the Cancer Plan 3 (developing in the certification of healthcare 
institutions an approach to help patients with their care, improve communication and 
coordination between general practice and hospital, try new modalities of organisation in the 
management of patients treated with oral targeted therapy involving health professional in 
general practice and in hospital). A regular nurse-led telephone follow-up at the beginning of 
treatment may improve patient compliance. Therefore, the impact of the implementation of 
such a follow-up program on patient compliance to therapy will be evaluated in this real-life 
study. 
2.2 
OBJECTIVES 
2.2.1 
Primary objective 
The primary objective of this study is to evaluate, during routine clinical practice, the impact 
of nurse-led telephone follow-up on overall patient treatment compliance with oral targeted 
therapy (cumulated dose* during the 3-month study). 
* The cumulated dose (mg) of oral targeted therapy taken between 2 visits is the sum of the doses 
(mg) of the tablets taken by the patient. The cumulated dose (mg) of the oral targeted therapy taken 
during the 3-month follow-up is the sum of the doses (mg) cumulated taken between 2 visits during 
the 3 months follow-up.  
 
2.2.2 
Secondary objectives 
The secondary objectives are to evaluate: 
 The impact of an additional nurse-led telephone follow-up on patient treatment 
compliance using Girerd questionnaire (Girerd 2001). 
 To evaluate, during routine clinical practice, the impact of nurse-led telephone follow-
up on overall patient treatment non-compliance with oral targeted therapy, following 
decision of the medical team (cumulated dose not taken* during the 3-month follow-
up). 
 To evaluate, during routine clinical practice, the impact of nurse-led telephone follow-
up on overall patient treatment non-compliance with oral targeted therapy, following 
decision of the patient (cumulated dose not taken* during the 3-month follow-up). 
* The cumulated dose (mg) of oral targeted therapy not taken between 2 visits is the sum of the doses 
(mg) of tablets not taken by the patient. The cumulated dose (mg) of oral targeted therapy not taken 
during the 3-month follow-up is the sum of the cumulated doses (mg) not taken between 2 visits 
during the 3-month follow-up. 

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 Overall patient satisfaction with the level of care provided (Visual Analogue Scale 
[VAS]). 
 Evolution of patient quality of life during the study (Functional Assessment of Cancer 
Therapy [FACT] Lung questionnaire; Cella, 1995). 
 Use of healthcare such as emergency department visits/admissions, number and 
duration of unplanned hospitalisations, number of unplanned visits during the 3-month 
follow-up (visits to the investigator, to any other specialist or to the general 
practitioner). 
 Overall satisfaction of the investigator (pneumologist/oncologist) and for the patients 
included in the group with a remote additional personalised nurse-led follow-up, the 
overall satisfaction of their pharmacist and general practitioner (VAS). 
 Safety (data collected according to the Common Terminology Criteria for Adverse 
Events [CTCAE] version 4.03). 
 Impact of the additional nurse-led follow-up on the frequency of calls to the general 
practitioners/specialists by the patient. 

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3. 
DESCRIPTION OF DESIGN AND STUDY POPULATION 
3.1 
OVERALL DESIGN AND PLAN 
This is a randomized, multicentre, routine clinical practice study. 
 
Selection of the participating investigators: 
Up to 450 specialized doctors will be contacted in order to recruit 130 participating medical 
team (investigators) in 75 centres. These centres should include around 400 patients in the 
study (about 5 to 6 patients per centre). 
 
In order to extrapolate the study results to the rest of the target population, the participating 
investigators will be selected by stratified random sampling of the PMSI 2011 file, which 
includes a list of all French hospitals providing healthcare for NSCLC patients. Stratification 
factors will be geographical breakdown and the size of the patient base. 
 
Study design: 
The study will take place over a period of 27 months. The recruitment phase will last 
approximately 24 months and each patient will participate for approximately 3 months. 
 
At the inclusion visit (D0), the investigator will ask the patient whether he would like to 
participate in the study and will obtain his written consent. Refusal to participate including the 
reason if available will be collected in a register specific to this study (study register). The 
collected data will allow any selection bias to be identified.  
 
Each patient agreeing to participate in the study will be randomised by receiving a 
randomisation number and assigned to its corresponding group. Randomisation will be done 
by envelopes (See Section 7.5). The investigators or medical team will send a randomisation 
fax to Patientys for each patient included in the study. Patientys will forward the anonymised 
data to the contract research organisation (CRO) in charge of the data monitoring.   
 
The randomisation will follow a 3:1 ratio and the patients will be included in one of the 
following 2 groups: 
 Group without ‘remote additional personalised nurse-led follow-up’: patients will 
receive the healthcare given routinely by their medical team (100 patients). 
OR 
 Group with ‘remote additional personalised nurse-led follow-up’: patients will receive 
telephone calls from a nurse in addition to the healthcare given routinely by their 
medical team (300 patients). 
 
All the patients will be seen according to normal practice by the study medical team. In this 
study, 3 data collection time-points at monthly intervals are defined (D30, D60, D90); 
however the frequency of visits should not be adjusted and the medical team should maintain 
his routine practice (example: if the investigator is used to see the patient on D15, the visit 
will still take place, but no information, except pharmacovigilance data, will be collected). As 

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such, the data from the closest defined visit will be reported in the case report form (CRF) at 
each time point (see Figure 1).  
 
During the inclusion consultation, the medical team will provide the patient with a patient 
diary with all the main information regarding its treatment and in which he should report 
some information (see Section 6.2). 
 
The telephone calls will be made by a nurse from a company specialised in patients support 
called Patientys. Patients in the group with ‘remote additional personalised nurse-led follow-
up’ will be contacted 8 times during the study (at D1, D7, D14, D21, D28, D44, D59 and 
D89, see Figure 1). The nurse will make sure that the treatment takes place in good 
conditions; she cannot intervene in the medical care of the patient, nor give answer to the 
questions relative to the disease or to the treatment of the patient. The medical team remains 
the privileged contact of the patient. 
 
During the informed consent process, the patient may authorize a relative (i.e. a person he 
trusts and who can be among other, a family member, a friend or a housemate) to assist him 
during the nurse-led phone call. The first and last name of this person will be specified on the 
informed consent form.  
 
During the first telephone call at D1, the nurse will confirm the enrolment of the patient in the 
study and will re-explain the calls schedule. Following this call, if the patient agrees to give 
the contact details of their physician and pharmacist, then the nurse will inform them, by letter 
or phone call, of the patient participation in the study. 
 
During the following telephone calls, the nurse will perform a clinical evaluation by using a 
pre-established questionnaire and will collect treatment related AEs (see Section 6.2.3) as 
well as the pharmacovigilance (PV) information. After each telephone call, the nurse will 
establish a report.  
 
The telephone call reports will be sent to the investigators on the same day of the nurse 
follow-up phone call. 
The investigator will verify the severity of the AE and will determine the causal relationship 
with the oral targeted therapy. 
 If case of serious adverse event (SAE), the investigator must complete and send 
immediately the serious adverse event (SAE) form (SAE form) to the CRO in charge 
of data monitoring (within 24h of the event). The causality will be determined by the 
investigator and recorded on SAE declaration form. In case of treatment exposure 
during pregnancy please refer to Section 5.3.2.2. 
 In case of non-serious AE and/or of any other PV information, the investigator should 
complete and send the AEs page of the CRF to the CRO in charge of data monitoring 
within 7 days of the event. The causality will be determined by the investigator and 
recorded on the AEs page of the CRF. 
 

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Patientys call-centre: 
PATIENTYS – DIRECTMEDICA 
31 rue des longs Prés 
92100 Boulogne Billancourt, France 
 
CRO in charge of study logistic and administrative management and data monitoring : 
 
  
 
 
3.2 
DISCUSSION OF STUDY DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP 
The main objective of this study is to evaluate the impact of an additional nurse-led telephone 
follow-up during routine clinical practice of patients with stage IIIb/IV NSCLC. Based on 
recommendations of the Plan Cancer, nurse-led follow-up of patients becomes more and more 
common in order to ensure a better patient care. The implementation of nurse-led telephone 
follow-up in this study fits into this approach.  
 
The current study is a routine clinical practice study and aims to evaluate the care provided to 
the patient and particularly the impact of the implementation of a nurse-led telephone follow-
up in the patients’ standard of care. In this routine clinical practice study, all the procedures 
and the products prescribed are part of the common practice. Only a particular method of 
follow-up is added for some patients. This method of monitoring has only negligible risks and 
constraints to patients enrolled in the study. The impact of the nurse-led telephone follow-up 
during healthcare given routinely will be assessed in terms of treatment compliance.  
 
A control group that includes patients without additional nurse-led follow-up is needed to 
assess the benefit of the phone calls. To minimise the risk of patient's refusal to participate in 
the study and to collect sufficient data for patients with additional telephone follow-up, 
randomisation will be unbalanced. A ratio of 3:1 will be used for randomisation, giving each 
patient a probability of 0.75 to be included in the group with nurse-led follow-up’ in addition 
to the healthcare given routinely by the specialised physician. 
3.3 
SELECTION OF STUDY POPULATION 
3.3.1 
Main diagnosis for study entry 
The study will be proposed to adult patients diagnosed with stage IIIb/IV NSCLC locally 
advanced or metastatic, with activating mutation(s) of EGFR and who are EGFR-TKI naïve. 
3.3.2 
Inclusion criteria 
Patients will be eligible to enter the study if they meet all the following inclusion criteria: 
 Male or female patient older than 18 years. 
 Adult patient diagnosed with stage IIIb/IV NSCLC locally advanced or metastatic, 
with activating mutation(s) of EGFR and who is EGFR-TKI naïve. 

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 Patient for whom a decision of treatment with afatinib monotherapy has been taken in 
the frame of its marketing authorization. 
 Out-patient. 
 Patient having given written consent for participation in the study. 
 Patient who is able to participate in the investigator’s opinion. 
 Patient affiliated with the French social security. 
 
A copy of the written consent will be given to the patient, and the second copy will be filed in 
the study record. 
3.3.3 
Exclusion criteria 
Patients meeting one of the following criteria will participating not be eligible  
 Patients participating in an interventional clinical study. 
 Patients for whom a participation in an interventional clinical study is foreseen within 
3 months following the study inclusion. 
 Patients participating in a therapeutic education program. 
3.3.4 
Removal of patients from therapy or assessments 
Patients can decide to discontinue their participation in this study at any time. 
 
Boehringer Ingelheim reserves the right to discontinue the overall study or in a particular 
centre for the following reasons: 
 Inability to recruit the planned number of subjects across centres or in a particular 
centre. 
 Evidence of information that could significantly affect the continuation of the study, or 
for other administrative reasons. 
 Violation of Good Clinical Practice (GCP) or contract, by a study centre or an 
investigator, preventing the proper conduct of the study. 
 
4. 
TREATMENTS 
Not applicable. 
 

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5. 
EVALUATION CRITERIA 
5.1 
PRIMARY ENDPOINT 
5.1.1 
Primary endpoint 
The primary endpoint of the study is the cumulated dose (mg) of oral targeted therapy during 
the 3-month follow-up. 
 
5.1.2 
Assessment methods  
At each visit, patients should bring their oral targeted therapy packet delivered by their 
pharmacist (empty or started). Missing and remaining tablets will be counted by the medical 
team and reported in the CRF according to their dose. 
 
The cumulated dose (mg) of the oral targeted therapy, taken between 2 visits, will be 
calculated as follows: sum of doses (mg) of the tablets used by the patient. Counting the 
tablets consumed by patients between consultations Vi-1 and Vi will be done by the study team 
during consultation Vi from boxes of tablets returned by the patient. The doctor will report, in 
the CRF, and for each possible dosage (20 mg, 30 mg, 40 mg, 50 mg [only as second 
intention dose if the treatment is well-tolerated and as per product sheet recommendations]), 
the number of tablets used by the patient. The cumulated dose between consultations Vi-1 and 
Vi will be calculated as follows: 
 
[Cumulated dose (mg)]i=


)]
(
[Dosage
40
 
30,
 
20,
in 
 
Dosages
Dosage
Nbtab


,  
Where Nbtab(Dosage) is the number of consumed tablets of 20 mg, 30 mg 40 mg or 50 mg 
respectively. 
 
The cumulated dose (mg) of oral targeted therapy over the 3-month study will be equal to the 
sum of the cumulated doses (mg) taken between the 2 visits, during the 3-month study. The 
total cumulated dose (mg) over 3 months will be calculated as follows: 
Cumulated dose (mg) = 
i
i
(mg)]
 
dose
 
[Cumulated
 
 
5.2 
SECONDARY ENDPOINTS 
5.2.1 
Secondary endpoints 
The following secondary endpoints will be evaluated in the study: 
 Score (0–6) obtained with the Girerd questionnaire at D30, D60 and D90. 
 Cumulated dose of oral targeted therapy not taken (all categories) following decision 
of the medical team.  
 Cumulated dose of oral targeted therapy not taken due to dose reduction following 
decision of the medical team. 

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 Cumulated dose of oral targeted therapy not taken due to temporary or definitive 
interruption following the medical team decision. 
 Cumulated dose of oral targeted therapy not taken (all categories) following patient 
decision. 
 Cumulated dose of oral targeted therapy not taken due to dose reduction following 
patient decision. 
 Cumulated dose of oral targeted therapy not taken due to temporary or definitive 
interruption following patient decision. 
 VAS score (0–10) for overall patient satisfaction with the level of care (information, 
advice) at D90. 
 Absolute variation observed for the quality of life questionnaire FACT Lung score 
between D30 and D0, between D90 and D30 and between D90 and D0. 
 Number of emergency admissions (related to the treatment) during the  
3-month follow-up. 
 Number and duration of unplanned hospitalizations (related to the treatment) during 
the 3-month follow-up. 
 Number of unplanned visits to the investigator during the 3-month follow-up. 
 Number of unplanned visits to a specialist, whatever is his specialty, other than the 
investigator during the 3-month follow-up.  
 Number of unplanned visits to the general practitioner during the 3-month follow-up. 
 VAS score (0–10) for overall investigator satisfaction with the level of patient care at 
D90. 
 VAS score (0–10) for overall general practitioner satisfaction with the level of patient 
care at D90 (only for the patients with ‘remote additional personalised nurse-led 
follow-up) 
 VAS score (0–10) for overall pharmacist satisfaction with the level of patient care at 
D90 (only for the patients with ‘remote additional personalised nurse-led follow-up). 
 Number of calls made by the patients to their general practitioner during the 3-month 
follow-up. 
 Number of calls made by the general practitioner to the patient during the 3-month 
follow-up. 
 Number of calls made by the patients to their medical team during the 3-month 
follow-up. 
 Number of calls made by the medical team to their patient during the 3-month follow-
up.  
 Number of calls between the general practitioners and the medical teams during the 3-
month follow-up. 
 
5.2.2 
Assessment methods  
Girerd questionnaire is a questionnaire composed of 6 binary questions (yes/no) and is used to 
assess treatment compliance. The final score obtained is the number of questions to which the 
patient responded 'yes'. Thus, the score ranges from 0 to 6. 
 
FACT Lung quality of life questionnaire is composed of 27 items of the FACT-G 
questionnaire, with the following 4 dimensions: physical well-being, social well-being, 

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emotional well-being, and functional well-being. It is composed of 9 questions specific to 
lung cancer. Each of the 36 questions is scored from 0 to 4 (cf. Section 7.3.3 for more details 
on the analysis of these questionnaires). 
 
Cumulated dose (mg) of oral targeted therapy not taken between 2 visits is the sum of the 
doses (mg) of the tablets not taken by the patient. The cumulated dose (mg) of the oral 
targeted therapy not taken during the 3-month follow-up is the sum of the doses (mg) 
cumulated not taken between 2 visits during the 3-month follow-up. This dose can be 
calculated overall and by reason for not taking the prescribed dose: dose reduction, temporary 
or definitive discontinuation following decision of the medical team / patient decision.  
 
VAS scores will be presented in the form of a horizontal ungraduated line of 10 cm, with the 
following extremities: left, 'completely unsatisfied' and right, 'very satisfied'. The number of 
points (0 to 10) obtained in VAS corresponds to the distance (cm) between the left extremity 
of the line and the mark placed on the line by the patient, investigator, general practitioner, or 
pharmacist to assess patient’s level of satisfaction. 
5.3 
SAFETY DATA TOLERANCE 
5.3.1 
Safety endpoints 
The current study will collect the AEs as follows: 
 Number of adverse events (AE) related to the oral targeted therapy.  
 Number of AE related to the oral targeted therapy of grade ≥ 3. 
 Number of serious adverse events (SAE) related to the oral targeted therapy. 
 Number of AE related to the oral targeted therapy and leading to a definitive or 
temporary discontinuation of the drug, or to a dose reduction. 
5.3.2 
Assessment of adverse events 
The AEs will be collected by the medical team during patient consultation or by the nurse of 
the specialised call centre Patientys during the follow-up phone call.  
 
The nurse will transmit to the investigator the telephone call report by e-mail or by FAX on 
the day of the follow-up phone call and will provide 
 with the AE page(s) of the CRF, if 
applicable. If needed the nurse may contact the medical team. The investigator will check, 
confirm, and comment the AEs reported by the nurse. 
 will add any relevant event. 
 will 
also complete the AEs page of the CRF sent by the nurse by adding the intensity and the 
causal relationship with the oral targeted therapy.  
 
Each AE will be recorded in the CRF and send to the CRO in charge of the data monitoring.  
The modalities of transmission to the CRO in charge of data monitoring and to the sponsor of 
the study are described in Sections 3.1, 6.2.3 and 8.4. 
 

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5.3.2.1 
Definition of adverse events 
Adverse event 
An AE is defined as any untoward medical occurrence, including an exacerbation of a pre-
existing condition, in a person taking part in a clinical study. The event does not necessarily 
have to have a causal relationship with the study. 
 
Serious adverse event 
A SAE is defined as any AE which: 
• 
Results in death. 
• 
Is immediately life-threatening. 
• 
Results in persistent or significant disability / incapacity. 
• 
Requires or prolongs patient hospitalization. 
• 
Is a congenital anomaly / birth defect. 
• 
Or is considered as medically relevant for any other reasons. 
 
Medical judgment is warranted to determine whether the event or adverse reaction is serious 
in other situations. Significant reactions or adverse events that are not immediately life-
threatening or do not result in death or hospitalization, but may put the subject at risk or may 
require intervention to prevent the occurrence of one of the above criteria, must also be 
considered serious. 
 
Intensity of adverse events 
The intensity of adverse events should be classified and recorded according to the CTCAE 
criteria version 4.03 in the CRF. 
 
Causal relationship of adverse events with the targeted oral therapy  
Medical judgment should be used to determine the relationship with the oral targeted therapy 
while considering all relevant factors, including pattern of reaction, temporal relationship, de-
challenge or re-challenge, confounding factors such as concomitant medication, concomitant 
diseases and relevant history.  
 
Worsening of the underlying disease or other pre-existing conditions 
Worsening of the underlying disease or other pre-existing conditions and changes in vital 
signs, ECG, physical examination, and laboratory test results will be recorded as an AE in the 
CRF, if they are judged clinically relevant by the investigator. 
 
Other pharmacovigilance information 
• 
Non-conform use of the product i.e. any use outside the marketing authorisation (for 
instance: overdose, medical error, intentional misuse or abuse, administration outside 
the marketing authorisation, not in conformity with the marketing authorisation, 
administrated for a condition not cover by the marketing authorisation), 
• 
Product’s exposure during pregnancy or breast-feeding,  
• 
Product’s exposure during conception (father), 
• 
Suspicion of contamination with an infectious agent, 
• 
Suspicion of AE related to a professional exposure, 
• 
Lack of efficacy or any increased in therapeutic effect or any unexpected benefit 
• 
Any interaction with other product (drugs, food, tobacco, alcohol, radiation).  

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5.3.2.2 Adverse event and reporting 
All SAEs, non-serious AEs and others PV information, occurring during the course of the 
study (i.e., from signing the informed consent onwards through D90) will be collected, 
documented and reported to the sponsor or the CRO in charge of the data monitoring by the 
investigator on the appropriate reporting forms (AE page of the CRF or SAE form). 
 
For each adverse event, the investigator will provide the onset date, end date, intensity, 
treatment required, outcome, seriousness, causal relationship, and action taken with the 
targeted oral therapy. The investigator will determine the relationship of the oral targeted 
therapy to all AEs. 
 
All personnel involved in the study (investigator, the Patientys call centre nurse, general 
practitioner, centre personnel…) must immediately report any SAE that they encounter to the 
CRO responsible of the data monitoring. The event must be notified within 24h, via telephone 
or FAX using the SAE reporting form to: 
 
 
Follow-up of SAEs - PARTAGE 
 
Fax: 
  
Back-up fax:
  
E-mail: 
 
 
The notification of the SAEs must be immediate whether the oral targeted therapy was 
administered or not, whether there is a causal relationship or not, or whether the information 
is initial information or additional information. 
 
All other non-serious AEs and PV information must be reported to the CRO in charge of the 
study management within 7 calendar days of knowledge The CRO must inform Boehringer 
Ingelheim within 7 calendar days of notification by the investigator. 
 
Pregnancy 
Any pregnancy occurring during the course of this study must be immediately reported 
following the same SAE reporting procedure using the pregnancy form. The pregnancy must 
be followed- up, its outcome documented, and the pregnancy form should be completed. In 
the absence of any AE, only the pregnancy monitoring is to be completed. 
 
Health professional should comply with the applicable legislation regarding reporting 
obligations (Article R5121-161 of the French public health code).  
 
5.3.3 
Assessment of other safety parameters 
Not applicable 
 

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5.4 
APPROPRIATENESS OF MEASUREMENTS 
All clinical evaluations made in this study are part of the routine monitoring of patients with 
NSCLC. The questionnaires used during patients follow-up are validated questionnaires, with 
the exception of the satisfaction questionnaires. 

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6. 
INVESTIGATIONAL PLAN 
6.1 
VISIT SCHEDULE 
Table 2 
Visit schedule and data collection 
 
D0 
D1a 
D7a 
D14a 
D21a 
D28a 
D30 
M1 
D45a D59a 
D60 
M2 
DJ89a D90b 
M3 
 
MV Incl NFPC 
1 
NFPC 
2 
NFPC 
3 
NFPC 
4 
NFPC 
5 
MV1 NFPC 
6 
NFPC 
7 
MV2 NFPC
8 
MV3 
Written consent   
X 
 
 
 
 
 
 
 
 
 
 
 
Verification of eligibility 
X 
 
 
 
 
 
 
 
 
 
 
 
Documentation of patient’s 
acceptance or rejection of 
participation in the study file 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographic information c 
X 
 
 
 
 
 
 
 
 
 
 
 
Physical exam d 
X 
 
 
 
 
 
 
 
 
 
 
 
NSCLC characteristics e 
X 
 
 
 
 
 
 
 
 
 
 
 
Past medical history, past 
treatments  
X 
 
 
 
 
 
 
 
 
 
 
 
Concomitant diseases, 
concomitant medications 
X 
 
 
 
 
 
X 
 
 
X 
 
X 
Randomisation 
X 
 
 
 
 
 
 
 
 
 
 
 
Patient diary delivery 
X 
 
 
 
 
 
 
 
 
 
 
 
Clinical evaluation by 
Patientys nurse 
 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
 
Collection of AEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Patient compliance 
(returned tablets and Girerd 
questionnaire) 
 
 
 
 
 
 
X 
 
 
X 
 
X 
Patient quality of life 
questionnaire 
X 
 
 
 
 
 
X 
 
 
 
 
X 
Patient global satisfaction 
questionnaires 
 
 
 
 
 
 
 
 
 
 
 
X 
Data collection on use of 
healthcare services 
 
 
 
 
 
 
X 
 
 
X 
 
X 
General practitioner and/or 
pharmacist global 
satisfaction questionnaires 
 
 
 
 
 
 
 
 
 
 
 
X 
Investigator global 
satisfaction questionnaires 
 
 
 
 
 
 
 
 
 
 
 
X 
a Only for patients ‘With nurse-led follow-up’ group 
b Or end of study visit if the patient withdraws prematurely from the study 
c Including age, gender, weight, height 
d Complete physical exam at inclusion visit including: Vital signs (Heart & respiratory rate, blood pressure, temperature), 
and collection of the cutaneous, gastro-intestinal, respiratory, eye, cardiovascular and allergic symptoms  
e Diagnosis date, disease stage, performance status (ECOG), biopsy date, type of mutation(s), method of mutation typing, 
previous treatments of NSCLC 
f The drug accountability of taken and not taken tablets will be made by the medical team in the Case Report Form 
D = day ; M = month ; MV = medical visit according to the routine practice of the centre, NFPC= nurse follow-up phone call, 
Incl.= inclusion, NSCLC = non-small-cell lung cancer ;  
AE= adverse event. 

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6.2 
DETAILS OF DATA COLLECTION AT EACH  VISIT/ PHONE CALL 
6.2.1 
Inclusion (Incl. MV) 
During the inclusion consultation, the medical team will ask the patient to participate in this 
study. Written consent will be obtained; however if the patient refuses to participate in the 
study, the refusal with the corresponding reason, if available, will be documented in the study 
registry. The patient accepting to participate in the study will be randomised to receive or not 
a remote additional nurse-led follow-up during the follow-up period (randomisation ratio of 
3:1). 
 
The registration form must be completed and forwarded to Patientys by e-mail or FAX. 
 
If the patient agrees to participate in the study, the investigator will collect the following data: 
 Demographic information (age, gender, weight, height). 
 NSCLC characteristics (date of first diagnosis, disease stage, performance status from 
the Eastern Cooperative Oncology Group [ECOG], biopsy date, type of mutation(s) 
detected, test/method used to assess mutation and previous treatments). 
 Medical history, concomitant diseases, previous and concomitant treatment. 
 Results of the complete physical examination: vital signs (heart and respiratory 
rate,blood pressure, temperature), and presence of any of the following symptoms: 
coetaneous, gastrointestinal, respiratory, ocular, cardiovascular and allergic.  
 
As with any initiation of oral targeted therapy treatment, the medical team will counsel the 
patient on the oral targeted therapy, treatment schedule and precautions (lifestyle changes) to 
be taken in order to prevent treatment related adverse events, in addition to giving the patient 
a diary to report information related to the utilisation of healthcare services (telephone calls 
with or visits to their general practitioner or specialist, with any specialty). 
 
During this consultation, and as per routine practice, the medical team will set the schedule of 
upcoming consultations. In this study, 3 data collection time-points at monthly intervals are 
defined (D30, D60, and D90). The frequency of visits should not be adjusted and the medical 
team should maintain his routine practice (example: if the investigator is used to see the 
patient on D15, the visit will still take place, but no information, except pharmacovigilance 
data, will be collected). As such, the data from the closest defined visit will be reported in the 
CRF. 
 
The patient will also be asked to complete quality of life questionnaire (FACT Lung).  
 
6.2.2 
Other visits (MV1, MV2, MV3) 
At the 2nd and 3rd consultation visits (D30 and D60) during which data will be collected, the 
patient will be asked to: 
 Complete the compliance questionnaire (Girerd). 
 Complete the quality of life questionnaire (FACT Lung; only on D30). 
 Bring their oral targeted therapy packets (empty or started) prescribed/consumed since 
the previous consultation visit. 

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 Bring their patient diary. 
 
All the questionnaires will be completed before the start of consultations, in the doctor’s 
office or any other available private place. 
 
The medical team will record the number of tablets taken and not taken, and will report this 
information in the patient’s CRF. 
 
Adverse events and concomitant diseases and medications will be collected during these 
consultations. Data on the utilization of healthcare services (hospitalizations, emergency room 
visits, unscheduled consultation visits), including the number of visits and the number of calls 
to the general practitioner, will also be collected using the information reported by the patient 
in their patient diary. 
 
During the last consultation visit (MV3 on D90), the patient will be asked to: 
 Complete the compliance questionnaire (Girerd),  
 Complete the quality of life questionnaire (FACT Lung), 
 Complete the global satisfaction questionnaire, 
 Bring their oral targeted therapy packets (empty or started) prescribed/consumed since 
the previous consultation visit, 
 Bring their patient diary. 
 
All the questionnaires will be completed before the start of consultations, in the doctor’s 
office or any other available private place. 
 
The medical team will record the number of tablets taken and not taken, and will report this 
information in the patient’s CRF. 
 
Adverse events and concomitant diseases and medications will be collected during these 
consultations. Data on the utilization of healthcare services will also be collected using the 
information reported by the patient in their patient diary. 
 
Assessment of overall level of satisfaction of the general practitioner and the pharmacist will 
be collected via paper questionnaires that will be sent by Patientys along with a stamped 
return envelope to the address of the CRO responsible for the data monitoring of the study. 
The evaluation document of the overall level of satisfaction of the investigator of the medical 
team is given in the last page of the CRF and should ideally be completed at the last patient 
visit. 
 
6.2.3 
Remote additional nurse-led follow-up 
This follow-up will be implemented only for patients in the ‘with nurse-led follow-up’ group. 
During each telephone call, the nurse will have to complete a pre-established questionnaire, 
an AE page, and a SAEs declaration form. 
 
During the informed consent process, the patient may authorize a relative (i.e. a person he 
trusts and who can be among other, a family member, a friend or a housemate) to assist him 

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during the nurse-led phone call. The first and last name of this person will be specified on the 
informed consent form.  
 
During the first telephone call (D1), nurses will confirm the registration of the patient. The 
name and contact details of the general practitioner and pharmacist of the patient will be 
collected in a study registry. These data will allow to inform the general practitioners and 
pharmacists of patients included in the ‘with remote additional personalised nurse-led follow-
up’ group of the patient's participation in the study and to send them the global satisfaction 
questionnaire at the end of the study. 
 
During subsequent telephone calls, the nurse will establish a ‘clinical evaluation’ using 
questions such as: 
 “How are you feeling today?” 
 “Did you take your medicine as your doctor has prescribed?” 
 “Did you complete patient diary of the study?” 
She will also collect AEs encountered during treatment intake. In particular, the following 
events will be collected: 
 Gastrointestinal disorders (diarrhea, stomatitis, dyspepsia, cheilitis). 
 Skin and subcutaneous tissue disorders (rash, acneiform dermatits, pruritus, dry skin, 
the palmar-plantar syndrome). 
 Infections (paronychia, cystitis). 
 Appetite or metabolic disorders (decreased appetite , dehydration, hypokalemia). 
 Nervous system disorders (dysgeusia). 
 Eye disorders (conjunctivitis, dry eye, keratitis, tearing, light sensitivity). 
 Respiratory disorders (epistaxis, rhinorrhea, interstitial lung disease, pneumonia, 
respiratory distress, allergic alveolitis). 
 Musculoskeletal disorders (muscular spasms). 
 General disorders (fever). 
 Investigations (weight loss). 
 Others. 
 
The nurse will transmit to the investigator the telephone call report by e-mail or by FAX on 
the day of the follow-up phone call and will provide him with the AE page(s) of the CRF, if 
applicable. If needed the nurse may contact the medical team. Each AE will be recorded in the 
CRF and send to the CRO in charge of the data monitoring. The investigator of the team will 
also complete the AEs page of the CRF sent by the nurse by adding the intensity and the 
causal relationship with the oral targeted therapy.  
 
 If case of serious adverse event (SAE), the investigator must complete and send the 
serious adverse event (SAE) form (SAE form) to the CRO in charge of data 
monitoring within 24h of the event. The causality will be determined by the 
investigator and recorded on SAE declaration form. 
 In case of non-serious AE, the investigator should complete and send the AEs page of 
the CRF to the CRO in charge of data monitoring within 7 days of the event. The 
causality will be determined by the investigator and recorded on the AEs page of the 
CRF. 
 

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The nurse will also send, on the same day of follow-up phone call, the information related to 
the SAEs and non-SAEs to the CRO in charge of data monitoring. 
 
7. 
STATISTICAL METHODS AND DETERMINATION OF 
PATIENTS SAMPLE SIZE 
7.1 
STATISTICAL DESIGN  
This is a routine clinical practice, randomised, open-label, multicentre, study. 
Patients will be randomised in one of the following 2 groups: 
 Group ‘without remote additional personalised nurse-led follow-up’: patients will 
receive the healthcare given routinely by the medical team (100 patients). 
 
 Group with ‘remote additional personalised nurse-led follow-up’: patients will receive 
telephone calls from a nurse in addition to the healthcare given routinely by their 
medical team (300 patients). 
 
7.2 
NULL AND ALTERNATIVE HYPOTHESES 
The null and alternative hypotheses are as follows:  
 
H0 : no difference exists between the average doses of the first 3-month oral targeted therapy 
between ‘with remote additional personalised nurse-led follow-up’ and ‘without remote 
additional personalised nurse-led follow-up’ groups.  
 
H0: average cumulated dose ‘With nurse-led follow-up’ = average cumulated dose ‘Without nurse-led follow-up’ 
 
H1 : a difference exists between the average doses of the first 3-month oral targeted therapy 
between ‘With nurse-led follow-up’ and ‘Without nurse-led follow-up’ groups. 
 
H1: average cumulated dose ‘With nurse-led follow-up’ ≠ average cumulated dose ‘Without nurse-led follow-up’ 
 
7.3 
PLANNED ANALYSES 
General considerations 
The statistical analysis will be performed using SAS (version 9.1 or a more recent version). 
All tests will be performed 2-sided with a cut-off of 5%. 
 
The primary analysis population will be the population of randomised patients who satisfy the 
essential inclusion and exclusion criteria, and for whom information is available for the major 
evaluation criteria (in particular the primary criterion). This population will be used for the 
analysis of the primary and secondary endpoints (except safety data). 
 

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The safety population, for which safety endpoints will be analysed, will include patients who 
had received at least one dose of the oral targeted therapy during the 3-month study. 
 
Quantitative variables will be described, overall and by group, using number of observed 
values, mean, standard deviation, median, lower quartile, upper quartile, minimum, 
maximum, 2-sided 95% confidence interval of the mean. Comparison between the 2 groups 
will be done using Student test or Wilcoxon rank sum test in case of non-normal data or non-
homogeneity of variance. 
 
Qualitative variables will be described, overall and by group using number of observed 
values, percentage and two-sided 95% confidence interval of the percentage by category. 
Comparison between the 2 groups will be done using Student test or Fisher’s exact test. 
 
7.3.1 
Demographic information and baseline characteristics 
Demographic information and baseline characteristics will be described for all patients 
included in the study. 
 
Past medical history and concomitant treatments will be described overall and per group. 
 
The frequency of the previous medications will be calculated according to "patient" approach: 
the frequency will be calculated globally and by ‘système organe classe’ (SOC) and Preferred 
Term (PT) of the terminology used in the dictionary for regulatory activities (MedDRA). 
 
The frequency of previous treatments will be presented in "patient" approach: the frequency 
of patients who received at least one concomitant medication and frequency of patients with 
at least one prior medication will be calculated. Frequencies will be calculated by term ATC 
(terminology WHO-DD). Each table will be sorted in a descending order of frequency of 
ATC terms. 
7.3.2 
Primary analyses 
The primary objective of the study is to evaluate overall treatment compliance after 3-months 
follow-up and to compare this compliance between the 2 study groups: the group of patients 
with additional nurse-led follow-up and the group without nurse-led follow-up. 
 
As such, the cumulated dose (mg) of the oral targeted therapy over the 3-month study will be 
described for each of the groups: number of observed values, mean, standard deviation, 
median, lower quartile, upper quartile, minimum, maximum, two-sided 95% confidence 
interval of the mean. 
 
The mean cumulated dose will be compared between groups by Student test, or Wilcoxon 
rank sum test in case of non-normal data and/or non-homeogeneity of variance. 
 

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A complementary analysis using a Kaplan-Meier curve will also be performed on the 
principal criteria, to evaluate the time between start of treatment and the first dose 
modification or interruption of the oral Targeted therapy. 
7.3.3 
Secondary analyses 
In addition to the primary analysis, a secondary analysis of Girerd questionnaire scores will be 
performed. 
 
This questionnaire is composed of 6 binary questions (yes/no) and is used to assess treatment 
compliance. The final score obtained is the number of questions to which the patient 
responded 'yes'. Thus, the score ranges from 0 to 6. 
 
A patient will be classified as: 
 Good compliant: score = 0. 
 Minor non-compliant: score = 1 or 2. 
 Non-compliant: score > 2. 
 
A sub-group descriptive analysis of patients per score category on D30, D60 and D90 will be 
presented: number of observed values, percentage, and 2-sided 95% confidence interval. 
 
In addition, the percentage of patients with good compliance (score = 0) to the percentage of 
patients with minor non-compliance and / or non-compliance (score> 0) will be compared at 
each time point (D30, D60, D90), between the 2 groups of patients (‘With nurse-led follow-
up’ and ‘Without nurse-led follow-up’), using Chi-2 or Fisher-exact test. 
 
The cumulated doses (mg) of the oral targeted therapy not taken during the 3-month follow-
up by decision of the medical team (with details by type: dose reduction, temporary or 
definitive discontinuation) / by decision of the patient him/herself (with details by type: dose 
reduction, temporary or definitive discontinuation) will be described for each follow-up 
group, using number of observed values, mean, standard deviation, median, lower quartile, 
upper quartile, minimum, maximum, 2-sided 95% confidence interval of the mean. 
 
Analysis of other secondary endpoints will simply be descriptive and inferential as described 
in the general statistical considerations, namely: 
 
 Quantitative variables: 
- 
VAS score (0–10) for overall patient satisfaction with the level of self-care 
(information, counselling, advice...) at D90. 
- 
Absolute variation observed for the quality of life questionnaire FACT Lung 
score between D30 and D0, between D90 and D0, and between D30 and D90. 
- 
Duration of unplanned hospitalisations during the 3-month follow-up. 
- 
VAS score (0–10) for overall investigator satisfaction with the level of patient 
self-care at D90. 
- 
VAS score (0–10) for overall general practitioner satisfaction with the level of 
patient self-care at D90 (only for the patients with ‘remote additional 
personalised nurse-led follow-up). 

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- 
VAS score (0–10) for overall pharmacist satisfaction with the level of patient 
self-care at D90 (only for the patients with ‘remote additional personalised 
nurse-led follow-up). 
 
 Qualitative variables: 
- 
Number of emergency admissions during the 3-month follow-up. 
- 
Number of unplanned hospitalisations during the 3-month follow-up. 
- 
Number of unplanned visits to the investigator during the 3-month follow-up. 
- 
Number of unplanned visits to a specialist, whatever is his specialty, other than 
the investigator during the 3-month follow-up.  
- 
Number of unplanned visits to the general practitioner during the 3-month 
follow-up. 
- 
Number of calls made by the patients to their general practitioner during the 3-
month follow-up. 
- 
Number of calls made by the general practitioner to their patient during the 3-
month follow-up. 
- 
Number of calls made by the patients to their medical team during the 3-month 
follow-up. 
- 
Number of calls made by the medical team to their patient during the 3-month 
follow-up.  
- 
Number of calls between the general practitioners and the medical team during 
the 3-month follow-up. 
 
Moreover, the impact of patient follow-up on the evolution of parameters measured 
repeatedly during the study will be studied using mixed model repeated measures, in which 
the patient will represent a random effect and the follow-up group will represent a fixed 
effect. A Follow-up*Visit interaction will demonstrate the existence of a different evolution 
of the parameters according to the type of follow-up. This analysis will only be performed for 
the criteria measured several times during the follow-up. 
 
The identification of possible predictors of non-compliance will be conducted using a 
generalized mixed effect model (proc GLIMMIX in SAS) by including the patients and 
investigators characteristics and the group (with/without additional nurse-led follow-up) as 
explanatory variables (these characteristics will be detailed with more precision in the 
Statistical Analysis Plan [SAP]). A non-compliant patient will be defined as a patient with the 
ratio between the cumulated dose actually taken during the first 3 months of treatment and the 
cumulated dose taken during the first 3 months of treatment without interruption and dose 
reduction is strictly less than 80%. This modelling will be exploratory. 
7.3.4 
Safety analyses 
Safety analyses will be performed on all patients who received at least one dose of oral 
targeted therapy during the 3-month follow-up. Only events considered related to oral targeted 
therapy will be considered in the statistical analysis. 
 
For each study group, the number of patients with at least one of the following will be 
described: 
 One AE related to the oral targeted therapy.  

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 One AE related to the oral targeted therapy of grade ≥ 3. 
 One SAE related to the oral targeted therapy.  
 One AE related to the oral targeted therapy leading to a definitive discontinuation of 
the drug. 
 One AE related to the oral targeted therapy leading to a temporary discontinuation of 
the drug. 
 One AE related to the oral targeted therapy leading to a dose reduction. 
7.3.5 
Interim analyses 
No interim analysis is planned for this study. 
7.4 
HANDLING OF MISSING DATA 
In general, no specific method of handling missing data is foreseen for this study. The 
analyses will be performed on all available data.  
 
However, for the primary endpoint, a sensitivity analysis with missing data handling should 
be planned and detailed in the Statistical Analysis Plan (SAP) before database lock. 
 
7.5 
RANDOMISATION 
Patients will be randomised in one of the 2 study groups following a ratio of 3:1 (3 patients in 
the with ‘remote additional personalised nurse-led follow-up’ group for each one patient in 
the without ‘remote additional personalised nurse-led follow-up’), and according to a list of 
randomisation previously defined.  
 
This list will be generated before the start of the study according to all the following criteria: 
 Blocks of different size: 4 and 8. 
 Parallel groups. 
 Including 2 treatment groups. 
 Following a 3:1 ratio.  
 
It will be implemented using a validated computer tool which allows generating a sequence of 
pseudo-random numbers and selecting of a number called ‘seed randomisation’, not 
communicated to operational involved in the project, to ensure the non-reproducibility and 
non-predictability of the generation of randomisation list. 
 
The allocation of a patient to one study group or the other (‘with remote additional 
personalised nurse-led follow-up’ versus ‘without remote additional personalised nurse-led 
follow-up’ will be done sequentially within each centre using randomisation envelope. To 
limit selection bias in the absence of central randomisation, the blocks of randomisation will 
be of varying size (4 or 8). 
 

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7.6 
DETERMINATION OF SAMPLE SIZE 
In the absence of dose discontinuation or reduction, the cumulated dose of oral targeted 
therapy should be 3600 mg of afatinib, which corresponds to a daily dose of 40 mg for 
90 days. 
 
Clinical trials performed with afatinib before its marketing authorisation showed that over 
the first 3-month follow-up the mean dose of 3000 mg was taken (which corresponds to a 
dose intensity of 83%) (Boehringer Ingelheim First Interim Study Report 1200.32). 
 
It was estimated that the mean dose observed in the group ‘without remote additional 
personalised nurse-led follow-up’ will be similar to the mean dose observed in the afatinib 
clinical trials and that adding an additional nurse-led follow-up will increase the mean dose 
by 6% (3180 mg, dose intensity of 88%). 
 
As such, the number of patients to be included in the study has been calculated on the basis 
of a t-test for 2 unmatched samples with the following hypotheses: 
 Mean cumulated dose of oral targeted therapy taken during the 3-month follow-up in 
the group ‘without remote additional personalised nurse-led follow-up’: 3000 mg 
(dose intensity of 83%). 
 Mean cumulated dose of oral targeted therapy taken during the 3-month study in the 
group ‘with remote additional personalised nurse-led follow-up’: 3180 mg (dose 
intensity of 88%). 
 Standard deviation of the cumulated dose of oral targeted therapy taken during the 3-
month follow-up in both groups: 500. 
 Type I error: α = 0.05. 
 Type II error: β = 0.20 (power = 80%). 
 Ratio ‘with remote additional personalised nurse-led follow-up’ group/‘without 
remote additional personalised nurse-led follow-up’ group = 3. 
 
Using these hypotheses, in order to show an increase in the cumulated dose with the addition 
of 3-month nurse-led follow-up, it is necessary to have 82 patients in the group ‘without 
remote additional personalised nurse-led follow-up’ and 246 patients in the group ‘with 
remote additional personalised nurse-led follow-up ’. 
 
If it is considered that 20% of included patients will be non-evaluable for the primary 
criterion, it is necessary to include 99 patients in the group ‘without remote additional 
personalised nurse-led follow-up’ and 297 patients in the group ‘with remote additional 
personalised nurse-led follow-up’, i.e. 396 patients in total which can be rounded up to 400. 

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8. 
INFORMED CONSENT, DATA PROTECTION, STUDY 
RECORDS 
This study will be conducted according to the protocol, following the principles of Helsinki 
Declaration, GCPs requirements (transposition into French law of "ICH-GCP" [International 
Conference of Harmonization-Good Clinical Practice]) and the applicable legislation, and 
according to standard procedures of Boehringer Ingelheim. Routine medical care remains the 
responsibility of the general practitioner of the patient. 
 
The medical team must immediately inform the sponsor or his representative of any 
emergency measures taken to protect patients from immediate danger, in addition to any 
violation of the protocol and GCPs. 
 
Insurance:  
This study is a clinical routine practice study and, in accordance with the law, is covered by 
the liability insurance of the participants in the study centres. 
8.1 
STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT 
This study will be initiated once all documents are reviewed by ethics committee (Comité de 
Protection des Personnes [CPP] Ile de France II) and other relevant health institutions 
concerned with studies of routine practice in accordance with applicable French legislation 
(Comité Consultatif sur le Traitement de l’Information en matière de Recherche dans le 
domaine de la santé [CCTRIS] / Commission Nationale de l’Informatique et des Libertés 
[CNIL], Conseil National de l’Ordre National des Médecins [CNOM]). Any substantial 
change to the protocol will be implemented only after receiving the approval of the CPP. 
Non-substantial changes will be informed to the CPP. 
 
Patients participating in a routine practice study should be informed of the purpose of the 
study, duration, number of participants and their right to refuse participation in the study. 
Patients will be verbally informed by the medical team and will receive a copy of the patient 
information consent form (Appendix 10.1) which they must sign. This written consent must 
be obtained prior to initiation of any procedure related to the study. 
 
The data collected during this study will be processed by computer. Treatment may be carried 
out in France or abroad, and will be conducted in compliance with the French law n° 78-17 of 
6 January 1978 relating to computers, files and freedoms, as amended by Law 2004-801 of 
August 6, 2004. All necessary measures to ensure data confidentiality will be taken in 
accordance with the applicable legislation. Patients will not be identified by name or date of 
birth on the case report form or any other study document submitted to the sponsor or his 
representative. Patients will receive a unique identification number upon their consent to 
participate in the study. Patients should be informed that their medical records may be 
reviewed by staff appointed by the sponsor or his representative or by inspectors from the 
related authorities. 
 

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8.2 
QUALITY CONTROL 
Investigators have the responsibility to collect and report data in the CRF. It shall ensure that 
data are fully and accurately reported and are consistent with the source data. 
 
An audit or inspection of this study can be made by the sponsor or any of 
 representatives, 
or by relevant authorities to ensure that the study is being conducted according to GCP and 
applicable legislation. 
 
8.3 
RECORDS MANAGEMENT 
8.3.1 
Data management 
All information required by the protocol will be recorded on paper CRFs which will be 
completed by the medical teams as well as on the self-administered questionnaires completed 
by patients. 
 
The CRFs and questionnaires will be sent by the medical team to the CRO in charge of data 
monitoring by postal mail as soon as the patient has completed the study. The nurses in the 
call centre specialised in following-up patients will also send, weekly, a copy of the AEs page 
of to the CRO in charge of data monitoring. 
 
A study-specific database will be created, tested and validated prior to data entry. Data entry 
will be performed by the team responsible for managing the duplicate data entry. A plan for 
data validation will be developed and will describe, in details, the controls run for each 
variable as well as the list of corrections that are obvious and authorized. 
 
The integrity of the case report forms will be checked upon receipt and then will be used for 
data entry. The data will then be controlled by the team responsible for data management, by 
using the error messages from the validation programs. Obvious errors will be corrected. 
Other errors, omissions or inconsistencies, will be mentioned on query forms that will be sent 
to the investigator for correction (this measure concerns only the CRF of doctors and is not 
applicable to patient self-report questionnaires). After receiving the query forms completed by 
the investigator, corrections will be included in the database. 
 
The database will be locked after a final quality control and finalisation of the SAP. 
 
8.3.2 
Source documents 
CRF will be provided for each patient. Predefined questionnaires will be given to Patientys 
nurses to use for data collection during the telephone call. Patients should complete the self-
administered questionnaires as specified in the protocol. All these documents are considered 
the source documents of the study. 
 
Data on patient demographics and their medical history will be collected from the patient's 
medical record (See Section 6.2). 
 

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8.3.3 
Access to source documents 
The investigator or study centre will authorise audit visits and review of data by auditors or 
inspectors. CRFs and any other source documents, including study notes and copies of 
medical examination must be available upon request for review by the sponsor or auditors. 
8.3.4 
Storage of records 
Investigators 
Documents related to this study will be archived in accordance with GCP for a period of 15 
years after the end of the study. Medical teams and the sponsor should archive documents 
related to the study in accordance with the applicable regulations. 
 
Any change in the arrangements for archiving or any document destruction cannot be done 
without the consent of the sponsor. After the archival life, the sponsor will be consulted for 
the disposal terms and will have to agree in writing. 

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8.4 
NOTIFICATION OF ADVERSE EVENTS AND OTHERS 
PHARMACOVIGILANCE INFORMATIONS 
SAEs must be immediately reported to the CRO in charge of data monitoring (within 24h 
following the knowledge of the event) and forwarded by the CRO to the sponsor 
pharmacovigilance department on the same day. Non-serious AEs and any other PV 
information must be reported to the CRO in charge of the data monitoring within 7 days of 
knowledge and forwarded to the sponsor pharmacovigilance department within the next 7 
days (Figure 2). 
 
The Patientys call centre nurses will send information related to AE and other PV information 
to the investigator of the medical team via the telephone call report (
 is responsible to assess 
the intensity and the causal relationship) on the day of the phone call. 
 
 In case of SAE: the investigator must immediately send the completed SAE from to 
the CRO in charge of the data monitoring (within 24h of knowledge). The CRO must 
inform the sponsor’s PV department and forward the SAE form on same day. 
 In case of non-serious AE or of any other PV information: the investigator must 
complete and send the AEs page of the CRF to the CRO in charge of the data 
monitoring within 7 calendar days following the event. The CRO will establish a list 
of non-serious AEs related to the oral targeted therapy and will provide it to the 
sponsor weekly.  
 
Figure 2 
Procedure for reporting serious and non-serious adverse events 
 
 
 
The telephone call report contains the AE page(s) of the CRF and the SAE form(s) 
TCR = telephone call report, AE= adverse event, SAE = serious adverse event, CRF = case report form, CRO = contract 
research organization. 
Patient
Nurse
Investigator
CRO
Sponsor pharmacovigilance department
SAE form
(same day)
Listing of AEs related to oral targeted
therapy (listing sent once a week)
SAE form (same day)
AE page of the CRF 
(7 days)
TCR* (same day)
AE page of 
the CRF 
SAE form
(same day)

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8.5 
STATEMENT OF CONFIDENTIALITY 
Individual medical information of each patient obtained as a result of this study are 
considered confidential and cannot be disclosed to a third party under any circumstances, 
except for cases mentioned below. Confidentiality will be ensured by the use of identification 
code. 
 
Data generated as results of this study will be available upon request for review by 
investigators, representatives of the study sponsor, the scientific committee and the ethics 
committee (CPP). 
8.6 
COMPLETION OF STUDY 
The sponsor or 
 representative will notify the CPP, in writing, of the termination of the 
study. 
8.7 
SCIENTIFIC COMMITTEE 
No specific risks have been identified in the conduct of this routine clinical practice study 
where only the impact of additional nurse-led follow-up is evaluated. Thus, it can be 
considered that the risks to the patient participating in the study are negligible. Moreover, no 
treatment is administered blindly because treatments are administered as part of the routine 
practice of the medical team and no interim analysis will be performed. Therefore, it was 
decided not to establish an independent surveillance committee for this study. 
 
A scientific committee was established for this study in order to participate in discussions on 
the study design, feasibility, implementation, monitoring, and analysis and interpretation of 
results. 
 
Composition: 
 
Institut Bergonié, Bordeaux. 
 
Centre Hospitalier, Mulhouse. 

 Institut Gustave Roussy, Paris. 

; Centre René Gauducheau, Saint Herblain. 
 
CHU Rennes. 

Hôpital Européen Georges Pompidou, Paris. 
 
 Hôpitaux civils, Paris. 
 
Hôpital Tenon, Paris. 
 
8.8 
RESULTS PUBLISHING 
Any information obtained from this study will be treated as confidential until the analysis and 
final review by Boehringer Ingelheim and by members of the Scientific Committee are carried 
out. Any written or oral communication of the study results must receive the prior approval of 
Boehringer Ingelheim and the Scientific Committee. 

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9. 
RÉFÉRENCES  
APM International. Cancer: une prise en charge humanisée grâce au parcours patient 
personnalisé. Mars 2012. http://www.apmnews.com/print_story.php?numero=224678. 
Dernier accès le 30 Octobre 2013.  
 
Allard. Evaluation d’une intervention infirmière téléphonique sur la douleur, le 
fonctionnement et la détresse émotionnelle suite à une chirurgie d’un jour chez les femmes 
atteintes d’un cancer du sein. L’infirmière clinicienne. 2008;5(1):53-62. 
 
Barbu. Le suivi téléphonique. Bulletin infirmier du Cancer. 2009;9(4):128-9. 
 
Barlési et al. Biomarkers (BM) France: Results of routine EGFR, HER2, KRAS, BRAF, 
PI3KCA mutations detection and EML4-ALK gene fusion assessment on the first 10,000 non-
small cell lung cancer (NSCLC) patients (pts). J Clin Oncol 31, 2013 (suppl; abstr 8000). 
 
Beaver et al. Colorectal cancer follow-up: patient satisfaction and amenability to telephone 
after care. Eur J Oncol Nurs. 2011;15(1):23-30.  
 
Beaver et al. An exploratory randomized controlled trial comparing telephone and hospital 
follow-up after treatment for colorectal cancer. Colorectal Dis. 2012;14(10):1201-9. 
 
Berhoune. PROCHE: Un programme d’amélioration de la qualité de la prise en charge des 
patients en hôpital de jour d’oncologie médicale. 2010. Symposium HAS-BMJ. 
 
Boehringer Ingelheim First Interim Study Report 1200.32. LUX-Lung 3; A randomised,  
open-label, phase III study of BIBW 2992 versus chemotherapy as first-line treatment for 
patients with stage IIIB or IV adenocarcinoma of the lung harbouring an EGFR-activating 
mutation. Boehringer Ingelheim data on file. 
 
Cella et al. Reliability and validity of the Functional Assessment of Cancer Therapy -- Lung 
(FACT-L) quality of life instrument. Lung Cancer 1995; 12:199-220. 
 
Cox and Wilson. Follow-up for people with cancer: nurse-led services and telephone 
interventions. J Adv Nurs. 2003;43(1):51-61. 
 
Cusak and Taylor. A literature review of the potential of telephone follow-up in colorectal 
cancer. J Clin Nurs. 2010;19(17-18):2394-405. 
 
ESMO 2012 : Cancer du poumon non à petites cellules : un guide pour les patients –
 Basé sur les recommandations de l’ESMO v.2012.2. 
http://www.esmo.org/content/download/7250/143186/file/ESMO-RCT-Cancer-Poumon-non-
a-Petites-Cellules-Guide-pour-les-Patients.pdf. Dernier accès 20 Janvier 2014. 
 
Geynisman DM and Wickersham KE. Adherence to targeted oral anticancer medications. 
Discov Med. 2013 Apr;15(83):231-41. 
 

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Girerd et al. Evaluation de l'observance du traitement antihypertenseur par un questionnaire : 
mise au point et utilisation dans un service spécialisé. Presse Med 2001;30:1044-8. 
 
Harisson et al. Localized versus centralized nurse-delivered telephone services for people in 
follow up for cancer: Opinions of cancer clinicians. Asia Pac J Clin Oncol. 2013. doi: 
10.1111/ajco.12082. [Epub ahead of print] 
 
Kimman et al. Nurse-led telephone follow-up and an educational group programme after 
breast cancer treatment: results of a 2 × 2 randomised controlled trial. Eur J Cancer. 
2011;47(7):1027-36.  
 
Lewis et al. Nurse-led vs. conventional physician-led follow-up for patients with cancer: 
systematic review. J Adv Nurs. 2009;65(4):706-23.  
 
Liu et al. Patient preferences for oral versus intravenous palliative chemotherapy.J Clin 
Oncol. 1997 Jan;15(1):110-5. 
 
Moore et al. Nurse led follow up and conventional medical follow up in management of 
patients with lung cancer: randomised trial. BMJ. 2002; 325(7373):1145. 
 
Plan Cancer 2. 2009-2013. http://www.sante.gouv.fr/IMG/pdf/Plan_cancer_2009-2013.pdf. 
Dernier accès le 20 Janvier 2014 
 
Plan Cancer 2. Résultats des expérimentations du parcours personnalisé des patients pendant 
et après le cancer. Septembre 2012.  
 
Recommandations pour le plan cancer 3. 
http://www.sante.gouv.fr/IMG/pdf/Recommandations-pour-le-3e-plan-cancer.pdf. Dernier 
accès le 20 Janvier 2014. 
 
Ruddy et al. Patient adherence and persistence with oral anticancer treatment. CA Cancer J 
Clin. 2009;59(1):56-66. 
 
Scotté et al. A practical approach to improve safety and management in chemotherapy units 
based on the PROCHE - programme for optimisation of the chemotherapy network 
monitoring program. Eur J Cancer. 2013 Feb;49(3):541-4. 
 
 
 

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10. 
APPENDICES 
10.1 
INFORMED CONSENT FORM 
 
10.2 
GIRERD QUESTIONNAIRE 
 
10.3 
FACT-LUNG QUESTIONNAIRE 
 
 

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11. 
SUMMARY OF NON-INTERVENTIONAL STUDY 
PROTOCOL MODIFICATIONS 
Not applicable.