An Observational Study of GIOTRIF (Afatinib) for First Line Therapy in Patients With Advanced Non Small Cell Lung Cancer (NSCLC) Harboring Epidermal Growth Factor Receptor (EGFR)-Mutations.
Conditions: Carcinoma, Non-Small-Cell Lung
Sponsor: Boehringer Ingelheim

BOEHRINGER INGELHEIM Pharma GmbH & Co. KG 
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BI No.: 1200.205 
 
 
1200.205; Follow-up Plan Version  4_01072014 
   
Boehringer Ingelheim Pharma  
GmbH & Co. KG  
 
ABCD 
Follow-up Plan 
Non-interventional Study (NIS) 
Boehringer Ingelheim Pharma 
GmbH & Co. KG  
 
BI No.: 
1200.205 
Medicinal Product: 
GIOTRIF® (Afatinib) 
Title: 
GIDEON:                                                                              
GIOTRIF® as first-line treatment for advanced NSCLC 
with activating EGFR mutations (original: GIOTRIF® in 
der Erstlinientherapie des fortgeschrittenen NSCLC mit 
aktivierenden EGFR-Mutationen) 
 Clinical Monitor: 
                                                
                                                
                                               
                                               
Follow-up plan date: 
01 July 2014 
Planned duration of the 
NIS: 
FPI: April 2014 
LPO: October 2017 
 
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Confidential 
 Boehringer Ingelheim 
This follow-up plan belongs to Boehringer Ingelheim Pharma GmbH & Co. KG 
and must not be disclosed, reproduced, published or otherwise utilised entirely or 
in part without explicit consent. 
 
Table of Contents 
1. 
Introduction .................................................................................................... 5 

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1200.205; Follow-up Plan Version 4_01072014 
1.1  
Medical Background ...................................................................................... 5 
1.2  
Rationale ........................................................................................................ 7 
2. 
Study objective............................................................................................... 7 
2.1 
Type of Investigation ...................................................................................... 7 
2.2 
Objectives of the Investigation ....................................................................... 8 
3. 
Patient cohorts/patient descriptions ............................................................... 8 
3.1 
Patient population .......................................................................................... 8 
3.2 
Number of patients and number of participating doctors ................................ 9 
3.3 
Inclusion criteria ............................................................................................. 9 
3.4 
Exclusion criteria: ........................................................................................... 9 
3.5 
Representativity ............................................................................................. 9 
4. 
Treatment .................................................................................................... 10 
4.1 
Posology and method of administration ....................................................... 10 
4.2 
Dose adjustments in the event of adverse reactions .................................... 10 
4.3 
Special warnings and precautions for use ................................................... 11 
5. 
Description of follow-up and implementation ............................................... 11 
5.1 
Follow-up ..................................................................................................... 11 
5.2 
Documentation ............................................................................................. 12 
5.3 
Survey period and procedure ....................................................................... 13 
5.4 
Termination of the Study .............................................................................. 13 
5.5 
Adverse events (AEs) .................................................................................. 13 
5.6 
Serious adverse events (SAEs) ................................................................... 14 
5.7 
Adverse reactions unknown to date ............................................................. 15 
6. 
Statistical Analysis ....................................................................................... 16 
6.1 
Description of the encoding, the data capturing and inspection ................... 16 
6.2 
Description of the statistical analysis including objectives and planned 
analyses ....................................................................................................... 16 
7. 
Medical Evaluation and Report Creation ...................................................... 19 
7.1 
Regulations for report creation including biometric and medical evaluation . 19 
7.2 
Responsibility Regulations ........................................................................... 19 
8. 
Administrative Specifications ....................................................................... 19 
8.1 
Contract Administration ................................................................................ 19 
8.2 
Remuneration .............................................................................................. 19 
8.3 
Quality Assurance Measures ....................................................................... 19 
8.4 
Ethical and Legal Considerations and Requirements .................................. 20 
8.5 
Data protection............................................................................................. 20 
8.6 
Duty to inform............................................................................................... 20 
8.7 
Storage ........................................................................................................ 21 
8.8 
Publication ................................................................................................... 21 
8.9 
Responsibilities ............................................................................................ 21 

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9. 
Signature regulations ................................................................................... 21 
10. 
References .................................................................................................. 23 
 

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1200.205; Follow-up Plan Version  4_01072014 
 
List of abbreviations  
 
 
AMG 
German Medicinal Products Act (original: Arzneimittelgesetz der 
Bundesrepublik Deutschland) 
AE 
 
 
Adverse Event 
BfArM  
German Federal Institute for Drugs and Medical Devices (original: 
Bundesinstitut für Arzneimittel und Medizinprodukte) 
CR  
 
 
Complete Remission 
CRF 
 
 
Case Report Form 
DCR   
 
Disease Control Rate 
EGF   
 
Epidermal Growth Factor 
EGFR   
 
Epidermal Growth Factor Receptor 
EORTC  
 
European Organisation for Research and Treatment of Cancer 
GCP   
 
Good Clinical Practice 
ITT  
 
 
Intent to Treat 
NIS  
 
 
Non-Interventional Study 
NSCLC  
 
Non-Small Cell Lung Cancer 
ORR   
 
Overall response rate 
PFS   
 
Progression-Free Survival 
PR  
 
 
Partial Remission 
PRO  
 
Patient Reported Outcome 
QoL 
 
 
Quality of Life 
SD  
 
 
Stable Disease 
SAE   
 
Severe Adverse Event 
TKI 
 
 
Tyrosine Kinase Inhibitor 
TSAP   
 
Trial Statistical Analysis Plan 
 
 
 
 
 
 
 
 
 
 
 

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1. Introduction 
1.1 Medical Background 
Lung and bronchial carcinoma is one of the most common cancer disorders in Germany, as 
well as around the world. Bronchial carcinoma is ranked third among tumour disorders in 
Germany with over 49,000 newly diagnosed cases in 2008 (34,000 men, 15,500 women) (1). 
At 26%, it also by far the most frequent cancer-related cause of death in men (29,500) and at 
13% the third most frequent cancer-related cause of death in women (13,000) in 2008. 
In contrast to other tumour disorders, due to the clinical course of the disease, which is 
initially asymptomatic for a long-period of time and usually associated with a non-specific 
constellation of symptoms, lung cancer is first diagnosed at an advanced stage in the 
majority of patients (2). Symptoms include coughing (with or without haemoptysis), 
respiratory distress, chronic lung inflammation, pain in the breast and shoulders, constant 
tiredness and exhaustion (fatigue) or anorexia (3). The relative 5-year survival rate for lung 
cancer in Germany is stated as approximately 15% in men and 18% for women and varies 
depending on the staging of the tumour disorder when the diagnosis is made (3). The 
median survival time for patients treated with chemotherapy alone in advanced stage IV 
(Union for International. Cancer Control UICC, 7th Edition) is limited and amounts to a 
median period of 8 - 12 months. The objectives of treatment are reduction of tumour-related 
symptoms and prolonged survival time.  
 
Non-small cell small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) can be 
differentiated histologically, based on differences in biological behaviour, prognosis and 
therapeutic options. Approximately 80 - 85% of lung cancers are NSCLC, which are 
differentiated into three main histological subgroups: Adenocarcinoma, squamous cell 
carcinoma and large cell carcinoma (4). The fact that lung cancers also can be differentiated 
genetically has also emerged during the last few years. Accordingly, approximately half of 
adenocarcinomas exhibit so-called driver mutations that are important for malignant 
transformation. A study of 516 patients with an adenocarcinoma of the lung showed that one 
form of these driver mutations could be proven in 280 (54%) of the patients and 17% 
occurred in the epidermal growth factor receptor (EGFR) (5). These activating EGFR 
mutations are present in approximately 10% of all NSCLC in Western patient cohorts and 
approximately 40% of all Asian NSCLC patients (6). These mutations occur frequently in 
female patients, non-smokers and adenocarcinoma of the lungs (7). EGFR mutations lead to 
a constitutive activation of intracellular tyrosine kinase, thereby leading to overactivation – 
irrespective of the presence of EGFR ligands - of the downstream signal cascades (8). Most 
mutations occur in the EGFR tyrosine kinase region (exon 18 - 21). Deletions in exon 19 and 
the point mutation L858R in exon 21 should be mentioned here, since they represent the 
most common activating mutations at approximately 85-90%. Mutations appear more rarely 
in exons 18 and 20 (9). EGFR-mutated lung cancer was first described in 2004 and is 
currently the most studied NSCLC subtype (10). These tumours exhibit a better prognosis 
than those with non-mutated, so-called wild type EGFR (11). The mean survival time of 
patients with advanced EGFR-mutated NSCLC is more than two years if they are treated 
with a tyrosine kinase inhibitor (TKI) targeting the EGFR (12). These TKIs bind with a high 
affinity to the mutated EGFR and as a result, these types of genetic changes are considered 
to be a positive predictive factor for the efficacy of this substances (10). Accordingly, TKIs 
are much more effective than platinum-based combination chemotherapy as first-line 
treatment for advanced or metastatic NSCLC in patients testing positive for EGFR mutations 
in terms of the response rate and progression-free survival (PFS) (13-20). A prerequisite for 
this treatment is molecular pathology evidence of activating EGFR mutations in the tumour 
tissues. Patients with one of these mutations could benefit from targeted treatment with an 
EGFR-TKI, such as gefitinib, erlotinib or afatinib, due to improved efficacy and tolerability in 
comparison to chemotherapy. 

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These substances block the receptor EGFR tyrosine kinase. This receptor belongs to the 
ErbB family of receptors. The ErbB family is considered to be one of the most commonly 
dysregulated systems in the signal transduction of malignant tumours (8). The discovery of 
other receptor tyrosine kinases in this family as potential target molecules, such as the 
receptors HER2 (ErbB2), ErbB3 and ErbB4, enable an extended therapeutic approach. After 
ligand binding, the ErbB family receptors are dimerised into homo- or heterodimers and this 
process is paralleled by activation of signal transduction (8). Since the signal transduction for 
the receptors occurs by means of various compound homo- and heterodimers, the blockade 
of a single ErbB family receptor may not be sufficient to effectively and continuously inhibit 
tumour growth and infiltration (21-23). Afatinib (GIOTRIF®) is a TKI that binds covalently and 
therefore irreversibly to the intracellular tyrosine kinase domains in EGFR, ErbB2 and ErbB4, 
which prevents them from being phosphorylated and prevents the transphosphorylation of 
ErbB3. These three ErbB family members are therefore inhibited directly, while ErbB3 is also 
inhibited indirectly (19, 20). This new mechanism of action therefore clearly differentiates 
these products from reversible TKIs, such as erlotinib and gefitinib, which only target EGFR 
and only permit reversible receptor binding. During NSCLC oncogenesis, however, multiple 
members of the ErbB family could play an important role due to their mutation (8). 
 
Patients with advanced NSCLC and activating EGFR mutations could benefit from first-line 
treatment with afatinib in several respects (20). During the marketing authorisation study 
LUX-Lung 3, the patients exhibited, in addition to significant prolongation of PFS during 
treatment with afatinib, also a significantly improved quality of life (QoL) and significant 
extended period of symptomatic control in comparison to chemotherapy (21).** re-read 
sentence, check words During this international, multicentre study, 230 patients with 
advanced adenocarcinoma of the lung and activating EGFR mutations received afatinib, 
while 115 received cisplatin/pemetrexed. During the course of a central and independent 
evaluation, treatment with afatinib resulted in a significant prolongation of the median PFS 
from 11.1 months vs. 6.9 months for chemotherapy (HR = 0.58; p = 0.001) for the total study 
population. The percentage of patients who survived after 12 months and had experienced 
no disease progression was more than doubled by afatinib and amounted to 47% vs. 22% for 
chemotherapy. In the predefined subgroup analysis of the patients with the frequent EGFR 
mutations Del19 and L858R (89% of the total population), the increase in PFS for afatinib 
even more pronounced at a median of 13.6 vs. 6.9 months (HR 0.47; p = 0.001). This 
increase in PFS was seen in virtually all subgroups investigated, irrespective of sex, age, 
ethnicity, performance status or smoking history. There were also significantly higher 
objective response rates in those treated with afatinib, compared to those treated with 
chemotherapy (56% vs. 23%, p = 0.001). During the LUX-Lung 3 study, QoL and tumour-
related symptoms as patient-reported outcomes (PRO) were evaluated using two-part 
standardised questionnaires (EORTC QLQ-C30 and QLQ-LC13). During the evaluation, 
afatinib fared significantly better than cisplatin/pemetrexed with regard to the general QoL (p 
= 0.015) as well as the physical (p<0.001), cognitive functions (p = 0.007) and the role 
function (p = 0.004). Patients reported clinically relevant improvement in disease-specific 
symptoms in comparison to chemotherapy when using afatinib: Coughing (p = 0.244), 
dyspnoea (p = 0.010) and pain (p = 0.051). The time until deterioration of coughing (p = 
0.007) and dyspnoea (p = 0.015) was significantly longer in the patients treated with afatinib 
than those treated with chemotherapy treatment. Time until deterioration of pain tended to be 
longer (p = 0.190). Adverse events (AE) with a therapy-related toxicity grade ≥3 occurred in 
49% of those treated with afatinib in comparison to 48% of those treated with 
cisplatin/pemetrexed. A total of 8% of those treated with afatinib and 12% of those treated 
with chemotherapy discontinued treatment due to treatment-related AEs. The grade ≥3 AEs 
that occurred frequently during treatment with afatinib were diarrhoea (14.4%), skin 
rash/acne (16.2%), stomatitis/mucositis (8.7%) and paronychia (11.4%). 

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Current data for the LUX-Lung 6 study confirms the results of the LUX-Lung 3 study (22). 
This phase III study performs a comparative investigation of the platinum duo 
cisplatin/gemcitabine and afatinib monotherapy in exclusively Asian patients (n = 364) with 
advanced adenocarcinoma of the lungs and activating EGFR mutations. Independent 
analysis of the primary endpoint revealed a median PFS of 11.0 months for afatinib and 5.6 
months for chemotherapy (HR 0.28; p<0.0001). The independent analysis also showed a 
significantly higher response to afatinib when compared to chemotherapy (67% vs. 23%; 
p<0.0001). The tumour response to afatinib treatment correlated to a significantly prolonged 
time until deterioration of the disease-associated symptoms of dyspnoea, coughing and pain. 
Furthermore, the patients treated with afatinib had a significantly better QoL than the patients 
treated with chemotherapy. The most common treatment-related AEs (grade ≥3) during the 
LUX-Lung 6 study during afatinib treatment were skin reactions (14.2%), diarrhoea (5.4%) 
and stomatitis/mucositis (5.4%). There are consistent results in this regard from two large, 
prospective phase III studies, which prove the efficacy of afatinib as first-line treatment in this 
patient population.  
 
1.2 Rationale 
Marketing authorisation in Europe was granted to afatinib in September 2013 as 
monotherapy for EGFR-TKI-naive, adult patients with locally advanced and/or metastasised 
non-small cell small cell lung cancer (NSCLC) with activating EGFR mutations.  
A non-interventional study (NIS) is particularly suitable for capturing additional data about 
efficacy, tolerability, safety, QoL and symptom control under everyday treatment conditions in 
the general patient population and to extend the level of knowledge of treatment with afatinib 
in routine practice using documentation. There is still no existing data from medical practice 
in this regard for afatinib in advanced NSCLC. The NIS instrument appears to be most 
suitable for prospectively investigating the open questions from routine treatment without 
influencing them. Elderly patients (> 65 years) and patients with an ECOG performance 
score of 2 in particular, who comprise the majority of the patients in clinical practice, are 
frequently not included or are under-represented in clinical trials.  
Patients at locally, widely-advanced or metastatic stages who no longer have any treatment 
options are treated with palliative intent. Treatment is symptom-orientated, i.e. in addition to 
the prolongation of survival time, achieving QoL and symptom control are at the foreground 
of treatment. Of particular interest in this NIS, therefore, is whether the data with regard to 
effectiveness, tolerability, safety, symptom control and QoL from the LUX-Lung 3 marketing 
authorisation study can be transferred to everyday clinical practice in Germany.  
 
 
2. Study objective 
2.1 Type of Investigation 
This investigation is a prospective, non-interventional study of afatinib as first-line treatment 
for patients with locally advanced or metastatic NSCLC and activating EGFR mutations. The 
treatment is given as part of the marketing authorisation of afatinib as first-line treatment of 
EGFR TKI-naive patients. The usual treatment regimen remains unchanged by participation 
in this NIS. No diagnostic or therapeutic measures are required that exceed the otherwise 
required scope. The decision of those administering treatment with regard to diagnosis and 
treatment before, during or at the end treatment are not affected by this NIS. 
 

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2.2 Objectives of the Investigation 
The objective is to capture and document data to extend the knowledge about the efficacy 
and tolerability, QoL and symptom control reported by the patient when using afatinib as first-
line treatment for locally advanced or metastatic NSCLC with activating EGFR mutations 
under routine conditions in everyday clinical practice. In addition to the primary inquiry, 
additional information should be captured regarding the course of treatment and 
management of treatment-related adverse reactions in everyday clinical practice: 
 
Primary endpoint: 
• The percentage of patients without tumour progression after 12 months (progression-
free survival rate after one year, %). 
 
Secondary endpoints: 
• Determination of the objective remission rate (CR + PR, %) 
• The percentage of patients with tumour control (CR + PR + SD, %) 
• Progression-free survival (PFS, months)  
• Safety data (incidence of SAEs and AEs) 
• Toxicity/side effect profile (frequency and severity of diarrhoea, skin reactions, 
stomatitis and paronychia)  
• Duration of treatment and modifications (dose adjustments, treatment withdrawals and 
interruptions) 
• Symptom control (coughing, dyspnoea and pain) using EORTC questionnaires QLQ-
C30/LC13 
3. Patient cohorts/patient descriptions 
3.1 Patient population 
EGFR-TKI-naive adult patients with locally advanced and/or metastasised non-small cell 
small cell lung cancer (NSCLC) with activating EGFR mutations could be included during the 
course of marketing authorisation of afatinib as first-line treatment. Patient EGFR mutation 
status must be determined using a validated and robust procedure in order to avoid false-
negative or false-positive results. The patient population consists of adult participants of both 
sexes. 
There is insufficient data for afatinib in pregnant and breastfeeding women. For this reason, it 
is urgently recommended that pregnant women and all women and men who are not using a 
reliable method of contraception do not use afatinib. 
The decision to treat occurs irrespective of participation in this NIS and is made by the 
attending doctor before considering participation. 

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3.2 Number of patients and number of participating doctors 
A total of n = 150 patients in 50 oncology centres within Germany were included. The 
number of patients is based on the assumptionα= 0.05 (two-sided) and an expected PFS 
rate over 12 months of 47% (see chapter 6).  
 
3.3 Inclusion criteria 
Patients who meet all of the following criteria can be included: 
• 
EGFR-TKI-naive men and women with pathologically confirmed NSCLC, Stage IV 
(UICC, 7th edition) with activating EGFR mutations (exons 18 - 21) 
• 
Age ≥ 18 years 
• 
No diagnostic or therapeutic measures are required that go beyond the scope of 
clinical routine practice.  
• 
The usual treatment regimen remains unchanged.  
• 
A signed declaration of informed consent must be present before inclusion in the NIS. 
 
3.4 Exclusion criteria:  
• 
Known hypersensitivity reaction to afatinib and its excipients 
• 
Concurrent participation in another NIS or interventional clinical study during the 
treatment phase or within the last 30 days 
• 
Previous treatment with systemic chemotherapy, except during the course of 
(neo)adjuvant therapy (within 12 months after treatment completion). 
• 
Previous treatment with therapy targeted towards EGFR 
• 
Patients unwilling or unable to complete questionnaires about their QoL 
• 
Patients with absent or diminished capacity 
• 
Pregnancy 
 
The decision to treat occurs irrespective of participation in this NIS and is made by the 
attending doctor before considering participation. 
The contraindications are to be observed prior to starting afatinib treatment. Also see the 
current scientific information for afatinib.  
 
3.5 Representativity 
The distribution of participating centres throughout the country and the number of patients 
guarantees that the data obtained will be representative. University medical centres, 
hospitals and registered doctors active in the field of oncology can participate in the NIS. The 
study will also strive for recruitment that is as equivalent as possible at the centres through 
contractual definition of a maximum number of three (3) patients. The number can be 
increased if necessary during the course of the study. The only centres considered during 
selection were those that were expected to enrol 3 patients based on the patient 
characteristics specified in this NIS.  
 

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4. Treatment 
4.1 Posology and method of administration  
Afatinib film-coated tablets each contain 50, 40, 30 or 20 mg of active substance (as afatinib 
dimaleate) and lactose (as monohydrate) as an excipient with known effects. Please consult 
the scientific information for the full list of excipients. 
 
Patient EGFR mutation status must be determined using a validated and robust procedure in 
order to avoid false-negative or false-positive results. 
 
In accordance with the scientific information, the recommended dose of afatinib during the 
course of first-line treatment is 40 mg once daily. Afatinib should not be taken together with 
food. Afatinib should be taken at least 1 hour before or 3 hours after a meal. Afatinib is taken 
orally and the tablets are to be taken whole with water. In patients who cannot swallow 
afatinib tablets whole, they should be dissolved in approximately 100 ml of uncarbonated 
drinking water. Do not use any other fluids for this purpose. These tablets are added to the 
water whole without crushing. Occasionally stir for up to 15 minutes thereafter, until the tablet 
has completely dissolved into small particles. Drink the suspension immediately, rinse the 
glass with approximately 100 ml of water and drink this water as well. This suspension can 
be administered through a gastric tube. A forgotten afatinib dose should still be taken on the 
same day, as soon as the patient remembers. If the period until the next planned dose is less 
than 8 hours, however, the forgotten dose must not be taken. 
Treatment with afatinib should be continued until there is progression of the disease or the 
patient no longer tolerates the medication. A dose increase up to a maximum of 50 mg/day 
can be considered in patients who tolerate the dose of 40 mg/day well (i.e. no onset of 
diarrhoea, skin rash, stomatitis or other medication-related events of CTCAE grade >1). No 
dose increase should occur after a dose reduction. The maximum daily dose is 50 mg. 
4.2 Dose adjustments in the event of adverse reactions 
Symptomatic side effects (e.g. severe/persistent diarrhoea or skin side effects) can be 
treated successfully by withdrawing the treatment, dose reduction or drug holidays from 
afatinib: 
 
Side effects according to the 
CTC1 
Recommended afatinib dose 
Grade 1 or grade 2 
No 
interruption2 
No dose adjustment 
Grade 2 (longer term3 or 
intolerable) or 
Grade >3 
Interruption up 
to grade 0/12 
 
Restarting 
treatment with dose 
reduction in 10 mg 
steps4 
 
1. NCI Common Terminology Criteria for Adverse Events  
2. If diarrhoea occurs, anti-diarrhoeals (e.g. loperamide) should be taken immediately, and in the 
event of persistent diarrhoea, their intake should be continued until the soft stools stop. 
3. Diarrhoea >48 hours and/or skin rash >7 days 
4. If the patient does not tolerate 20 mg/day, permanent discontinuation of treatment with afatinib 
should be considered. 
 

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4.3 Special warnings and precautions for use 
Diarrhoea has been reported in patients treated with afatinib, including severe cases. 
Diarrhoea can lead to dehydration (with or without impairment of kidney function), which may 
lead to death in rare cases. Diarrhoea occurred as a rule in the first two weeks of treatment 
and grade 3 diarrhoea usually occurred in the first 6 weeks of treatment. Therefore, you must 
proactively treat patients with sufficient hydration and anti-diarrhoeals from the appearance 
of the first signs, particularly in the first 6 weeks of treatment. In addition, the dose of the anti-
diarrhoeals (e.g. loperamide) used should be increased to the highest recommended 
authorised dose if required. Anti-diarrhoeals must be quickly accessible to the patients, so 
that they can start and continue treatment from the first signs of diarrhoea independently, 
until they have had no further soft stools for a minimum of 12 hours. If severe diarrhoea 
occurs, an interruption of treatment with afatinib, a dose reduction or completely withdrawal 
of treatment may be required. Dehydrated patients require intravenous electrolyte and fluid 
replacement where necessary. These patients are therefore advised to start anti-diarrhoeal 
treatment independently if diarrhoea occurs and to inform the attending doctor of this 
immediately.  
 
Skin rash/acne have been reported in patients treated with afatinib. The skin rash in question 
is usually a mild to moderate, erythematous, acneiform rash that may appear in areas of skin 
exposed to light or be more prominent there. Early treatment of dermatological reaction (e.g. 
with skin care agents, antibiotics) increases the probability that treatment can be continued. If 
severe skin reactions occur, temporary interruption of treatment, dose reductions other 
therapeutic interventions or transfer to a specialist with experience treating these types of 
dermatological reactions is required.  
 
If acute or deteriorating respiratory symptoms occur, interstitial lung disease should be 
considered and the treatment with afatinib is to be withdrawn until detailed investigation 
takes place. If a diagnosis of interstitial lung disease is confirmed, treatment with afatinib 
must be discontinued and suitable treatment should be started.  
 
Afatinib is not recommended for patients with severely impaired kidney function (< 30 ml/min) 
with liver function (Child-Pugh class C).  
An increased afatinib plasma level has been observed in women, patients with low body 
weight and patients with impaired kidney function. This increases the risk of side effects such 
as diarrhoea, skin rash/acne and stomatitis. Strict monitoring of patients with these risk 
factors is recommended. The respective prescribing information is to be observed in this 
regard, particularly the sections “Contraindications”, “Special warnings and precautions for 
use”, “Interactions with other medicinal products” and “Fertility, Pregnancy and Lactation”.  
 
Additional information about afatinib can be obtained from the enclosed scientific information. 
 
5. Description of follow-up and implementation 
5.1 Follow-up 
No appointments for special doctor’s visits are required for the NIS. After the decision to 
introduce first-line treatment with afatinib for the treatment of adult patients with locally 
advanced or metastatic NSCLC with activating EGFR mutations and before prescribing the 
substance, the doctor considers whether the patient is suitable for participating in the NIS, 
taking the scientific information provided into consideration. The doctor explains the nature of 
the study and includes the written declaration of informed consent for processing the patient 
information for the purpose of this study and source data verification. It is important that this 

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step occur before the patient is enrolled in the NIS and the observations are entered into the 
eCRF. The fact that informed consent was obtained from the patient before the start of 
follow-up is to be documented in the eCRF.  
 
5.2 Documentation  
The following parameters are captured using an internet-based data capturing system 
(eCRF):  
 
Basic Documentation 
• 
general anonymised patient information (year of birth, sex, height, weight), vital 
parameters, laboratory parameters, blood profile, diagnosis date, location of the 
primary tumour, location of the metastases, risk factors, medical history, associated 
disorders, associated medication, ECOG performance score, histology, TNM status 
and EGFR mutation analysis (investigation methodology and biomarker analysis)  
• 
Determination of co-morbidity using the Charlson score 
• 
Operation: Date, nature of the procedure and outcome  
 
• 
Previous treatment during the course of neo- or adjuvant therapy: Time, duration, 
chemotherapeutic agents used or radiotherapy 
• 
QoL and symptom control (coughing, dyspnoea and pain) using EORTC QLQ-C30 
and LC13 questionnaires 
 
Documentation of the clinical course 
• 
Use of afatinib (dose, time, duration, dose adjustments) are captured during each visit 
(1x month) 
• 
ECOG performance status  
• 
Vital parameters, laboratory parameters and blood profile  
• 
Adverse events and severe adverse events (nature of the event, clinical course and 
measures taken)  
• 
Therapeutic management of skin reactions and diarrhoea (prophylactic or reactive 
measures, treatment plan, duration of treatment and clinical course)  
• 
QoL and symptom control using the EORTC questionnaires QLQ-C30 and LC13 
every 8 weeks (= 2 months of treatment) or at the end of treatment 
• 
Response (imaging procedures according to what is normally done at the centre)  
• 
Patient status at the end of treatment with afatinib (date treatment ended, reason for 
ending treatment, date disease progressed, location of the progression or the 
recurrence, new secondary disorders and/or comorbidities, cause and date of death) 
 
Follow-up Documentation 
The following parameters are captured 12 and 24 months after first-line treatment with 
afatinib has ended: 
• 
Patient status (patient living/deceased, ECOG performance score, date disease 
progressed, location of new metastases, date of death) 
• 
Ongoing treatment (number, nature, response, duration of treatment) 
 
 

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If intolerable side effects occur during treatment with afatinib that require treatment to be 
withdrawn, treatment is to be discontinued.  
 
The patient QoL and tumour symptoms are determined using the EORTC QLQ-C30 and 
LC13 questionnaires, which the patient should complete before the start of treatment and 
every 8 weeks during the course of treatment (= 2 months of treatment), irrespective of 
staging and treatment. The two standardised EORTC questionnaires contain a total of 43 
questions. 
 
The attending doctor hands each patient one copy of to EORTC QLQ-C30 and LC13 at 
enrolment (baseline) and then every 8 weeks (= 2 months of treatment). Before or during the 
appointment, Each patient is requested to answer questions 1 to 28 and 31 to 43 by making 
a tick mark on a scale from 1 to 4 (“not at all applicable” to “very applicable”) independently 
and to estimate their current general condition of health/QoL (questions 29 and 30) by 
making a cross on a scale from 1 (“very bad”) to 7 (“excellent”). 
5.3 Survey period and procedure  
 
First patient enrolment:  
April 2014 
Last patient enrolment: 
December 2015 
Duration of treatment:  
until progression of the disease or  
until the occurrence of intolerable, severe toxicities or  
 
until revocation of informed consent 
Follow-up period:  
24 Months 
Database closure/lock:  
December 2017 
Final report:  
December 2018 
 
 
The survey period of this NIS should amount to a total of 4 years. The follow-up period per 
patient is a maximum of 3 years from the time that they are enrolled in the NIS. An extension 
of the follow-up deadline for individuals or all patients is possible through consultation. 
 
5.4 Termination of the Study 
The individual patient has the right to revoke their consent to participate in the NIS. 
Termination of the NIS has no influence on the routine treatment of the patients. 
 
After one or all of the following events occur, the study can be terminated at the discretion of 
the sponsor: 
• The presence of medical or ethical reasons that may influence the continuation of the 
study in the interest of the patient  
• Problems with recruitment 
 
It is assumed that recruitment of less than 1/4 of the planned patients 1 year after the start of 
recruitment is insufficient for achieving the study objectives. Should, as a consequence, less 
than 40 patients be enrolled in the study one year after recruitment, a decision will be taken 
about a premature termination of the study.  
 
5.5 Adverse events (AEs) 
All adverse events that occur during the course of this NIS are captured in eCRF. Adverse 
events are all harmful, pathological or inadvertent changes to anatomical, physiological or 

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metabolic functions, recognisable by physical signs, symptoms and/or changes in laboratory 
values that occur during the course of the NIS, irrespective of whether there is an association 
to the medicinal product. This also includes the deterioration of existing disorders or events 
that appear in the interim or interactions between medicinal products. Expected daily 
fluctuations during the clinical course of a disease or a progression of the disorder under 
investigation must not be considered to be an adverse event.  
 
The documentation of all adverse events in the eCRF must take place during treatment with 
afatinib and in the 30 days soon after the last intake of afatinib.  
The capturing of changes in the laboratory values is done using the documentation for the 
laboratory values; these must not be separately documented as adverse events. 
 
Exceptions to this are changes in the laboratory values that represent a severe 
adverse event (SAE) 
 
5.6 Serious adverse events (SAEs) 
A severe adverse event is any adverse event that 
• 
results in death, 
• 
is life-threatening, 
• 
requires hospitalisation or prolongation of existing hospitalisation (excluding for the 
purpose of chemotherapy or tumour staging, or before the start of an elective hospital 
stay) 
• 
results in persistent or significant disability or incapacity,  
• 
malignant disorder or a birth defect (in the descendants) 
• 
is medically significant 
 
Abuse and overdose of medicinal products is to be considered severe, even if it does not 
fulfil the above-mentioned criteria. 
 
Events that are associated with “progression of the underlying disease” must not be reported 
as SAEs, even if the criteria for severity (e.g. hospitalisation) are fulfilled. Tumour 
progression, however, is documented in eCRF as a primary endpoint.  
 
SAEs must be reported to the pharmacovigilance department at Boehringer Ingelheim within 
24 hours. AEs must be documented in the eCRF within 14 days. All adverse events (SAE 
and AE) are automatically reported to the pharmacovigilance department at Boehringer 
Ingelheim according to the documentation in the eCRF within 24 hours in the form of a PDF 
file. The Boehringer Ingelheim SAE/AE form is generated from the eCRF.  
 
If there is no Internet access on the reporting date, a fax must be sent to the following 
address as an alternative: 
 
Boehringer Ingelheim Pharma GmbH & Co. KG 
Pharmacovigilance Germany (PV Germany) 
Binger Straße 173 
55216 Ingelheim 
Fax: +49 (6132) 72 - 141522 
PV_local_Germany@boehringer-ingelheim.com 
 

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The causal relationship of the event to afatinib should be evaluated by the attending doctor.  
 
5.7 Adverse reactions unknown to date 
The significant adverse reactions of afatinib are diarrhoea (in over 95% of patients, all 
grades), skin reactions (89%), stomatitis (70%) and paronychia (58%). 
 
The frequency of adverse reactions is defined using the following convention: 
very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1,000, <1/100), rare 
(≥1/10,000, <1/1,000) and very rare (<1/10,000) 
 
Infections and infestations 
Very common: Paronychia 
Common: Cystitis 
Metabolism and nutrition disorders 
Very common: Decreased appetite 
Common: Dehydration, hypokalaemia  
Nervous system disorders 
Common: Dysgeusia 
Eye disorders 
Common: Conjunctivitis, dry eye 
Uncommon: Keratitis. 
Respiratory, thoracic and mediastinal disorders 
Very common: Epistaxis 
Common: Rhinorrhoea 
Uncommon: Interstitial lung disease. 
Gastrointestinal disorders 
Very common: Diarrhoea, stomatitis 
Common: Dyspepsia, cheilitis 
Hepatobiliary disorders 
Common: Increased alanine aminotransferase (ALT) values 
Increased aspartate aminotransferase (AST) values 
Skin and subcutaneous tissue disorders 
Very common: Rash, acneiform dermatitis, pruritus, dry skin 
Common: Palmar plantar erythrodysesthesia 
Musculoskeletal and connective tissue disorders 
Common: Muscle spasms 
Renal and urinary disorders 
Common: Impaired renal function, renal failure 
General disorders and administration site conditions 
Common: Fever  
Investigations 
Common: Weight loss 
 
Additional information can be obtained from the enclosed scientific information. 
 
 
 
 

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6. Statistical Analysis 
6.1 Description of the encoding, the data capturing and inspection 
 
Coding 
Adverse events are coded using the current version of MedDRA. Medications are coded in 
accordance with the WHO-DD. 
 
Data capturing 
The data is captured using an electronic documentation (eCRF). 
Data validation 
Data checks are performed automatically in eCRF directly during electronic entry. Source 
data verification is planned. 
 
6.2 Description of the statistical analysis including objectives and planned analyses 
 
Sample size 
A PFS rate of 47% was determined after 12 months in the afatinib arm in the marketing 
authorisation study. A sample size of 150 patients is required to confirm this rate with a 
precision of ± 8% (two-sided 95% confidence interval based on normal approximation of the 
sampling distribution). This calculation justifies the assumption ofα= 0.05 (two-sided) and an 
expected PFS rate of 47% over 12 months. 
 
Handling of missing value 
Based on the non-interventional nature of the study, only data that are routinely used by the 
doctor should be made available. The data completeness in the documentation questionnaire 
will therefore vary from doctor to doctor. All available information is used. There is no 
planned imputation of missing values during the course of the statistical analysis. 
 
Evaluation of the Study Data 
The evaluation is based on all the patients enrolled in the study (i.e. all patients who signed 
the declaration of informed consent and have entered data for the doctor). The following 
statistical parameters are reported for constant variables in descriptive tables: 
N/Mean/Standard 
Deviation/Minimum/Q1 
(25% 
quantile)/Median/Q3 
(75% 
quantile)/Maximum. Frequency tables for categorical variables will represent all possible 
categories and will report the number of observations and the percentage per manifestation. 
Percentages are rounded to two decimal places. The number of patients with missing values, 
as well as the percentage they make up of the total sample size, is also shown (if required). 
A 95% confidence interval is also determined. All analyses are represented in the total 
population. These analyses are additionally performed according to the subgroups sex, 
smoking status and EGFR mutation status, or in the case of special interests, also according 
to other subgroups. The details of the statistical analyses are described in the trial statistical 
analysis plan (TSAP), which is prepared in complete form before the database lock. 
 
 

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Primary Analyses 
The primary endpoint of this NIS is the progression-free survival (PFS) rate after one year. 
This is defined as relative frequency of the patients, who have no tumour progression and 
survive after 12 months of treatment. The Kaplan-Meier survival rate with two-sided 95% 
confidence interval after 12 months is shown. The Greenwood estimator of variance was 
used to calculate the confidence interval.  
Secondary Analyses 
Each patient is allocated into one of the following categories based on their response to 
treatment: 
1 = CR (complete response) 
2 = PR (partial response) 
3 = SD (stable disease) 
4 = PD (progressive disease) 
9 = unknown (cannot be evaluated, insufficient data available). 
 
Objective remission rate 
Patients in the categories 1 and 2 (CR and PR) have objective remission. The objective 
remission rate is the relative frequency of patients with objective remission and is calculated 
together with the exact 95% confidence interval. 
Tumour control rate 
Patients in the categories 1 - 3 (CR, PR, SD) have tumour control. The tumour control rate is 
the percentage of patients from the total population with tumour control. They are calculated 
together with the exact 95% confidence interval.  
Progression-free survival (PFS) 
Progression-free survival is the time from the start of treatment until progression occurs or 
until death. The date of progression is the earliest date from: 
(1) Date of the investigation that showed progression or 
(2) Date given by the doctor for progression  
 
If the date of progression is known, the PFS is calculated using the following formula:  
PFS [days] = date of progression (or death, if not progression occurred) – date of the start of 
treatment + 1. 
The censored PFS was calculated for patients without progression: 
PFS (censored) [days] = date of the last investigation – date of the start of treatment +1. 
Kaplan-Meier estimators and 95% confidence intervals are shown. 
 
 

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Duration of treatment and modifications 
Treatment schedules, duration of treatment and treatment interruptions are shown. The 
number of patients with no/one/two or more dose modifications are shown. 
Symptom control 
The duration until deterioration of the following clinically-relevant symptoms is calculated: 
- 
Coughing (question 1 in the QLQ-C30 questionnaire) 
- 
Dyspnoea (total of the questions 3 - 5 in the QLQ-LC13 questionnaire) 
- 
Pain (total of the questions 9 and 19 in the QLQ-C30 questionnaire) 
 
Deterioration occurs when the score increases by 10 points in comparison to baseline during 
a transformation according to EORTC with possible value of 0 to 100. Details are described 
in the TSAP.  
 
Safety Analyses 
All patients who have received at least one dose of afatinib are included in the safety 
analyses. All analyses were conducted descriptively. Adverse events are classified according 
to the CTCAE (version 4.3).  
The safety analyses include: 
- 
Frequency, severity and causal relationship of adverse events 
- 
Frequency, severity and causal relationship of diarrhoea, skin reactions, stomatitis 
and paronychia 

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SAEs are shown in the table. In addition, significant adverse events and adverse events that 
lead to dose reduction or withdrawal of treatment are investigated. 
Descriptive statistics are performed to describe changes in laboratory values during the 
course of the study. All abnormalities of potential clinical relevance are reported. In general, 
potential clinical relevance is defined as a CTCAE grade ≥2 or an increase in the CTCAE 
classification by at least one grade in comparison to baseline.  
 
 
7. Medical Evaluation and Report Creation 
7.1 Regulations for report creation including biometric and medical evaluation 
The analysed data will be documented within the usual period in the form of a report and 
published in an appropriate form. An entry in the publicly accessible database 
clinicaltrials.gov is planned. 
 
7.2 Responsibility Regulations 
The clinical monitor and principal investigator of the NIS are responsible for evaluating the 
medical data and creating the NIS report. 
 
 
8. Administrative Specifications 
This NIS is conducted in accordance with the recommendations from the German Federal 
Institute for Drugs and Medical Devices and the Paul-Ehrlich Institute for Planning, 
conducting and evaluation of observational studies (24) and definitive Boehringer Ingelheim 
Pharma GmbH & Co. KG standard operating procedures. 
 
8.1 Contract Administration 
The participating doctor is obliged to conduct the NIS responsibly in accordance with the 
agreements made in the contract. The rights and obligations of the participating doctor and 
Boehringer Ingelheim Pharma GmbH & Co. KG are stipulated in the contract concluded 
regarding the implementation of this NIS.  
 
8.2 Remuneration 
Boehringer Ingelheim Pharma GmbH & Co. KG grants the participating doctor 
remuneration/compensation in accordance with the specifications in the contract. 
 
8.3 Quality Assurance Measures 
The validity of the data obtained is guaranteed by the validations integrated into the 
documentation system, which notify the documenter/doctor of missing or illogical entries. 
Additionally a random source data comparison is conducted by a monitor appointed by 
 at the participating study centre.  

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All participating doctors are obliged to record the participation of patients in the NIS in the 
patient’s original documents. In the event of possible queries, the participating doctor must 
be able to identify the patient who was followed up. Medical information about the patients 
must only be communicated and analysed using the patient number. By signing the 
agreement, the participating centre gives its consent to source data verification, which will 
take place at the participating centres. Then, a source data verification from 100% of the 
patients enrolled in the NIS takes place at a participating centre. Additional inspection/review 
of the quality assurance for this NIS may be conducted. The monitor appointed by 
 
 will have access to all treatment documentation, the files and reports of the 
participating doctors relating to the NIS and the declaration of informed consent documents 
for this NIS. 
 
8.4 Ethical and Legal Considerations and Requirements 
This NIS is conducted in accordance with Section 67, paragraph 6 of the German Medicinal 
Products Act (Arzneimittelgesetzes der Bundesrepublik Deutschland or AMG) The medicinal 
product afatinib used during the course of this NIS has obtained marketing authorisation in 
Germany during the course of central European marketing authorisation. The medicinal 
product under observation is not provided by the pharmaceutical company, but instead is 
ordered by the participating doctor. The selection of treatment lies at the sole discretion of 
the doctor involved. The NIS has no influence on the treatment of patients. The decision to 
include a patient in an NIS is separate to ordering medicinal products. This means that there 
are no additional risks to the patient from participation in this NIS. There are no additional 
medical procedures required beyond the scope that the patient would obtain if they were not 
enrolled in the NIS. The treatment, including the diagnosis and monitoring, are conducted in 
accordance with treatment during routine medical practice.  
The patient is provided with a comprehensive explanation and provides their consent to 
participate and to the disclosure of their data. The NIS was approved by the ethics committee 
at Dresden University before the start of the study. The same applies to the implementation 
of changes. The ethics committees for the participating doctors are notified of the NIS. 
 
8.5 Data protection 
Before a patient can be enrolled in this NIS, they will be provided with an explanation of how 
their personal data will be handled and informed comprehensively about the disclosure of 
their data to involved third parties. They are requested to grant their informed consent in 
writing. The patient information is captured in anonymised form. The allocation occurs based 
on the year of birth and patient numbers stated in the participating study centre. All 
information collected during the NIS is always handled confidentially. Data regarding medical 
history and therapeutic measures, adverse reactions that occur and the clinical course of the 
disease is captured from patients during the course of this NIS. All data was used to answer 
the above-mentioned questions and was captured in accordance with GCP using 
 
electronic documentation system (eCRF). 
 
8.6 Duty to inform 
The commercial medicinal product GIOTRIF® (afatinib) is used during the course of the NIS, 
which is used or prescribed by a doctor in a medical practice and procured from a pharmacy.                        
The NIS is conducted in accordance with Section 67, paragraph 6 of the German Medicinal 
Products Act, the Central Federal Association of Health Insurance Funds and the competent 
federal authorities shown by Boehringer Ingelheim Pharma GmbH & Co. KG or the institution 
appropriately commissioned by them. In terms of the National Association of Statutory Health 

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1200.205; Follow-up Plan Version 4_01072014 
Insurance Physicians, the Central Federal Association of Health Insurance Funds and the 
Association of Private Health Insurance Funds, the doctors involved are also stated by name 
with the nature and amount of the compensation given to them and a certified copy of their 
concluded contracts should be sent over. In addition, an entry corresponding to the 
notification from the German Association of Research-Based Pharmaceutical Companies 
(Verbandes forschender Arzneimittelhersteller or VFA) in the publicly accessible database 
clinicaltrials.gov is planned. 
 
8.7 Storage 
All study-specific documents are stored over a period of 10 years after the end of this NIS by 
Boehringer Ingelheim Pharma GmbH & Co. KG Ingelheim Pharma GmbH. 
 
8.8 Publication 
Boehringer Ingelheim Pharma GmbH & Co. KG endeavours to support the process of free 
exchange of relevant scientific information. Every publication resulting from this NIS must 
conform to the Boehringer Ingelheim Pharma GmbH & Co. KG publication guidelines. The 
rights of the monitoring doctors and Boehringer Ingelheim Pharma GmbH & Co. KG with 
regard to the publication of the results of this NIS are stipulated in a contract concluded with 
the doctor. 
 
 
8.9 Responsibilities 
 
Principal investigator of the NIS: 
Clinical Monitor: 
 
 
 
 
 
 
 
9. Signature regulations 
 
The Follow-up Plan must be signed by the clinical monitor and by the statistician. 

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1200.205; Follow-up Plan Version 4_01072014 
 
 
Trial Clinical Monitor: 
  
 
 
01 July 
2014 
  
  
  
 
 
[signature] 
 
Name:
 
 
 
  
 
 
 
Trial Statistician: 
  
 
 
  
01 July 2014 
  
  
 
[signature] 
 
Name:
 
 
 
  
 
 
 

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1200.205; Follow-up Plan Version 4_01072014 
10. 
 References 
1. Robert-Koch Institute and the German Society of Epidemiological Cancer Registries 
(original: Gesellschaft der epidemiologischen Krebsregister in Deutschland e.V. 
2007/2008, 8th Edition. Berlin, 2012. 
2. D'Addario G et al.; Annals of Oncology 2010:116-119. 
3. Goeckenjan G et al.; Pneumology 2010:e1-e164.  
4. Herbst RS et al.; N Engl J Med. 2008:1367-1380. 
5. Kris MG et al.; J Clin Oncol 2011:29 (suppl; abstract #CRA7506)  
6. Rosell R et al.; N Engl J Med. 2009:958-967. 
7. Zhang X et al.; J Med Genet 2007:166-172. 
8. Yarden Y et al.; Nat Rev Cancer 2012:553-63. 
9. Heukamp, LC et al.; Onkologe 2011:670-678. 
10. Lynch TJ et al.; N Engl J Med. 2004:2129-2139.  
11. Marks JL et al.; J Thorac Oncol 2008:111-116.  
12. Mok TS et al.; Expert Rev Anticancer Ther. 2010:1601-1611. 
13. Mok TS et al.; N Engl J Med. 2009:947-957. 
14. Maemondo M et al.; N Engl J Med. 2009:2380-2388. 
15. Mitsudomi T et al.; Lancet Oncol. 2010:121-128. 
16. Zhou C et al.; Lancet Oncol. 2011:735-742. 
17. Rosell R et al.; Lancet Oncol 2012:239-246.  
18. Sequist LV et al.; J Clin Oncol. 2013 Jul 1. [Epub ahead of print] 
19. Yang JC et al.; J Clin Oncol. 2013 Jul 1. [Epub ahead of print] 
20. Wu YL et al.; Abstract # 8016 ASCO 2013. 
21. Solca F et al.; J Pharmacol Exp Ther. 2012:342-350. 
22. Li D et al.; Oncogene 2008:4702-4711. 
23. Ou SH; Crit Rev Oncol Hematol. 2012:407-421. 
24. Recommendations by the German Federal Institute for Drugs and Medical Devices 
and the Paul-Ehrlich Institute for Planning, Implementation and Evaluation of 
Observational Studies (07.07.2010). 

001-MCS-40-106_RD-07 (3.0) / Saved on: 15 Jul 2014 
 
 
TITLE PAGE 
 
 
Observational Plan 
Non-interventional study 
Local Amendment 
 
 
Local 
Amendment 
Number: 
Local Amendment 1 
Country Germany 
 
Date: 
01.08.2015 
□ 
To be implemented only after 
documented approval of the IRB / 
IEC / Competent Authorities 
EudraCT No.: 
BI Trial No.: 
n.a. 
1200.205 
□ 
To be implemented immediately in 
order to eliminate hazard – IRB / 
IEC / Competent Authority to be 
notified of change with request for 
approval 
Investigational 
Product(s): 
GIOTRIF® (Afatinib) 
x 
Can be implemented without IRB / 
IEC / Competent Authority 
approval as changes involve 
logistical or administrative aspects 
only 
Title: 
GIDEON: 
GIOTRIF® in der Erstlinientherapie des fortgeschrittenen NSCLC mit aktivierenden 
EGFR-Mutationen 

Boehringer Ingelheim 
Page 2 of 5 
Final, 12. Aug 2015 
BI Trial No.: 1200.205 
Protocol Local Amendment 1 
Country Germany 
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
001-MCS-40-106_RD-07 (3.0) / Saved on: 15 July 2014 
Rationale for 
Local 
Amendment: 
After ca. 15 months of site and patient recruitment it becomes evident that the targeted 
patient number of 150 will not be met within the given timeframe of 20 months 
recruitment time until December 2015.  
Recruitment time will thus be prolonged to 32 months (FPI April 2014 to LPI 
December 2016). Study duration will also increase. LPO is now planned for December 
2018. 
Other timelines will change accordingly. 
One exclusion criterion has been phrased mistakably and thus needs clarification.  
This will also be taken care of in this amendment. 
For readability reasons we marked changes in front page and sections 4.3 and 5.3. 
bold. 
 
Page 1 of 5 
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. 
 

Boehringer Ingelheim 
Page 3 of 5 
Final, 12. Aug 2015 
BI Trial No.: 1200.205 
Protocol Local Amendment 1 
Country Germany 
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
001-MCS-40-106_RD-07 (3.0) / Saved on: 15 July 2014 
SIGNATURE PAGE(S) 
This amendment  
 
concerns administrative matters only so that the coordinating investigator's signature 
will not be obtained. 
 
concerns matters dealing with design elements of the study, in- / exclusion criteria, 
observations, or safety or efficacy related study elements so that the coordinating 
investigator's signature needs to be obtained. 
 
  
  
Trial Clinical Monitor 
  
  
 
 Date 
 
 
  
 Boehringer Ingelheim 
Medical Affairs Germany 
 
  
  
Trial Statistician  
  
  
 
 Date 
 
 
  
 Boehringer Ingelheim 
Boehringer Ingelheim 
Biometrics & Data Management  
 
  
  
Team Member Medicine  
  
  
 
 Date 
 
 
  
 Boehringer Ingelheim 
Corporate Medical Affairs  
 
  
  
Local Clinical Monitor  
  
  
 
 Date 
 
 
  
 Boehringer Ingelheim 
Medical Affairs Germany 
 
  
  
 
 

Boehringer Ingelheim 
Page 4 of 5 
Final, 12. Aug 2015 
BI Trial No.: 1200.205 
Protocol Local Amendment 1 
Country Germany 
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
001-MCS-40-106_RD-07 (3.0) / Saved on: 15 July 2014 
CHANGE 1: SHORT DESCRIPTION OF CHANGE 
Section of the protocol: Front page 
Planned duration of the 
NIS: 
FPI:   April 2014 
LPO: October 2017 
 
Was changed to: 
Planned duration of the 
NIS: 
FPI:   April 2014 
LPO: December 2018 
 
Reason(s) for change 1: 
After ca. 15 months of site and patient recruitment it becomes evident that the targeted patient number of 150 
will not be met within the given timeframe of 20 months recruitment time until December 2015.  
Recruitment time will thus be prolonged to 32 months (FPI April 2014 to LPI December 2016). Study 
duration will also increase. LPO is now planned for December 2018. 
 
CHANGE 2: SHORT DESCRIPTION OF CHANGE 
Section of the protocol: 3.4. Exclusion criteria 
• 
Previous treatment with systemic chemotherapy, except during the course of (neo)adjuvant 
therapy, previous treatment with therapy targeted against EGFR (within 12 months after 
treatment completion). 
Was changed to: 
• 
Previous treatment with systemic chemotherapy, except during the course of (neo)adjuvant 
therapy, previous treatment with therapy targeted against EGFR  
 
Reason for change 2: 
The exclusion criterion has been phrased mistakably and thus needs clarification. 
 
 

Boehringer Ingelheim 
Page 5 of 5 
Final, 12. Aug 2015 
BI Trial No.: 1200.205 
Protocol Local Amendment 1 
Country Germany 
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
001-MCS-40-106_RD-07 (3.0) / Saved on: 15 July 2014 
CHANGE 3: SHORT DESCRIPTION OF CHANGE 
Section of the protocol: 5.3. Survey period and procedure 
Last patient enrolment:   
December 2015 
 
 
Database closure/lock:  
December 2017 
Final report:  
December 2018 
 
 
The survey period of this NIS should amount to a total of 4 years.  
Was changed to: 
Last patient enrolment:   
December 2016 
 
 
Database closure/lock:  
March 2018 
Final report:  
December 2019 
 
 
The survey period of this NIS should amount to a total of 5 years.  
Reason for change 3: 
After ca. 15 months of site and patient recruitment it becomes evident that the targeted patient number of 400 
will not be met within the given timeframe of 20 months recruitment time until December 2015.  
Recruitment time will thus be prolonged to 32 months (FPI April 2014 to LPI December 2016). Study 
duration will also increase. LPO is now planned for December 2018. 
Other timelines will change accordingly. 
 
 

001-MCS-40-106_RD-07 (3.0) / Saved on: 15 Jul 2014001-MCS-40-106_RD-07 (3.0) / Saved on: 15 Jul 2014 
 
 
 
 
TITLE PAGE 
 
 
Observational Plan 
Non-interventional study 
Local Amendment 
 
 
Local 
Amendment 
Number: 
Local Amendment 2 
Country Germany 
 
Date: 
11.07.2016 
□ 
To be implemented only after 
documented approval of the IRB / 
IEC / Competent Authorities 
EudraCT No.: 
BI Trial No.: 
n.a. 
1200.205 
□ 
To be implemented immediately in 
order to eliminate hazard – IRB / 
IEC / Competent Authority to be 
notified of change with request for 
approval 
Investigational 
Product(s): 
GIOTRIF® (Afatinib) 
x 
Can be implemented without IRB / 
IEC / Competent Authority 
approval as changes involve 
logistical or administrative aspects 
only 
Title: 
GIDEON: 
GIOTRIF® in der Erstlinientherapie des fortgeschrittenen NSCLC mit aktivierenden 
EGFR-Mutationen 
 
 

Boehringer Ingelheim 
Page 2 of 4 
Final, 11. Jul 2016 
BI Trial No.: 1200.205 
Protocol Local Amendment 2 
Country Germany 
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
001-MCS-40-106_RD-07 (3.0) / Saved on: 15 Jul 2014 
Rationale for 
Local 
Amendment: 
 
 
One exclusion criterion prohibiting simultaneous participation in other NIS 
recently showed not to reflect clinical reality.  
New registries and NIS have been implemented by Boehringer Ingelheim or 
scientific collaboration groups, in which to include also GIDEON patients is of 
scientific interest.  
The parallel inclusion will not interfere with the primary endpoints of the 
respective NIS or registry. Patient data will be documented for both projects 
after receiving written informed consent for the respective study.  
This exclusion criterion will thus be rephrased. 
For readability reasons we marked changes in front page and sections 4.3 and 
5.3. bold. 
 
Page 1 of 5 
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 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. 
 

Boehringer Ingelheim 
Page 3 of 4 
Final, 11. Jul 2016 
BI Trial No.: 1200.205 
Protocol Local Amendment 2 
Country Germany 
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
001-MCS-40-106_RD-07 (3.0) / Saved on: 15 Jul 2014 
CHANGE 1: SHORT DESCRIPTION OF CHANGE 
Section of the protocol: 3.4. Exclusion criteria 
• 
… 
• 
Concurrent participation in another NIS or interventional clinical study during the treatment 
phase or within the last 30 days 
Was changed to: 
• 
… 
• 
Concurrent participation in an interventional clinical study during the treatment phase or 
within the last 30 days 
 
Reason for change: 
The exclusion criterion was rephrased to better reflect clinical reality. 
 
 

Boehringer Ingelheim 
Page 4 of 4 
Final, 11. Jul 2016 
BI Trial No.: 1200.205 
Protocol Local Amendment 2 
Country Germany 
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
001-MCS-40-106_RD-07 (3.0) / Saved on: 15 Jul 2014 
 
SIGNATURE PAGE(S) 
This amendment  
 
 
concerns administrative matters only so that the coordinating investigator's signature 
will not be obtained. 
 
concerns matters dealing with design elements of the study, in- / exclusion criteria, 
observations, or safety or efficacy related study elements so that the coordinating 
investigator's signature needs to be obtained. 
 
 
 
  
Trial Clinical Monitor 
 
 
  
 
 
Date 
 
 
 
 
 Boehringer Ingelheim 
Medical Affairs Germany 
 
 
 
  
Trial Statistician  
 
 
  
 
 
Date 
 
 
 
 
 Boehringer Ingelheim 
Boehringer Ingelheim 
Biometrics & Data Management  
 
 
 
  
Team Member Medicine  
 
 
  
 
 
Date 
 
 
 
 
 Boehringer Ingelheim 
Corporate Medical Affairs  
 
 
 
  
Local Clinical Monitor  
 
 
  
 
 
Date 
 
 
 
 
 Boehringer Ingelheim 
Medical Affairs Germany