A Phase 3 Randomized, Double-Blind, Placebo-Controlled, Multicenter Study to Evaluate the Efficacy and Safety of Anamorelin HCl for the Treatment of Malignancy Associated Weight Loss and Anorexia in Adult Patients With Advanced Non-Small Cell Lung Cancer (NSCLC)
Phase: PHASE3
Conditions: Cachexia; Cancer, Non Small Cell Lung Cancer
Sponsor: Helsinn Healthcare SA

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A PHASE 3, RANDOMIZED, DOUBLE-BLIND, PLACEBO-
CONTROLLED, MULTICENTER STUDY TO EVALUATE THE 
EFFICACY AND SAFETY OF ANAMORELIN HCL FOR THE 
TREATMENT OF MALIGNANCY ASSOCIATED WEIGHT LOSS AND 
ANOREXIA IN ADULT PATIENTS WITH ADVANCED NON-SMALL 
CELL LUNG CANCER (NSCLC) 
 
Study Number 
ANAM-17-21 
Protocol Version 
Final (v5.0) 
Protocol Date 
EudraCT No. 
13 Jul 2022 
2018-002927-40 
Sponsor 
Helsinn Healthcare SA 
Via Pian Scairolo 9 
6912 Lugano, Switzerland 
Phone: +41 91 985 21 21 
Fax: +41 91 985 21 22 
 
Clinical CRO 
PSI CRO AG 
Baarerstrasse 113a 
6300 Zug, Switzerland 
CRO for Statistics and Data Management 
 
 
 
 
Business & Decision Life Sciences 
141 rue Saint Lambert 
1200 Brussels, Belgium 
 
 
 
Confidential Information 
The information contained in this document is confidential. Acceptance of this document constitutes agreement by the recipient that no 
information contained herein will be published or disclosed without prior written authorization from an official of Helsinn except that this 
document may be disclosed to appropriate Institutional Review Boards and Ethics Committees or duly authorized representatives of a 
Regulatory Authority under the condition that they are requested to keep it confidential. 
The clinical trial will be conducted, and essential study documentation archived, in compliance with this protocol, applicable SOP’s 
and standards, which incorporate the requirements of the EU Clinical Trials Directive 2001/20/EC or European Regulation 536/2014, 
whichever applies, FDA Guidance on Conduct of Clinical Trials of Medical products and ICH Guideline for Good Clinical Practice. 
 
 

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Signature Page, Helsinn Healthcare SA 
 
Medical & Scientific Expert, Clinical Research & Development: 
 
________________________________________ __________
(Signature) 
 
 
 
 
 
(Date) 
 
 
Clinical Operations Lead, Clinical Research & Development
 
_______________________________________ 
_______
(Signature) 
 
 
 
 
 
(Date) 
 
 
Lead Statistician, Clinical Research and Development:
 
________________________________________ __
(Signature) 
 
 
 
 
 
(D
 
 
Drug Safety Manager, Regulatory Affairs & Drug Safety:
 
________________________________________ ____
(Signature) 
 
 
 
 
 
(Date
 
 
Medical Writer, Clinical Research & Development: 
 
________________________________________ 
(Signature) 
 
 
 
 
 
 
 
 

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Signature Page, Study Site Investigator  
Study Title 
A phase 3, randomized, double-blind, placebo-controlled, multicenter study to evaluate 
the efficacy and safety of anamorelin HCl for the treatment of malignancy associated 
weight loss and anorexia in adult patients with advanced non-small cell lung cancer 
(NSCLC) 
 
Study Number 
ANAM-17-21  
I have read and understood all pages of this clinical trial protocol and appendices and I 
agree that they contain all information required to conduct this trial. I agree to conduct 
the trial as outlined in the protocol and to comply with all terms and conditions set out 
therein. I confirm that I will conduct the trial in accordance with local regulations, ICH 
GCP guidelines and the provisions of the Declaration of Helsinki. I will direct, assist and 
oversee sub-investigator(s) and other relevant staff members under my control and will 
ensure that all trial staff members have access to copies of this protocol and to all 
information relating to preclinical and prior clinical experience (e.g., Investigator’s 
Brochure), ICH GCP guidelines, local regulations and the Declaration of Helsinki to 
enable them to work in accordance with the provisions of these documents.  
I will use only the informed consent form approved by the Institutional Review 
Board/Independent Ethics Committee (IRB/IEC) and will fulfil all responsibilities for 
submitting pertinent information to the IRB/IEC responsible for this trial.  
I agree that Helsinn or its representatives or Health Authorities shall have access to any 
source documents from which (e)CRF information may have been generated.  
I agree that all documentation supplied to me by Helsinn and the CRO(s) concerning this 
trial will be kept in the strictest confidence. 
 
 
________________________________________ __________________ 
(Signature) 
(Date) 
Printed Name:  
 
Institution: 
 
 

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TABLE OF CONTENTS 
 
General information ..........................................................................................................9 
STUDY SYNOPSIS .........................................................................................................12 
STUDY FLOW CHART .................................................................................................24 
LIST OF ABBREVIATIONS .........................................................................................28 
1 
INTRODUCTION AND RATIONALE .................................................................31 
1.1 
Background Information ....................................................................................31 
1.2 
Anamorelin: preclinical and clinical data..........................................................32 
1.2.1 
Preclinical Data ..............................................................................................32 
1.2.2 
Phase 1 Clinical Data .....................................................................................33 
1.3 
Other Clinical Data ..............................................................................................33 
1.4 
Study Rationale ....................................................................................................34 
1.4.1 
Rationale for Study Population ....................................................................34 
1.4.2 
Rationale for Study Protocol and Design.....................................................35 
1.4.3 
Rationale for Selected Dose Range ...............................................................35 
1.5 
Rationale for protocol amendment.....................................................................35 
2 
STUDY OBJECTIVES ............................................................................................36 
2.1 
Primary Objective ................................................................................................36 
2.1.1 
Estimand .........................................................................................................36 
2.2 
Secondary Objectives...........................................................................................37 
3 
STUDY ENDPOINTS ..............................................................................................38 
3.1 
Efficacy Endpoints ...............................................................................................38 
3.1.1 
Primary Efficacy Endpoint ...........................................................................38 
3.1.2 
Secondary Efficacy Endpoints ......................................................................38 
3.1.3 
Exploratory Efficacy Endpoints ...................................................................38 
3.2 
Safety Assessments ...............................................................................................39 
4 
STUDY PLAN ...........................................................................................................40 
4.1 
Study Design .........................................................................................................40 
4.2 
Study Duration .....................................................................................................40 
4.3 
Study population ..................................................................................................40 
4.3.1 
Number of Subjects........................................................................................40 
4.3.2 
Inclusion Criteria ...........................................................................................40 
4.3.3 
Exclusion Criteria ..........................................................................................42 
5 
STUDY DRUG MANAGEMENT ...........................................................................44 
5.1 
Description of Study Treatments ........................................................................44 
5.2 
Treatment Groups ...............................................................................................44 
5.3 
Dose and Administration .....................................................................................44 
5.4 
Packaging, Labelling and Shipment ...................................................................44 
5.5 
Storage ..................................................................................................................44 
5.6 
Drug Depots ..........................................................................................................45 
5.7 
Accountability ......................................................................................................45 
5.8 
Administration of Study Treatment ...................................................................45 
5.9 
Blinding .................................................................................................................46 

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5.10 
Treatment Assignment and Randomization - Use of IWRS ............................46 
5.11 
Management of Treatment Overdosage ............................................................46 
5.12 
Occupational safety ..............................................................................................47 
5.13 
Prior and concomitant medications ...................................................................47 
5.13.1 
Use of corticosteroids .....................................................................................47 
5.13.2 
Prohibited Medications .................................................................................47 
5.13.3 
Concurrent NSCLC Treatment ....................................................................48 
5.13.4 
Use of contraceptive measures ......................................................................49 
5.14 
Rescue Medication ...............................................................................................49 
5.15 
Treatment Compliance ........................................................................................49 
6 
STUDY CONDUCT..................................................................................................50 
6.1 
Study Procedures by Time Point ........................................................................50 
6.1.1 
Visit 1 (Screening, Day -7 to Day -1) ............................................................50 
6.1.2 
Visit 2 (Randomization/Treatment Period, Day 1): Week 1 ......................51 
6.1.3 
Visit 3 (Day 22+3): Week 3 ............................................................................52 
6.1.4 
Visit 4 (Day 43+3days): Week 6 ....................................................................53 
6.1.5 
Visit 5 (Day 64+3 days): Week 9 ...................................................................54 
6.1.6 
Visit 6 (Day 85+3): Week 12 ..........................................................................55 
6.1.7 
Visit 7 (Day 106+3): Week 15 ........................................................................56 
6.1.8 
Visit 8 (Day 127+3) – Week 18 ......................................................................57 
6.1.9 
Visit 9 (Day 148+3): Week 21 ........................................................................58 
6.1.10 
Visit 10 (Day 169+3): Week 24 ......................................................................59 
6.1.11 
Visit 11 (Follow-up visit): Week 26 ..............................................................60 
6.2 
Definition of study Completion ...........................................................................60 
6.3 
Premature Discontinuation of Study Drug ........................................................60 
6.4 
Diet and Lifestyle .................................................................................................61 
7 
METHODS OF ASSESSMENT ..............................................................................62 
7.1 
Efficacy Assessments ...........................................................................................62 
7.1.1 
Assessment of Body Weight ..........................................................................62 
7.1.2 
Assessment of anorexia symptoms and other patient reported 
outcomes..........................................................................................................63 
7.1.3 
Patient Reported Outcome ............................................................................63 
7.2 
Safety Assessments ...............................................................................................65 
7.2.1 
Demographic/Medical History ......................................................................65 
7.2.2 
Physical examination .....................................................................................65 
7.2.3 
Vital signs ........................................................................................................66 
7.2.4 
Height and BMI..............................................................................................66 
7.2.5 
12-lead ECG ...................................................................................................66 
7.2.6 
Clinical Laboratory Tests..............................................................................66 
7.2.7 
CT scan for Tumor Assessment ....................................................................67 
8 
ADVERSE EVENTS ................................................................................................68 
8.1 
Definition of Adverse Events...............................................................................68 
8.1.1 
Classification of Adverse Events...................................................................69 
8.1.2 
Reporting Adverse Events .............................................................................71 

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8.1.3 
Reporting Serious Adverse Events ...............................................................72 
8.1.4 
Pregnancy Report ..........................................................................................73 
9 
STATISTICS .............................................................................................................74 
9.1 
Stratification factors ............................................................................................74 
9.2 
Sample Size Determination .................................................................................74 
9.3 
Definition of Study Populations for Analysis (Analysis Set) ............................75 
9.4 
Statistical Analysis ...............................................................................................75 
9.4.1 
Missing Data ...................................................................................................75 
9.4.2 
Multiplicity .....................................................................................................76 
9.4.3 
Subgroups .......................................................................................................77 
9.4.4 
Analysis of Demographics, Baseline Variables and Disease 
Characteristics................................................................................................77 
9.4.5 
Efficacy Analysis ............................................................................................77 
9.4.6 
Safety Analysis ...............................................................................................82 
9.4.7 
Determination of the responder threshold in the 5-item Anorexia 
Symptom Subscale .........................................................................................83 
9.4.8 
Determination of the clinically meaningful responder threshold in 
weight change .................................................................................................84 
9.5 
Interim Analysis ...................................................................................................85 
10 ETHICAL AND REGULATORY ASPECTS........................................................86 
10.1 
Ethical Considerations.........................................................................................86 
10.1.1 
Laws and Regulations ....................................................................................86 
10.1.2 
Patient’s information sheet and informed consent form ............................86 
10.1.3 
Protocol amendments ....................................................................................86 
10.1.4 
Protocol deviations .........................................................................................87 
10.1.5 
Data collection ................................................................................................87 
10.1.6 
Monitoring and Quality Assurance ..............................................................88 
10.1.7 
Study Documentation and Records retention .............................................88 
10.1.8 
Confidentiality ................................................................................................89 
10.1.9 
Publication policy ...........................................................................................89 
10.1.10 
Insurance ........................................................................................................90 
11 REFERENCES .........................................................................................................91 
12 APPENDICES ...........................................................................................................95 
APPENDIX 1: 
EASTERN COOPERATIVE ONCOLOGY GROUP 
PERFORMANCE SCALE ......................................................................................96 
APPENDIX 2: 
BODY WEIGHT MEASUREMENTS-STUDY SPECIFIC 
PROCEDURES .........................................................................................................97 
APPENDIX 3: 
CYP3A4 INHIBITORS AND INDUCERS ......................................98 
APPENDIX 4: 
FACIT MEASUREMENTS ..............................................................99 
APPENDIX 5: 
SCORING GUIDELINES ...............................................................104 
APPENDIX 6: 
PATIENT GLOBAL IMPRESSION OF SEVERITY 
(PGIS) AND PATIENT GLOBAL IMPRESSION OF CHANGE (PGIC) .......107 
APPENDIX 7: 
HUNGER ASSESSMENT SCALE ................................................109 

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APPENDIX 8: 
NEW YORK HEART ASSOCIATION (NYHA) 
CLASSIFICATION ................................................................................................110 
 

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GENERAL INFORMATION 
Sponsor 
Helsinn Healthcare SA 
Via Pian Scairolo 9 
6912 Lugano, Switzerland 
Phone: +41 91 985 21 21 
Fax: +41 91 985 21 22 
Clinical CRO  
 
 
 
CRO for Statistics and Data 
Management 
PSI CRO AG  
Baarerstrasse 113a 
6300 Zug, Switzerland 
 
Business & Decision Life Sciences SA 
141 rue Saint Lambert 
1200 Brussels, Belgium 
24h-Contact 
for 
Serious
Adverse Events (SAEs) 
 
  
 
 
Drug Safety Officer 
Helsinn Healthcare SA: 
 
  
CRO: 
 
 
 
 
  
Sponsor Medical Expert 
Helsinn Healthcare SA: 
 
 

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Study Project Manager 
Helsinn Healthcare SA: 
 
 
  
CRO: 
 
 
 
 
 
Statistics  
Helsinn Healthcare SA: 
 
 
CRO: 
 
 
 
  
Data Management 
Helsinn Healthcare SA: 
 
 
  
CRO: 
  
 
 
 
  

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Quality Assurance 
Helsinn Healthcare SA: 
 
 
CRO: 
 
 
 
 
Clinical Drug Supplies 
Packaging and Labeling 
 
Catalent Germany Schorndorf GmbH 
Steinbeisstr. 1-2 
D-73614 Schorndorf, Germany 
Central laboratory 
Corporate HQ: 
Eurofins Central Laboratory 
Bergschot 71 
4817 PA Breda, The Netherlands 
US HQ: 
Eurofins Central Laboratory 
2430 New Holland Pike, D100 
Lancaster, PA 17601, USA 
Central ECG Reader 
eResearch Technology, Inc. 
1818 Market Street, Suite 1000 
Philadephia PA 19103, USA 
Central eCOA Solution 
eResearch Technology, Inc. 
1818 Market Street, Suite 1000 
Philadephia PA 19103, USA 
 
 
 

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STUDY SYNOPSIS 
Study Title 
A Phase 3 Randomized, Double-Blind, Placebo-Controlled, 
Multicenter Study to Evaluate the Efficacy and Safety of 
Anamorelin HCl for the Treatment of Malignancy 
Associated Weight Loss and Anorexia in adult patients with 
Advanced Non-Small Cell Lung Cancer (NSCLC) 
Study Number 
ANAM-17-21 
Sponsor 
Helsinn Healthcare SA, Via Pian Scairolo 9, 6912 Lugano, 
Switzerland 
Countries and Sites 
Multi-center international study, with sites including, but not 
limited to, North America, Australia and Europe 
Clinical Phase 
Phase 3 
Indication 
Treatment of malignancy associated weight loss or anorexia 
in patients with NSCLC 
Study Design 
Multicenter, 
randomized, 
double-blind, 
parallel-group, 
placebo-controlled study to evaluate the efficacy and safety 
of anamorelin HCl. Approximately 316 patients with 
advanced NSCLC with cachexia will be randomized 1:1 to 
anamorelin HCl 100 mg or placebo, taken orally once daily 
(QD) for a total of 24 weeks. Patients will be instructed to 
take the study drug at least 1 hour before their first meal of 
the day. 
Objectives  
Primary: To demonstrate superiority of anamorelin HCl vs 
placebo on the gain in body weight and improvement in 
anorexia symptoms.   
Secondary: To evaluate the safety and tolerability of 
anamorelin HCl, and to further evaluate anamorelin efficacy 
profile. 
Treatment Groups 
Group 1 / Test group – 100 mg anamorelin HCl 
(administered as 100 mg tablets in the fasted condition) 
Group 2 / Control group – Placebo (administered as 
matching placebo tablets in the fasted condition) 
Drug Administration 
Patients will take 1 tablet on Day 1 (if a fasting state is not 
possible on Day 1, the patient will start study drug on Day 2) 
and daily thereafter until Visit 10 (Week 24). Patients will 
be supplied with study drug and re-supplied at Visit 3 (Week 
3), Visit 4 (Week 6), Visit 5 (Week 9), Visit 6 (Week 12), 
Visit 7 (Week 15), Visit 8 (Week 18), and Visit 9 (Week 
21). Tablets of study drug will be taken orally in mornings 

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while fasting at least 1 hour before breakfast. Water is 
permitted prior to and with study drug. 
Study Duration 
Total of 24 weeks double-blind treatment with anamorelin or 
placebo. A follow-up telephone visit is scheduled at Week 
26. 
Number of Patients  
A total of 316 patients with advanced NSCLC with cachexia 
will be randomized 1:1 to anamorelin HCl 100 mg or 
placebo (158 patients per treatment arm). 
Target 
Study 
Population 
Advanced NSCLC adult patients with body mass index < 20 
kg/m2 with involuntary weight loss of >2% within 6 months 
prior to screening and anorexia 
Inclusion Criteria 
1. Signed written informed consent. 
2. Female or male ≥18 years of age. 
3. Documented histologic or cytologic diagnosis of 
American Joint Committee on Cancer (AJCC) Stage III 
or IV NSCLC. Stage III patient must have unresectable 
disease. 
4. Body mass index < 20 kg/m2 with involuntary weight 
loss of >2% within 6 months prior to screening. 
5. Ongoing problems with appetite/eating associated with 
the underlying cancer, as determined by having score of 
≤ 17 points on the 5-item Anorexia Symptom Scale and 
≤ 37 points on the 12-item FAACT A/CS. 
6. Patient receiving or not receiving systemic anti-cancer 
treatment at the time of screening are eligible to 
participate. Systemic anti-cancer treatment includes first, 
second, third treatment line with chemotherapy/radiation 
therapy, immunotherapy or targeted therapy.   
Patient not receiving systemic anti-cancer treatment is 
eligible if: 
a. 
Not planning to receive anti-cancer treatment and/or 
at least 14 days must be elapsed from the completion 
of prior treatment at the day of screening, in case 
underwent previous cycle, 
OR 
b. Planning to receive anti-cancer treatment within 14 
days from randomization and/or at least 14 days 
must be elapsed from the completion of prior 
treatment at the day of screening, in case underwent 
previous cycle, 

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OR 
c. 
Patient on palliative care treatment. 
7. ECOG performance status 0, 1 or 2 at screening (see 
APPENDIX 1). 
8. AST (SGOT) and ALT (SGPT) ≤ 3 x ULN or if hepatic 
metastases are present ≤ 5 x ULN. 
9. Adequate renal function, defined as creatinine ≤ 2 × 
ULN, or calculated creatinine clearance >30 ml/minute.  
10. Female patient shall be: a) of non-childbearing potential 
or b) of childbearing potential using reliable 
contraceptive measures and having a negative urine 
pregnancy test within 24 hours prior to first dose of 
investigational product*. 
Notes:  
a) Female patient of non-childbearing potential is defined as being in 
post-menopausal state since at least 1 year; or having documented 
surgical sterilization or hysterectomy at least 3 months before study 
participation.  
b) Reliable contraceptive measures include implants, injectables, 
combined oral contraceptives, intrauterine devices, vasectomized partner 
or complete (long term) sexual abstinence. 
11. The patient must be willing and able to comply with the 
protocol tests and procedures. 
All inclusion criteria will be checked at screening visit (Visit 
1). *Inclusion criterion #10 will be re-checked and verified at 
Day 1 (Visit 2). 
Exclusion Criteria 
 
1. Patient with other forms of lung cancer (e.g., small cell, 
neuroendocrine tumors). 
2. Woman who is pregnant or breast-feeding. 
3. Reversible causes of reduced food intake, as determined 
by the Investigator*. These causes may include but are 
not limited to: 
a. 
NCI CTCAE Grade 3 or 4 oral mucositis,  
b. NCI CTCAE Grade 3 or 4 GI disorders [nausea, 
vomiting, diarrhea, and constipation],  
c. 
mechanical obstructions making patient unable to 
eat, or 
d. severe depression. 
4. Patient undergoing major surgery (central venous access 
placement and tumor biopsies are not considered major 
surgery) within 4 weeks prior to randomization. Patient 
must be well recovered from acute effects of surgery 

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prior to screening. Patient should not have plans to 
undergo major surgical procedures during the treatment 
period. 
5. Patient currently taking androgenic compounds including 
but not limited to testosterone, testosterone-like agents, 
oxandrolone,  
Megestrol acetate, 
Corticosteroids [for details see Section 5.13.1], 
Olanzapine [for details see Section 5.13.2], 
Mirtazapine (however, long-term use of mirtazapine for 
depression for at least four weeks prior to screening is 
allowed), 
Dronabinol, 
Marijuana (cannabis), or  
Any other prescription medication or off-label products 
intended to increase appetite or treat unintentional 
weight loss*. 
6. Patient with pleural effusion requiring thoracentesis, 
pericardial effusion requiring drainage, edema or 
evidence of ascites*.  
7. Patient with uncontrolled or significant cardiovascular 
disease, including: 
a. History of myocardial infarction within the past 3 
months, 
b. A-V block of second or third degree (may be 
eligible if currently have a pacemaker), 
c. Unstable angina, 
d. Congestive heart failure within the past 3 months, if 
defined as NYHA class III-IV,  
e. Any history of clinically significant ventricular 
arrhythmias [such as ventricular tachycardia, 
ventricular fibrillation, Wolff-Parkinson-White 
(WPW) syndrome, or torsade de pointes], 
f. Uncontrolled hypertension (blood pressure >150 
mm Hg systolic and >95 mm Hg diastolic), 
g. Heart rate < 50 beats per minute on pre-entry 
electrocardiogram and patient is symptomatic*. 
8. Patient on drugs that may prolong the PR or QRS 

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interval durations, such as any of the antiarrhythmic 
medications Class I (Fast sodium (Na) channel blockers) 
[Additional details are provided in Section 5.13.2]. 
9. Patient unable to readily swallow oral tablets*.   
10. Patient with severe gastrointestinal disease (including 
esophagitis, gastritis, malabsorption).  
11. Patient with history of gastrectomy.  
12. Patient with uncontrolled diabetes mellitus or 
unmonitored diabetes mellitus. 
13. Patient with cachexia caused by other reasons, as 
determined by the investigator such as: 
a. Severe COPD requiring use of home O2,  
b. New York Heart Association (NYHA) class III-IV 
heart failure (see APPENDIX 8), 
c. AIDS, 
d. Uncontrolled thyroid disease. 
14. Patient receiving strong CYP3A4 inhibitors within 14 
days of randomization (see APPENDIX 3). 
15. Patient currently receiving tube feedings or parenteral 
nutrition (either total or partial).   
16. Current excessive alcohol or illicit drug use.  
17. Any condition, including the presence of laboratory 
abnormalities, which in the Investigator’s opinion, places 
the subject at unacceptable risk if he/she were to 
participate in the study or confounds the ability to 
interpret data from the study.  
18. Enrollment in a previous study with anamorelin HCl 
19. Patient actively receiving a concurrent investigational 
agent, or having received an investigational agent within 
28 days of Day 1. 
All exclusion criteria will be checked at screening visit 
(Visit 1). *Exclusion Criteria #3, 5, 6, 7g, and 9 are to be re-
checked and verified before study drug administration 
(Visit 2). 

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Efficacy Assessments 
Primary Efficacy Endpoints: 
The co-primary efficacy endpoints are: 
• Mean change in body weight from baseline over 
12 weeks. 
• Mean change in 5-item Anorexia Symptom 
Subscale from baseline over 12 weeks. 
Secondary Efficacy Endpoints: 
• Duration of treatment benefit in weight (≥0) from 
baseline over 12 weeks. 
• Duration of treatment benefit in weight (≥ to a 
predefined threshold) from baseline over 12 
weeks. 
• Duration of treatment benefit in anorexia 
symptoms (≥0) from baseline over 12 weeks, as 
measured by the 5-item Anorexia Symptom 
Subscale. 
• Duration of treatment benefit in 5-item Anorexia 
Symptom Subscale (≥ to a predefined threshold) 
from baseline over 12 weeks. 
 
Note: The duration of treatment benefit is measured as the 
duration for which the patient observed a change from 
baseline superior or equal to zero, or to the predefined 
thresholds of clinical meaningfulness, the latter defined 
through a fully anchor based method using PGIS and PGIC 
as anchors. 
• Mean change in FAACT 12-item A/CS domain 
from baseline over 12 weeks. 
• Mean change in FACIT-F from baseline over 12 
weeks. 
• Mean change in FAACT total score from 
baseline over 12 weeks. 
 
 
Exploratory Efficacy Endpoints: 
• Mean change in body weight from baseline up to 
Week 6, 9, 15, 18, 21, and 24. 

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• Mean 
change 
in 
patient-reported 
anorexia 
symptom from baseline up to Week 6, 9, 15, 18, 
21, and 24 as measured by the 5-item Anorexia 
Symptom Subscale. 
• Mean change in FAACT total score from baseline 
up to Week 6, 9, 15, 18, 21, and 24. 
• Composite Clinical Response (CCR) at Week 3, 
6, 9, 12, 15, 18, 21, and 24. 
• Change in body weight from baseline to Week 3, 
6, 9, 12, 15, 18, 21, and 24. 
• Change in patient-reported anorexia symptoms 
from baseline to Week 3, 6, 9, 12, 15, 18, 21, and 
24 as measured by the 5-item Anorexia Symptom 
Subscale. 
• Achievement of a clinically meaningful gain in 
body weight from baseline to Week 3, 6, 9, 12, 
15, 18, 21, and 24. 
• Achievement of a clinically meaningful increase 
in 5-item Anorexia Symptom Subscale from 
baseline to Week 3, 6, 9, 12, 15, 18, 21, and 24. 
• Percentage of change in body weight from 
baseline to Week 3, 6, 9, 12, 15, 18, 21, and 24. 
• Changes from baseline to Week 3, 6, 9, 12, 15, 
18, 21, and 24 in the FAACT (including FAACT 
total score, FACT-G total score, FAACT TOI, 
the 12-item A/CS domain and the 4-item 
Anorexia Concerns Subscale derived from the 
FAACT). 
• Changes from baseline to Week 3, 6, 9, 12, 15, 
18, 21, and 24 in patient-reported fatigue as 
measured by the Functional Assessment of 
Chronic Illness Therapy-Fatigue (FACIT-F) 
domain as well as the FACIT-F TOI score. 
• Changes from baseline to Week 3, 6, 9, 12, 15, 
18, 21, and 24 in the Hunger Assessment Scale.  
• Changes from baseline to Week 6 and 9 in the 
Patients’ Global Impression of Severity (PGIS) 
scale and the Patients' Global Impression of 
Change (PGIC) scale at Week 6 and 9. 

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Safety Assessments 
The following safety assessments will be obtained during the 
Study: physical examination (PE), vital signs, 12-lead 
electrocardiogram (ECG), laboratory test (hematology, 
blood 
chemistry, 
urinalysis), 
adverse 
events 
(AEs) 
assessment, the overall survival on all patients and tumor 
assessments using CT scan at all sites as per standard local 
practice.  
Stratification 
 
Central randomization will be stratified by line of systemic 
anti-cancer treatment (first line vs second line vs third line), 
by type of anti-cancer therapy (immunotherapy vs non-
immunotherapy) and by Baseline score of 5-item Anorexia 
Symptom Subscale (≤10 vs >10). 
Statistical Analysis of 
Efficacy  
 
Analysis Sets 
Statistical analyses will be performed on the following 
patients’ sets: 
• Intent-to-Treat (ITT): all randomized patients will be 
analyzed as per planned treatment. 
• The 
Full 
Analysis 
Set 
(FAS) 
includes 
all 
randomized patients who take at least one dose of trial 
medication and for which post randomization data are 
collected. The definition may be updated at the time of 
the blind review of the data at the end of the trial. 
• Per-Protocol (PP): subset of the randomized patients 
who do not have major protocol violations.  
• Safety: all patients who receive any study drug and 
will be analyzed as per actual treatment.   
Primary Efficacy Endpoint Hypotheses and Tests  
H0w: MWa = MWp 
H1w: MWa ≠ MWp 
Where MWa is the mean change of weight for the 
anamorelin arm and MWp is the mean change of weight for 
the placebo arm. 
H0a: MAa = MAp 
H1a: MAa ≠ MAp 
Where MAa is the mean change of 5-item Anorexia 
Symptom Subscale score for the anamorelin arm and MAp is 
the mean change of 5-item Anorexia Symptom Subscale 
score for the placebo arm. 
The experimental false positive error rate will be preserved 

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because, in order to declare the test component (anamorelin) 
superior to the placebo, both co-primary endpoints must be 
significant, meaning that both H0w and H0a must be rejected 
simultaneously. 
The primary efficacy analyses will be conducted on the ITT. 
H0w and H0a will be tested using an ANOVA to compare the 
two treatment groups, at a type-I error threshold of 0.05 two-
sided. For each of the imputation the estimate of difference 
between treatments and its standard error (SE) will be 
computed, then pooled using the Rubin rule, the pooled 
difference and the related p-value will be interpreted for the 
primary efficacy analyses. The mean change effect will be 
computed as mean of the changes from baseline over 12 
weeks by the time of the last assessment (either Week 12 or 
before, for the analysis at Week 12), and then divided by the 
number of assessments (observed or imputed) from baseline 
up to the time of the last assessment (either week 12 or 
before, in case of death, for the analysis at Week 12). 
The mean change from baseline over 12 weeks in the 
secondary efficacy endpoints will be analyzed by means of 
ANOVA with explanatory variables being the randomized 
treatment, and the stratification factors.  
 
Sensitivity Analyses  
A sensitivity analysis regarding imputation of missing will 
be performed using data from the placebo group only 
(control-based imputation) for patients who do not have 
properly matched patients with complete follow-up. 
An analysis similar to the primary efficacy analysis will be 
also conducted after having imputed the values of weight 
obtained in presence of fluid retention.  
 
Supportive Analyses 
Two analyses similar to the primary efficacy analysis will be 
conducted, one on the FAS population and another one on 
the PP for each of the primary endpoints. 
Primary efficacy endpoints will be presented for all the 
subgroups (listed in Section 9.4.3). 
 
 

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Secondary Efficacy Endpoints Hypotheses and Tests  
H0d0w: D0Wa = D0Wp 
H1d0w: D0Wa ≠ D0Wp 
Where D0Wa is the duration of treatment benefit in weight 
(≥0) for the anamorelin arm and D0Wp is the duration of 
benefit in weight for the placebo arm. 
H0dtw: DtWa = DtWp 
H1dtw: DtWa ≠ DtWp 
Where DtWa is the duration of treatment benefit in weight (≥ 
to a predefined threshold) for the anamorelin arm and DtWp 
is the duration of benefit in weight for the placebo arm. 
H0d0A: D0Aa = D0Ap 
H1d0A: D0Aa ≠ D0Ap 
Where D0Aa is the duration of treatment benefit in 5-item 
Anorexia Symptom Subscale (≥0) for the anamorelin arm 
and D0Ap is the duration of benefit in 5-item Anorexia 
Symptom Subscale for the placebo arm. 
H0dtA: DtAa = DtAp 
H1dtA: DtAa ≠ DtAp 
Where DtAa is the duration of treatment 
benefit in 5-item Anorexia Symptom 
Subscale (≥ to a predefined threshold) for the 
anamorelin arm and DtAp is the duration of 
benefit in 5-item Anorexia Symptom 
Subscale for the placebo arm.H0mf: MFa = 
MFp 
H1mf: MFTa ≠ MFp 
Where MFa is the mean change in FAACT 12-item A/CS 
domain score in the anamorelin arm and MFTp is the mean 
change in FAACT 12-item A/CS domain score in the 
placebo arm. Similar hypothesis systems are set-up for 
FAACT total score (H0mFt, H1mFt) and FACIT-F (H0mFF, 
H1mFF). 
If the co-primary analysis leads to rejection of H0w and H0a, 
then the following hypothesis will be tested sequentially: 
secondary efficacy endpoint related to the duration of 
treatment benefit in weight (≥0) (H0d0w), the secondary 
efficacy endpoint related to the duration of treatment benefit 

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in weight (≥ to a predefined threshold) (H0dtw), the secondary 
efficacy endpoint related to the duration of treatment benefit 
in 5-IASS (≥0) (H0d0A), the secondary efficacy endpoint 
related to the duration of treatment benefit in 5-IASS ((≥ to a 
predefined threshold) (H0dtA) and then the secondary efficacy 
endpoint related to the mean change in FAACT 12-item 
A/CS domain score (H0mF), FAACT total score and FACIT-
F. Each of these tests will be done sequentially at the level 
of 0.05 bilateral.  
This hierarchy of testing will allow formal confirmation for 
the effect on the primary endpoints as well as on the 
secondary endpoints. This will guarantee the study-wise 
type-1 error, while not requiring any adjustment for multiple 
testing. 
The duration of treatment benefit is measured as the duration 
for which the patient observed a change from baseline 
superior or equal to zero, or to the predefined thresholds of 
clinical meaningfulness. For the purpose of computation, it 
will be assumed a linear evolution between two 
measurements. 
 
Exploratory Efficacy Analysis 
The duration of benefit and mean change from baseline 
endpoints will be analyzed like the main analysis for the 
primary efficacy endpoints or the analyses of the secondary 
endpoints.  
All the change from baseline exploratory endpoints except 
the HAS and the PGIS/C will be analyzed using an 
ANCOVA model, with explanatory variables being the 
randomized treatment, the stratification factors and the 
baseline value.  
All the responder analyses (CCR and achievement of 
responder threshold) will be analyzed using a logistic 
regression, with explanatory variables being the randomized 
treatment, and the stratification factors. 
To explore the correlation between the weight gain and the 
improvement on the patient-reported anorexia score, the 
Pearson’s correlation coefficient will be estimated within 
each treatment group.  

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Statistical Analysis of 
Safety 
All safety and tolerability data will be summarized 
descriptively. 

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STUDY FLOW CHART 
Study Design and Schedule of Assessments (Screening to Week 9) 
Assessment 
Screening 
Visit Day14 
Treatment Period 
Day 
-7 to -1 
1 
22 (+3) 
43 (+3) 
64 (+3) 
Week 
-1 
1 
3 
6 
9 
Visit 
1 
2 
3 
4 
5 
Informed consent1 
X 
 
 
 
 
Medical history 
X13 
 
 
 
 
Physical exam2 
X 
X 
X 
X 
X 
ECOG PS 
X 
 
 
 
X 
Vital signs 
X 
X 
X 
X 
X 
Height and BMI3 
X 
 
 
 
 
Body weight3 
X 
X 
X 
X 
X 
12-Lead ECG4 
X 
X 
X 
X 
X 
Chemistry/Hematology5 
X 
X 
X 
X 
X 
HbA1c 
X 
 
 
 
 
Urine pregnancy6 
X 
X 
 
 
X 
Urinalysis7 
X 
 
 
 
X 
Administer FAACT questionnaire 12-item A/CS domain 
only8, 9 
X 
 
 
 
 
Administer FACIT questionnaires (includes all 4 domains, 
PWB, FWB, SWB, and EWB of FACT-G, 12-item A/CS 
domain and 13-item FACIT-F fatigue domain) and Hunger 
Assessment Scale questionnaires 8, 9 
 
X 
X 
X 
X 
Administer PGIS questionnaires for body weight and 
anorexia8, 9 
X 
 
 
X 
X 
Administer PGIC questionnaires for body weight, anorexia 
and overall condition, 8,9 
 
 
 
X 
X 
CT scan10 
X 
 
 
 
 
Adverse events11 
X 
X 
X 
X 
X 
Prior and concomitant medications (including NSCLC 
treatment)12 
X 
X 
X 
X 
X 
Randomization 
 
X 
 
 
 
Dispense new and/or return blister card for study drug 
dosing; check compliance  
 
X 
X 
X 
X 
1 
Informed consent will be obtained prior to any study-related screening procedures. Procedures may be 
completed over several visits if desired.  
2 
A complete Physical Exam will be conducted and will also focus on evaluation for any signs of pedal 
edema, pericardial effusion, pleural effusions, and ascites. 
3 Height will be measured in cm. Body weight will be measured in kg using a calibrated scale dedicated for 
use in this study, and following study-specific procedures as described in APPENDIX . 

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4 All patients will have a 12-lead ECG performed in triplicate at 1 hour (±5 minutes) post dose at each visit, 
with the exception of Screening Visit (where ECG will be taken only pre-dose) and Visit 2, Day 1 (where 
ECG will be taken also pre-dose).  Every effort will be made to perform ECG at the assigned timepoint. 
5 Chemistry and hematology testing will be done under fasting condition. Hematology: CBC with 
differential count. Chemistry: sodium, potassium, chloride, calcium, total protein, albumin and pre-
albumin, AST (SGOT), alkaline phosphatase (ALP), ALT (SGPT), total bilirubin, creatinine, C-reactive 
protein and glucose. 
6 To be performed for females of childbearing potential within 24 hours prior to the first IMP administration 
on Day 1. If at the screening visit urine pregnancy test has been done within the 24 hours before the first 
IMP administration, no urine pregnancy test is to be performed at Visit 2 (Day 1). 
7 Urinalysis will be performed pre-dose and under fasting conditions and will include: Protein, glucose, 
WBC, erythrocytes, and bacteria. 
8 Patients should complete questionnaires in their native language. Every effort should be made to have the 
patient complete questionnaires alone. If they cannot physically complete the surveys by themselves, then 
site personnel may read the questions to the patients and record their answers, and document details of who 
completed the survey. 
9 
Preferred order of the ePRO administration at each visit is based on importance of endpoints: At screening 
visit FAACT followed by PGIS questionnaires for body weight and anorexia. At Week 1 and Week 3 visits 
FAACT followed by FACT-G, FACIT-F, and HAS. At Week 6 and Week 9 visits: FAACT, FACT-G, 
FACIT-F, PGIS questionnaires for body weight and anorexia, PGIC questionnaires for body weight, 
anorexia and overall condition, and HAS. Of note, the FAACT contains 12 items, and 5 of these items will 
be used to score the 5-item Anorexia Symptom Subscale and 4 of these items will be used to score the 4-
item Anorexia Concerns Subscale (see Section 7.1.2). 
10 All patients will undergo CT scan assessment as per standard local practice for tumor assessment. The 
baseline tumor assessment may have been obtained within 28 days of the first dose of study drug. Any 
tumor assessment outside of the screening visit will be assessed and recorded; for details, please see 
Section 7.2.7. 
11 Adverse events will be collected from Informed consent signature up to the end of the study Week 26 
(Visit 11). SAEs must be reported within 24 hours. 
12 Baseline NSCLC treatment regimen will be captured at screening and adherence to this, and all future 
regimens will be captured throughout the treatment period. 
13 Information on histological or cytological tumor type, genotype and treatment will be collected. 
14 On study days that coincide with chemotherapy administration, all study procedures should be obtained 
prior to administration of chemotherapy. Patients should arrive for visits prior to dosing, and every effort 
should be made to have patient blood draws under fasted conditions; fasting status will be documented 
within the CRF. Patients who withdraw from study prematurely will be requested to complete the Day 64 
visit (Week 9) procedures. 

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Study Design and Schedule of Assessments (Week 12 to 26) 
Assessment 
Visit Day9 
Treatment Period 
Follow-up 
Period10 
(telephone) 
Day 
85 (+3) 
106 (+3) 
127 (+3) 
148(+3) 
169 (+3) 
183 (+3) 
Week 
12 
15 
18 
21 
24 
26 
Visit 
6 
7 
8 
9 
10 
11 
Physical exam1 
X 
X 
X 
X 
X 
 
Vital signs 
X 
X 
X 
X 
X 
 
Body weight2 
X 
X 
X 
X 
X 
 
12-Lead ECG 
X 
X 
X 
X 
X 
 
Chemistry/Hematology3 
X 
X 
X 
X 
X 
 
HbA1c 
X 
 
 
 
X 
 
Urine pregnancy testing (women of 
childbearing potential only) 
 
 
 
 
X 
 
Urinalysis4  
 
 
 
 
X 
 
Administer FACIT questionnaires (includes 
all 4 domains, PWB, FWB, SWB, and EWB 
of FACT-G, 12-item A/CS domain and 13-
item FACIT-F fatigue domain) and Hunger 
Assessment Scale questionnaires5 
X 
X 
X 
X 
X 
 
CT scan6 
X 
 
 
 
 
 
Adverse events7 
X 
X 
X 
X 
X 
X 
Concomitant medications (including 
chemotherapy)8 
X 
X 
X 
X 
X 
 
Dispense new and/or return blister card for 
study drug dosing; check compliance  
X 
X 
X 
X 
End 
 
1 Physical Exam will focus on evaluation for any signs of pedal edema, pericardial effusion, pleural 
effusions, and ascites. 
2 Body weight will be measured in kg using a calibrated scale dedicated for use in this study and following 
study-specific procedures as described in APPENDIX 2. 
3 All tests will be done under fasting condition. Hematology: CBC with differential count. Chemistry: 
sodium, potassium, chloride, calcium, total protein, albumin and pre-albumin, AST (SGOT), alkaline 
phosphatase (ALP), ALT (SGPT), total bilirubin, creatinine, C-reactive protein and glucose. 
4 Urinalysis will be performed pre-dose and under fasting conditions and will include: Protein, glucose, 
WBC, erythrocytes, and bacteria. 
5 Patients should complete questionnaires in their native language. Every effort should be made to have the 
patient complete questionnaires alone. If they cannot physically complete the surveys by themselves, then 
site personnel may read the questions to the patients and record their answers, and document this. Order 
of questionnaires should be the 12-item FAACT, FACT-G, FACIT-F, and HAS. 
6 All patients will undergo CT scan assessment as per standard local practice for tumor assessment. Any 
tumor assessment outside of the screening visit will be assessed and recorded (please see Section 7.2.7). 
7 Adverse events will be collected from Informed consent signature up to the end of the study Week 26 
(Visit 11, follow-up visit). All SAEs must be reported within 24 hours.  
8 Adherence to baseline NSCLC treatment regimen and all future regimens will be captured throughout the 
treatment period. 

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9 On study days that coincide with chemotherapy administration, all study procedures should be obtained 
prior to administration of chemotherapy. Patients should arrive for visits prior to dosing, and patient 
blood draws under fasted conditions; fasting status will be documented within the CRF. Patients who 
withdraw prematurely will be requested to complete the Day 183+3 visit (Week 26) procedures. 
10 Follow- up visit on Day 183 +3 (Visit 11) will be conducted by telephone. 
 

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LIST OF ABBREVIATIONS 
A/CS 
12-item Additional Concerns Subscale of the FAACT 
ADL 
Activities of Daily Living  
AE 
Adverse Event 
AESI 
Adverse Events of Special Interest 
AJCC 
American Joint Committee on Cancer  
ALP 
Alkaline Phosphatase 
ALT 
Alanine transaminase (SGPT) 
ANC 
Absolute Neutrophil Count 
AST 
Aspartate transaminase (SGOT) 
BDRM 
Blind Data Review Meeting 
BMI 
Body Mass Index 
CBC 
Complete Blood Count 
CCR 
Composite Clinical Response 
CI 
Confidence interval 
CRO 
Clinical Research Organization 
CT 
Computerized Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
Cytochrome P450  
EC50 
half maximal Effective Concentration 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
ECOG PS 
Eastern Cooperative Oncology Group Performance Status  
eCRF 
Electronic Case Report Form 
EDC 
ePRO 
Electronic Data Capture 
Electronic Patient Reported Outcome 
EGFR 
Epidermal Growth Factor Receptor 
FAACT 
Functional Assessment of Anorexia/Cachexia Treatment 
FACIT 
Functional Assessment of Chronic Illness Therapy 
FACIT-F 
Functional Assessment of Chronic Illness Therapy-Fatigue 
FACT-G 
Functional Assessment of Cancer Therapy - General 

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FAS 
Full Analysis Set  
GCP 
Good Clinical Practice 
GH 
Growth Hormone 
GI 
Gastrointestinal 
H0 
Null hypothesis 
H1 
Alternative hypothesis 
HbA1c 
Hemoglobin A1c 
5-IASS 
5-Item Anorexia Symptoms Subscale 
IC 
Informed Consent  
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 
IWRS 
Interactive Web Response System 
LBM 
Lean Body Mass 
LS 
Least Squares 
MedDRA 
Medical Dictionary for Regulatory Activities  
MI  
Multiple Imputation  
MITT 
Modified Intent-to-Treat 
NCI 
National Cancer Institute 
NSCLC 
Non-Small Cell Lung Cancer 
OR 
Odds Ratio 
PCS 
Potentially Clinically Significant 
PD-1 
Programmed cell death protein 1 
PD-L 1 
Programmed death-ligand 1 
PE 
Physical Examination 
PGIC 
Patient Global Impression of Change 
PGIS 
Patient Global Impression of Severity 
PI 
Principal Investigator 
The investigator who leads the study conduct at an individual study center.  
Every study center has a principal investigator. 
PK 
Pharmacokinetic 

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PP 
Per protocol 
PR 
Interval from beginning of the P wave to the beginning of the QRS 
Q1 
First quartile 
Q3 
Third quartile 
QD 
Once Daily 
QRS 
Duration of QRS complex in the frontal plane 
QT 
Interval from beginning of the QRS complex to end of the T wave in the 
frontal plane 
QTc  
Corrected QT interval 
QTcF 
Fridericia-corrected QT interval 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD  
Standard Deviation 
SGOT  
Serum Glutamic Oxaloacetic Transaminase (AST) 
SGPT 
Serum Glutamic Pyruvic Transaminase (ALT) 
SOC 
 
System Organ Class 
SUSAR 
Suspected Unexpected Serious Adverse Reaction  
TEAE 
Treatment-Emergent Adverse Event 
TOI 
Trial Outcome Index 
ULN 
Upper limit of normal 
USA 
United States of America 

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1 INTRODUCTION AND RATIONALE 
1.1 
Background Information 
Weight loss and anorexia are among the symptoms that characterize cancer cachexia, a 
multifactorial syndrome that occurs in more than 80% of patients with cancer before 
death [Kumar-2010; von Haehling-2010; Aoyagi-2015].  
Following the current consensus criteria cancer cachexia is primarily diagnosed either by 
[Fearon-2011]:  
- recent weight loss > 5% over past 6 months (in absence of simple starvation), or  
- recent weight loss > 2% and body-mass index (BMI) <20 kg/m2, or  
- sarcopenia.  
Reduced food intake in patients with cancer is caused by primary anorexia and can be 
compounded by secondary nutrition impact symptoms; according to a number of reports, 
cancer patients describe weight loss and anorexia symptoms as sources of concern/worry, 
with significant impacts on their daily lives [Hinsley-2007; Hopkinson-2014; McGrath-
2002; Hopkinson-2015; Oberholzer-2013]. 
To better understand the experiences of weight loss/low BMI in lung cancer patients, 
Helsinn collaborated with PatientsLikeMe [Rodriguez-2017], an online patient network 
that connects patients and facilitates research. Ninety-five patients participated in an 
online survey, and 35 of them (36.8%) were classified as having considerable weight loss 
(defined as ≥ 5% loss of body weight in the past 6 months or ≥ 2% for a BMI less than 20 
kg/m2). Weight loss was found to represent a substantial problem for NSCLC patients, 
associated with lower quality of life, higher distress level and more severe symptoms 
(including appetite loss).  Patients were also asked to identify which symptoms they 
experience because of their weight loss had the most significant impact on their life. For 
these patients the most frequently reported symptoms with significant impacts were 
changes in food taste (38%), fatigue (38%), and decrease in appetite (33%); early satiety, 
which is another relevant component of anorexia together with food taste and decreased 
appetite, was also noted as a symptom having a significant impact in 14% of the patients 
surveyed [Rodriguez-2017].  
Anorexia is a major contributor to the weight loss. Anorexia in cancer may be 
characterized as a general loss of appetite, early satiety, altered food preferences, or a 
combination of these [Molfino-2015]. Cancer related anorexia is also a major clinical 
problem and adversely influences nutritional status in advanced cancer [Yavuzsen-2005] 
and has been associated with poorer survival in multiple studies [Montazeri-2009; 
Sundstrøm-2006; Fielding-2007; McKernan-2008; Collette2004Yeo-2006; Sullivan-
2006]. Anorexia is the second most common symptom after fatigue in patients with 
advanced cancer [Lis-2009]. In a study conducted by Sundstrom et al. appetite loss 
emerged as the most significant independent indicator for survival in advanced NSCLC 
patients and concluded that assessment of anorexia, including appetite loss is a valuable 
tool in determining thoracic radiotherapy strategy [Sundstrøm-2006]. 

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Reduced dose intensity of chemotherapy and increased toxicity have been noted in 
patients with weight loss, which can be of sufficient severity to require dose reductions, 
treatment delays or definitive termination of treatment, such that weight-losing patients 
do not achieve the full potential benefit of their cancer therapy [Ross -2004; Andreyev-
1998]. Furthermore, in a study in advanced NSCLC patients comparing non-weight 
losing patients to weight losing/underweight patients (≥5% weight loss in prior 6 months 
or >2% weight loss with BMI<20 kg/m2), it was found that all patient-reported outcome 
(PRO) measures (FACT-G and specific domains from FAACT, FACIT-F, FACIT-L) and 
performance status (Karnofsky PS and ECOG) were worse in the weight 
losing/underweight patients compared to non-weight losing patients, and that while all 
these measures declined over a 6 month period, the rate of decline was more rapid in the 
weight-losing/underweight group [LeBlanc-2015]. 
In summary, weight loss, along with anorexia (including appetite loss), are common, 
debilitating, and concerning occurrences for advanced cancer patients. Despite the high 
prevalence and the association with poor prognosis, there has been a lack of therapeutic 
advance in managing these symptoms of advanced cancer patients, and pharmacological 
interventions remain limited.  
Therefore, the treatment of malignancy associated weight loss and anorexia in cancer 
patients are an area of unmet medical need. 
Anamorelin HCl is an orally-active selective ghrelin receptor agonist. Ghrelin is the 
endogenous ligand for the G-protein-coupled ghrelin receptor, GRLN (formerly known 
as the growth hormone [GH] secretagogue receptor, GHS-R) [Kojima-1999]. It is 
synthesized predominantly in the stomach and has a short circulating half-life (~15 
minutes) in both animals and humans, which limits its therapeutic potential since long-
term efficacy would necessitate continuous infusion. Nevertheless, research into the 
effects of ghrelin or longer-acting ghrelin mimetics has revealed that ghrelin possesses 
anabolic, appetite-enhancing, adiposity-increasing, and anti-inflammatory properties 
[Guillory-2013]; along with GI-prokinetic activity [Trudel-2002].  
In vitro, anamorelin displays high affinity and selective binding to the ghrelin receptor 
and is a highly potent GH secretagogue by in vitro assay (EC50 = 1.5 nM). In vivo, 
anamorelin HCl elicited a robust GH release following oral administration to dogs and a 
potent appetite enhancing effect in rats following intracerebral administration; increases 
in food intake and body weight were also noted in animal models [Trudel-2002]. In 
clinical studies, anamorelin treatment is also associated with increases in appetite and 
body weight, along with gains in lean body mass (LBM) and improvements in health-
related QoL measures [Temel-2016; Currow-2014]. 
1.2 
Anamorelin: preclinical and clinical data 
1.2.1 
Preclinical Data 
The pharmacological profile of anamorelin was studied in vitro and in vivo models. In 
particular anamorelin was screened for specificity against over 100 receptors, enzymes, 
transporters and ion channels. Moreover, cardiovascular and other safety pharmacology 
studies were conducted. Studies were conducted to determine the absorption, distribution, 

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metabolism and excretion of anamorelin in rats and mice. Toxicology studies were 
carried out in rats and dogs, including single and repeated-dose studies for up to 26-week 
duration. Additional toxicology studies were performed to evaluate potential effects on 
fertility in rats, embryo-fetal development in rats and rabbits and assess the effects on 
tumor growth in mice. Overall, these studies allowed to characterize the non-clinical 
profile of anamorelin as required to support its clinical development and marketing 
authorization applications in the future. 
A detailed description of the preclinical data available is provided in the relevant sections 
of the Investigator’s Brochure.   
1.2.2 
Phase 1 Clinical Data 
Anamorelin HCl has been studied in 12 Phase 1 studies in healthy volunteers of both 
genders including elderly with dosing up to 400 mg for a single-dose and up to 150 mg 
for multiple-doses. Anamorelin HCl increased GH, insulin-like growth factor-1, and 
insulin-like growth factor binding protein-3 and produced the desired biologic effects of 
significant appetite stimulation, increase of food intake, body weight gain. The threshold 
dose for body weight gain is 50 mg once daily (QD). QD dosing in the fasting state is 
appropriate for anamorelin HCl; a split dose regimen offers no advantage over QD dosing 
and available data suggest that it may be less efficacious. No dose-limiting toxicity was 
observed up to 150 mg with multiple dosing; a single dose of 400 mg was determined to 
be the maximum tolerated dose. A significant drug-drug interaction was observed with 
CYP3A4 perpetrators. CYP2D6 inhibition did not cause a clinically meaningful 
interaction with anamorelin HCl. 
The most common adverse events observed from Phase 1 studies were fatigue, headache, 
diarrhea, visual focus impairment, and dizziness. The primary adverse events of special 
interest from the Phase 1 studies included increases in serum transaminases and 
electrocardiogram (ECG) abnormalities including transient PR, QRS and QT 
prolongations at the supratherapeutic doses of 300 and 400 mg (based on 24-hour Holter 
monitoring data from Study HT-ANAM-112). Of note, none of the QTcF absolute values 
were above 450 ms. The PR, QRS and QT increases were considered not clinically 
significant by the Investigator. To better assess the ECG effects of anamorelin HCl, a 
thorough QT/QTc study (Study HT-ANAM-113) was then conducted, and the overall 
results showed that anamorelin had no meaningful effect on ventricular repolarization. 
1.3 
Other Clinical Data 
Anamorelin HCl was additionally evaluated in one Phase 2 program (including four 
studies), and in one Phase 3 program (including two studies) where 361 and 972 patients, 
respectively, were treated for a total of 915 patients with cancer treated with anamorelin 
HCl. 
Phase 2 program consisted of studies RC-1291-203/205 and RC-1291-206 which 
evaluated a total of 135 patients with a variety of tumor types and weight loss, while the 
fourth Phase 2 study- Study ST-ANAM-207 included 226 patients with NSCLC and 
randomized patients 1:1:1 to placebo, anamorelin HCl 50 mg, or anamorelin HCl 100 mg. 

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The Phase 2 program demonstrated that anamorelin HCl significantly increased LBM and 
body weight. Treatment with anamorelin HCl at dose levels of 50 mg and 100 mg QD for 
up to 12 weeks was generally well tolerated. No dose limiting toxicity was observed. 
The Phase 3 ROMANA program consisted of two studies (HT-ANAM-301 and HT-
ANAM-302) and an associated safety extension study (HT-ANAM-303) and together 
evaluated a total of 972 NSCLC patients for up to 24 weeks.  
Results from HT-ANAM-301 and HT-ANAM-302 demonstrated that patients assigned to 
anamorelin experienced an increase in lean body mass, body weight and improvement in 
their anorexia/cachexia symptoms compared to those assigned to placebo in both the 
studies, but no difference in handgrip strength was observed.  
In a Phase 3, multicenter, open-label, uncontrolled non-Helsinn sponsored clinical study 
conducted in Japan (ONO-7643-05), at a dose level of 100 mg QD of anamorelin for 12 
weeks, the proportion of patients with cancer cachexia who maintained or gained lean 
body mass was 63.3% (31/49 subjects). Moreover, patients experienced an increase in 
body weight, improved appetite, stimulated protein synthesis, as measured by biomarkers 
IGF-1 and IGFBP-3, and improved the nutritional status, as measured by prealbumin.  
In another Phase 3 multicenter, open-label, uncontrolled non-Helsinn sponsored clinical 
study conducted in Japan (ONO-7643-06), at a dose level of 100 mg QD of anamorelin 
for 24 weeks, the increase in body weight and the improved appetite in patients with 
cancer cachexia were confirmed, and its efficacy was maintained throughout the 24-week 
treatment period.  
Safety results from Phase 3 ROMANA program indicated that anamorelin HCl was well 
tolerated.  
A positive safety profile was also confirmed in studies ONO-7643-05 and ONO-7643-06; 
although there was a high incidence of adverse drug reactions related to the increased 
blood glucose and cardiac function, no event was indicative of a significant risk. 
Additional information on currently available clinical data is provided in the relevant 
sections of the Investigator’s Brochure. 
The primary purpose of the present ANAM-17-21 study is to further evaluate the impact 
of anamorelin HCl on body weight and anorexia symptoms in patients with advanced 
non-small cell lung cancer (NSCLC). 
1.4 
Study Rationale 
1.4.1 
Rationale for Study Population 
This study will be conducted in adult patients with advanced NSCLC. Patients with 
NSCLC are being chosen for investigation because of the prevalence of weight loss and 
anorexia and the prognostic implications of weight loss for these patients including 
reduced quality of life and increased symptom burden, as well as shortened survival.  
Among patients with NSCLC, those with BMI < 20 kg/m2 represent a more 
malnourished/at-risk population, which therefore has a more pressing need for an 

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effective therapy to address weight loss and anorexia symptoms. Therefore ANAM-17-21 
will enroll only patients with BMI < 20 kg/m2 and will also require >2% weight loss over 
the past 6 months to better align with the consensus definition of anorexia-cachexia 
[Fearon-2011]. In addition, as this study is investigating improvements in anorexia 
symptoms, patients enrolled must also demonstrate ongoing problems with their 
appetite/eating. 
1.4.2 
Rationale for Study Protocol and Design 
Helsinn is proposing to target weight loss and anorexia in cancer cachectic patients, as 
these two conditions are rated amongst the top concerns of these advanced stage patients 
and there are currently limited treatment options. This study will be an adequate and 
well-controlled study designed to demonstrate superiority of anamorelin HCl vs placebo 
on the gain in body weight and improvement in anorexia symptoms.  
A total of 316 patients with advanced NSCLC with cachexia will be randomized 1:1 to 
anamorelin HCl 100 mg or placebo, taken orally once daily for a total of 24 weeks. 
In this study, the primary and secondary efficacy analysis will be conducted at 12 weeks. 
Additional exploratory efficacy and safety analyses will also be conducted at 24 weeks in 
order to collect data over longer treatment duration.   
1.4.3 
Rationale for Selected Dose Range 
In this study, 100 mg was selected as the dose of anamorelin HCl. This 100 mg dose had 
been evaluated in previously conducted Phase 3 studies (HT-ANAM-301 and HT-
ANAM-302) in NSCLC patients indicating that it was well tolerated and had a positive 
anabolic effect through both increased body weight and lean mass. An improvement in 
cancer anorexia symptoms/concerns in patients with NSCLC-C was also observed. In the 
safety extension study (HT-ANAM-303), whereby patients from Studies HT-ANAM-
301/302 continued dosing for up to an additional 12 weeks, a 100 mg dose level was also 
well tolerated, with no new safety signals identified in the longer dosing period. 
Due to the lack of safe and effective treatments for weight loss and anorexia in cancer 
patients with cachexia, placebo treatment will be used in the control group in this study.  
1.5 
Rationale for protocol amendment 
Further to FDA advice obtained on the primary endpoints analysis, the Sponsor redefined 
the primary efficacy endpoints to duration of treatment benefit from baseline to Week 12 
for body weight and anorexia (5-IASS). Based on this new approach a redefinition of the 
secondary and exploratory endpoints was also included. Such changes were implemented 
in protocol v4.0 dated 22 Mar 2021 and 4.A dated 03 Sep 2021.  
However, during the course of the study, an error was discovered in the algorithm used to 
determine the statistical power for the evaluation of the duration of treatment benefit 
from baseline to Week 12 for body weight and anorexia (5-IASS) co-primary endpoints.   
Corrected calculations revealed that each trial, with the current planned sample size of 
316 patients, would be underpowered for the 5-IASS endpoint. Indeed, new simulations 

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correcting for the programming error were performed and these results confirmed high 
power (over 98%) for the weight-based co-primary endpoint but showed low power for 
the 5-IASS co-primary endpoint (between 60% and 70%).  
Based on corrected simulations and calculations, obtaining an acceptable power would 
require to at least double the sample size.  
At the current stage of the studies, such a huge change in sample size would be of great 
impact for cachectic cancer patients who are looking at anamorelin as the only promising 
investigational agent in development for treating the two important unmet needs of 
malignancy associated weight loss and anorexia and hoping in its prompt approval.  
The Sponsor endorses the importance of having two adequate and well controlled trials, 
each achieving statistical significance. To achieve a proper power for the analysis of the 
5-IASS co-primary endpoint, the Sponsor will perform the analysis by adopting same 
methodological approach and same variables, i.e., two co-primary endpoints still keeping 
body weight and 5-IASS as efficacy variables, but measuring the mean change from 
baseline in replacement of the duration of treatment benefit, as defined based on scientific 
and clinical experts’ feedback and confirmed as a feasible endpoint by sample size 
calculations. 
 
2 STUDY OBJECTIVES 
2.1 
Primary Objective 
To demonstrate superiority of anamorelin HCl vs placebo on the gain in body weight and 
improvement in anorexia symptoms. 
2.1.1 
Estimand 
The analysis to address this objective has been developed in consideration of ICH Topic 
E9(R1) Statistical Principles for Clinical Trials: Note for Guidance on Statistical 
Principles in Clinical Trials [ICH-1998]. Specifically, we have anticipated two 
intercurrent events: study drug discontinuation and death. We consider appropriate to 
assess a treatment effect “regardless of” whether patients continue with treatment or not. 
Therefore, we will implement a treatment policy estimand. Efforts will be made to retain 
all patients in study follow-up whether they have discontinued the study treatment or not. 
The method of data imputation will take into account that patients have discontinued 
study treatment. Deaths likely will be due to underlying disease. The aim of anamorelin 
treatment is to increase body weight and improve anorexia symptoms while the patient is 
alive. Hence, it is necessary and sufficient to obtain regular assessments on body weight 
and anorexia symptoms between randomization and death. 
 

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2.2 
Secondary Objectives 
To evaluate the safety and tolerability of anamorelin HCl, and to further evaluate 
anamorelin efficacy profile. 

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3 STUDY ENDPOINTS  
3.1 
Efficacy Endpoints 
3.1.1 
Primary Efficacy Endpoint 
The co-primary efficacy endpoints are: 
• Mean change in body weight from baseline over 12 weeks. 
• Mean change in 5-item Anorexia Symptom Subscale from baseline over 12 
weeks. 
3.1.2 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints are: 
• Duration of treatment benefit in weight (≥0) from baseline over 12 weeks. 
• Duration of treatment benefit in weight (≥ to a predefined threshold) from 
baseline over 12 weeks. 
• Duration of treatment benefit in anorexia symptoms (≥0) from baseline over 
12 weeks, as measured by the 5-item Anorexia Symptom Subscale. 
• Duration of treatment benefit in 5-item Anorexia Symptom Subscale (≥ to a 
predefined threshold) from baseline over 12 weeks. 
The duration of treatment benefit is measured as the duration for which the patient 
observed a change from baseline superior or equal to zero, or to the predefined thresholds 
of clinical meaningfulness, the latter defined through a fully anchor based method using 
PGIS and PGIC as anchors.  
• Mean change in FAACT 12-item A/CS domain from baseline over 12 weeks. 
• Mean change in FACIT-F from baseline over 12 weeks. 
• Mean change in FAACT total score from baseline over 12 weeks. 
3.1.3 
Exploratory Efficacy Endpoints 
• Mean change in body weight from baseline up to Week 6, 9, 15, 18, 21, and 24. 
• Mean change in patient-reported anorexia symptoms from baseline up to Week 6, 9, 
15, 18, 21, and 24, as measured by the 5 item Anorexia Symptom Subscale. 
• Mean change in FAACT total score from baseline up to Week 6, 9, 15, 18, 21, and 24. 
• Composite Clinical Response (CCR) at Week 3, 6, 9, 12, 15, 18, 21, and 24. 
• Change in body weight from baseline to Week 3, 6, 9, 12, 15, 18, 21, and 24. 
• Change in patient-reported anorexia symptoms from baseline to Week 3, 6, 9, 12, 15, 
18, 21, and 24 as measured by the 5-item Anorexia Symptom Subscale. 

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• Achievement of a clinically meaningful gain in body weight from baseline to Week 3, 
6, 9, 12, 15, 18, 21, and 24. 
• Achievement of a clinically meaningful increase in 5-item Anorexia Symptom 
Subscale from baseline to Week 3, 6, 9, 12, 15, 18, 21, and 24. 
• Percentage of change in body weight from baseline to Week 3, 6, 9, 12, 15, 18, 21, and 
24. 
• Changes from baseline to Week 3, 6, 9, 12, 15, 18, 21, and 24 in the FAACT 
(including FAACT total score, FACT-G total score, FAACT TOI, the 12-item A/CS 
domain and the 4-item Anorexia Concerns Subscale derived from the FAACT). 
• Changes from baseline to Week 3, 6, 9, 12, 15, 18, 21, and 24 in patient-reported 
fatigue as measured by the Functional Assessment of Chronic Illness Therapy-
Fatigue (FACIT-F) domain as well as the FACIT-F TOI score. 
• Changes from baseline to Week 3, 6, 9, 12, 15, 18, 21, and 24 in the Hunger 
Assessment Scale.  
• Changes from baseline to Week 6 and 9 in the Patients’ Global Impression of 
Severity (PGIS) scale and the Patients' Global Impression of Change (PGIC) scale at 
Week 6 and 9. 
3.2 
Safety Assessments 
The following safety assessments will be performed: physical examination (PE), vital 
signs, 12-lead electrocardiogram (ECG), laboratory test (hematology, blood chemistry, 
urinalysis), adverse events (AEs) assessment, tumor assessment using CT scan and the 
overall survival on all patients. 
Overall Survival 
• Overall survival up to the end of study (i.e., week 26, follow-up visit). 
Tumor Assessments 
• Change in tumor assessment (overall response categorized into complete response, 
partial response, stable disease and progressive disease) using CT scans at all sites as 
per standard local practice. For additional information please refer to Section 7.2.7. 

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4 STUDY PLAN 
4.1 
Study Design 
The study is a multicenter, randomized, double-blind, parallel-group, placebo-controlled 
study to evaluate the efficacy and safety of anamorelin HCl. Approximately 316 patients 
with advanced NSCLC with cachexia will be randomized 1:1 to anamorelin HCl 100 mg 
or placebo, taken orally once daily (QD) for a total of 24 weeks. Patients will be 
instructed to take the study drug at least 1 hour before their first meal of the day.  
Central randomization will be stratified by line of systemic anti-cancer treatment (first 
line vs second line vs third line), by type of anti-cancer therapy (immunotherapy vs non-
immunotherapy) and by Baseline score of 5-item Anorexia Symptom Subscale (≤10 vs 
>10). Patients will visit the site every 3 weeks for the study duration of 24 weeks. A 
follow-up telephone visit is scheduled at Week 26. 
Regarding Patients that never received anticancer treatment prior to enter the study, still 
qualifying to participate following full compliance to eligibility criteria, will be eligible 
to enter the study and will be allocated to first line treatment in IWRS. 
4.2 
Study Duration  
Each patient will stay on study for a maximum of 27 Weeks (including 1 week screening 
period and 2 weeks follow-up period). 
Total number of visits per patient: 10 visits plus 1 telephone contact for follow-up visit. 
The study will be approximately 27 Weeks in duration including the following:  
• A screening period from Day -7 to -1 (on-site Visit 1) 
• A 24-week treatment period (on-site Visit 2 to Visit 10) 
• A 2-week follow-up period (telephone Visit 11) 
A patient will be defined as having completed the Study if patient completes the follow-
up visit (Visit 11). 
The overall study completion date is defined as the date of last patient’s last visit or 
telephone contact. 
4.3 
Study population 
4.3.1 
Number of Subjects 
A total of 316 patients with advanced NSCLC with cachexia will be randomized 1:1 to 
anamorelin HCl 100 mg or placebo (158 patients per treatment arm). 
4.3.2 
Inclusion Criteria 
1. Signed written informed consent. 
2. Female or male ≥18 years of age. 

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3. Documented histologic or cytologic diagnosis of American Joint Committee on 
Cancer (AJCC) Stage III or IV NSCLC. Stage III patient must have unresectable 
disease. 
4. Body mass index < 20 kg/m2 with involuntary weight loss of >2% within 6 months 
prior to screening. 
5. Ongoing problems with appetite/eating associated with the underlying cancer, as 
determined by having score of ≤ 17 points on the 5-item Anorexia Symptom Scale 
and ≤ 37 points on the 12-item FAACT A/CS. 
6. Patient receiving or not receiving systemic anti-cancer treatment at the time of 
screening are eligible to participate. Systemic anti-cancer treatment includes first, 
second, third treatment line with chemotherapy/radiation therapy, immunotherapy or 
targeted therapy.   
Patient not receiving anti-cancer treatment is eligible if: 
a. 
Not planning to receive anti-cancer treatment and/or at least 14 days must be 
elapsed from the completion of prior treatment at the day of screening, in case 
underwent previous cycle,  
OR 
b. Planning to receive anti-cancer treatment within 14 days from randomization 
and/or at least 14 days must be elapsed from the completion of prior treatment at 
the day of screening, in case underwent previous cycle, 
OR 
c. 
Patient on palliative care treatment. 
7. ECOG performance status 0, 1 or 2 at screening (see protocol APPENDIX 1) 
8. AST (SGOT) and ALT (SGPT) ≤ 3 x ULN or if hepatic metastases are present ≤ 5 x 
ULN. 
9. Adequate renal function, defined as creatinine ≤2 × ULN, or calculated creatinine 
clearance >30 ml/minute.  
10. Female patient shall be: a) of non-childbearing potential or b) of childbearing 
potential using reliable contraceptive measures and having a negative urine 
pregnancy test within 24 hours prior to dose of investigational product* 
Notes:  
a) Female patient of non-childbearing potential is defined as being in post-menopausal state since at 
least 1 year; or having documented surgical sterilization or hysterectomy at least 3 months before 
study participation.  
b) Reliable contraceptive measures include implants, injectables, combined oral contraceptives, 
intrauterine devices, vasectomized partner or complete (long term) sexual abstinence. 
11. The patient must be willing and able to comply with the protocol tests and 
procedures.  
All inclusion criteria will be checked at screening visit (Visit 1).  

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*Inclusion criterion #10 will be re-checked and verified at Day 1 (Visit 2). 
4.3.3 
Exclusion Criteria 
1. Patient with other forms of lung cancer (e.g., small cell, neuroendocrine tumors).  
2. Woman who is pregnant or breast-feeding. 
3. Reversible causes of reduced food intake, as determined by the Investigator*. These 
causes may include, but are not limited to: 
a. 
NCI CTCAE Grade 3 or 4 oral mucositis, 
b. NCI CTCAE Grade 3 or 4 GI disorders [nausea, vomiting, diarrhea, and 
constipation], 
c. 
mechanical obstructions making patient unable to eat, or 
d. severe depression. 
4. Patient undergoing major surgery (central venous access placement and tumor 
biopsies are not considered major surgery) within 4 weeks prior to randomization.  
Patient must be well recovered from acute effects of surgery prior to screening.  
Patient should not have plans to undergo major surgical procedures during the 
treatment period. 
5. Patient currently taking androgenic compounds including but not limited to 
testosterone, testosterone-like agents, oxandrolone; 
Megestrol acetate;  
Corticosteroids [for details see Section 5.13.1]; 
Olanzapine, mirtazapine (however, long-term use of mirtazapine for depression for at 
least four weeks prior to screening is allowed); 
Dronabinol;  
Marijuana (cannabis), or  
Any other prescription medication or off-label products intended to increase appetite 
or treat unintentional weight loss* 
6. Patient with pleural effusion requiring thoracentesis, pericardial effusion requiring 
drainage, edema or evidence of ascites* 
7. Patient with uncontrolled or significant cardiovascular disease, including: 
a. 
History of myocardial infarction within the past 3 months 
b. A-V block of second or third degree (may be eligible if currently have a 
pacemaker) 
c. 
Unstable angina 
d. Congestive heart failure within the past 3 months, if defined as NYHA class III-
IV  

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e. 
Any history of clinically significant ventricular arrhythmias [such as ventricular 
tachycardia, ventricular fibrillation, Wolff-Parkinson-White (WPW) syndrome, 
or torsade de pointes] 
f. 
Uncontrolled hypertension (blood pressure >150 mm Hg systolic and >95 mm 
Hg diastolic) 
g. Heart rate < 50 beats per minute on pre-entry electrocardiogram and patient is 
symptomatic.* 
8. Patient on drugs that may prolong the PR or QRS interval durations, such as any of 
the antiarrhythmic medications Class I (Fast sodium (Na) channel blockers) 
9. Patient unable to readily swallow oral tablets*.   
10. Patient with severe gastrointestinal disease (including esophagitis, gastritis, 
malabsorption).  
11. Patient with history of gastrectomy.  
12. Patient with uncontrolled diabetes mellitus or unmonitored diabetes mellitus.  
13. Patient with cachexia caused by other reasons, as determined by the investigator such 
as: 
a. 
Severe COPD requiring use of home O2,  
b. New York Heart Association (NYHA) class III-IV heart failure 
c. 
AIDS 
d. Uncontrolled thyroid disease. 
14. Patient receiving strong CYP3A4 inhibitors within 14 days of randomization (see 
APPENDIX 3) 
15. Patient currently receiving tube feedings or parenteral nutrition (either total or 
partial).   
16.  Current excessive alcohol or illicit drug use.  
17. Any condition, including the presence of laboratory abnormalities, which in the 
Investigator’s opinion, places the subject at unacceptable risk if he/she were to 
participate in the study or confounds the ability to interpret data from the study.  
18. Enrollment in a previous study with anamorelin HCl. 
19. Patient actively receiving a concurrent investigational agent or having received an 
investigational agent within 28 days of Day 1. 
All Exclusion Criteria should be checked at the day of screening visit (Visit 1).  
*Exclusion Criteria #3, 5, 6, 7g, and 9 are to be re-checked and verified before study drug 
administration (Visit 2). 

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5 STUDY DRUG MANAGEMENT 
5.1 
Description of Study Treatments 
Investigational product  
Name: 
Anamorelin HCl 
Dosage form: 
Tablets 
Strength: 
100 mg 
Dosing 
At least 1 hour before the first meal of the day 
Route of 
administration: 
Oral 
Placebo 
Name:  
Placebo to match 100 mg tablets 
Dosage form: 
Tablets 
Strength: 
N/A 
Dosing: 
At least 1 hour before the first meal of the day 
Route of 
administration: 
Oral 
5.2 
Treatment Groups 
Group 1 / Test group – 100 mg anamorelin HCl 
Group 2 / Control group – Placebo 
5.3 
Dose and Administration 
Investigational product: Anamorelin HCl 
Patients will take 1 tablet on Day 1 and daily thereafter. Patients will be supplied with 
study drug at visit 2 and re supplied at Visit 3 (Week 3), Visit 4 (Week 6), Visit 5 (Week 
9), Visit 6 (Week 12), Visit 7 (Week 15), Visit 8 (Week 18) and Visit 9 (Week 21). 
Tablets of study drug will be taken orally in mornings while fasting at least 1 hour before 
breakfast. Water is permitted prior to and with study drug. 
5.4 
Packaging, Labelling and Shipment 
Study drug will be primary packed in the form of blisters; this will be secondary packed 
in form of carton wallet cards. Each wallet card will contain either 100 mg anamorelin 
HCl tablets or matching placebo tablets. The amount of tablets to be used for a single 3-
weeks cycle of treatment will be included in the wallet card, that will be labelled with 
individual kit number for identification. 
5.5 
Storage 
An exact inventory of all study kits must be maintained at the investigational site.  The 
study kits must be stored in a locked storage area under controlled environmental 

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conditions appropriate for the product. Anamorelin HCl tablets and placebo tablets 
should be stored at 20°C-25°C (68°F-77°F); excursions permitted between 15°C and 
30°C (59°F-86°F). 
5.6 
Drug Depots 
The study kits will be shipped to clinical sites either from central depot, or from local 
drug depots as applicable for further distribution to sites. Study kits shipments to the 
investigational sites are triggered via the IWRS. 
5.7 
Accountability 
Once the study kits are received at the study site, the pharmacist or designated 
responsible person will record receipt of study kits both in dedicated paper forms and via 
IWRS. Adequate records of the receipt, dispensation and return of study kits must be 
maintained throughout the study.  
Used study kits will undergo drug accountability performed by the study monitor during 
the course of the study. 
Following drug accountability, used study kits are to be retained at the site until study 
end. Used and unused study kits remaining at sites at the end of the study will be returned 
to the drug depots for destruction.  
In case the site is strictly required by local regulation not to retain used study kits, site is 
authorized to destroy them locally, following site destruction procedure, only after 
accountability done and authorization provided by Sponsor.   
A detailed description of study drug handling will be provided in Study Drug Manual. 
5.8 
Administration of Study Treatment 
At Day 1 (Visit 2), after confirming patient’s eligibility, the Investigator or designee will 
get connected to the IWRS to randomize the patient. An IWRS will be employed for the 
randomization activities taking into account the stratification factors (See Section 9.1). 
The IWRS will assign a study kit number to the patient and the Investigator (or 
Investigator’s designee) will receive the IWRS notification mentioning the study kit 
number assigned to the patient for which the request was made. The hospital pharmacist, 
or designated responsible person, will select from the study kits stored at the site 
pharmacy the corresponding kit as indicated by the IWRS and fill-in the blank space(s) 
on the outer study kit label with the patient’s identification number which was assigned 
by IWRS during screening.  
Allocation and distribution of the study kit to the Investigator or Investigator’s designee 
is tracked by attaching the study kit label peel-off portion onto the study site drug 
accountability log (or similar document).  
Adequate written instructions (in form of a Study Drug Manual) for use for the 
pharmacist or designated person will be provided to him/her for the management of the 
study kit at each study site. 

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The relevant labels on the study kits will be filled in according to the provided 
instructions. 
Patients will take 1 tablet on Day 1 (if a fasting state is not possible on Day 1, the patient 
will start study drug on Day 2) and daily thereafter.  Patients will be supplied with study 
drug at Visit 2 and resupplied at Visit 3 (Week 3), Visit 4 (Week 6), Visit 5 (Week 9), 
Visit 6 (Week 12), Visit 7 (Week 15), Visit 8 (Week 18) and Visit 9 (Week 21).  
Tablets of study drug will be taken orally in mornings while fasting at least 1 hour before 
breakfast. Water is permitted prior to and with study drug. 
5.9 
Blinding 
This is a double-blind study. The blinding of the study drugs is guaranteed by the use of 
identical placebo to the active drug.   
As far as possible, without compromising patient safety the Investigator may discuss the 
case with the medical monitor prior to breaking the blind. The Investigator has in any 
case unrestricted and immediate access to break the treatment code, and irrespective of 
the medical monitor’s advice. If the treatment code is broken, the Investigator(s) must 
document and report it to Sponsor within 24 hours. 
Any unblinding of the study treatment will be performed by IWRS (24-hour 7-day 
coverage). If the code is broken by the Investigator, the patient should be discontinued 
from the study drug, but every effort will be made to collect data from the protocol-
specified assessments as detailed in Section 6.3. The unblinding procedure will be 
detailed in the IWRS manual that will be provided separately to the Investigator. 
The Drug safety officer may proceed to unblinding. The unblinding procedure will be 
managed through the IWRS. The patient will not be discontinued from the study 
treatment. No notification of unblinding will be disclosed.   
5.10 Treatment Assignment and Randomization - Use of IWRS 
Randomization will be used to avoid bias in assigning treatments to patients. 
Randomization tends to produce treatment groups in which the distributions of prognostic 
factors, known and unknown are similar; it also enhances the validity and the efficiency 
of statistical comparisons between the treatment groups. 
The 5-item Anorexia Symptom Subscale score will be read from electronic diary then 
entered into the IWRS. 
Central randomization in a double-blind manner will stratify patients using strata defined 
in Section 9.1.  
5.11 Management of Treatment Overdosage 
In case of overdose, conservative management of signs and symptoms is advised. No 
case of over-dosage has been reported with anamorelin to date. No antidote for 
anamorelin overdose is known. Supratherapeutic doses of up to 400 mg were 

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administered in two phase 1 studies (one dose escalation study and one QT/QTc study). 
No clinically relevant ECG abnormalities were recorded for doses up to 300 mg. 
5.12 Occupational safety 
No studies have been performed on the ability to drive vehicles and operate machinery. 
5.13 Prior and concomitant medications 
Concomitant medications must be recorded from 14 days prior to the first dose of study 
drug through the last dose of study drug.   
Use of diuretics and changes in diuretics use will be collected and recorded at each visit. 
Prophylactic infusion of saline or other hydration solutions prior to or after chemotherapy 
in order to prevent toxic reactions related to chemotherapy is to be recorded on the 
appropriate eCRF page; this should also include rehydration events that occur outside of 
the clinical site. 
Infusion of blood products is to be recorded. 
All medications administered in relation to diagnostic procedures, e.g., anesthetics and 
antibiotics are not to be recorded. 
5.13.1 
Use of corticosteroids 
Corticosteroids are permitted for a maximum of 5 consecutive days per each 
chemotherapy and/or radiation cycle if administered as co-medication in chemotherapy 
and/or radiotherapy protocols and for any use other than “appetite stimulant”.  
As well, even single intake of corticosteroids to increase appetite or treat unintentional 
weight loss is not permitted. 
Inhaled steroids for respiratory disorders and topical steroids for skin disease are allowed 
at any time.   
5.13.2 
Prohibited Medications 
The primary CYP isoforms responsible for the metabolism of anamorelin HCl are 
CYP3A4 and CYP2D6. Cytochrome P450 in vitro inhibition testing demonstrated 
modest inhibitory effects against CYP3A4 and no inhibitory effects against CYP2D6. 
The use of strong CYP3A4 inhibitors is an exclusion criterion and drugs known to 
strongly inhibit CYP3A4 (ketoconazole, clarithromycin, itraconazole, nefazodone, 
telithromycin) should be avoided two weeks prior to study entry and throughout the trial. 
If a patient is required to take a strong CYP3A4 inhibitor while enrolled in this trial, then 
anamorelin dosing must be discontinued. Although moderate or weak CYP3A4 inhibitors 
may be used, they should be avoided when possible. Verapamil although listed as 
moderate CYP3A4 inhibitor (see APPENDIX 3), is not allowed at any time during the 
course of the study as may prolong PR intervals. Furthermore, the concomitant 
administration of anamorelin with strong CYP3A4 inducers such as rifampicin should 

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also be discouraged, as it may result in a reduction of the clinical effect. See APPENDIX 
3.  
Systematic long-term application of topical lidocaine preparations is allowed. Drugs that 
may prolong the PR or QRS interval durations, such as any of the antiarrhythmic 
medications Class I (Fast sodium (Na) channel blockers) are prohibited for the study 
duration. 
The use of beta-blockers agents to control hypertension could be allowed only for those 
drugs that do not interfere with PR and QRS interval; sotalol, being classified as class III 
antiarrhythmic agent and also as beta-blocker, is to be avoided [Yap-2003]. Other beta-
blockers, like nebivolol or metoprolol, could be allowed if hypertension is controlled 
before entering the study.  
Patients should not take any prescription medication or off-label products intended to 
increase appetite or treat unintentional weight loss during the study; these include, but are 
not limited to, androgenic compounds (including but not limited to testosterone, 
testosterone-like agents, oxandrolone), megestrol acetate, corticosteroids (please see 
Section 5.13.1 for regulation regarding use of corticosteroids), dronabinol or marijuana 
(cannabis). 
The recently released version of NCCN guidelines [NCCN guidelines on antiemesis 
version 2.2020] for CINV prophylaxis has introduced the possibility to use olanzapine as 
part of the antiemetic regimen; the recommended dose is 5-10 mg on day 1-4 as used in 
the phase 2-3 trials [Navari-2016]. Although weight gain has been reported as side effect 
of olanzapine in psychiatric settings trials [Allison-2001], it has not been observed in 
oncology trials and, consequently, its use as part of the CINV prophylaxis is admitted. 
Based on the above, the use of olanzapine is accepted providing that the investigators 
adhere to the NCCN recommendations with special regard to dose and schedule of 
administration. 
Use of mirtazapine is also prohibited, however, mirtazapine is allowed if taken for 
depression and for at least 4 weeks prior to screening. 
Patients should not be on treatment with methylphenidate; tube feeding at the time of the 
study start and during the study is forbidden.   
 
5.13.3 
Concurrent NSCLC Treatment 
Depending on the genetic variant and on the treatments’ lines, anti-cancer treatment for 
type and stage of NSCLC, proposed anticancer treatment includes the use of platinum- 
and non- platinum- based chemotherapy, immune checkpoint inhibitors therapy and 
targeted therapy as per NCCN guidelines [NCCN-2018].  
Details on the allowed treatments are listed below:  
1. 
Patients on chemotherapy and/or radiation therapy 

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• 
This includes patients initiating/planning to initiate chemotherapy and/or 
radiation therapy within ±14 days of randomization. 
• 
This also includes patients receiving maintenance chemotherapy. For these 
patients, they should continue maintenance chemotherapy as indicated during 
the study.  
• 
For all patients receiving chemotherapy, if study visits coincide with 
chemotherapy administration, all study procedures should be performed prior 
to administration of chemotherapy.  
2. 
Patients on immunotherapy 
• 
This includes patients initiating/planning to initiate PD-1/PD-L 1 inhibitor 
regimens within ±14 days of randomization. 
3. 
Patients on Targeted therapy 
• 
This includes patients initiating/planning to initiate targeted therapy regimens 
within ±14 days of randomization. 
4. 
Patients currently not taking any treatment for their NSCLC 
• 
This includes patients on palliative care treatment. 
If the primary treatment for NSCLC is changed, interrupted, or permanently discontinued 
during the planned duration of this trial, therapy with anamorelin HCl or placebo will 
continue until completion of this study.  
Treatment with all chemotherapeutic and targeted agents should be given in accordance 
with the manufacturer’s warnings and directions and recorded as concomitant 
medication. Treatment for NSCLC should not be held or delayed in order to begin this 
trial.  
5.13.4 
Use of contraceptive measures 
Female patient of childbearing potential or male patients of fathering potential shall use 
reliable contraceptive measures for the whole duration of the study and until Visit 11 
(Week 26). Reliable contraceptive measures include implants, injectables, combined oral 
contraceptives, intrauterine devices, vasectomized partner, condoms, spermicide or 
complete (long term) sexual abstinence. 
5.14 Rescue Medication 
Not applicable. 
5.15 Treatment Compliance 
Patients will be instructed to bring all blister cards to each study visit during the treatment 
period for a compliance/accountability check. A patient will be considered to be 
compliant with therapy if s/he takes all study drugs provided. Compliance will be defined 
overall. 

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6 STUDY CONDUCT 
6.1 
Study Procedures by Time Point 
6.1.1 
Visit 1 (Screening, Day -7 to Day -1) 
If the Investigator considers a patient to be potentially eligible for the study, written 
informed consent for participation in the study must be obtained before any study-related 
procedures starts. The patient will be screened within 7 days prior to randomization (Day 
1) and study drug administration; the following procedures will be performed, and data 
collected during this visit for eligibility purposes: 
• 
Informed consent. 
• 
Significant medical history. 
• 
A dedicated physical examination with focus to monitoring signs and symptoms of 
edema (see Section 7.2.2.1 for details); Results of this PE will be inserted in source 
data and in the relevant pages of eCRF. 
• 
ECOG Performance Status. 
• 
Vital signs (including pulse rate, systolic and diastolic blood pressure after at least 5 
minutes rest in semi-supine position, respiratory rate and body temperature). 
• 
Body weight, height and BMI. 
• 
Prior body weight loss will be verified by the use of patient medical charts; this 
information can be retrieved either by hospital or family doctor medical charts. 
• 
12-Lead ECG, in triplicate. 
• 
Chemistry and hematology testing, including HbA1c under fasting conditions.  
• 
Urine pregnancy test for females of childbearing potential. 
• 
Urinalysis under fasting status. 
• 
Administration of FAACT 12-item A/CS domain and PGIS questionnaires for body 
weight and anorexia. 
• 
CT scan for tumor assessment. The baseline tumor assessment may have been 
obtained within 28 days of the first dose of study drug (see Section 7.2.7). 
• 
AEs will be collected from the Informed consent signature up to Follow-up visit. 
• 
Prior and concomitant medications data will be collected.  
Based on the relevant above mentioned assessments outcome, the Investigator will decide 
if the patient is eligible for the study. If eligible, patient will be reminded to come back to 
clinical site under fasting condition for Visit 2 for laboratory assessments and to be 
administered with study drug. 

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6.1.2 
Visit 2 (Randomization/Treatment Period, Day 1): Week 1 
Patient will arrive at the clinical site under fasting condition. Once at the site, Investigator 
or designated personnel will re-check the following criteria: 
• 
inclusion criterion # 10 (Urine pregnancy test) and  
• 
exclusion criteria # 3, 5, 6, 7g, 9. 
If patient is confirmed eligible, authorized study personnel will proceed with 
randomization procedures. The IWRS will provide the study kit number to be dispensed 
to the patient only after all the following pre-dose assessments are completed for 
baseline measurements: 
• 
Laboratory assessments, including: 
o 
Chemistry, 
o 
Hematology. 
• 
Body weight via scale measurement, to be done prior to study drug administration. 
• 
12-Lead ECG pre dose, in triplicate. 
• 
A dedicated physical examination with focus to monitoring signs and symptoms of 
edema (see Section 7.2.2.1 for details); results of this PE will be inserted in source 
data and in the relevant pages of eCRF. 
• 
Vital signs (including pulse rate, systolic and diastolic blood pressure after at least 5 
minutes rest in semi-supine position, respiratory rate and body temperature). 
• 
Adverse events recording. 
• 
Prior and concomitant medications (not including NSCLC treatment) recording. 
• 
Administration and completion of: 
o FACIT questionnaires (includes all 4 domains PWB, FWB, SWB, and EWB of 
FACT-G, 12-item A/CS domain and 13-item FACIT-F fatigue domain), 
o Hunger Assessment Scale questionnaire. 
• 
Once completed these pre-dose assessments the patient will be “randomized” and 
new study kit will be dispensed.  
• 
CT scan for tumor assessment. The baseline tumor assessment may have been 
obtained within 28 days prior the first dose of study drug (see Section 7.2.7). 
• 
Study drug will therefore be administered. The date and the precise time (hh:mm) of 
the study drug must be recorded in the source records as well as on the relevant 
eCRF page. 
• 
One hour post study drug administration patient will undergo ECG measurement in 
triplicate. 

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• 
NSCLC treatment regimen will be collected at Baseline and any dose adjustments, as 
and if applicable. 
• 
Before leaving the clinic, the patient will be reminded about the prohibited 
concomitant medications (see Section 5.13.2 for details).  
• 
Patient will also be reminded to come back to clinical site in 3 weeks for next visit 
and be reminded to arrive at the hospital under fasting conditions. 
6.1.3 
Visit 3 (Day 22+3): Week 3 
The patient will return to the trial site on Visit 3, at Day 22 (+3), approximately 3 weeks 
after Visit 2. Patient will arrive at the hospital under fasting conditions. 
The patient will undergo the following procedures/assessments: 
• 
Study drug administration. 
• 
Laboratory assessments, including: 
o 
Chemistry, 
o 
Hematology.  
• 
Vital signs including pulse rate, systolic and diastolic blood pressure after at least 5 
minutes rest in semi-supine position, respiratory rate and body temperature). 
• 
Body weight via scale measurement, to be done prior to study drug administration. 
• 
A dedicated physical examination with focus to monitoring the signs and symptoms 
of edema (see Section 7.2.2.1 for details); results of this PE will be inserted in source 
data and in the relevant pages of eCRF. 
• 
12-Lead ECG (1 hour post dose), in triplicate.  
• 
Adverse Events, procedures, and hospitalizations assessment. 
• 
Administration and completion of  
o 
FACIT questionnaires (includes all 4 domains PWB, FWB, SWB, and EWB 
domains of FACT-G, 12-item A/CS domain and FACIT-F fatigue domain), 
o 
Hunger Assessment questionnaire.  
Questionnaires will be administered in the order presented here and administered from 1 
to 4 hours post study drug administration. 
• 
CT scan may be performed as per standard local practice. Exact time point for CT 
scan will depend on the investigator’s standard plan at each site (see Section 7.2.7). 
• 
Check and record concomitant medications (not including NSCLC treatment 
regimen). 
• 
NSCLC treatment regimen and any dose adjustments, as and if applicable.  

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• 
New study kit will be dispensed, and patient will return wallet card from previous 
visit; compliance will be checked. 
• 
The patient will also be reminded about the prohibited concomitant medications (see 
Section 5.13.2 for details). 
• 
Patient will also be reminded to come back to clinical site in 3 weeks for next visit 
and be reminded to arrive at the hospital under fasting conditions. 
6.1.4 
Visit 4 (Day 43+3days): Week 6 
The patient will return to the trial site on Visit 4, at Day 43 (+3), approximately 3 weeks 
after Visit 3. Patient will arrive at the hospital under fasting conditions. 
The patient will undergo the following procedures/assessments: 
• 
Study drug administration. 
• 
Laboratory assessments, including: 
o 
Chemistry, 
o 
Hematology. 
• 
Vital signs including pulse rate, systolic and diastolic blood pressure after at least 5 
minutes rest in semi-supine position, respiratory rate and body temperature). 
• 
Body weight via scale measurement, to be done prior to study drug administration. 
• 
A dedicated physical examination with focus to monitoring signs and symptoms of 
edema (see Section 7.2.2.1 for details); Results of this PE will be inserted in source 
data and in the relevant pages of eCRF. 
• 
12-Lead ECG (1 hour post dose), in triplicate. 
• 
CT scan may be performed as per standard local practice. Exact time point for CT 
scan will depend on the investigator’s standard plan at each site (see Section 7.2.7). 
• 
Adverse Events, procedures, and hospitalizations assessment.  
• 
Administration and completion of  
o 
FACIT questionnaires (includes all 4 domains PWB, FWB, SWB, and EWB 
domains of FACT-G, 12-item A/CS domain and FACIT-F fatigue domain),  
o 
PGIS and PGIC questionnaires for body weight, anorexia and overall conditions, 
o 
Hunger Assessment questionnaire.  
Questionnaires will be administered in the order presented here and administered from 1 
to 4 hours post study drug administration.  
• 
Check and record Concomitant medications (not including NSCLC treatment 
regimen).  
• 
NSCLC treatment regimen and any dose adjustments, as and if applicable. 

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• 
New study kit will be dispensed, and patient will return wallet card from previous 
visit; compliance will be checked. 
• 
The patient will also be reminded about the prohibited concomitant medications (see 
Section 5.13.2 for details). 
• 
Patient will also be reminded to come back to clinical site in 3 weeks for next visit 
and be reminded to arrive at the hospital under fasting conditions. 
6.1.5 
Visit 5 (Day 64+3 days): Week 9 
The patient will return to the trial site on Visit 5, at Day 64 (+3), approximately 3 weeks 
after Visit 4. Patient will arrive at the hospital under fasting conditions. 
The patient will undergo the following procedures/assessments: 
• 
Study drug administration. 
• 
Laboratory assessments, including: 
o 
Chemistry, 
o 
Hematology.  
• 
Urine pregnancy test for females of childbearing potential. 
• 
Urinalysis under fasting status. 
• 
Vital signs including pulse rate, systolic and diastolic blood pressure after at least 5 
minutes rest in semi-supine position, respiratory rate and body temperature). 
• 
ECOG PS. 
• 
Body weight via scale measurement, to be done prior to study drug administration. 
• 
A dedicated physical examination with focus to monitoring signs and symptoms of 
edema (see Section 7.2.2.1 for details); results of this PE will be inserted in source 
data and in the relevant pages of eCRF. 
• 
12-Lead ECG (1 hour post dose), in triplicate. 
• 
CT scan may be performed as per standard local practice. Exact time point for CT 
scan will depend on the investigator’s standard plan at each site (see Section 7.2.7). 
• 
Adverse Events, procedures, and hospitalizations assessment.  
• 
Administration and completion of  
o 
FACIT questionnaires (includes all 4 domains PWB, FWB, SWB, and EWB 
domains of FACT-G, 12-item A/CS domain and FACIT-F fatigue domain).  
o 
PGIS and PGIC questionnaires for body weight, anorexia and overall conditions. 
o 
Hunger Assessment questionnaire.  
Questionnaires will be administered in the order presented here and administered from 1 
to 4 hours post study drug administration. 

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• 
Check and record Concomitant medications (not including NSCLC treatment 
regimen).  
• 
NSCLC treatment regimen and any dose adjustments, as and if applicable. 
• 
New study kit will be dispensed, and patient will return wallet card from previous 
visit; compliance will be checked. 
• 
The patient will also be reminded about the prohibited concomitant medications (see 
Section 5.13.2 for details). 
• 
Patient will also be reminded to come back to clinical site in 3 weeks for next visit 
and be reminded to arrive at the hospital under fasting conditions. 
6.1.6 
Visit 6 (Day 85+3): Week 12 
The patient will return to the trial site on Visit 6, at Day 85 (+3), approximately 3 weeks 
after Visit 5. Patient will arrive at the hospital under fasting conditions. 
The patient will undergo the following procedures/assessments: 
• 
Study drug administration. 
• 
Laboratory assessments, including: 
o 
Chemistry, 
o 
Hematology,  
o 
HbA1c Assessment. 
• 
Vital signs including pulse rate, systolic and diastolic blood pressure after at least 5 
minutes rest in semi-supine position, respiratory rate and body temperature). 
• 
Body weight via scale measurement, to be done prior to study drug administration. 
• 
A dedicated physical examination with focus to monitoring signs and symptoms of 
edema (see Section 7.2.2.1 for details); Results of this PE will be inserted in source 
data and in the relevant pages of eCRF. 
• 
12-Lead ECG (1 hour post dose), in triplicate. 
• 
CT scan may be performed as per standard local practice. Exact time point for CT 
scan will depend on the investigator’s standard plan at each site (see Section 7.2.7). 
• 
Adverse Events, procedures, and hospitalizations assessment.  
• 
Administration and completion of  
o 
FACIT questionnaires (includes all 4 domains PWB, FWB, SWB, and EWB 
domains of FACT-G, 12-item A/CS domain and FACIT-F fatigue domain),  
o 
Hunger Assessment questionnaire.  
Questionnaires will be administered in the order presented here and administered from 1 
to 4 hours post study drug administration. 

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• 
Check and record Concomitant medications (not including NSCLC treatment 
regimen).  
• 
NSCLC treatment regimen and any dose adjustments, as and if applicable. 
• 
CT scan at all sites as per standard local practice. 
• 
New study kit will be dispensed, and patient will return wallet card from previous 
visit; compliance will be checked. 
• 
The patient will also be reminded about the prohibited concomitant medications (see 
Section 5.13.2 for details). 
• 
Patient will be reminded to come back to clinical site in 3 weeks for next visit and be 
reminded to arrive at the hospital under fasting conditions. 
6.1.7 
Visit 7 (Day 106+3): Week 15 
The patient will return to the trial site on Visit 7, at Day 106 (+3), approximately 3 weeks 
after Visit 6. Patient will arrive at the hospital under fasting conditions. 
The patient will undergo the following procedures/assessments: 
• 
Study drug administration. 
• 
Laboratory assessments, including: 
o 
Chemistry, 
o 
Hematology.  
• 
Vital signs including pulse rate, systolic and diastolic blood pressure after at least 5 
minutes rest in semi-supine position, respiratory rate and body temperature). 
• 
Body weight via scale measurement, to be done prior to study drug administration. 
• 
A dedicated physical examination with focus to monitoring signs and symptoms of 
edema (see Section 7.2.2.1 for details); results of this PE will be inserted in source 
data and in the relevant pages of eCRF. 
• 
12-Lead ECG (1 hour post dose), in triplicate. 
• 
CT scan may be performed as per standard local practice. Exact time point for CT 
scan will depend on the investigator’s standard plan at each site (see Section 7.2.7). 
• 
Adverse Events, procedures, and hospitalizations assessment.  
• 
Administration and completion of  
o 
FACIT questionnaires (includes all 4 domains PWB, FWB, SWB, and EWB 
domains of FACT-G, 12-item A/CS domain and FACIT-F fatigue domain),  
o 
Hunger Assessment questionnaire,  
Questionnaires will be administered in the order presented here and administered from 1 
to 4 hours post study drug administration. 

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• 
Check and record Concomitant medications (not including NSCLC treatment 
regimen).  
• 
NSCLC treatment regimen and any dose adjustments, as and if applicable. 
• 
New study kit will be dispensed, and patient will return wallet card from previous 
visit; compliance will be checked. 
• 
The patient will also be reminded about the prohibited concomitant medications (see 
Section 5.13.2 for details). 
• 
Patient will also be reminded to come back to clinical site in 3 weeks for next visit 
and be reminded to arrive at the hospital under fasting conditions. 
6.1.8 
Visit 8 (Day 127+3) – Week 18 
The patient will return to the trial site on Visit 8, at Day 127 (+3), approximately 3 weeks 
after Visit 7. Patient will arrive at the hospital under fasting conditions. 
The patient will undergo the following procedures/assessments: 
• 
Study drug administration. 
• 
Laboratory assessments, including: 
o 
Chemistry, 
o 
Hematology.  
• 
Vital signs including pulse rate, systolic and diastolic blood pressure after at least 5 
minutes rest in semi-supine position, respiratory rate and body temperature). 
• 
Body weight via scale measurement, to be done prior to study drug administration. 
• 
A dedicated physical examination with focus to monitoring signs and symptoms of 
edema (see Section 7.2.2.1 for details); results of this PE will be inserted in source 
data and in the relevant pages of eCRF. 
• 
12-Lead ECG (1 hour post dose), in triplicate. 
• 
CT scan may be performed as per standard local practice. Exact time point for CT 
scan will depend on the investigator’s standard plan at each site (see Section 7.2.7). 
• 
Adverse Events, procedures, and hospitalizations assessment.  
• 
Administration and completion of  
o 
FACIT questionnaires (includes all 4 domains PWB, FWB, SWB, and EWB 
domains of FACT-G, 12-item A/CS domain and FACIT-F fatigue domain),  
o 
Hunger Assessment questionnaire.  
Questionnaires will be administered in the order presented here and administered from 1 
to 4 hours post study drug administration. 

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• 
Check and record Concomitant medications (not including NSCLC treatment 
regimen). 
• 
NSCLC treatment regimen and any dose adjustments, as and if applicable. 
• 
New study kit will be dispensed, and patient will return wallet card from previous 
visit; compliance will be checked. 
• 
The patient will also be reminded about the prohibited concomitant medications (see 
Section 5.13.2 for details). 
• 
Patient will also be reminded to come back to clinical site in 3 weeks for next visit 
and be reminded to arrive at the hospital under fasting conditions. 
6.1.9 
Visit 9 (Day 148+3): Week 21 
The patient will return to the trial site on Visit 9, at Day 148 (+3), approximately 3 weeks 
after Visit 8. Patient will arrive at the hospital under fasting conditions. 
The patient will undergo the following procedures/assessments: 
• 
Study drug administration, 
• 
Laboratory assessments, including: 
o 
Chemistry, 
o 
Hematology.  
• 
Vital signs including pulse rate, systolic and diastolic blood pressure after at least 5 
minutes rest in semi-supine position, respiratory rate and body temperature). 
• 
Body weight via scale measurement, to be done prior to study drug administration. 
• 
A dedicated physical examination with focus to monitoring signs and symptoms of 
edema (see Section 7.2.2.1 for details); Results of this PE will be inserted in source 
data and in the relevant pages of eCRF. 
• 
12-Lead ECG (1 hour post dose), in triplicate. 
• 
CT scan may be performed as per standard local practice. Exact time point for CT 
scan will depend on the investigator’s standard plan at each site (see Section 7.2.7). 
• 
Adverse Events, procedures, and hospitalizations assessment.  
• 
Administration and completion of  
o 
FACIT questionnaires (includes all 4 domains PWB, FWB, SWB, and EWB 
domains of FACT-G, 12-item A/CS domain and FACIT-F fatigue domain),  
o 
Hunger Assessment questionnaire.  
Questionnaires will be administered in the order presented here and administered from 1 
to 4 hours post study drug administration. 
• 
Check and record Concomitant medications (not including NSCLC treatment 
regimen).  

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• 
NSCLC treatment regimen and any dose adjustments, as and if applicable. 
• 
New study kit will be dispensed, and patient will return wallet card from previous 
visit; compliance will be checked. 
• 
The patient will also be reminded about the prohibited concomitant medications (see 
Section 5.13.2 for details). 
• 
Patient will also be reminded to come back to clinical site in 3 weeks for next visit 
and be reminded to arrive at the hospital under fasting conditions. 
6.1.10 
Visit 10 (Day 169+3): Week 24 
The patient will return to the trial site on Visit 10, at Day 169 (+3), approximately 3 
weeks after Visit 9. Patient will arrive at the hospital under fasting conditions. 
The patient will undergo the following procedures/assessments: 
• 
Patient will return wallet card from previous visit; compliance will be checked. 
• 
Study drug administration (last dose). 
• 
Laboratory assessments, including: 
o 
Chemistry, 
o 
Hematology,  
o 
HbA1c Assessment. 
• 
Urine pregnancy test for females of childbearing potential. 
• 
Urinalysis under fasting status. 
• 
Vital signs including pulse rate, systolic and diastolic blood pressure after at least 5 
minutes rest in semi-supine position, respiratory rate and body temperature). 
• 
Body weight via scale measurement, to be done prior to study drug administration. 
• 
A dedicated physical examination with focus to monitoring signs and symptoms of 
edema (see Section 7.2.2.1 for details); Results of this PE will be inserted in source 
data and in the relevant pages of eCRF. 
• 
12-Lead ECG (1 hour post dose), in triplicate. 
• 
CT scan may be performed as per standard local practice. Exact time point for CT 
scan will depend on the investigator’s standard plan at each site (see Section 7.2.7). 
• 
Adverse Events, procedures, and hospitalizations assessment.  
• 
Administration and completion of  
o 
FACIT questionnaires (includes all 4 domains PWB, FWB, SWB, and EWB 
domains of FACT-G, 12-item A/CS domain and FACIT-F fatigue domain),  
o 
Hunger Assessment questionnaire.  

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Questionnaires will be administered in the order presented here and administered from 1 
to 4 hours post study drug administration. 
• 
Check and record Concomitant medications (not including NSCLC treatment 
regimen).  
• 
NSCLC treatment regimen and any dose adjustments, as and if applicable. 
• Patient will also be reminded that will be contacted by study stuff for follow-up visit 
in two weeks. 
6.1.11 
Visit 11 (Follow-up visit): Week 26   
A follow-up visit, at Day 183 (+3), approximately 2 weeks after Visit 10 will be 
conducted over the telephone.  
The patient will undergo the following procedures/assessments: 
• Patient will be inquired for safety; information related to AEs, procedures, and 
hospitalizations’ assessment will be collected over telephone. 
6.2 
Definition of study Completion 
A patient will be defined as having “completed” the study when the patient completes 
Visit 11. Termination of the study before performing Visit 11 will be considered as a 
premature study discontinuation. 
Overall study end date is defined as the date of last patient’s last visit.  
6.3 
Premature Discontinuation of Study Drug 
Patients may withdraw their consent and discontinue the study treatment at any time. 
Every effort should be made to encourage patients to return for scheduled visits to 
undergo study procedures even if they discontinue study drug. Patients who prematurely 
discontinue will be classified as follows (only one category may be selected): 
1. 
An AE occurs that, in the opinion of the Investigator, makes it unsafe for the patient 
to continue in the study. 
2. 
The patient is lost to follow-up. 
3. 
The patient dies. 
4. 
The patient withdraws consent. 
5. 
The Investigator, for any reason, terminates the entire study, or terminates the study 
for that patient; or the attending physician requests that the patient be withdrawn for 
any medical reason. 
6. 
The Sponsor or the Regulatory Authorities or the Ethics Committee(s), for any 
reason, terminates the entire study, or terminates the study for this trial site or this 
particular patient. 
If a patient is discontinued from the study after treatment with the investigational 
medicinal product, the Investigator must try his/her best to contact the patient for 
scheduled visits especially Week 9 (64+3) visit assessments in view of completing the 
study safety assessment by collecting information that may be suggestive of AEs. Every 
effort will be made to collect data from the protocol-specified assessments; patients will 

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be asked to continue to participate in the study and complete planned visits up to the end 
of the treatment period (Week 24) even if they have permanently discontinued treatment 
with anamorelin/placebo (“retrieved dropout” approach). 
Patients discontinued after randomization will not be replaced. 
6.4 
Diet and Lifestyle 
There are no dietary restrictions during the study. Patients will receive standard dietary 
counseling as per the routine clinical practice.  
Subjects will be instructed to refrain from any alcohol use from 48 hours prior to their 
first treatment and throughout the duration of the study. As per National Institute on 
Alcohol Abuse and Alcoholism (NIAAA), in the United States, one "standard" drink 
contains roughly 14 grams of pure alcohol, which is found in: a) 12 ounces (~ 360 ml) of 
regular beer, which is usually about 5% alcohol; b) 5 ounces (~ 150 ml) of wine, which is 
typically about 12% alcohol; c) 1.5 ounces (~ 50 ml) of distilled spirits, which is about 
40% alcohol. 
Excessive alcohol use is according to Substance Abuse and Mental Health Services 
Administration (SAMHSA) is a binge drinking on 5 or more days in the past month. 
Binge drinking is ≥ 5 drinks for males or ≥ 4 drinks for females on the same occasion 
(i.e., at the same time or within a couple of hours of each other) on at least 1 day in the 
past month.  
There are no restrictions on exercise or activity. 

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7 METHODS OF ASSESSMENT 
7.1 
Efficacy Assessments 
Primary efficacy assessments include body weight and anorexia symptoms via the 5-item 
Anorexia Symptom Subscale.  
Other assessments include other scoring derived from the FAACT (total domain score 
and the 4-item Anorexia Concerns Subscale derived from the FAACT), as well as 
additional patient-reported outcome assessments including the FACIT-F, Hunger 
Assessment Scale, PGIS and PGIC questionnaires for body weight, anorexia and overall 
conditions.  
All questionnaires will be provided to the sites and will be completed by the patients at 
the specified visits. Every effort should be made to have the patient complete the 
questionnaires alone. If they cannot physically complete them by themselves, then site 
personnel may read the questions to the patients and record their answers. Patient 
caregivers should not influence/contribute to patient responses.  
These instruments will be provided in appropriate validated translations and will be 
completed by the patients in their native language. 
The PRO data will be collected by the mean of electronic diary, the data will be 
automatically transferred and the sum score of the different questionnaires used for 
screening and randomization purposes will be displayed on the device. 
Site personnel should ensure all questions were answered and that the intended answers 
were clearly marked. The site personnel should ask the patient to complete any missed 
questions and to clarify any unclear answers. If a patient is unable to complete the 
questions, the reason must be documented in the source documentation and in the eCRF. 
The order of the questionnaires to be completed at each visit is specified within the study 
flow chart. 
7.1.1 
Assessment of Body Weight 
Data from literature [Patel-2013] and post-hoc analyses of the previous Phase 3 
anamorelin studies suggest that increases in body weight of a magnitude of ≥ 5% from 
baseline are relevant, associated with corresponding improvements in anorexia-related 
concerns proximal to the weight loss, and are noticeable and clinically meaningful to 
patients.  
Body weight will be measured in kg at each visit (for details see study flow chart). 
Measurements will be performed by a Sponsor-trained and certified healthcare 
professional.  
Body weight will be assessed for the purpose of primary, secondary and exploratory 
efficacy endpoints, as indicated in Section 3. 
Calibrated and validated scale will be used at every visit, including screening visit (Visit 
1). Scales will be used on hard flooring, such as tile, wood, or cement for accuracy of 

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measurement. Sites will be instructed to weigh the participants at approximately the same 
time of the day every visit, on empty stomach (in the morning, before breakfast). Study 
participants will be instructed to remove shoes and clothing for accurate weight 
measurement. Patients will be weighed wearing only a hospital gown or hospital scrubs 
and, if desired, underwear only. Sponsor will make sure the same scale is used at each 
site. 
7.1.2 
Assessment of anorexia symptoms and other patient reported 
outcomes  
In this study, three different types of patient-reported outcome measures will be 
administered to patients, following instructions provided in study flow chart. These 
questionnaires are listed below, and additional details are provided in each of the 
following sections: 
• FACIT measurements, 
• PGI System,  
• Hunger Assessment Scale. 
7.1.3 
Patient Reported Outcome 
7.1.3.1 
FACIT measurements (Functional Assessment of Chronic Illness 
Therapy) 
This is a collection of questionnaires targeted to the management of chronic illness 
[FACIT.org] and includes (please see APPENDIX 4 for details):  
• 
FAACT-A/CS (Functional Assessment Anorexia Cachexia Therapy): this domain 
is a 12-item measure of patients’ perceptions of anorexia/cachexia symptoms and 
concerns [Ribaudo-2001]. From this questionnaire the 5-item section referring to 
anorexia symptoms will be used to assess primary efficacy endpoint. 
• 
FACIT-F (Fatigue): this domain is a 13-item measure specifically to address the 
physical and functional consequences of fatigue [FACIT.org]. 
• 
FACT-G (Functional Assessment Cancer Therapy- General Version); this is a 27-
item compilation of general questions divided into four primary domains: Physical 
Well-Being, Social/Family Well-Being, Emotional Well-Being, and Functional 
Well-Being.  For this study, patients will be administered all four domains. 
Regarding FACIT questionnaires, 5-item Anorexia Symptom Subscale and a 4-item 
Anorexia Concerns Subscale have been developed by Helsinn from the FAACT A/CS 
domain, whereby the validity of both are supported through a qualitative study in NSCLC 
patients and a retrospective psychometric evaluation using data from the two previous 
Phase 3 trials with anamorelin [Gelhorn-2016].  

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In terms of scoring the questionnaires, all negatively worded item responses are reverse 
coded and summed in accordance with the recommendations of the FACIT 
Administration and Scoring Guidelines so that higher scores indicate lower levels of 
QoL/symptom burden (see APPENDIX 5 for details). 
Definitions of the different scores from these questionnaires, are as follows: 
• 
FACT-G total score: obtained by summing Physical Well-Being, Social/Family 
Well-Being, Emotional Well-Being, and Functional Well-Being subscale scores of 
the FACT-G; the range of possible scores is 0-108. 
• 
FAACT total score: obtained by summing the FACT-G and the A/CS domain; the 
range of possible scores is 0-156. 
• 
FAACT TOI: obtained by summing the Physical Well-Being and Functional Well-
Being subscale scores of the FACT-G plus the A/CS domain; the range of possible 
scores is 0-104. 
• 
FAACT A/CS Domain: obtained by summing the 12-items of the A/CS domain; 
the range of possible scores is 0-48,  
• 
5-item Anorexia Symptom Subscale: obtained by summing the 5 anorexia 
symptom items derived from the A/CS domain (i.e., “good appetite,” “interest in 
food drops,” “food tastes unpleasant,” “get full quickly,” and “difficulty eating 
rich/heavy foods”); the range of possible scores is 0-20 
• 
4-item Anorexia Concerns Subscale: obtained by summing the 4 anorexia 
concern items derived from the A/CS domain (i.e., “amount I eat sufficient,” 
“worried about weight,” “concerned about thinness,” and “pressured to eat”); the 
range of possible scores is 0-16,  
• 
FACIT-F Fatigue Domain: obtained by summing the 13-items of the fatigue 
domain; the range of possible scores is 0-52,  
• 
FACIT-F TOI: obtained by summing the Physical Well-Being and Functional 
Well-Being subscale scores of the FACT-G plus the fatigue domain; the range of 
possible scores is 0-108.  
7.1.3.2 
PGI (Patient Global Impression) System  
This is a collection of two questionnaires (please see APPENDIX 6 for details): 
• 
PGIS (Patient Global Impression of Severity): This is a two-items PRO, each 
with a 4-point Likert-type response scale, one ranging from ‘‘do not have” 
symptoms to “severe” symptoms related to appetite/eating, and the other one 
ranging from ‘‘have not had” concerns to “have had severe” concerns related to 
weight. 
 

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• 
PGIC (Patient Global Impression of Change): This is a three-item PRO (overall, 
anorexia and body weight), each with a 7-point Likert-type response scale ranging 
from ‘‘very much worse’’ to ‘‘very much improved’’ appetite/eating-related 
symptoms and overall condition. 
7.1.3.3 
HAS (Hunger Assessment Scale) 
This questionnaire consists of two questions and each question can be ranked from 0 (not 
at all) to 4 (very much) scale (please see APPENDIX 7 for details). 
 
7.2 
Safety Assessments 
7.2.1 
Demographic/Medical History 
A complete medical history will be recorded at the Screening Visit and will include 
evaluations for past or present conditions. Demographic information (including age, 
gender, race and ethnicity) and information on histological or cytological tumor type, 
genotype and treatment will also be collected at the Screening Visit.  
7.2.2 
Physical examination 
A complete physical examination will be performed by principal or sub investigator, as 
applicable at Visit 1 (Screening Visit) and at each visit during the treatment period [Visit 
2 (Week 1), Visit 3 (Week 3), Visit 4 (Week 6), Visit 5 (Week 9), Visit 6 (Week 12), 
Visit 7 (Week 15), Visit 8 (Week 18), Visit 9 (Week 21), and Visit 10 (Week 24)]. This 
evaluation will include an examination of general appearance, head, eyes, ears, nose, 
throat, skin, neck, lungs, cardiovascular, breast, lymph nodes, abdomen, musculoskeletal 
and neurological. For details see study flow charts. 
Information about the physical examinations will be recorded in the source 
documentation at the site and any abnormalities at screening will be recorded in the 
eCRF. After signing the informed consent, any new or worsening of existing pathological 
findings noted since previous examination performed under the present protocol should 
be reported on the Adverse Event eCRF form. 
7.2.2.1 
Monitoring Signs and symptoms of edema 
Since excess in body water may contribute to a change in body weight and confound the 
primary efficacy analysis, all patients will be monitored for the signs and symptoms of 
edema during the study. Signs and symptoms of edema will be recorded in patient charts 
at each study visit. For scheduling details see study flow chart. 
A dedicated PE aiming to monitor signs and symptoms of edema should be performed on 
limbs, abdominal and thoracic landmarks. Edema should be evaluated for pitting, 
tenderness to palpation (by applying pressure), and skin temperature, color, and texture 
changes. 

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Limbs Edema: 
PE should focus on dorsum of the foot, all foot including ankle, the medial malleolus, and 
the bony portion of the tibia. In general, PE should focus on the assessment of edema 
involving all part of limb distal to middle point (knee, elbow), all limb involved from 
proximal joint (hip, elbow), and all limbs. 
Abdominal and Thoracic Edema 
PE should focus on visual and palpation assessment of the abdominal area, while for the 
evaluation of thoracic edema will be complemented by auscultation. 
Data of patients with fluid retention will be handled as described in Section 9.4.1. 
7.2.3 
Vital signs 
Vital signs will be measured at Visit 1 (Screening Visit) and at each visit during the 
treatment period [Baseline Visit 2 (Week 1), Visit 3 (Week 3), Visit 4 (Week 6), Visit 5 
(Week 9), Visit 6 (Week 12), Visit 7 (Week 15), Visit 8 (Week 18), Visit 9 (Week 21), 
and Visit 10 (Week 24)], for details see study flow charts. 
Vital sign assessments include body temperature, pulse rate, blood pressure (systolic and 
diastolic), and respiratory rate. Pulse rate, systolic and diastolic blood pressure will be 
measured after the patient has been resting in the semi-supine position for at least 5 
minutes.  
7.2.4 
Height and BMI 
Height will be measured in cm at the Screening Visit (Day -7 to -1, Week -1), and BMI 
will also be calculated and recorded. 
7.2.5 
12-lead ECG 
12-lead ECGs will be conducted in triplicate at each visit Screening Visit, Visit 2 (Week 
1), Visit 3 (Week 3), Visit 4 (Week 6), Visit 5 (Week 9), Visit 6 (Week 12), Visit 7 
(Week 15), Visit 8 (Week 18), Visit 9 (Week 21), and Visit 10 (Week 24). These 12-lead 
ECGs will be obtained in triplicate at each time-point and the reading will be carried out 
at a central facility by an independent cardiologist blind to the study treatment. Any new 
or worsening ECG abnormalities assessed to be clinically significant by each study 
investigator will be reported as adverse events. 
ECG will be recorded in triplicate at 1 hour (±5 minutes) post dose at each visit to align 
with occurrence of Cmax, with the exception of Screening Visit (where ECG will be taken 
only pre-dose) and Visit 2, Day 1, where ECG will be taken also at pre-dose. 
7.2.6 
Clinical Laboratory Tests 
Samples for safety laboratory assessments will be taken in fasting conditions at pre-set 
time points as specified in the study flow charts. All samples will be sent to the central 
laboratory for analysis. The instructions on how the samples must be processed and 
shipped will be provided to the Investigator in the relevant laboratory manual. 

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HbA1c will be performed at Visit 1 (Screening visit), Visit 6 (Week 12), and Visit 10 
(Week 24) visits.  
7.2.6.1 
Hematology 
The hematology assessments will include CBC with differential count and will be 
performed at every visit: Screening Visit, Visit 2 (Week 1), Visit 3 (Week 3), Visit 4 
(Week 6), Visit 5 (Week 9), Visit 6 (Week 12), Visit 7 (Week 15), Visit 8 (Week 18), 
Visit 9 (Week 21), and Visit 10 (Week 24). 
7.2.6.2 
Blood Chemistry 
Blood Chemistry will include sodium, potassium, chloride, calcium, total protein, 
albumin and pre-albumin, AST (SGOT), alkaline phosphatase (ALP), ALT (SGPT), total 
bilirubin, creatinine, C-reactive protein and glucose. These will be performed at every 
visit in fasting state: Screening Visit, Visit 2 (Week 1), Visit 3 (Week 3), Visit 4 (Week 
6), Visit 5 (Week 9), Visit 6 (Week 12), Visit 7 (Week 15), Visit 8 (Week 18), Visit 9 
(Week 21), and Visit 10 (Week 24). 
7.2.6.3 
Urinalysis 
Urinalysis will be performed at Visit 1 (Screening), Visit 5 (Week 9), and Visit 10 (Week 
24). Urinalysis will be performed pre-dose and under fasting conditions and will include 
protein, glucose, WBC, erythrocytes, and bacteria. 
7.2.6.4 
Pregnancy Screen 
Urine pregnancy testing for women of childbearing potential only will be performed at 
Screening visit (Week -1), Visit 2 (Week 1), Visit 5 (Week 9), and Visit 10 (Week 24). 
7.2.7 
CT scan for Tumor Assessment 
All patients will undergo CT scan assessment as per standard local practice for tumor 
assessment. Responses will be evaluated by the Investigator according to RECIST 1.1 
and will be recorded on the eCRF. 
It is upon the judgment of the investigator, following local practice for CT scan 
frequency and according to patient overall clinical conditions, to decide applicability and 
timing of CT scan during the course of the study, including screening visit. 
For CT scans performed earlier than 28 days prior to first dose of anamorelin, and for 
data traceability purpose, it is kindly requested to report date on the eCRF, as available 
even if date is earlier than 28 days prior to first dose of anamorelin. 
Tumor responses, including disease progression, will be evaluated by the Investigator 
according to RECIST 1.1 [Eisenhauer-2009] and will be recorded in the eCRF. 
 
 

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8 ADVERSE EVENTS 
AE recording will begin at the time the informed consent form is signed. Thereafter, AEs 
will be ascertained by asking the patient how he/she has been since the last visit. 
8.1 
Definition of Adverse Events 
Adverse Event (AE) 
As defined by the current ICH Guideline for Good Clinical Practice [ICH-2002] an 
Adverse Event (AE) is: 
Any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have to have a 
causal relationship with this treatment. An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational) product, whether or 
not considered related to the medicinal (investigational) product. 
Within the scope of this study, such untoward medical occurrences would be considered 
as “AEs” even if the subject was not administered the study drugs but had already signed 
the Informed Consent Form. 
AEs include the following types of occurrences: 
− Suspected adverse drug reactions 
− Other medical experiences, regardless of their relationship to the study drugs, 
such as injury, surgery, accidents, increased severity of pre-existing symptoms, 
apparently unrelated illnesses, and significant abnormalities in clinical laboratory 
values, physiological testing, or physical examination findings 
− Reactions from drug overdose, abuse, withdrawal, hypersensitivity, or toxicity. 
Planned surgical interventions or planned hospitalizations scheduled prior to the informed 
consent but performed during the study (study procedures, chemotherapy cycles, etc.) 
should not be considered (serious) AEs.  
Serious Adverse Event (SAE) 
A serious adverse event is any event that suggests a significant hazard, contraindication, 
side effect, or precaution, whether or not it is considered to be associated with the study 
product. A SAE is an AE that meets any of the following criteria: 
− Results in death. This includes any death that occurs during the conduct of a 
clinical study, including deaths that appear to be completely unrelated to the study 
drugs (e.g., car accident). 
− Is life-threatening. This includes any AE during which the subject is, in the view 
of the Investigator, at immediate risk of death from the event as it occurs. This 
definition does not include events that may have caused death if they had 
occurred in a more severe form. 
− Requires inpatient hospitalization or prolongation of existing hospitalization 
− Results in persistent or significant disability or incapacity 

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− Is a congenital anomaly or birth defect 
− Other medical events that based upon appropriate medical judgment are thought 
to jeopardize the patient and/or require medical or surgical intervention to prevent 
one of the outcomes defining a SAE. 
Unexpected Adverse Event 
An Unexpected Adverse Event is any experience not previously reported (in nature, 
severity or incidence) in the current Investigator’s Brochure. 
 
Pre-existing Condition 
A pre-existing condition is one that is present at the start of the study. A pre-existing 
condition should be recorded as an adverse event if the frequency, intensity, or the 
character of the condition worsens during the study period based on patient’s clinical 
evaluation. 
8.1.1 
Classification of Adverse Events 
The Investigator will classify AEs based on their severity and relationship to IMP. Every 
effort must be made by the Investigator to categorize each AE according to its severity 
(see Section 8.1.1.1 Severity), and its relationship (see Section 8.1.1.2 Relationship to 
Investigational Medicinal Product). 
8.1.1.1 
Severity 
The severity of an AE will be rated by the Investigator according to the descriptions and 
grading scales of the Common Terminology Criteria for Adverse Events (CTCAE) (for 
details please refer to the integral document Terminology Criteria for Adverse Events 
[CTCAE-2017]; USA Department of Health and Human Services, National Institutes of 
Health, National Cancer Institute), as summarized below: 
Severity of AE according to CTC Grading Scale and related Guideline 
Grade 1  
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated; 
Grade 2  
Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental Activities of Daily Living (ADL)*; 
Grade 3  
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care ADL**; 
Grade 4  
Life-threatening consequences; urgent intervention indicated; 
Grade 5  
Death related to AE. 
(*) Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing 
money, etc.  
(**) Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not 
bedridden. 

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8.1.1.2 
Relationship to Investigational Medicinal Product 
For this trial, an AE cause and effect relationship to the study drug will be classified by 
the Investigator as reported hereafter. 
Scale 
Definition 
Definitely 
Related 
The evidence is compelling that the study drug caused the adverse 
event. There is a clear temporal relationship of the event to the study 
drug; the event is consistent with a known pattern of drug (or drug class) 
effects; the event cannot be explained by concurrent disease or other 
drugs or chemicals; the event diminished upon cessation of study drug 
exposure or reduction in dose; the event worsened or recurred upon 
unintentional re-exposure to the study drug (intentional rechallenge for 
the purpose of assigning causality should not be performed). 
Probably 
Related 
It is more likely that the event is due to the study drug than due to other 
aetiologies, an alternative explanation is unlikely. There is a reasonable 
temporal relationship of the event to the study drug; the event may be 
consistent with a known pattern of drug (or drug class) effects; the drug 
seems more likely than other aetiologies to cause the effect; the event 
diminished upon cessation of study drug exposure or reduction in dose. 
Possibly 
Related 
It is equally likely that the event is due to the study drug as it is due to 
other aetiologies. There is a reasonable temporal relationship of the 
event to the study drug; follows a known or expected response pattern of 
the suspected drug but could also have been easily produced by a 
number of other aetiologies. 
Unlikely 
related 
 
It is more likely that the event is due to other aetiologies than due to the 
study drug. The event could have been reasonably related to patient's 
underlying diseases or concomitant treatments and/or the temporal 
relationship is doubtful between the study drug and the suspected 
adverse event. 
It the temporal relationship of the event to the study drug is reasonable, 
but there are important confounding factors/reasonably convincing 
alternative explanations, causality is considered unlikely. 
Not related 
The study drug almost certainly (or certainly) did not cause the event. 
Sufficient information exists to indicate that the aetiology is unrelated to 
the study drug, e.g., the event is more likely related to patient's 
underlying diseases or concomitant treatments and/or there is no 
temporal relationship between the study drug and the suspected adverse 
event, e.g. the event occurred before the study drug was administrated. 
Unassessable 
The data are insufficient or contradictory to make a meaningful medical 
assessment. 

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8.1.2 
Reporting Adverse Events 
AE reporting has to be in accordance with the ICH E6 Guidance on GCP and ICH E2A 
Guidance on Clinical Safety Management [ICH-1997; ICH-1994]. 
During the course of the study, all AEs (including SAEs), irrespective of the relatedness 
to the study drugs, must be recorded in detail in the source records and transcribed onto 
the AEs pages of the eCRF. During each monitoring visit, the Investigator and the site 
monitor will review all AEs and perform Source Data Verification (SDV). The 
Investigator will be responsible for ensuring that the correct information concerning all 
AEs is entered on the appropriate eCRF pages. 
In case clinically significant laboratory abnormalities are detected, the etiology of the 
abnormality should be identified, and the diagnosis should be recorded as an AE. 
Otherwise, if the etiology cannot be identified, the laboratory abnormality as such should 
be recorded as the AE. 
Similarly, clinically significant laboratory abnormalities detected at the screening visit 
(before any administration of the investigational medicinal product or additional non-
investigational drug), if not justified by an underlying disease already recorded in the 
medical history, are to be recorded as AEs. 
The reporting period for AEs is the period starting from the time of Informed Consent 
signature and lasting until Day 183 (+3) days post study drug administration on Day 1. 
All unresolved AEs (including SAEs) will be documented on the eCRF as “ongoing”. 
8.1.2.1 
Adverse Events of Special Interest (AESI) 
Adverse Events of Special Interest are defined as pre-specified events, under monitoring 
by the Sponsor and for which detailed information by the Investigator may be needed.  
In this study protocol AESIs are considered the following: 
1. 
AST increase (CTCAE G ≥ 3) 
2. 
ALT increase (CTCAE G ≥ 3) 
3. 
Presyncope 
4. 
Syncope 
5. 
Ventricular arrhythmia (CTCAE G ≥ 3) 
6. 
Heart failure (CTCAE G ≥ 3) 
7. 
Unexplained sudden death 
8. 
Seizure (any CTCAE Grade) 
9. 
Hyperglycemia (CTCAE G ≥ 3) 
8.1.2.2 
Adverse Events Associated with an Overdose 
An overdose is any dose of study treatment given to a patient or taken by a patient that 
exceeds the dose described in the protocol. An overdose is the accidental or intentional 

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use of a drug in an amount higher than the dose being studied. An overdose or incorrect 
administration of study treatment is not itself an AE, but it may result in an AE. All 
overdoses should be recorded, independently from an association with AEs.  
All AEs associated with an overdose or incorrect administration of study drug should be 
recorded. If an overdose results in an SAE, it must be reported to the Sponsor as an SAE 
within 24 hours of identifying the event. 
8.1.3 
Reporting Serious Adverse Events 
All SAEs occurring from the time of signing of the informed consent until Follow-up 
period must be reported immediately to the safety desk of the CRO. Information on the 
contact details are provided in the Investigator file as well as at Section General 
Information of the present protocol. The Investigator or designated study coordinator 
must report the SAE to the CRO within 24 hours of observation or notification of a 
serious AE. All of these events must also be recorded on the appropriate eCRF pages. 
It is the responsibility of the Investigator to inform his or her local Institutional Review 
Board (IRB)/Ethics Committee (EC) about SAEs according to the local IRB/EC 
requirements. It is the responsibility of the Sponsor (or Sponsor’s designee) to submit 
applicable SAE Reports to the Competent Authorities. Reporting of suspected 
unexpected serious adverse reactions (SUSARs) to the relevant IRB/EC, in accordance 
with the EU Clinical Trial Directive 2001/20/EC, the US Code of Federal Regulations 
313.32 and ICH E6 Guidance on GCP and ICH E2A Guidance on Clinical Safety 
Management, will also be the responsibility of the Sponsor (or Sponsor’s designee) [ICH-
1997; ICH-1994]. 
A safety contact sheet will be provided to the Investigator and will be maintained in the 
Investigator file at the site. Instructions will be provided to the investigators for 
submission of the SAEs to the CRO. 
Any serious and unexpected AE that the Investigator or the Sponsor considers to be at 
least possibly related to study drug is subject to expedited reporting to the appropriate 
Health Authorities. Events for which causality is unknown/unassessable or unreported by 
the Investigator are considered to be possibly related. 
The procedure to unblind a patient is described in Section 5.9. 
8.1.3.1 
Follow-up of Serious Adverse Events 
SAEs will be followed by the Investigator until the outcome is resolved, has reached a 
stable condition in the Investigator’s opinion, or until the patient is lost to follow-up. 
When the investigational site receives any information about a serious adverse event 
which changes or adds further information about the initial SAE, the site will send this 
information within 24 hours to the safety desk of the CRO, especially if this new 
information has an effect on the seriousness, relatedness or expectedness of an adverse 
event. 

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8.1.4 
Pregnancy Report 
In the unlikely eventuality that a patient becomes pregnant during the trial, the 
Investigator will be requested to complete the Pregnancy Report Form and any relevant 
document. They must be forwarded to the CRO e-mail address or sent by mail or fax (see 
Section General Information). After check of consistency, designated personnel at the 
CRO will then forward the information to the Sponsor within 24 hours of becoming 
aware of the pregnancy. Even though pregnancy is not considered as SAE itself, 
pregnancy has to be reported within the timelines as defined for SAE. 
Pregnant patients will be followed by the Investigator and CRO / Sponsor until the fetus / 
newborn is delivered. At the study end and database closure, reports of Pregnancy 
Outcome will be sent by the sites directly to Helsinn Safety. The subject’s primary care 
physician (or obstetrician) will be requested by the Investigator to provide further 
information on the pregnancy using the Pregnancy Outcome Information Form. If 
pregnancy occurs while the patient is on study treatment or up to 28 days after last study 
drug administration, the subject will be discontinued from the study. 
If a female partner of a male patient becomes pregnant during the male patient’s 
participation in this study and gives consent to collect information, the investigator must 
fill the pregnancy form and forward it to the CRO. The pregnancy must be followed for 
the final pregnancy outcome and the development of the child after birth. The pregnancy 
outcome form must be filled in by the investigator and sent to the study sponsor. 
 

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9 STATISTICS 
This section summarizes the statistical principles and methods planned to analyze the 
data for the ANAM-17-21 clinical study. The reference document is the ICH Topic 
E9(R1) Statistical Principles for Clinical Trials: Note for Guidance on Statistical 
Principles in Clinical Trials [ICH-1998]. 
Further details of the statistical analyses and data presentations to be used in reporting the 
study will be provided in the Statistical Analysis Plan (SAP), which will be finalized 
prior to breaking the blind. Changes from analyses planned in this protocol will be 
documented in the SAP and/or study report. The database will be locked after all queries 
are resolved, and a blinded review of data is performed, and decisions made about study 
populations and handling of unused or missing data. 
9.1 
Stratification factors 
The stratification aims to balance investigational treatment within group of prognostic 
factors.  
Central randomization will be stratified by line of systemic anti-cancer treatment (first 
line vs second line vs third line), by type of anti-cancer therapy (immunotherapy vs non-
immunotherapy) and by Baseline score of 5-item Anorexia Symptom Subscale (≤10 vs 
>10). 
9.2 
Sample Size Determination 
At the time the trial was initiated, the primary endpoint was the Composite Clinical 
Response (CCR) rate. The sample size was determined based on results obtained on 
patients participating to the previous trials (HT-ANAM-301 and HT-ANAM-302). A 
logistic regression of the CCR on the randomized treatment with a sample size of 316 
patients (158 patients per arm) would achieve 90% power at a 2-sided 0.05 significance 
level to detect a change in CCR from the placebo expected rate of 0.075 to 0.200. This 
level of effect corresponds to an odds ratio of 3.083. (SAS® - PROC POWER) 
From the v4.A, the protocol has been amended in order to change from a primary 
efficacy endpoint based on the CCR at week 9 to two co-primary efficacy endpoints: the 
duration of treatment benefit in weight at Week 12, and duration of treatment benefit in 
5-item Anorexia Symptom Subscale at Week 12.  
Adequate power was confirmed by simulation for those co-primary endpoints (joint 
power greater than 90%). However, during the course of the study an error was 
discovered in the algorithm used to determine the statistical power for the evaluation of 
the duration of treatment benefit from baseline to Week 12 for body weight and anorexia 
(5-IASS) co-primary endpoints. New simulations correcting for the programming error 
were performed and these results confirmed high power (over 98%) for the weight-based 
co-primary endpoint but showed low power for the 5-IASS co-primary endpoint 
(between 60 and 70%).  

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Power for the new co-primary endpoints (mean change in body weight and mean change 
in 5-IASS) with the fixed sample size of 158 patients per arm was computed by means of 
simulations. Power for mean change in body weight was showed to be close to 100%, 
while power for mean change in 5-IASS was showed to range between 78% and 87%, so 
leading to a joint power for the two co-primary endpoints of at least 78%. 
9.3 
Definition of Study Populations for Analysis (Analysis Set) 
Study populations are defined as follows: 
Safety Set 
The Safety Set includes all patients who receive any study drug and will be analyzed as 
per actual treatment. 
ITT Set 
The Intent-to-Treat (ITT) Set includes all randomized patients and will be analyzed as per 
planned treatment. 
Full Analysis Set 
The Full Analysis Set (FAS) includes all randomized patients who take at least one dose 
of trial medication, and for which post randomization data are collected. The definition 
may be updated at the time of the blind review of the data at the end of the trial.  
Per-Protocol (PP) Set 
The Per-Protocol Set is the subset of the randomized patients who do not have major 
protocol violations.    
9.4 
Statistical Analysis 
9.4.1 
Missing Data 
A detailed presentation of missing data will be produced, indicating their amount and 
incidence by treatment, visit and reason (For instance: visit not done, assessment not 
done).  
Every effort will be made to collect data from the protocol-specified assessments; 
patients will be asked to continue to participate in the study and complete planned visits 
up to the end of the treatment period (Week 24) even if they have permanently 
discontinued treatment with anamorelin/placebo (“retrieved drop-out” approach). Reason 
for treatment discontinuation will be precisely collected in the CRF and will be used to 
investigate possible unexpected patterns of missing data and for the imputation itself. 
However, due to the nature of the patients’ underlying disease, a non-ignorable amount of 
missing data is expected in this trial. To minimize the risk of bias in the analysis, ad hoc 
rules for single/multiple imputation will be adopted. The multiple imputation (MI) 
method for missing data, is described in the literature [Ratitch -2014; Ratitch -2013].  
The missing data of the variables being part of the primary efficacy endpoints (weight, 5-
item Anorexia Symptom Subscale score) and the secondary/exploratory efficacy 

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endpoints will be imputed. No imputation will be performed for survival status and no 
data will be imputed after patient death. All observed data will be included in the 
analyses, except for a sensitivity analysis in which the weight of the patients with fluid 
retention at the date of the assessment will be replaced with imputation approach as if 
they were missing. 
Death from underlying disease is rather inevitable in this target population and does not 
reflect a failure of study treatment. According to the ICH E9(R1) guideline [ICH-1998], 
death is considered as an intercurrent event, after which no value is measurable. In order 
to measure the treatment effect for these patients, the “while alive” strategy will be used. 
Therefore, only values collected before death for patients dying before the endpoint will 
be used for the analyses.  
9.4.2 
Multiplicity 
The primary and the secondary efficacy endpoints will be tested using a hierarchy for 
testing in order to control type I error rate.  
The order of testing will be as follows: the co-primary efficacy endpoints related to the 
mean change in weight (H0w) and related to the mean change in 5-item Anorexia 
Symptom Subscale (H0a), then the secondary efficacy endpoints: the duration of benefit in 
weight (≥0) (H0d0w), the duration of benefit in weight (≥ to a predefined threshold) 
(H0dtw), the duration of benefit in 5-IASS (≥ 0) (H0d0a), the duration of benefit in 5-IASS 
(≥ to a predefined threshold) (H0dta), then the mean change in FAACT 12-item A/CS 
domain score (H0mF), in FACIT-F (H0mFF) and in FAACT total score (H0mFT) . Each of 
these tests will be done sequentially at the level of 0.05 bilateral. The experimental false 
positive error rate will be preserved because, in order to declare the test component 
(anamorelin) superior to the placebo, both co-primary endpoints must be significant, 
meaning that both H0w and H0a must be rejected simultaneously. Additional details are 
presented in Section 9.4.5.  

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9.4.3 
Subgroups 
Subgroup analysis will be conducted for the following subgroups, as far as adequate 
number of patients in subgroups is confirmed at the BDRM: 
• 
Age (≤ 65 years or > 65 years) 
• 
Gender 
• 
Geographic region  
• 
Systemic anti-cancer treatment line (first line vs second line vs third line) – 
stratification factor 
• 
Cancer treatment (immunotherapy vs no immunotherapy) – stratification factor 
• 
The 5-item Anorexia Symptom Subscale (≤10 vs >10) – stratification factor 
• 
Patients who completed 24 weeks treatment 
• 
Patients with at least one treatment emergent adverse event with preferred term 
belonging to fluid retention related (codified under PT ‘Fluid retention’, ‘Ascites’, 
‘Pleural effusion’, ‘Oedema peripheral’, ‘Oedema’, a specific review of the LLT 
will be done during the BDRM to confirm if adverse events are possibly impacting 
the weight measurement) and/or patients with signs of edema as defined in Section 
7.2.2.1. 
• 
Race and Ethnicity 
9.4.4 
Analysis of Demographics, Baseline Variables and Disease 
Characteristics 
Continuous demographic, and baseline characteristics will be summarized using mean, 
median, SD, Q1, Q3, minimum and maximum, by treatment group and overall. 
Qualitative demographic, and baseline characteristics will be summarized by counts and 
percentages by treatment group.  
Demographics and baseline characteristics will be summarized for the ITT, the Safety, 
the FAS and the Per Protocol analysis sets.  
Medical history will be coded with MedDRA dictionary.   
Individual subject listing for all data will be provided.  
9.4.5 
Efficacy Analysis 
The efficacy analysis will be performed on the ITT population. Some supportive analyses 
of the primary efficacy endpoints will be performed on different populations (PP set and 
FAS set). 
The analyses will be produced after the imputation of the missing data. The imputed 
datasets used for the primary endpoint analysis will be used for the analyses of the 
secondary and exploratory endpoints. When the data will be considered as missing (see 

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Section 9.4.1), the imputation of the values will be done at the level of the visit for the 
raw values (for instance weight). Then, the primary endpoints (for instance mean change 
in weight) and the secondary endpoints will be derived from the imputed raw values and 
not directly imputed. 
Individual subject listing for all data observed (not imputed) will be provided.  
 
9.4.5.1 
Primary Efficacy Analysis 
The primary efficacy endpoints are defined in Section 3.1.1 
• Mean change in body weight from baseline over 12 Weeks.  
• Mean change in 5-item Anorexia Symptom Subscale form baseline over 12 
Weeks. 
The null hypothesis concerning the first co-primary endpoint of mean change in body 
weight (H0w) and the corresponding alternative hypothesis (H1w) are defined as: 
H0w: MWa = MWp 
H1w: MWa ≠ MWp 
Where MWa is the mean change in body weight for the anamorelin arm and MWp is the 
mean change in body weight for the placebo arm. 
The null hypothesis concerning the second co-primary endpoint of mean change in 
patient 5-item Anorexia Symptom Subscale (H0a) and the corresponding alternative (H1A) 
are defined as: 
H0a: MAa = MAp 
H1a: MAa ≠ MAp 
Where MAa is the mean change in 5-item Anorexia Symptom Subscale score for the 
anamorelin arm and MAp is the mean change in 5-item Anorexia Symptom Subscale 
score for the placebo arm. 
The mean change effect will be computed as mean of the changes from baseline over 12 
weeks by the time of the last assessment (either Week 12 or before), and then divided by 
the number of assessments (observed or imputed) from baseline up to the time of the last 
assessment (either Week 12 or before, in case of death, for the analysis at Week 12). 
The primary efficacy analyses will be conducted on the ITT. H0w and H0a will be tested 
using an ANOVA to compare the two treatment groups, at a type-I error threshold of 0.05 
two-sided. For each of the imputation the estimate of difference between treatments and 
its standard error (SE) will be computed, then pooled using the Rubin rule, the pooled 
difference and the related p-value will be interpreted for the primary efficacy analyses. In 
addition, the least squares (LS)-mean and 95% confidence interval will be presented per 
treatment group. 

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9.4.5.2 
Sensitivity and supportive analyses of the primary efficacy 
endpoints 
9.4.5.2.1 
Sensitivity analyses of the primary efficacy endpoints 
The sensitivity analyses are aimed to confirm robustness of the conclusion of the primary 
efficacy analysis but are not part of the multiplicity adjustment.  
A sensitivity analysis regarding imputation of missing will be performed using data from 
the placebo group only (control-based imputation) for patients who do not have properly 
matched patients with complete follow-up. 
An analysis similar to the primary efficacy analysis will be also conducted after having 
imputed the values of weight obtained in presence of fluid retention (See Section 9.4.3). 
The details of the patients regarding the fluid retention will be summarized. 
9.4.5.2.2 
Supportive analyses of the primary efficacy endpoints 
Two analyses similar to the primary efficacy analysis will be conducted, one on the FAS 
population and another one on the PP for each of the primary endpoints. The FAS and the 
PP are impacted by the treatment adherence. The results of these analyses are expected to 
be similar to the one of the primary efficacy analysis. 
Primary efficacy endpoints will be presented for all the subgroups (listed in Section 
9.4.3). 
9.4.5.3 
Secondary Efficacy Analysis 
All the analyses of the secondary endpoints will be conducted on the ITT. 
The secondary endpoints (See Section 3.1.2) will be evaluated following a hierarchal 
approach, as follows: duration of treatment benefit (≥0) in body weight up to Week 12 as 
the first secondary endpoint, then duration of treatment benefit (≥ to a predefined 
threshold) in body weight up to Week 12, duration of treatment benefit (≥0) in 5-IASS up 
to Week 12, duration of treatment benefit in 5-IASS (≥ to a predefined threshold) up to 
Week 12, mean change in FAACT 12-item A/CS domain score from baseline up to Week 
12, mean change in FAACT total score from baseline up to Week 12 and mean change in 
FACIT-F from baseline up to Week 12.  
The null hypothesis concerning the first secondary endpoint of duration of treatment 
benefit in body weight (≥0) ((H0d0w) and the corresponding alternative hypothesis (H1d0w) 
are defined as: 
H0d0w: D0Wa = D0Wp 
H1d0w: D0Wa ≠ D0Wp 
Where D0Wa is the duration of treatment benefit in body weight (≥0) for the anamorelin 
arm and D0Wp is the duration of treatment benefit in body weight for the placebo arm. 
H0d0W will be tested using a two-sided type-I error threshold of 0.05 only if both H0w and 
H0a (i.e., the null hypothesis concerning the primary endpoints) are rejected. 

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The null hypothesis concerning the secondary endpoint of duration of treatment benefit in 
body weight (≥ to a predefined threshold) (H0dtW) and the corresponding alternative 
(H1dtW) are defined as: 
H0dtW: DtWa = DtWp 
H1dtW: DtWa ≠ DtWp 
Where DtWa is the duration of treatment benefit in weight (≥ to a predefined threshold) 
for the anamorelin arm and DtWp is the duration of treatment benefit in weight for the 
placebo arm. 
H0dtW will be tested using a type-1 error threshold of 0.05 two sided only if H0d0W (i.e., 
the null hypothesis concerning the first secondary endpoint) is rejected; note the latter 
rejection requiring the rejection of if both H0w and H0a. 
The following hypothesis systems will then be tested based on the rules above described. 
H0d0A: D0Aa = D0Ap 
H1d0A: D0Aa ≠ D0Ap 
Where D0Aa is the duration of treatment benefit in 5-item Anorexia Symptom Subscale 
(≥0) for the anamorelin arm and D0Ap is the duration of benefit in 5-item Anorexia 
Symptom Subscale for the placebo arm. 
H0dtA: DtAa = DtAp 
H1dtA: DtAa ≠ DtAp 
Where DtAa is the duration of treatment benefit in 5-item Anorexia Symptom Subscale (≥ 
to a predefined threshold) for the anamorelin arm and DtAp is the duration of benefit in 5-
item Anorexia Symptom Subscale for the placebo arm. 
H0mf: MFa = MFp 
H1mf: MFTa ≠ MFp 
Where MFa is the mean change in FAACT 12-item A/CS domain score in the anamorelin 
arm and MFTp is the mean change in FAACT 12-item A/CS domain score in the placebo 
arm. Similar hypothesis systems are set-up for FAACT total score (H0mFt, H1mFt) and 
FACIT-F (H0mFF, H1mFF). 
If the co-primary analysis leads to rejection of H0w and H0a, then the following hypothesis 
will be tested sequentially: secondary efficacy endpoint related to the duration of 
treatment benefit in weight (≥0) (H0d0w), the secondary efficacy endpoint related to the 
duration of treatment benefit in weight (≥ to a predefined threshold) (H0dtw), the 
secondary efficacy endpoint related to the duration of treatment benefit in 5-IASS (≥0) 
(H0d0A), the secondary efficacy endpoint related to the duration of treatment benefit in 5-
IASS ((≥ to a predefined threshold) (H0dtA) and then the secondary efficacy endpoint 
related to the mean change in FAACT 12-item A/CS domain score (H0mF), FACIT-F and 
FAACT total score. Each of these tests will be done sequentially at the level of 0.05 
bilateral.  

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This hierarchy of testing will allow formal confirmation for the effect on the primary 
endpoints as well as on the secondary endpoints. This will guarantee the study-wise type-
1 error, while not requiring any adjustment for multiple testing. 
The duration of treatment benefit is measured as the duration for which the patient 
observed a change from baseline superior or equal to zero or to the predefined thresholds 
of clinical meaningfulness. For the purpose of computation, it will be assumed a linear 
evolution between two measurements. 
The mean change effect will be computed as mean of the changes from baseline over 12 
weeks by the time of the last assessment (either week 12 or before and then divided by 
the number of assessments (observed or imputed) from baseline up to the time of the last 
assessment (either week 12 or before, in case of death). 
All the secondary endpoints (duration of treatment benefit and mean change from 
baseline) will be analyzed by means of ANOVA with explanatory variables being the 
randomized treatment, and the stratification factors.  
The least squares (LS)-mean and 95% confidence interval will be presented per treatment 
group together with the LS-mean treatment effect and its 95% confidence interval. 
Statistics will be evaluated in each imputed datasets and pooled using Rubin’s method. 
9.4.5.4 
Exploratory Efficacy Analysis 
All the analyses of the exploratory endpoints will be conducted on the ITT. 
The exploratory efficacy analyses are aimed to explore the effect of the anamorelin on 
different endpoints but are not part of the multiplicity adjustment, thus have no 
confirmatory value. The exploratory efficacy endpoints are detailed in Section 3.1.3.  
The duration of benefit and mean change from baseline endpoints will be analyzed like 
the main analysis for the primary efficacy endpoints or the analyses of the secondary 
endpoints.  
All the changes from baseline exploratory endpoints except the HAS and the PGIS/C will 
be analyzed using an ANCOVA model, with explanatory variables being the randomized 
treatment, the stratification factors and the baseline value. Specifically, for the imputation 
of the 5-item Anorexia Symptom Subscale, the stratification based on the 5-IASS 
baseline will not be introduced in the model as the 5-IASS baseline value itself will be 
part of the model.  
The estimator of the effect will be the difference in change from baseline between the test 
group and the placebo group estimated as the difference in LS means of the ANCOVA 
model. The least squares (LS)-mean and 95% confidence interval will be presented per 
treatment group together with the LS-mean placebo-corrected treatment effect and its 
95% confidence interval. Statistics will be evaluated in each imputed datasets and pooled 
using Rubin’s method. 
All the responder analyses (CCR and achievement of responder threshold) will be 
analyzed using a logistic regression, with explanatory variables being the randomized 
treatment, and the stratification factors. CCR is a composite measure including both a ≥ 

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5% body weight gain from baseline and increase ≥ 2 points in the 5-item Anorexia 
Symptom Subscale score from baseline in patients who survive until the Visits of the 
analysis. CCR at week 9 was defined as primary efficacy endpoint in protocol version 3.0 
and previous editions. 
Frequency and rate of responders will be reported with 95% confidence intervals (CIs). 
For the treatment comparison, the odds ratio will be reported with 95% CIs. Statistics will 
be evaluated in each imputed datasets and pooled using Rubin’s method. 
To explore the correlation between the weight gain and the improvement on the patient-
reported anorexia score, the Pearson’s correlation coefficient will be estimated within 
each treatment group. In addition, a scatter plot of the change from baseline of the two 
variables will be presented, with a display of the distribution of each single variable. The 
analysis will be using all available data at each Study Visit. If a sufficient amount of data 
will be available, relation between numerical endpoints and survival will be explored, as 
well as relation between changes in weight and anorexia score at other time points. 
 
9.4.6 
Safety Analysis 
The safety analysis will be performed on the Safety population. 
Clinical evaluations for safety assessments will include adverse events (AEs) assessment, 
physical examination (PE), vital signs, 12-lead electrocardiogram (ECG), laboratory test 
(hematology, blood chemistry, urinalysis), Tumor assessments, Overall Survival.  
Adverse events, 12-lead ECGs, vital signs, and laboratory assessments will be 
summarized by treatment group. All safety summaries and analyses will be performed 
based on the Safety Set. All safety and tolerability data will be listed. A treatment-
emergent AE is one with an onset date on or after the date of the first dose of the study 
drug and up to Visit 11 (Day 183 +3 days) the last study visit.  
AEs will be coded using Medical Dictionary for Regulatory Activities (MedDRA) 
dictionary (the version will be provided in the SAP and in the Data Management Plan 
[DMP]) to give a preferred term (PT) and a system organ class (SOC) for each event. The 
number and percentage of patients who experienced at least one TEAE, drug-related 
TEAE (defined as AEs with relationship classified by the investigator as definitely, 
probably, possibly, unassessable or missing), serious TEAE, serious related, severe 
TEAE (i.e. TEAE with CTCAE grade ≥ 3), AESI (as described below), and the number 
and percentage of patients withdrawn due to TEAE will be summarized by treatment arm. 
For each SOC and PT, summaries will be made with respect to the proportion of patients 
having at least one occurrence of that event during the study and the total number of 
events. The incidence of TEAEs in each treatment arm will be presented overall, by SOC 
and PT, and by additional grouping by severity according to the CTCAE grade and 
relationship to the study treatment. Tables of TEAEs will be presented by relationship to 
study drug. Additional tables including any relationship to study drug will be presented. 
Adverse events of Special Interest are described in Section 8.1.2.1. 

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No formal test will be used for “between groups” comparison. All AEs will be listed. 
Physical examination results at screening will be summarized in a frequency table 
(normal/abnormal). Results and relevant findings will be listed. 
Vital signs will be summarized by treatment using descriptive statistics for absolute 
values and change from baseline (i.e., last value before first study drug intake). 
Shift tables from baseline to the worst post-baseline results will be provided for the ECG 
overall interpretation. ECG measurements (HR, QT, QTcF, PR, RR, and QRS) will be 
summarized by treatment group and visit. Outliers’ analysis will be conducted.  
Shift tables from baseline to the Last Value according to NCI CTCAE grade will be 
provided for selected chemistry parameters (ALT, AST, total bilirubin, ALP, creatinine, 
and glucose) and hematology parameters (hemoglobin, platelet count, white blood cells, 
neutrophils, and ANC). In addition, a change and % change from baseline will also be 
measured for HbA1c and pre-albumin. 
The best overall tumor responses will be summarized by treatment group with 
frequencies and percentages.  
Overall survival will be described using Kaplan-Meier estimates. 
Individual subject listing for all data will be provided.  
9.4.7 
Determination of the responder threshold in the 5-item Anorexia 
Symptom Subscale 
In order to measure the duration of treatment benefit, the threshold for the changes in 5-
IASS will be determined before the unblinding.  
Previously, a 2-point threshold to detect clinically meaningful change was determined 
from a psychometric evaluation using the completed Phase 3 studies (HT-ANAM-301 
and HT-ANAM-302) [Gelhorn-2016].  
The PGIS and PGIC questionnaires will be administered in this study. Both the PGIS and 
PGIC will consist of a single question each to assess the severity and change in 
appetite/eating-related symptoms (for actual questionnaires, see APPENDIX 6). The 
PGIS is a single-item questionnaire and has a 4-point Likert-type response scale ranging 
from ‘‘do not have” symptoms to “severe” symptoms related to appetite/eating. The 
PGIC is also a single-item questionnaire with a 7-point Likert-type response scale 
ranging from ‘‘very much worse’’ to ‘‘very much improved.’’ To note, the terminology of 
“appetite/eating symptoms” is consistent with that used in the cognitive interviews from a 
qualitative study (Study EVA-16879-00), as it was seen as more easily interpretable by 
patients than “anorexia symptoms.” The PGIS will be administered at baseline, Week 6 
and Week 9, and the PGIC will be administered at Week 6 and Week 9.  
The responder definition threshold will be determined as per standard practice for these 
anchors and supported by distribution-based methods [Norman-2003; Revicki-2008]. 
Specifically, the responder definition threshold will be determined as the smallest 
difference or change in score from baseline that is considered important to the patient 

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(i.e., those improving on the PGIS and on the PGIC). As such, the difference in scores on 
the PGIS from baseline to Week 6 and Week 9 will be determined, and an improvement 
on the PGIS will be used to define meaningful change based on mean values of the 5-
item Anorexia Symptom Subscale. Similarly, mean values of the 5-item Anorexia 
Symptom Scale among patients who indicate that their appetite/eating symptoms have 
improved since starting treatment (based on the PGIC) will be calculated; this value will 
be used to aid in defining a meaningful change in the symptom measure. The results of 
these anchor-based methods will be supported by distribution-based methods calculating 
a 0.2 standard deviation (SD), 0.3 SD, and 0.5 SD, whereby the 0.5 SD estimate can be 
considered to provide an upper boundary for what would constitute a meaningful change, 
while 0.2 SD provides a lower boundary [Revicki-2008]. Both anchor-based and 
distribution-based estimates will be plotted together for comparison and triangulation, 
whereby different responder thresholds will be graphed to visually depict the range of 
estimates, and the anchor-based estimates will be assigned more weight than the 
supportive distribution-based methods. A cumulative distribution of response curve for 
the 5-item Anorexia Symptom Subscale, one for the treatment group and one for the 
placebo group, will also be generated to allow a variety of response thresholds to be 
examined simultaneously and collectively, encompassing all available data. 
9.4.8 
Determination of the clinically meaningful responder threshold in 
weight change 
In order to measure the duration of treatment benefit, the threshold for the changes in 
body weight will be determined before the unblinding.  
As detailed in Section 1.5, the primary efficacy endpoints has changed during the course 
of the study due to interaction with FDA. In protocol version 4.0, the patients will be 
assessed for specific PGIS and PGIC questions related to body weight. The aim of this 
analysis is to determine which value of percent change from baseline will be suitable to 
determine a meaningful change. 
Briefly, both the PGIS and PGIC will consist of a single question each to assess the level 
of concern about weight and change in worry about weight (for actual questionnaires, see 
APPENDIX 6). The PGIS is a single-item questionnaire and has a 4-point Likert-type 
response scale ranging from ‘‘I have not had any concerns about my weight” to “I have 
had severe concerns about my weight”. The PGIC is also a single-item questionnaire with 
a 7-point Likert-type response scale ranging from ‘‘very much worse’’ to ‘‘very much 
improved.’’ To note, the terminology of “worry about weight” and “weight concerns” is 
consistent with that used in the cognitive interviews from a qualitative study (Study 
EVA- 16879-00). The PGIS will be administered at baseline, Week 6 and Week 9, and 
the PGIC will be administered at Week 6 and Week 9.  
The responder definition threshold will be determined as per standard practice for these 
anchors and supported by distribution-based methods [Norman-2003; Revicki-2008]. 
Specifically, the responder definition threshold will be determined as the smallest 
difference or change in score from baseline that is considered important to the patient 
(i.e., those improving on the PGIS and on the PGIC). As such, the difference in scores on 

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the PGIS from baseline to Week 6 and Week 9 will be determined, and an improvement 
on the PGIS will be used to define meaningful change based on mean values of weight 
change in percentage. Similarly, mean values of weight change in percentage among 
patients who indicate that their weight concerns have improved since starting treatment 
(based on the PGIC) will be calculated; this value will be used to aid in defining a 
meaningful change in the concerns measure. The results of these anchor-based methods 
will be supported by distribution-based methods calculating a 0.2 standard deviation 
(SD), 0.3 SD, and 0.5 SD, whereby the 0.5 SD estimate can be considered to provide an 
upper boundary for what would constitute a meaningful change, while 0.2 SD provides a 
lower boundary [Revicki-2008]. Both anchor-based and distribution-based estimates will 
be plotted together for comparison and triangulation, whereby different responder 
thresholds will be graphed to visually depict the range of estimates, and the anchor-based 
estimates will be assigned more weight than the supportive distribution-based methods. A 
cumulative distribution of response curve for the weight change in percentage, one for the 
treatment group and one for the placebo group, will also be generated to allow a variety 
of response thresholds to be examined simultaneously and collectively, encompassing all 
available data. 
9.5 
Interim Analysis 
No interim efficacy analysis is planned for this study. 
The unblinding of the study will take place only after thresholds for the changes in body 
weight and 5-IASS have been determined. 

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10 ETHICAL AND REGULATORY ASPECTS 
10.1 Ethical Considerations 
The study will be performed in accordance with the principles outlined in the Declaration 
of Helsinki [Helsinki2013] as amended by the World Medical Association in Fortaleza in 
2013, and the ICH GCP guidelines as well as all local laws and regulations of the 
countries in which the study is conducted. 
10.1.1 
Laws and Regulations 
This clinical study will be conducted in compliance with all international laws and 
regulations and national laws and regulations of the countries in which the trial is 
performed, as well as any applicable guidelines.  
10.1.2 
Patient’s information sheet and informed consent form 
All patients invited to participate in the clinical trial are entitled to make their decision 
based on all current available information provided to them by the Investigator/designee. 
In addition, they will be given a document in native language written in clear concise lay 
language for review and consideration. The document will previously have been 
approved by relevant independent Ethics Committee(s) (EC[s]/Institutional Review 
Boards [IRBs]) and may further be updated as new important information becomes 
available that may affect subject’s willingness to participate or continue in the trial. This 
document will tell potentially eligible subjects about the nature of the study drug, its 
efficacy and safety profile, the route of administration, and the human experience 
available. It will also outline the steps of the protocol as they will apply to the individual, 
including the number of visits and types of procedures/assessments/measurements to be 
performed so that the individual has a clear picture of the risks, inconveniences and 
benefits that may accrue from the trial. The patient must be made aware that he/she may 
refuse to join the trial or may withdraw his/her consent at any time without prejudicing 
further medical care and that he/she is covered by the Sponsor's indemnity insurance in 
the event of a trial related injury. Contact details to report and discuss suspected trial-
related injuries will be provided. Patients must also know that their personal medical 
records may be reviewed in confidence by the Sponsor's staff or representatives and by 
Regulatory Authorities and IRB/EC and that personal information will be collected and 
retained in a confidential database. Conditions for ensuring the anonymity of data and the 
security and confidentiality of the database should be explained. Consent will always be 
given in writing after the patient has had adequate time to review the information and ask 
questions, if need be. Both the patient and the Investigator or responsible site staff 
member conducting the informed consent discussion will personally write the name, sign 
and date the consent form.  
10.1.3 
Protocol amendments 
Changes to the protocol may only be made by means of a written amendment, which has 
to be approved and signed by the authorized individuals of the Sponsor and by the 

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Investigator. The study code, the title of the study, the progressive number and the date of 
the amendment must be recorded on the first page of the document. Exhaustive 
justifications that motivate the amendment to the protocol should clearly be addressed in 
the document. All protocol amendments must be submitted to the IRB/EC for review and 
approval unless it covers administrative issues only. In this case, the IRB/EC will be 
notified of the amendment for information purposes only. 
10.1.4 
Protocol deviations 
The Investigator has to conduct the study in accordance with the approved current 
protocol and will not be allowed to make any changes with the only exception when 
immediate changes are necessary to protect the safety, rights, and welfare of the subjects. 
In order to obtain interpretable results, neither the Investigator nor the Sponsor/CRO will 
alter the study conditions agreed upon and set out in this protocol.  
In the event of an isolated, unforeseen instance resulting in a protocol deviation, the 
Investigator is to document this deviation and notify it to the CRO as soon as possible, in 
writing. In no instance should this increase the subject’s risk or affect the validity of the 
study data. 
10.1.5 
Data collection  
Electronic Case Report Forms (eCRFs) will be used for recording patient’s study data 
using a validated web-based Electronic Data Capture (EDC) system. It is the 
responsibility of the Investigator to ensure that the eCRFs are properly and completely 
filled in. The eCRFs must be completed for all patients who have been included in the 
study.  
Each authorized site personnel will be assigned a login and password to enter the EDC 
system via a secure network. Each login uniquely identifies the user and appropriate 
permissions will be set-up according to the user role. The access to the system will be 
granted once the user’s training will be completed and documented.  
Queries will be used to validate/clarify data entered on an eCRF page. Some queries will 
be generated automatically by the system when the user saves data that does not meet the 
criteria pre-defined for the data field. In addition, others will be created manually in the 
system and sent either by the study monitor (as result of Source Data Verification) or by 
Clinical Data Management. 
Discrepancies raised will be reviewed online to determine the corrective action needed. 
Changes will be made directly by authorized site staff. The EDC system’s audit trail will 
keep track of any information entered, modified and deleted. The audit trail will include, 
as a minimum, what was entered/changed/modified, who made the action and when the 
action was made. Any answered query will be reviewed and closed by authorized users. 
The Investigator will electronically sign the eCRF to validate the content. 
Patient’s source documentation (i.e., hospital charts) will be maintained at the clinic. 
Source data to be recorded directly onto the eCRFs will be communicated in advance. In 
cases where source documents are not eCRFs, the information on the eCRFs must match 

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the source documents. Source data verification will be regularly performed by the blinded 
study monitor.  
All the study questionnaires will be filled on electronic diary at the timepoints mentioned 
in the study flow chart. Data from study questionnaires will be then automatically 
transferred to EDC.  
10.1.6 
Monitoring and Quality Assurance 
The study will be monitored by CRO’s adequately qualified and trained clinical monitors 
on a regular basis throughout the study period to ensure the proper conduct of the clinical 
trial. The purposes of clinical trial monitoring are to verify that the rights and well-being 
of study patients are protected, that the reported trial data are accurate, complete and 
verifiable against the source documents, and that the study is conducted in accordance 
with the current protocol, Good Clinical Practice guideline and applicable regulatory 
requirements. During the monitoring visits, monitors will verify the following including, 
but not limited to, patient informed consent, patient’s eligibility, safety data and 
reporting, quality of source documents and eCRF data against patient’s medical records. 
If inconsistencies are identified, the corresponding corrections to the eCRF data will have 
to be made by the Investigator. Monitors will also check patient compliance, accrual, 
drug handling, including dispensing procedures and accountability logs, delegation of 
responsibilities within the Investigator’s team, relevant communications with family 
doctors, if any, ancillary equipment and facilities, including refrigerators and freezers, 
local labs, etc. The Investigator and other site staff involved in the study must allocate 
enough time to the monitor at these visits. 
Upon request by the Sponsor, or following the CRO’s audit plan, on-site study audits 
may be conducted in order to ensure the study is in compliance with GCP, applicable 
regulatory requirements, and the study protocol. The auditing activities may also be 
conducted after study completion. 
In addition, Regulatory Authorities may wish to conduct on-site inspections (during the 
study or after its completion). If a Regulatory Authority notifies the Investigator of an 
inspection or visits the site unannounced for purposes of conducting an inspection, the 
Investigator must inform the study Sponsor and CRO immediately. The Investigator will 
make all efforts to facilitate the conduct of the audits and inspections giving access to all 
necessary facilities, data and documents. 
10.1.7 
Study Documentation and Records retention 
The medical (hospital) files of trial patients should be retained in accordance with 
national legislation (and in accordance with the maximum period of time permitted by the 
hospital (or institution/private practice). 
The Sponsor should ensure that it is specified in the protocol or other written agreement 
that the investigator(s)/institution(s) will permit trial-related monitoring, audits, IRB/EC 
review, and regulatory inspection(s), providing direct access to source data/documents. 
All the essential study documents should be retained at the sites for the period required 
by the Applicable Regulatory Requirements, or for a period of at least fifteen (15) years 

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following the completion or discontinuation of the study, whichever is longer and in any 
case in accordance with FDA regulation 21 CFR 312.62(b) and (c) and ICH-GCP 
guidelines [Reilly2013]. Should the Investigator wish to assign the study documentation 
to another party or move to another location, the Sponsor should promptly be notified. 
10.1.8 
 Confidentiality 
The Sponsor and the CRO must ensure that the Investigator keeps secret from third 
parties any confidential information disclosed or provided by the Sponsor and regarding 
the Sponsor and its study-related products. The Investigator agrees to use such 
information only to accomplish the present study tasks and not to use it for any other 
purposes without the prior written consent by the Sponsor. Prior to the study start-up, 
each Institution/Investigator as well as each subcontractor to be involved in the study 
should sign a confidentiality agreement with the CRO on behalf of the Sponsor. 
10.1.9 
Publication policy 
Helsinn Healthcare SA is committed to public disclosure of research results that involve 
Helsinn products and for Helsinn sponsored publications, the International Committee if 
Medical Journal Editors (ICMJE) will apply to all named authors. As a general rule, the 
Sponsor and the Investigator(s) agree that no publications presenting or discussing data 
and/or results from clinical trials sponsored by Helsinn Healthcare SA will take place 
until the participating center(s) has/have completed the study, the data have been 
interpreted, and the final report has been issued. As a rule, the Sponsor is free to use the 
data collected in the sponsored study for the drug registration, world-wide scientific 
product documentation, and for publication. 
The Sponsor shall have the sole and exclusive right to the first publication of the study 
data. Such Sponsor publication is intended to be a multi-center publication of the study 
data, collected from all investigators and institutions participating in the study. If the 
Investigator is interested in contributing to or participating in the Multi-Center 
Publication, he or she must contact the Sponsor. Selection of authors/participants will be 
governed by the Sponsor, considering individuals’ contribution to the Study. 
The Institution and the Investigator may publish or otherwise present the results of the 
Study Data obtained by the Institution and/or the Investigator  provided that all of the 
following conditions have been satisfied: (i) the Multi-Center Publication has occurred; 
or, if no such publication has occurred, a manuscript should be submitted within 12 
months of Study Drugs’ first approval or within 18 months of the decision to discontinue  
Study Drugs’ development, allowing for congress presentation first; (ii) before 
submitting the Independent Submission to a publisher, reviewer or other outside party, 
the Institution and/or the Investigator must submit the proposed Independent Submission 
to the Sponsor and allow the Sponsor at least sixty (60) days to review and provide 
comments; (iii) the Institution and/or the Investigator shall, as requested by the Sponsor, 
delete all references to Confidential Information (excepting the results of the Study 
obtained by the Institution and the Investigator); (iv) the Institution and the Investigator 
shall consider the Sponsor’s comments and proposed revisions in good faith; and (v) if at 
any point during the initial sixty (60) day review the Sponsor so requests, the Institution 

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and/or the Investigator shall delay the publication or presentation of the Independent 
Submission for up to sixty (60) additional days in order to permit the Sponsor time to 
obtain Intellectual Property protections. 
10.1.10 
Insurance 
The Sponsor/designee will obtain clinical study liability insurance, which covers health 
impairments 
resulting 
from 
drugs 
and/or 
substances/investigational 
products 
administered in the course of this study for which the patient has given his/her written 
informed consent.  

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12 APPENDICES 
APPENDIX 1: 
EASTERN 
COOPERATIVE 
ONCOLOGY 
GROUP 
PERFORMANCE SCALE 
APPENDIX 2: 
BODY 
WEIGHT 
MEASUREMENTS-STUDY 
SPECIFIC 
PROCEDURES 
APPENDIX 3: 
CYP3A4 INHIBITORS AND INDUCERS 
APPENDIX 4: 
FACIT MEASUREMENTS 
APPENDIX 5: 
SCORING GUIDELINES  
APPENDIX 6: 
PATIENT GLOBAL IMPRESSION OF SEVERITY (PGIS) AND 
PATIENT GLOBAL IMPRESSION OF CHANGE (PGIC) 
APPENDIX 7: 
HUNGER ASSESSMENT SCALE 
APPENDIX 8: 
NEW YORK HEART ASSOCIATION (NYHA) 
CLASSIFICATION 
 
 

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APPENDIX 1: 
EASTERN COOPERATIVE ONCOLOGY GROUP 
PERFORMANCE SCALE  
ECOG Performance Status (To be rated by Investigator) 
Score Description 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
 
Work of a light or sedentary nature (e.g., light house work, office work) 
2 
Ambulatory and capable of all selfcare but unable to carry out any work activities.  
Up and about more than 50% of waking hours 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of 
waking hours 
4 
Completely disabled.  Cannot carry on any selfcare.  Totally confined to bed or 
chair  

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APPENDIX 2: 
BODY WEIGHT MEASUREMENTS-STUDY 
SPECIFIC PROCEDURES  
Sites will be instructed to follow: 
• 
Patient weighing for this study (Visit 1 to Visit 10) may only be performed by a 
Sponsor-trained and certified healthcare professional 
• 
Body weight should be measured at each visit 
• 
Calibrated scale dedicated for use in this study will be used every visit for the 
study, including for screening visits. Sponsor will make sure the same scale is used 
at each site. 
• 
Scales will be used on hard flooring, such as tile, wood, or cement for accuracy 
• 
Sites will be instructed to weigh the participants at approximately the same time of 
the day every visit, on empty stomach (in mornings before breakfast) 
• 
Study participants will be instructed to void before getting on weighing scale 
• 
Study participants will be instructed to remove shoes and clothing for accurate 
weight measurement. Patients will be weighed wearing only a hospital gown or 
hospital scrubs and, if desired, underwear only 
 
 

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APPENDIX 3: 
CYP3A4 INHIBITORS AND INDUCERS 
CYP3A4 Inhibitors 
Strong CYP3A4 Inhibitors 
ketoconazole 
clarithromycin 
itraconazole 
nefazodone 
telithromycin 
Moderate CYP3A4 Inhibitors 
aprepitant 
erythromycin 
fluconazole 
grapefruit juice 
verapamil 
diltiazem 
Weak CYP3A4 Inhibitors 
cimetidine 
 
CYP3A4 Inducers 
efavirenz 
nevirapine 
barbiturates 
carbamazepine 
enzalutamide 
glucocorticoids 
modafinil 
oxcarbazepine 
phenobarbital2 
phenytoin2 
pioglitazone 
rifabutin 
rifampin1 
St. John's Wort 
troglitazone 
Refer to the following website for a complete list: 
http://medicine.iupui.edu/flockhart/table.htm  

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APPENDIX 4: 
FACIT MEASUREMENTS 
The FACIT Measurement System is a collection of QOL questionnaires targeted to the 
management of chronic illness: “FACIT” (Functional Assessment of Chronic Illness 
Therapy).  FACIT is a broader, more encompassing term that includes the FACT 
questionnaires. The FACT-G is a 27-item compilation of general questions divided into 
four primary domains: Physical Well-Being, Social/Family Well-Being, Emotional Well-
Being, and Functional Well-Being. For this study we plan to administer all four domains. 
The FAACT A/CS domain is a 12-item measure of patients’ perceptions of 
anorexia/cachexia symptoms and concerns. The FACIT-F domain is a 13-item measure 
specifically to address the physical and functional consequences of fatigue [FACIT.org]. 
FACIT questionnaires are all formatted for self-administration, and use a 5-point Likert-
type scale where patients rate each item from 0 to 4 (0 = Not at all; 1 = A little bit; 2 = 
Somewhat; 3 = Quite a bit; and 4 = Very Much); the recall period for each question is 
“during the past 7 days”. 
 
 

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5-item-Anorexia Symptom Subscale consists of items C6, ACT3, ACT 6, ACT 7 and 
ACT10 
4-item-Anorexia Concerns Subscale consists of items ACT 1, ACT 2, ACT 4 and ACT 9 
 

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APPENDIX 5: 
SCORING GUIDELINES 
 
 
 

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Additionally, based on the Item codes of the here-above FAACT ACS, the following 
scores will be computed: 
- 5-item Anorexia Symptom Subscale = C6+(4-ACT3)+(4-ACT6)+(4-ACT7)+(4-
ACT10)  
- 4-item Anorexia Concerns Subscale = ACT1+(4-ACT2)+(4-ACT4)+(4-ACT9) 

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Additionally, based on the here-above Fatigue Subscale (FACIT-F), the Physical well-
being and the Functional well-being, the FACIT-F TOI will be computed as: 
FACIT-F TOI = FACIT-F + PWB + FWB. 

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APPENDIX 6: 
PATIENT GLOBAL IMPRESSION OF SEVERITY 
(PGIS) AND PATIENT GLOBAL IMPRESSION OF CHANGE (PGIC) 
 
Patient Global Impression of Severity (PGIS)  
Which of the following statements best describes your current appetite/eating-related 
symptoms? (Please pick ONE box) 
 I currently do not have any appetite/eating-related symptoms  
 I currently have minor appetite/eating-related symptoms  
 I currently have moderate appetite/eating-related symptoms  
 I currently have severe appetite/eating-related symptoms  
 
Please choose the response below that best describes your current concerns about your 
weight. (Please pick ONE box) 
 I have not had any concerns about my weight 
 I have had minor concerns about my weight 
 I have had moderate concerns about my weight 
 I have had severe concerns about my weight 
 
 
 

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Patient Global Impression of Change (PGIC)  
Since the start of the treatment, how would you describe your change in appetite/eating-
related symptoms? (Please pick ONE box) 
 Very much improved  
 
 Much improved 
 
 Minimally improved 
 
 No change  
 
 Minimally worse  
 Much worse 
 
 
 Very much worse  
 
Since the start of treatment, how would you describe the change in how much you worry 
about your weight?  (Please pick ONE box) 
 
 Very much improved  
 
 Much improved 
 
 Minimally improved 
 
 No change  
 
 Minimally worse  
 Much worse 
 Very much worse 
 
Since the start of the treatment, how would you describe your change in overall 
condition? (Please pick ONE box) 
 Very much improved  
 
 Much improved 
 
 Minimally improved 
 
 No change  
 
 Minimally worse  
 Much worse 
 Very much worse 

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APPENDIX 7: 
HUNGER ASSESSMENT SCALE 
 
Please circle or mark one number per line to indicate your response as it applies to the 
past 7 days. 
 
I have felt hungry. 
 
 
 
 
 
 
My family and friends are 
pleased with my appetite. 
 
 
 
 
 
 
 
 
 
 
Not at all 
A little bit 
Somewhat 
Quite a bit 
Very much 
0 
1 
2 
3 
4 
Not at all 
A little bit 
Somewhat 
Quite a bit 
Very much 
0 
1 
2 
3 
4 
 
 
 
 
 
 
 
 

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2 
2
APPENDIX 8: 
NEW YORK HEART ASSOCIATION (NYHA) 
CLASSIFICATION 
 
NYHA grading 
MET* 
Class I 
No limitations. Ordinary physical activity does not cause 
undue fatigue, dyspnoea or palpitations (asymptomatic 
LV dysfunction). 
>7 
Class II 
Slight limitation of physical activity. Ordinary physical 
activity results in fatigue, palpitation, dyspnoea or angina 
pectoris (mild CHF). 
5 
Class III 
Marked limitation of physical activity. Less than ordinary 
physical activity leads to symptoms (moderate CHF). 
2–3 
Class IV 
Unable to carry on any physical activity without 
discomfort. Symptoms of CHF present at rest (severe 
CHF). 
1.6 
*MET (metabolic equivalent) is defined as the resting VO for a 40-year-old 70kg man.1 MET = 3.5mL O 
/min/kg body weight. 
Reproduced from: National Heart Foundation of Australia and the Cardiac Society of Australia and New 
Zealand (Chronic Heart Failure Guidelines 
Expert Writing Panel). Guidelines for the prevention, detection and management of chronic heart failure in 
Australia. Updated Oct 2011